Co-complexes of MASP-1 and MASP-2 associated with the soluble pattern-recognition molecules drive lectin pathway activation in a manner inhibitable by MAp44.
The lectin pathway of complement is an integral component of innate immunity. It is activated upon binding of mannan-binding lectin (MBL) or ficolins (H-, L-, and M-ficolin) to suitable ligand patterns on microorganisms. MBL and ficolins are polydisperse homo-oligomeric molecules, found in complexes with MBL-associated serine proteases (MASP-1, -2, and -3) and MBL-associated proteins (MAp19 and MAp44). This scenario is far more complex than the well-defined activation complex of the classical pathway, C1qC1r(2)C1s(2), and the composition of the activating complexes of the lectin pathway is ill defined. We and other investigators recently demonstrated that both MASP-1 and MASP-2 are crucial to lectin pathway activation. MASP-1 transactivates MASP-2 and, although MASP-1 also cleaves C2, MASP-2 cleaves both C4 and C2, allowing formation of the C3 convertase, C4bC2a. Juxtaposition of MASP-1 and MASP-2 during activation must be required for transactivation. We previously presented a possible scenario, which parallels that of the classical pathway, in which MASP-1 and MASP-2 are found together in the same MBL or ficolin complex. In this study, we demonstrate that, although MASPs do not directly form heterodimers, the addition of MBL or ficolins allows the formation of MASP-1-MASP-2 co-complexes. We find that such co-complexes have a functional role in activating complement and are present in serum at varying levels, impacting on the degree of complement activation. This raises the novel possibility that MAp44 may inhibit complement, not simply by brute force displacement of MASP-2 from MBL or ficolins, but by disruption of co-complexes, hence impairing transactivation. We present support for this contention.


Retinal Tissue Perfusion in Patients with Multiple Sclerosis.
Purpose: The goal of this work was to determine whether the retinal tissue perfusion (RTP) is impaired in patients with multiple sclerosis (MS). Methods: Seventy-four patients [66 relapsing-remitting MS (RRMS) and 8 clinically isolated syndrome (CIS)] and 74 age- and gender-matched healthy controls were recruited. RTP was calculated as the retinal blood flow (measured using retinal function imager) supplying the macular area divided by the corresponding tissue volume of the inner retina from the inner limiting membrane to the outer plexiform layer, as measured by ultrahigh-resolution optical coherence tomography. Results: The RTP in the MS group was 2.37 ± 0.59 nl/s/mm3 (mean ± standard deviation), which was significantly lower than the control group (4.06 ± 0.89 nl/s/mm3, P < .001), reflecting a decrease of 42%. The blood flow volume was 2.50 ± 0.50 nl/s in MS, which was 45% lower than in the control group (4.56 ± 0.91 nl/s, P < .001). In addition, the tissue volume of the inner retina was significantly lower than in the control group (P < .05). The RTP in patients with MS was significantly correlated with the retinal blood flow volume (r = 0.84, P < .001) and retinal tissue volume (r = -0.56, P < .001). However, the retinal blood flow in patients with MS was not related to the tissue volume (r = -0.06, P = .59). Conclusions: Impaired retinal tissue perfusion occurred in patients with MS, which could be developed as a possible biomarker in monitoring disease progression in MS.


Care Professionals Manage the Future, Frail Older Persons the Past. Explaining Why Frailty Management in Primary Care Doesn't Always Work.
Frailty management focuses on optimizing the physical and psychological functioning of older people with frail health through early risk identification and intervention in primary care. Such care programs demand a joint effort by primary care professionals and older persons, one in which professionals are expected to promote or facilitate self-management practices and older persons are expected to adhere to the professional advice. It is known that patients and professionals hold different perspectives on frailty, but we know little about how this may affect their cooperation in frailty management. In this article, we therefore study how different perspectives of older persons and their primary care professionals play a role frailty management in practice. Nine cases of frailty management were reconstructed through semi-structured interviews with older persons, their family doctor and practice nurse. Drawing from literature on managing complex problems, we analyzed how "factual" and "normative" orientations played a role in their perspectives. We observe that the perspectives of care professionals and older persons on frailty management were substantially different. Both actors "manage" frailty, but they focus on different aspects of frailty and interestingly, care professionals' rationale is future-oriented whereas older person's rationale past-oriented. Primary care professionals employed practices to manage the medical and social factors of frailty in order to prevent future loss. Older persons employed practices to deal with the psychological, emotional and social aspects of the different types of loss they already experienced, in order to reconcile with loss from the past in the present. These findings raise fundamental questions regarding the different perceptions of and priorities around not only care for frail older people in general, but also implied professional-patient relations and the value of a risk-management approach to care for older people with frail health. The distinction between these perspectives could help care professionals to better respond to older patients' preferences and it could empower older persons to voice preferences and priorities that might not fit within the proposed care program.


Visual working memory for letters varies with familiarity but not complexity.
Visual working memory (VWM) is limited in both the capacity of information it can retain and the rate at which it encodes that information. We examined the influence of stimulus complexity on these 2 limitations of VWM. Observers performed a change-detection task with English letters of various fonts or letters from unfamiliar alphabets. Average perimetric complexity (κ)-an objective correlate of the number of features comprising each letter-differed among the fonts and alphabets. Varying the time between the memory array and mask, we used change-detection performance to estimate the number of items held in VWM (K) as a function of encoding time. For all alphabets, K increased over 270 ms (indicating the rate of encoding) before reaching an asymptote (indicating capacity). We found that rate and capacity for each alphabet were unrelated to complexity: Performance was best modeled by assuming that both were limited by number of items (K), rather than by number of features (K × κ). We also found a higher encoding rate and capacity for familiar alphabets (∼45 items s-1; ∼4 items) than for unfamiliar alphabets (∼12 items s-1; ∼1.5 items). We then compared the familiar English alphabet to an unfamiliar artificial character set matched in complexity. Again, rate and capacity was higher for the familiar than for the unfamiliar stimuli. We conclude that rate and capacity for encoding into visual working memory is determined by the number of familiar feature-integrated object representations. (PsycINFO Database Record (c) 2019 APA, all rights reserved).


Gap junctions in human umbilical cord endothelial cells contain multiple connexins.
We investigated the expression pattern of gap junctional proteins (connexins, Cx) in situ and in vitro and their functional characteristics in cultured human umbilical vein endothelial cells (HUVEC) and cultured human umbilical artery endothelial cells (HUAEC). In both arteries and veins, Cx37, Cx40, and Cx43 could be detected in situ and in vitro (passages 2-4). Distribution patterns of Cx40 and Cx43 were homogeneous in situ but more heterogeneous in vitro. Cx37 is heterogeneously expressed both in situ and in vitro. Among most cells, no Cx37 staining could be detected; when present, it was found as bright spots between some clusters of cells. Cx40 was more abundant in cultured arterial endothelium than in cultured venous endothelium. Dye-coupling experiments with Lucifer yellow CH revealed extensive dye spread in HUVEC (15.2 +/- 0.4, mean +/- SE, n = 110) but was significantly restricted in HUAEC (9.8 +/- 0.3, n = 110). Electrophysiological gap junctional characteristics were determined in cultured HUVEC and HUAEC pairs by use of the dual voltage-clamp technique. In contrast to the dye-coupling experiments, mean macroscopic electrical conductance was significantly larger for HUAEC pairs (31.4 +/- 6.0 nS, n = 12) than for HUVEC pairs (16.6 +/- 2.8, n = 18). In HUVEC, we measured multiple single gap junctional channel conductances in the range of 19-75 pS. Interestingly, additional conductances of 80-200 pS were measured in HUAEC, possibly partially reflecting activity of channels formed of Cx40, which are more abundant in the cultured arterial endothelial cells.


Minority stress and mental health in gay and lesbian youth: A comparative study of Italy and Spain.
The present study was carried out based on the minority stress model. The purpose was to compare Italian and Spanish gay and lesbian youth on minority stressors and mental health outcomes and test the minority stress model in Italy and Spain. The sample consisted of 490 participants (307 Italians, Mage = 25.30 and 183 Spanish, Mage = 27.57). They completed an online questionnaire measuring everyday discrimination, coming out to family members, coming out to friends/one's social network, internalized sexual stigma, depression, and anxiety. A multivariate analysis of covariance was performed to explore the effect of nationality on all measures. Structural equation modeling was applied to test the direct and indirect (through internalized sexual stigma) effects of stressors on mental health outcomes. The results demonstrate an impact of nationality on three dimensions: Spanish youth presented higher levels of everyday discrimination, while Italian youth had lower levels of both coming out to family members and coming out to friends/one's social network. Further, in both countries, all stressors had both direct and indirect (through internalized sexual stigma) associations with depression and anxiety. These findings have some social implications: studying the effect of nationality can be useful in suggesting changes in political and social macrosystems. Additionally, studying the associations among these variables is helpful for intervening more efficiently, for example, clinically, on the impact of minority stress. (PsycInfo Database Record (c) 2023 APA, all rights reserved).


Ambient air particulate matter exposure and tissue factor expression in atherosclerosis.
Recent studies have suggested a link between inhaled particulate matter (PM) exposure and atherogenesis. We investigated tissue factor (TF) expression with ambient fine particulate matter (diameter < 2.5 microm, PM(2.5)) exposure and in response to in vitro exposure to fine and ultrafine PM in cultured human bronchial epithelial cells, vascular smooth muscle cells (hSMCs), and monocytes. ApoE-/- mice, fed with normal chow (NC) or high-fat chow (HFC), were exposed to concentrated PM(2.5) or filtered air (FA) for 6 mo (6 h/day, 5 day/wk, n = 28). Following in vivo ultrasound bio-microscopy (UBM) assessment of plaque area, macrophage infiltration (CD68) and TF expression in the aorta were quantified. Cultured cells were incubated with size-fractionated PM from cascade impactors, or with standard reference PM material (SRM, number 1649a) and assayed for TF protein, mRNA, and activity. UBM-derived plaque areas were 7 +/- 1% larger in the PM(2.5)-HFC than the FA-HFC group (p = .04), but not significantly different between the PM(2.5)-NC and FA-NC groups (p = .07). Immunohistochemistry revealed increased TF (15 +/- 3% vs. 8 +/- 2%, p < .01) and macrophage infiltration (19 +/- 2% vs. 14 +/- 3%, p < .01) in the plaques of PM(2.5)-HFC compared with FA-HFC groups. Impactor-collected PM(2.5) and ultrafine particles consistently increased TF protein in bronchial epithelial cells, monocytes, and hSMCs. TF mRNA expression increased rapidly (within 1 h) in response to SRM PM. We conclude that in vivo and in vitro exposure to ambient air PM(2.5) induces TF expression.


Study on the preparation of collagen-modified silk fibroin films and their properties.
Blended films were prepared from a silk fibroin (SF) solution by adding a small amount of type I collagen (<5%). The mechanical properties of the wet films modified by collagen were improved obviously. The elongation at break reached 42%, and the smaller contact angles revealed that modified films had better hydrophilicity. 1% heparin was also added to modify the SF films to further improve the in vitro antithrombogenecity. The internal structure of the modified SF films was investigated with scanning electron microscopy, x-ray diffraction and Fourier transform infrared attenuated total reflection spectroscopy. The result indicates that the addition of a small amount of collagen and heparin did not change their conformation.


Severe intestinal involvement in Wegener's granulomatosis: report of two cases and review of the literature.
The clinical and pathological manifestations of severe intestinal involvement in Wegener's granulomatosis were studied by a review of the literature and reports of two patients. Altogether, six cases, two females and four males, were studied. One patient developed two episodes of bowel manifestations necessitating immediate surgical interventions. The average age at onset of intestinal symptoms was 43.3 yr (26-55 yr) and, in all cases, the first signs of such manifestations developed within the first 2 yr of disease. Prior to the onset of intestinal symptoms, immunosuppressive therapy was administered in six of seven instances. Acute abdominal pain with signs of peritonitis or distention only constituted the main clinical picture in six of the seven events. The last episode was manifested clinically with profuse diarrhoea with blood and mucus. Of the seven instances of severe intestinal manifestations, the small bowel was involved in two, the large bowel in three, and both the small and large bowel were affected in two episodes. Histological evidence of vasculitis in the bowel was demonstrated in three of the seven biopsy specimens, while in four, ischaemia, inflammation and ulceration were the pathological findings. Intestinal perforation was seen four times and surgery was performed in six of seven episodes. Severe intestinal involvement is rare in Wegener's granulomatosis. The initial bowel manifestations occur within the first 2 yr of disease, and affect both the large and small bowel. Histologically, vasculitis, ischaemia, inflammation and ulceration are the prevailing findings. Death due to intestinal catastrophy occurred in one of the six patients reported. Most likely, the manifestations are associated with the disease process rather than related to the use of immunosuppressive agents.


The Use of Intra-aortic Balloon Pump in a Real-World Setting: A Comparison between Survivors and Nonsurvivors from Acute Coronary Syndrome Treated with IABP. The Jakarta Acute Coronary Syndrome Registry.
Real-world data on acute coronary syndrome (ACS) patients who received intra-aortic balloon pump (IABP) support are limited. The objective of this study was to evaluate the characteristics of ACS patients who received IABP support from a real-world ACS registry. Patients with ACS (N = 121) who received IABP support were enrolled. Characteristics of survivors and nonsurvivors were compared at 30 days. Mortality rate of patients with ACS who received IABP was 47%. The survivors (N = 64) had less often cardiogenic shock (p < 0.001), more often IABP usage as back-up for a revascularization procedure (p = 0.002), less often resuscitation (p = 0.043), and less mechanical ventilator support (p < 0.001) than nonsurvivors. The nonsurvivors had a significantly higher leukocyte count (p = 0.033), a higher serum creatinine level (p < 0.001), a higher blood sugar on admission (p = 0.001), higher creatine kinase MB levels (p = 0.002), and a higher serum uric acid level (p < 0.001), but significantly lower left and right ventricular function (p = 0.014 and p = 0.003, respectively) than survivors. At 30 days, non-ST elevation (STE)-ACS patients had lower mortality rate than ST segment elevation myocardial infarction patients (log-rank test, p < 0.001), and non-STE-ACS patients who had not suffered from cardiogenic shock showed the lowest mortality rate (log-rank test, p < 0.001). By multivariate analysis, a heart rate ≥ 100 beats per minute before IABP insertion was the strongest predictor of 30-day mortality (hazard ratio = 5.69; 95% confidence interval, 1.49 to 21.78; p = 0.011). In ACS patients presenting with either cardiogenic shock, resuscitated, or patients who needed mechanical ventilation suffered from high mortality, despite the use of IABP. IABP appears to be safe and tended to be favorable in noncardiogenic shock ACS patients, particularly non-STE-ACS. A heart rate of ≥ 100 beats per minute prior to IABP insertion was the strongest predictor of 30-day mortality.


Numerical Discrimination of Thermodynamic Monte Carlo Simulations in All Eight Statistical Ensembles.
Generalized expressions for thermodynamic properties in terms of ensemble averages are discussed for adiabatic and isothermal ensembles. They are implemented in the simulation code ms2 and validated by Monte Carlo simulations for the Lennard-Jones fluid. A comparison of the eight statistical ensembles regarding size scaling behavior, convergence, and stability is provided for state points throughout the homogeneous fluid region. The resulting data are in good agreement but differ in their statistical distributions. In closed systems, the statistical quality of the data is better than in open systems. Overall, the microcanonical ensemble performs best.


Lysophosphatidylcholine induces inflammatory activation of human coronary artery smooth muscle cells.
Lysophosphatidylcholine (LPC) is the major bioactive lipid component of oxidized LDL, thought to be responsible for many of the inflammatory effects of oxidized LDL described in both inflammatory and endothelial cells. Inflammation-induced transformation of vascular smooth muscle cells from a contractile phenotype to a proliferative/secretory phenotype is a hallmark of the vascular remodeling that is characteristic of atherogenesis; however, the role of LPC in this process has not been fully described. The present study tested the hypothesis that LPC is an inflammatory stimulus in coronary artery smooth muscle cells (CASMCs). In cultured human CASMCs, LPC stimulated time- and concentration-dependent release of arachidonic acid that was sensitive to phospholipase A2 and C inhibition. LPC stimulated the release of arachidonic acid metabolites leukotriene-B4 and 6-keto-prostaglandin F1alpha, within the same time course. LPC was also found to stimulate basic fibroblast growth factor release as well as stimulating the release of the cytokines GM-CSF, IL-6, and IL-8. Optimal stimulation of these signals was obtained via palmitic acid-substituted LPC species. Stimulation of arachidonic acid, inflammatory cytokines and growth factor release, implies that LPC might play a multifactorial role in the progression of atherosclerosis, by affecting inflammatory processes.


Characterization of the subunit nature of nuclear estrogen receptors by chemical cross-linking and dense amino acid labeling.
We have used chemical cross-linking and dense amino acid labeling of estrogen receptors to characterize the subunit nature and rate of turnover of nuclear 5S estrogen-receptor complexes. When MCF-7 human breast cancer cells are incubated with [3H]estradiol or [3H]antiestrogen [alpha-[4-pyrrolidinoethoxy]phenyl-4-hydroxy-alpha'-nitrostilbe ne (CI628M) or (Z)-1-[4-(2-[N-aziridinyl]ethoxy)phenyl] 1,2-diphenyl-1-butene (tamoxifen aziridine)] and nuclear estrogen-receptor complexes are extracted with 0.6 M KCl and then chemically cross-linked with the cross-linker 2-iminothiolane, the cross-linked receptor complexes sediment as a 5.4S species on 3 M urea-containing sucrose gradients, while the noncross-linked species are 4S. Sodium dodecyl sulfate-polyacrylamide gel analyses of these cross-linked nuclear receptor complexes labeled with the covalently attaching ligand [3H]tamoxifen aziridine reveal a species of about 130,000 mol wt, while the noncross-linked or the cross-linked but mercaptan-cleaved receptor is 65,000 mol wt. Both receptor species are also detectable by interaction with an immunoadsorbent column containing antireceptor monoclonal antibody. For analyses of receptor turnover rates, cells exposed for different time periods to medium containing dense (15N, 13C, and 2H) amino acids were labeled with [3H]antiestrogen [1-[4-(2-dimethylaminoethoxy)phenyl]1-[4-hydroxyphenyl] 2-phenylbut-1-(2)ene (trans-hydroxytamoxifen) or CI628M] or [3H]estradiol, and salt-extracted nuclear estrogen receptors were analyzed on sucrose gradients. The normal density 5S form shifted to a broader, more dense peak at 2 and 4 h and finally, by 8-10 h, to a more dense, sharply sedimenting species. The time course of this shift is the same as that seen for the 4S urea-dissociated nuclear receptor form (t1/2 approximately 4h), suggesting that the 5.4S nuclear receptor is composed of two species which turn over at the same rate. We conclude from these cross-linking and density shift experiments that the nuclear 5S receptor complex consists of two similarly sized units, which turn over with similar half-lives. These data provide strong evidence that the 5S nuclear receptor complex is a homodimer of two 4S, 65,000 mol wt monomers.


Human milk glycomics and gut microbial genomics in infant feces show a correlation between human milk oligosaccharides and gut microbiota: a proof-of-concept study.
Human milk oligosaccharides (HMOs) play a key role in shaping and maintaining a healthy infant gut microbiota. This article demonstrates the potential of combining recent advances in glycomics and genomics to correlate abundances of fecal microbes and fecal HMOs. Serial fecal specimens from two healthy breast-fed infants were analyzed by bacterial DNA sequencing to characterize the microbiota and by mass spectrometry to determine abundances of specific HMOs that passed through the intestinal tract without being consumed by the luminal bacteria. In both infants, the fecal bacterial population shifted from non-HMO-consuming microbes to HMO-consuming bacteria during the first few weeks of life. An initial rise in fecal HMOs corresponded with bacterial populations composed primarily of non-HMO-consuming Enterobacteriaceae and Staphylococcaeae. This was followed by decreases in fecal HMOs as the proportion of HMO-consuming Bacteroidaceae and Bifidobacteriaceae increased. Analysis of HMO structures with isomer differentiation revealed that HMO consumption is highly structure-specific, with unique isomers being consumed and others passing through the gut unaltered. These results represent a proof-of-concept and are consistent with the highly selective, prebiotic effect of HMOs in shaping the gut microbiota in the first weeks of life. The analysis of selective fecal bacterial substrates as a measure of alterations in the gut microbiota may be a potential marker of dysbiosis.


Voice Navigation Created by VIP Improves Spatial Performance in People with Impaired Vision.
The difficulty associated with spatial navigation is one of the main obstacles to independent living for visually impaired people. With a lack of visual feedback, visually impaired people must identify information from the external environment through other sense organs. This study employed an observational survey to assess voice navigation version A, created by visually impaired people, and voice navigation version B, created by non-visually impaired people. Thirty-two simulated visually impaired people were assigned to conduct task assessments of voice navigation version A and version B. For mission 1, the mean completion rate is 0.988 ± 0.049 (version A); the mean error rate is 0.125 ± 0.182 (version A). For mission 2, the mean completion rate is 0.953 ± 0.148 (version A); the mean error rate is 0.094 ± 0.198 (version A). The assessment results concluded that version A has a higher completion rate (p = 0.001) and a lower error rate (p = 0.001). In the assessment of subjective satisfaction, all the indicators regarding the impression of navigation directives in version A were significantly superior to those indicators in version B. It appears that version A has a different logic of framing than version B. In future applications, a voice navigation version shall be built, according to the way visually impaired people think, because it will facilitate the direction guide when there is a lack of visual feedback.


Identification of the epitopes of monoclonal antibodies against P74 of Helicoverpa armigera nucleopolyhedrovirus.
P74 is a per os infectivity factor of baculovirus. Here, we report the production of three monoclonal antibodies (mAbs), denoted as 20D9, 20F9 and 21E1, raised against P74 of Helicoverpa armigera nucleopolyhedrovirus (HearNPV), and the identification of their recognition epitopes. The full-length P74, without the transmembrane domains at the C-terminus, was first divided into three segments (N, M and C, respectively), based on the proposed cleavage model for the protein, which were then expressed individually. Western blot analyses revealed specific cross-reactions with the N fragment, for both 20D9 and 21E1. Extensive truncation, followed by prokaryotic expression, of the P74 N fragment was then performed in order to screen for linear epitopes of P74. The recognition regions of 20D9 and 21E1 were revealed to be localized at R144-T153 and T199-C219, respectively. In addition, immunofluorescence microscopy indicated that 20D9 and 20F9 could recognize native P74 in HearNPV-infected cells. These findings will facilitate further investigations of the proteolytic processing of HearNPV P74, and of its involvement in virus-host interactions.


Origins of the brain networks for advanced mathematics in expert mathematicians.
The origins of human abilities for mathematics are debated: Some theories suggest that they are founded upon evolutionarily ancient brain circuits for number and space and others that they are grounded in language competence. To evaluate what brain systems underlie higher mathematics, we scanned professional mathematicians and mathematically naive subjects of equal academic standing as they evaluated the truth of advanced mathematical and nonmathematical statements. In professional mathematicians only, mathematical statements, whether in algebra, analysis, topology or geometry, activated a reproducible set of bilateral frontal, Intraparietal, and ventrolateral temporal regions. Crucially, these activations spared areas related to language and to general-knowledge semantics. Rather, mathematical judgments were related to an amplification of brain activity at sites that are activated by numbers and formulas in nonmathematicians, with a corresponding reduction in nearby face responses. The evidence suggests that high-level mathematical expertise and basic number sense share common roots in a nonlinguistic brain circuit.


Dissecting enzyme regulation by multiple allosteric effectors: nucleotide regulation of aspartate transcarbamoylase.
The enzyme aspartate transcarbamoylase (ATCase, EC 188.8.131.52 of Escherichia coli), which catalyzes the committed step of pyrimidine biosynthesis, is allosterically regulated by all four ribonucleoside triphosphates (NTPs) in a nonlinear manner. Here, we dissect this regulation using the recently developed approach of random sampling-high-dimensional model representation (RS-HDMR). ATCase activity was measured in vitro at 300 random NTP concentration combinations, each involving (consistent with in vivo conditions) all four NTPs being present. These data were then used to derive a RS-HDMR model of ATCase activity over the full four-dimensional NTP space. The model accounted for 90% of the variance in the experimental data. Its main elements were positive ATCase regulation by ATP and negative by CTP, with the negative effects of CTP dominating the positive ones of ATP when both regulators were abundant (i.e., a negative cooperative effect of ATP x CTP). Strong sensitivity to both ATP and CTP concentrations occurred in their physiological concentration ranges. UTP had only a slight effect, and GTP had almost none. These findings support a predominant role of CTP and ATP in ATCase regulation. The general approach provides a new paradigm for dissecting multifactorial regulation of biological molecules and processes.


Prognostic factors of resected pathological stage I lung adenocarcinoma: evaluating subtypes and PD-L1/CD155 expression.
We aimed to compare the prognostic impacts of adenocarcinoma subtypes, programmed death-ligand I (PD-L1), and CD155 expression on patients with resected pathological stage (p-stage) I lung adenocarcinoma. In total, 353 patients with completely resected p-stage I lung adenocarcinomas were retrospectively reviewed. The expression levels of PD-L1 and CD155 in tumour cells from each adenocarcinoma subtype were evaluated using several clinicopathological and histological features, such as the presence of a micropapillary pattern. A total of 52 patients (14.7%) had PD-L1-positive tumours, whereas 128 patients (36.3%) had CD155-positive tumours, with a tumour proportion score of 5% for both PD-L1 and CD155 expression. Compared with patients with other adenocarcinoma subtypes, those with solid-predominant adenocarcinomas were significantly more positive for PD-L1 and CD155. Multivariate analysis showed that PD-L1 expression status was significantly associated with progression-free survival and overall survival, whereas CD155 expression and the presence of a micropapillary pattern were not significantly associated with either parameter. Patients with PD-L1-positive tumours had poorer prognoses than those with CD155-positive tumours. Moreover, PD-L1 and CD155 were significantly expressed in solid-predominant adenocarcinomas. The results of this study suggest that immune checkpoint inhibitors can be used as adjuvants in the treatment of patients with p-stage I adenocarcinoma.


October to July precipitation reconstruction for Burabai region (Kazakhstan) since 1744.
The history of climate is crucially important for any part of the world to understand the nature of climate change. In this context, precipitation reconstruction is still lacking in northern Kazakhstan. The purpose of this study is to present a reconstruction for the total precipitation of October of the previous year to July of the current year in northern Kazakhstan. Pinus sylvestris L. (Scots pine) forests in Burabai Region are quite important to collect samples to study the climate history. A regional chronology, covering the years of 1702-2014 of Pinus sylvestris constructed by using 289/466 trees/cores was used in the reconstruction. The gridded climate data for the years of 1950-2014 were used in the calibration and verification process. High and significant correlations were obtained between tree-ring widths and October to July precipitation in Burabai Region. Based on this significant relationship, reconstruction was performed for the years of 1744-2014. Adjusted R2, F-value, sign test, and r value were found as 0.38, 39.7 (P ≤ 0.001), 47+/17, and 0.62 for reconstruction, respectively. The reconstruction showed that 43 dry and 42 wet years occurred during the years of 1744-2014. Only a one-time four-year duration of the wet period was determined covering the years 1978-1981. However, three of six very dry years occurred after the 1950s. As a conclusion, extremity in recent decades is getting an increase in Burabai region.


Moving efficiently through a crowd: A nature-inspired traffic rule.
In this article, we propose a traffic rule inspired from nature that instructs how a crowd made up of inert agents should respond to an elite agent to facilitate its motion through the crowd. When an object swims in a fluid medium or an intruder is forced through granular matter, characteristic flow fields are created around them. We show that if inert agents made small movements based on a traffic rule derived from these characteristic flow fields, then they efficiently reorganize and transport enough space for the elite to pass through. The traffic rule used in the article is a dipole field which satisfactorily captures the features of the flow fields around a moving intruder. We study the effectiveness of this dipole traffic rule using numerical simulations in a two-dimensional periodic domain, where one self-propelled elite agent tries to move through a crowd of inert agents that prefer to stay in a state of rest. Simulations are carried out for a wide range of strengths of the traffic rule and packing densities of the crowd. We characterize and analyze four regions in the parameter space-free-flow, motion due to cooperation and frozen and collective drift regions-and discuss the consequence of the traffic rule in light of the collective behavior observed. We believe that the proposed method can be of use in a swarm of robots working in constrained environments.


Aqueous synthesis of Mn-doped CuInSe2 quantum dots to enhance the performance of quantum dot sensitized solar cells.
Herein, we present the direct aqueous synthesis of manganese (Mn) doped CuInSe2 (Mn-CISe) quantum dots (QDs) under microwave irradiation to improve the photochemical properties of solar cells. As a result of Mn doping, the narrower bandgap energy of Mn-CISe leads to higher visible light absorption. The Mn-CISe QDs are therefore used as photosensitizers in quantum dot sensitized solar cells (QDSSCs), exhibiting enhanced performance which is dependent on Mn concentration. To the best of our knowledge, this is the first time to construct an Mn-CISe sensitized-TiO2 photoanode to boost the photovoltaic performance of QDSSCs. The incorporation of Mn into CISe increases short-circuit current, which is ascribed to the effective injection of the excited electrons from QDs into TiO2 and the consequent higher electron lifetime, likely through a newly formed Mn midgap in the CISe band structure. Compared to the undoped QDs, Mn-CISe QDSSCs show a shorter electron transport time (τt) and a longer electron recombination time (τr) which are studied by intensity-modulated photocurrent spectroscopy and intensity-modulated photovoltage spectroscopy, respectively. In fact, a combination of higher light-harvesting efficiency, slower charge recombination, and a longer electron lifetime gives rise to a maximum photovoltaic performance of 6.28%.


Collagen degradation and platelet-derived growth factor stimulate the migration of vascular smooth muscle cells.
Cell migration is a key event in many biological processes and depends on signals from both extracellular matrix and soluble motogenic factors. During atherosclerotic plaque development, vascular smooth muscle cells migrate from the tunica media to the intima through a basement membrane and interstitial collagenous matrix and proliferate to form a neointima. Matrix metalloproteinases have previously been implicated in neointimal formation and in this study smooth muscle cell adhesion and migration on degraded collagen have been evaluated. Vascular smooth muscle cells adhered to native intact collagen type I and to its first degradation by-product, 3/4 fragment (generated by collagenase-3 cleavage), unwound at 35 degrees C to mimic physiological conditions. PDGF-BB pre-treatment induced a fourfold stimulation of smooth muscle cell motility on the collagen 3/4 fragment whereas no increase in smooth muscle cell motility on collagen type I was observed. Cell migration on collagen type I was mediated by alpha2 integrin, whereas PDGF-BB-stimulated migration on the 3/4 collagen fragment was dependent on alphavbeta3 integrin. alphavbeta3 integrin was organised in clusters concentrated at the leading and trailing edges of the cells and was only expressed when cells were exposed to the 3/4 collagen fragment. Tyrphostin A9, an inhibitor of PDGF receptor-beta tyrosine kinase activity, resulted in complete abolition of migration of PDGF-BB treated cells on collagen type I and 3/4 fragment. These results strongly support the hypothesis that the cellular migratory response to soluble motogens can be regulated by proteolytic modification of the extracellular matrix.


Oral health-related quality of life impacts are low 27 years after periodontal therapy.
This pilot study assessed the oral-health-related quality of life (OHRQoL) after long-term periodontal therapy and explored OHRQoL differences along the 2018 Classification of Periodontal Diseases. Sixty patients were examined before (T0) and after active periodontal therapy (APT/T1) and 32.0 ± 2.9 [range: 27-38] years of supportive periodontal therapy (SPT/T2). Periodontal diagnosis at T0 was assessed according to the 2018 Classification of Periodontal Diseases (stage 1/2/3/4: n = 1/3/44/13; grade n = A/B/C: 0/8/53). OHRQoL at T2 was measured using the Oral Health Impact Profile-G14 (OHIP-G14). Patients' Eichner's classification, accumulated tooth loss and treatment outcomes (SSO criteria) were assessed at T2. Generalized linear modelling (GLM) assessed associations between different factors and OHrQoL. Mean OHIP-G14 sum score was 3.7 (SD 5.6). There was no statistically significant association between OHIP-G14 and gender, stage, SSO criteria and tooth loss. OHIP-G14 was significantly lower in older patients (-0.2[-0.3;0] per year, p = .008), non-smokers (-5.9[-9.9;-1.9] p = .003) and former smokers (-7.4[-11.6;-3.2]; p < .001) versus current smokers, patients with Eichner class A1-B2 versus C2 (p < .05), sufficient adherence during SPT (-2.3[-4.6;-0.1], p = .044) versus insufficient ones. Patients with grade B (4.4[1.3;7.4]; p < .005) showed higher OHIP-G14 than those with grade C. A number of aspects, grounded in the initial diagnosis, the adherence to SPT, the resulting dentition, socio-demographic and behavioural covariates, were associated with good OHrQoL.


Hyperphosphatemia, Phosphoprotein Phosphatases, and Microparticle Release in Vascular Endothelial Cells.
Hyperphosphatemia in patients with advanced CKD is thought to be an important contributor to cardiovascular risk, in part because of endothelial cell (EC) dysfunction induced by inorganic phosphate (Pi). Such patients also have an elevated circulating concentration of procoagulant endothelial microparticles (MPs), leading to a prothrombotic state, which may contribute to acute occlusive events. We hypothesized that hyperphosphatemia leads to MP formation from ECs through an elevation of intracellular Pi concentration, which directly inhibits phosphoprotein phosphatases, triggering a global increase in phosphorylation and cytoskeletal changes. In cultured human ECs (EAhy926), incubation with elevated extracellular Pi (2.5 mM) led to a rise in intracellular Pi concentration within 90 minutes. This was mediated by PiT1/slc20a1 Pi transporters and led to global accumulation of tyrosine- and serine/threonine-phosphorylated proteins, a marked increase in cellular Tropomyosin-3, plasma membrane blebbing, and release of 0.1- to 1-μm-diameter MPs. The effect of Pi was independent of oxidative stress or apoptosis. Similarly, global inhibition of phosphoprotein phosphatases with orthovanadate or fluoride yielded a global protein phosphorylation response and rapid release of MPs. The Pi-induced MPs expressed VE-cadherin and superficial phosphatidylserine, and in a thrombin generation assay, they displayed significantly more procoagulant activity than particles derived from cells incubated in medium with a physiologic level of Pi (1 mM). These data show a mechanism of Pi-induced cellular stress and signaling, which may be widely applicable in mammalian cells, and in ECs, it provides a novel pathologic link between hyperphosphatemia, generation of MPs, and thrombotic risk.


The interaction of affective states and cognitive vulnerabilities in the prediction of non-suicidal self-injury.
Non-suicidal self-injury (NSSI) is a serious public health concern and remains poorly understood. This study sought to identify both cognitive and affective vulnerabilities to NSSI and examine their interaction in the prediction of NSSI. A series of regressions indicated that low levels of positive affect (PA) moderated the relationships between self-criticism and brooding and NSSI. The associations of self-criticism and brooding with greater frequency of NSSI were attenuated by higher levels of PA. The interaction of cognitive and affective vulnerabilities is discussed within the context of current NSSI theory.


Anatomy and histology of reproductive system of adult male mint leaf beetle Chrysolina herbacea (Duftschmid, 1825) (Coleoptera: Chrysomelidae).
In this study, anatomy and histology of the male reproductive system of Chrysolina herbacea (Duftschmid 1825) (Coleoptera: Chrysomelidae) are described and illustrated by using light and scanning electron microscopies. Data from the male gonad of this species provide more extended and precise knowledge regarding the histoanatomical structure of the reproductive system in Chrysomelidae. The male reproductive system in C. herbacea consists of paired bilobed testes, two paired vas efferentia, paired seminal vesicles, paired vas deferentia, paired tubular accessory glands, a ductus ejaculatorius, and an aedeagus. Each testis consists of 40 follicles enveloped in a yellow pigmented sheath. In the light and scanning electron microscope examinations of male reproductive system of C. herbacea, different spermatogenesis stages (spermatocytes, spermatids, and spermatozoa) are found. Each testes follicle joins with the vas efferens surrounded by monolayered cubic epithelium with oval nuclei. Epithelial cells are covered from the outside with a thin layer of muscle and sheath. Vas efferens connect to vas deferens that may have an enlarged and differentiated region = seminal vesicle. Mature spermatozoa are seen in the lumen of the vas efferens, seminal vesicle, and vas deferens. There is a pair of accessory glands with a convoluted appearance in the tubular structure around the vas deferens. The vas deferens is a straight tube which leads into the proximal end of the ductus ejaculatorius. Ductus ejaculatorius wall is surrounded by intima, monolayer epithelium, and a thick muscle layer with many nuclei. The distal section of the ductus ejaculatorius is housed within the aedeagus.


Sulforaphane and its analogues inhibit CYP1A1 and CYP1A2 activity induced by benzo[a]pyrene.
CYP1A1 and CYP1A2 enzymes metabolize polycyclic aromatic hydrocarbons (PAHs) to the reactive oxyderivatives. PAHs can induce the activity of both enzymes, which increases its conversion and enhances risk of carcinogenesis. Thus, the inhibition of CYP enzymes is recognized as a cancer chemoprevention strategy. A well-known group of chemopreventive agents is isothiocyanates, which occur naturally in Brassica vegetables. In this paper, a naturally occurring sulforaphane and its two synthetic analogues isothiocyanate-2-oxohexyl and alyssin were investigated. The aim of the study was to determine whether the differences in the isothiocyanate structure change its ability to inhibit CYP1A1 and CYP1A2 activity induced by benzo[a]pyrene in HepG2 and Mcf7 cells. Also a mechanistic study was performed including isothiocyanates' influence on CYP1A1 and CYP1A2 catalytic activity, enzymatic protein level, and AhR translocation. It was shown that both enzymes were significantly induced by benzo[a]pyrene, and isothiocyanates were capable of decreasing the induced activity. The inhibitory properties depend on the types of isothiocyanate and enzyme. In general, CYP1A2 was altered in the more meaningful way than CYP1A1 by isothiocyanates. Sulforaphane exhibited weak inhibitory properties, whereas both analogues were capable of inhibiting BaP-induced activity with the similar efficacy. The mechanistic study revealed that analogues decreased the CYP1A2 activity via the protein-level reduction and CYP1A1 directly. The results indicate that isothiocyanates can be considered as potent chemopreventive substances and the change in the sulforaphane structure increases its chemopreventive potency.


Intrauterine detection of cystic fibrosis.
Thirteen pregnancies of obligate heterozygotes of cystic fibrosis have been prospectively monitored utilizing quantitative and qualitative measurements of methylumbelliferylguanidinobenzoate (MUGB) reactive proteases in amniotic fluid. In each case the diagnosis was accurately ascertained in midtrimester and confirmed after delivery. The measurement of MUGB reactivity in midtrimester amniotic fluid by three different procedures, quantitative analysis, polyacrylamide isoelectric focusing, and column filtration appears to provide a practical and reliable approach for the intrauterine detection of cystic fibrosis.


Anti-carcinogenic properties of curcumin on colorectal cancer.
Curcumin has been used in traditional Indian medicine for many centuries for its anti-inflammatory and anti-carcinogenic properties. There has been some promising research concerning curcumin as a safe therapeutic agent for many cancers, colorectal cancer being among them. This has been shown through research in cell cultures, animal models, and humans. At this time, it appears that curcumin's anti-carcinogenic properties are most likely due to its effects on multiple molecular targets, such as nuclear factor κ-light-chain-enhancer of activated B cells (NF-κB) and activator protein 1 (AP-1). NF-κB and AP-1 are both major transcription factors that regulate inflammation and thus affect cell proliferation, differentiation and even apoptosis. Curcumin has also been shown to affect a variety of other key players involved in carcinogenesis, such as cyclooxygenase-2, matrix metallopeptidases 2 and 9 and tumor necrosis factor α induced vascular cell adhesion molecule, just to name a few. Although many molecular targets are involved, curcumin has been well tolerated in many studies: doses up to 8 g a day have been confirmed to be safe for humans. In this brief review, we will examine the current studies and literature and touch upon many molecular pathways affected by curcumin, and demonstrate the exciting possibility of curcumin as a chemopreventive agent for colorectal cancer.


The serine-threonine kinase LKB1 is essential for survival under energetic stress in zebrafish.
Mutations in the serine-threonine kinase (LKB1) lead to a gastrointestinal hamartomatous polyposis disorder with increased predisposition to cancer (Peutz-Jeghers syndrome). LKB1 has many targets, including the AMP-activated protein kinase (AMPK) that is phosphorylated under low-energy conditions. AMPK phosphorylation in turn, affects several processes, including inhibition of the target of rapamycin (TOR) pathway, and leads to proliferation inhibition. To gain insight into how LKB1 mediates its effects during development, we generated zebrafish mutants in the single LKB1 ortholog. We show that in zebrafish lkb1 is dispensable for embryonic survival but becomes essential under conditions of energetic stress. After yolk absorption, lkb1 mutants rapidly exhaust their energy resources and die prematurely from starvation. Notably, intestinal epithelial cells were polarized properly in the lkb1 mutants. We show that attenuation of metabolic rate in lkb1 mutants, either by application of the TOR inhibitor rapamycin or by crossing with von Hippel-Lindau (vhl) mutant fish (in which constitutive hypoxia signaling results in reduced metabolic rate), suppresses key aspects of the lkb1 phenotype. Thus, we demonstrate a critical role for LKB1 in regulating energy homeostasis at the whole-organism level in a vertebrate. Zebrafish models of Lkb1 inactivation could provide a platform for chemical genetic screens to identify compounds that target accelerated metabolism, a key feature of tumor cells.


Antimicrobial Peptides and Interleukins in Cleft Soft Palate.
Cleft palate is one of the most common and well-studied congenital anomalies; however, the role of protective tissue factors in its pathophysiology is still debated. The aim of our study was to evaluate interleukin and antimicrobial peptide appearance and distribution in cleft palate. Eight soft palate samples were obtained during veloplasty procedures. Immunohistochemical staining was applied to detect HBD-2-, HBD-3-, HBD-4-, LL-37-, IL-10-, and CD-163-positive cells via light microscopy. For statistical evaluation, the Mann-Whitney U test and Spearman's rank correlation coefficient were used. A significant difference between study groups was observed for HBD-2 and IL-10 in epithelial and connective tissue as well as HBD-4 in connective tissue. The number of HBD-3-positive cells was moderate in the patients, and few were observed in the controls. The number of LL-37-positive cells varied from a moderate amount to a numerous amount in both study groups, whilst CD-163 marked a moderate number of positive cells in patients, and a few-to-moderate amount was observed in the controls. Numerous correlations between studied factors were revealed in cleft tissues. The increase in antimicrobial peptides HBD-2 and HBD-4 and anti-inflammatory cytokine IL-10 suggested a wide compensatory elevation of the local immune system against cleft-raised tissue changes. The correlations between the studied factors (HBD-2, HBD-3, HBD-4, LL-37, and IL-10) proved the synergistic involvement of common local defense factors in postnatal cleft palate morphopathogenesis.


Disruption of the young-adult synchrony between luteinizing hormone release and oscillations in follicle-stimulating hormone, prolactin, and nocturnal penile tumescence (NPT) in healthy older men.
The healthy human male hypothalamo-pituitary-gonadal axis exhibits age-dependent loss of coordinate LH-testosterone secretion. A putative independent defect in Leydig-cell steroidogenesis with aging would confound the attribution of such LH-testosterone asynchrony to a hypothalamo-pituitary locus per se. Accordingly, here we appraise by sampling every 2.5 min overnight the joint synchrony of moment-to-moment LH release with simultaneously monitored pituitary FSH secretion, prolactin release, and nocturnal penile tumescence (NPT) oscillations, as a neurophysiological correlate of sleep regulation) in 10 young (ages 21-34) and 8 older (ages 62-72) healthy men. Joint synchrony for paired LH-FSH, LH-prolactin, and LH-NPT observations in young vs. older individuals was quantified by the cross-approximate entropy (cross-ApEn) statistic, with larger cross-ApEn values indicating greater two-variable asynchrony. Concomitantly, we assessed (possible) univariate changes with age for each of LH, FSH, prolactin, and NPT, as quantified by approximate entropy (ApEn). Hormone assays were performed by random-access direct chemiluminescence analyzer. Overnight mean (+/- SEM) serum LH concentrations (IU/L) were equivalent in older (3.1 +/- 0.31 IU/L) and younger (2.9 +/- 0.29) men, as were their serum total testosterone concentrations; viz., 425 +/- 48 (older) and 523 +/- 40 (younger) ng/dL. However, all three sets of paired time-series were significantly more asynchronous in the older cohort. First, cross-ApEn of paired LH-FSH release was significantly higher (or more asynchronous) in older subjects; viz., 1.902 +/- 0.022 in older men vs. 1.607 +/- 0.058 in younger individuals (P = 0.0005). Second, cross-ApEn of paired LH and prolactin release was 1.744 +/- 0.085 in older volunteers vs. 1.346 +/- 0.084 in younger subjects (P = 0.0046). Third, and most notably, cross-ApEn for the joint LH-NPT observation time-series was significantly greater in older subjects at 1.771 +/- 0.056 vs. 1.223 +/- 0.086 (young) (P = 0.0001), thereby denoting loss of coordination between (neural) signals directing intermittent LH secretion and those governing sleep-associated penile tumescence in older men. Among one-variable results, only ApEn of LH release was significantly higher in older individuals at 1.323 +/- 0.058 vs. 0.897 +/- 0.089 in younger subjects (P = 0.0019), signifying greater disorderliness of the LH secretory process in aged men. Individual ApEn values of FSH and prolactin release and NPT were age-invariant. In ensemble, the present clinical experiments indicate that, within the aging male reproductive axis, bihormonal network disruption is more pronounced than individual signal disruption. We suggest that abrogation of joint synchrony among hypothalamically directed pituitary hormones and a neurogenically organized sexual response (nocturnal penile tumescence) can be unified thematically under an hypothesis of disrupted central nervous system hypothalamo-pituitary network coordination in human aging. Such implicit disarray of multinodal communication is of consequence both scientifically and clinically, especially in proposing aging theories and intervention strategies.


Total wash elimination for solid phase peptide synthesis.
We present a process for solid phase peptide synthesis (SPPS) that completely eliminates all solvent intensive washing steps during each amino acid addition cycle. A key breakthrough is the removal of a volatile Fmoc deprotection base through bulk evaporation at elevated temperature while preventing condensation on the vessel surfaces with a directed headspace gas flushing. This process was demonstrated at both research and production scales without any impact on product quality and when applied to a variety of challenging sequences (up to 89 amino acids in length). The overall result is an extremely fast, high purity, scalable process with a massive waste reduction (up to 95%) while only requiring 10-15% of the standard amount of base used. This transformation of SPPS represents a step-change in peptide manufacturing process efficiency, and should encourage expanded access to peptide-based therapeutics.


The effects of coal tar based pavement sealer on amphibian development and metamorphosis.
Coal tar based pavement sealers are applied regularly to parking lots and contain significant levels of polycyclic aromatic hydrocarbons (PAHs). Recently a connection between elevated levels of PAHs in streams and storm water runoff from parking lots has been identified. We tested the hypothesis that coal tar based pavement sealers could alter the survival, growth, and development of amphibians using a model species, Xenopus laevis. Ten fertilized individuals were placed singly into containers containing one of four treatment groups: control, low, medium, and high (respective nominal concentrations 0, 3, 30, and 300 ppm TPAH). All of the individuals in the high exposure group died by the sixth day of exposure. By day 14 there were significant patterns of stunted growth (p<0.0001) and slower development (p=0.006) in the medium and high exposure groups relative to the control and low treatment groups. When the experiment ended on day 52 the control and low-dose individuals had achieved more advanced developmental stages than the medium group (p=0.0007). These data indicate that these commonly used coal tar based pavement sealers may potentially affect the amphibian taxa living in areas that receive storm water runoff.


Treatment of sex offenders in Israeli prison settings.
The number of incarcerated sex offenders in the Israeli prison system has steadily increased during the past decade. While treatment of sex offenders is complex, treatment of those in prison seems to be more challenging. This publication presents major considerations and dilemmas, clinical as well as ethics-related, derived from the experience of the psychiatric division in the Israeli prison service in treating sex offenders in this special setting. The psychiatrist treating the incarcerated offender must always maintain a sensitive balance between the needs and wishes of his patient and the potential threat to society stemming from recidivism.


Effects of chemical inhibition of N-WASP, a critical regulator of actin polymerization on aqueous humor outflow through the conventional pathway.
The integrity of actin cytoskeletal organization in aqueous humor outflow pathway is thought to play a critical role in modulation of aqueous humor outflow through the trabecular meshwork. Our understanding of the regulation of actin cytoskeletal dynamics in outflow pathway, however, is very limited. To explore the potential importance of Neural Wiskott-Aldrich syndrome protein (N-WASP), a critical regulator of actin polymerization/nucleation in aqueous humor outflow pathway, the effects of Wiskostatin, a selective pharmacological inhibitor of N-WASP, on aqueous humor outflow facility were evaluated using enucleated porcine eyes and a constant pressure perfusion system. Further, drug induced effects on actin cytoskeletal organization, cell adhesions, myosin II phosphorylation, matrix metalloproteinase (MMP) activity, and cytoskeletal protein profile in porcine trabecular meshwork (TM) cells were determined by immunofluorescence, zymography, and mass spectrometry. Aqueous humor outflow facility was increased significantly and progressively in the Wiskostatin perfused porcine eyes. The Wiskostatin perfused eyes appear to exhibit increased giant vacuoles in the inner wall of aqueous plexi and deformation of aqueous plexi. The Wiskostatin treated TM cells demonstrated extensive vacuoles in their cytosol, and both actin stress fibers and focal adhesions were decreased in a reversible manner. The drug-treated TM cells also revealed decreased myosin II and actin in the cytoskeletal enriched triton insoluble fraction but did not affect myosin II phosphorylation or MMP-2 activity. These data demonstrate that the chemical inhibition of N-WASP increases aqueous humor outflow facility in association with decreased actomyosin interaction and cell adhesive interactions revealing the importance of N-WASP in homeostasis of aqueous humor outflow.


ACTH-receptor expression, regulation and role in adrenocortial tumor formation.
The regulation of the ACTH-receptor gene is unique in that it is up-regulated by its own ligand, ACTH. Ligand-induced up-regulation of ACTH-receptor expression may be an important adaptive process directed towards optimizing adrenal responsiveness to ACTH in the context of physiological stress and the maintenance of metabolic homeostasis in which the adrenals play a pivotal role. Whereas enhancement by ligand-induced up-regulation permits a more efficient and rapid glucocorticoid response, negative feedback regulation of glucocorticoids in the hypothalamus and pituitary inhibits ACTH secretion and allows a balanced adrenal response to stress. Since the cloning of the promoter region of the ACTH receptor, considerable progress in the understanding of the regulatory processes has been made. The effects of ACTH on ACTH-receptor expression is dependent on cAMP, probably mediated through AP-1. The profound effect of three SF-1-binding sites in the ACTH-receptor promoter was demonstrated by deletion experiments. Conversely, ACTH-receptor expression can be suppressed by adrenal-specific transcription factors,like DAX-1. Despite an extensive search, no activating ACTH-receptor mutations have been found in adrenal tumors,excluding the ACTH receptor as a relevant oncogene in adrenal tumorigenesis. However, the ACTH receptor may act as a differentiation factor as suggested by LOH in adrenal carcinomas with an undifferentiated tumor type. In benign adrenal tumors, a strong correlation between ACTH-receptor expression and expression of P450 steroidogenic enzymes is evident. This close regulative relationship is lost in adrenal carcinoma, probably as a result of tumor dedifferentiation. Down-regulation of ACTH-receptor expression in normal and neoplastic tissue can be achieved by adrenostatic compounds such as aminoglutethimide and metyrapone.


Effect of granulocyte-colony stimulating factor on generation of oxygen-derived free radicals and myeloperoxidase activity in neutrophils from poorly controlled NIDDM patients.
To evaluate whether granulocyte-colony stimulating factor (G-CSF) improves an impaired production of oxygen-derived free radicals by neutrophils from poorly controlled NIDDM patients, we studied the effect of G-CSF on myeloperoxidase (MPO) activity and chemiluminescence amplified by a Cypridina luciferin analog (CLA-DCL), which is dependent on O2 generation, and luminol (L-DCL), which is dependent on OCl(-) generation, in response to formyl-methonyl-leucyl-phenylalanine. Both CLA-DCL and L-DCL by neutrophils from the diabetic group (n = 15, HbA(1c) >10%) were significantly decreased (26 and 37%, respectively: P < 0.01) compared with the age-matched normal control group (n = 15), and L-DCL was more sensitive to this inhibition than CLA-DCL (P < 0.05). In both control and diabetic neutrophils, G-CSF significantly enhanced both CLA-DCL (175% in control and 156% in diabetic) and L-DCL (283% in control and 346% in diabetic). In diabetic neutrophils, the enhancing effect of G-CSF on L-DCL was more sensitive than on CLA-DCL (P < 0.001). There was a positive correlation between HbA(1c) and the enhancing effect of G-CSF on L-DCL in diabetic patients (P < 0.05), but not on CLA-DCL. MPO activity was also decreased in the diabetic group (63%, P < 0.05), and G-CSF improved this impaired MPO activity (184%, P < 0.01). Furthermore, there was a positive correlation between HbA(1c) and the improving effect of G-CSF on MPO activity (P < 0.05). Because bacterial infection still accounts for an important cause of morbidity and mortality in diabetic patients, these data suggest that G-CSF may be useful as a drug to prevent the aggravation of bacterial infection by improving neutrophil function, especially through H2O2-MPO-OCl(-) mechanism, in poorly controlled diabetic patients.


Validation of the Readiness for Return-To-Work Scale in Outpatient Occupational Rehabilitation in Canada.
Purpose To examine construct and concurrent validity of the Readiness for Return-To-Work (RRTW) Scale with injured workers participating in an outpatient occupational rehabilitation program. Methods Lost-time claimants (n = 389) with sub-acute or chronic musculoskeletal disorders completed the RRTW Scale on their first day of their occupational rehabilitation program. Statistical analysis included exploratory and confirmatory factor analyses of the readiness items, reliability analyses, and correlation with related scales and questionnaires. Results For claimants in the non-job attached/not working group (n = 165), three factors were found (1) Contemplation (2) Prepared for Action-Self-evaluative and (3) Prepared for Action-Behavioural. The precontemplation stage was not identified within this sample of injured workers. For claimants who were job attached/working group in some capacity (n = 224), two factors were identified (1) Uncertain Maintenance and (2) Proactive Maintenance. Expected relationships and statistically significant differences were found among the identified Return-To-Work (RTW) readiness factors and related constructs of pain, physical and mental health and RTW expectations. Conclusion Construct and concurrent validity of the RRTW Scale were supported in this study. The results of this study indicate the construct of readiness for RTW can vary by disability duration and occupational category. Physical health appears to be a significant barrier to RRTW for the job attached/working group while mental health significantly compromises RRTW with the non-job attached/not working group.


The need and demand for orthodontic treatment in 13- to 15-year-olds in Nairobi, Kenya.
The need for orthodontic treatment in Kenya was previously not been investigated. This study was undertaken to assess the need for orthodontic treatment in 13- to 15-year-old children in Nairobi. The objective need was assessed in 919 children by using the Norwegian treatment need index, and the subjective need was assessed in 739 children by using a structured questionnaire. Objective treatment need was recorded in 29% and subjective need in 33% of the children. Less than 1% were allocated the 'very great need' category. Relatively more girls than boys were dissatisfied with the appearance of their teeth, and a significantly higher number of girls (P < 0.001) said they would like to have their teeth straightened. The children's perceived need for treatment correlated significantly with the treatment need index. Fixed appliances were found necessary for correcting malocclusion in 23% of the children and removable appliances in 6%. Future studies in Kenya should be directed at determining the societal perception of malocclusion, upon which treatment standards may be based.


A guided self-help intervention targeting psychological distress among head and neck cancer and lung cancer patients: motivation to start, experiences and perceived outcomes.
Recent results of a randomized clinical trial showed that a guided self-help intervention (based on problem-solving therapy) targeting psychological distress among head and neck cancer and lung cancer patients is effective. This study qualitatively explored motivation to start, experiences with and perceived outcomes of this intervention. Data were collected from semi-structured interviews of 16 patients. All interviews were audio-recorded and transcribed verbatim. Data were analyzed individually by two coders and coded into key issues and themes. Patients participated in the intervention for intrinsic (e.g. to help oneself) and for extrinsic reasons (e.g. being asked by a care professional or to help improve health care). Participants indicated positive and negative experiences with the intervention. Several participants appreciated participating as being a pleasant way to work on oneself, while others described participating as too confrontational. Some expressed their disappointment as they felt the intervention had brought them nothing or indicated that they felt worse temporarily, but most participants perceived positive outcomes of the intervention (e.g. feeling less distressed and having learned what matters in life). Cancer patients have various reasons to start a guided self-help intervention. Participants appreciated the guided self-help as intervention to address psychological distress, but there were also concerns. Most participants reported the intervention to be beneficial. The results suggest the need to identify patients who might benefit most from guided self-help targeting psychological distress and that interventions should be further tailored to individual cancer patients' requirements.


Effect of long-term food restriction on cardiac mechanics.
Food restriction (FR) is the only known intervention capable of increasing mammalian life span. It not only increases longevity, but reduces the incidence of a broad spectrum of age-related pathologies, including cardiomyopathy, and retards the physiological decline associated with aging. Previous work from this laboratory has shown that long-term FR affects the contractile machinery of the heart, shifting the cardiac myosin profile from the fast, V1 isoform to the slow, V3 isoform. The aim of the present study was to determine whether FR also induces changes in cardiac mechanics. Isolated, isovolumically beating hearts were examined from four groups of rats: 1) ad libitum-fed rats killed at 10-13 mo of age, 2) FR rats offered only 60% of the calories consumed by ad libitum-fed rats and killed at the same age, 3) young ad libitum-fed rats having the same heart weights as the FR rats, and 4) ad libitum-fed rats subjected to short-term FR, i.e., for the last 3 wk of life, and also killed at 10-13 mo of age. Both short- and long-term FR profoundly and to approximately the same extent affected cardiac mechanics. Hearts from FR rats developed much higher pressures than hearts from the ad libitum-fed rats under conditions of low-calcium perfusate. This difference disappeared, however, when contractility was enhanced by either calcium or isoproterenol. FR prolonged both contraction and relaxation times. Long-term ad libitum-fed rats (adult, 10-13 mo of age) had a lower isoproterenol sensitivity than the young ad libitum-fed rats (10 wk of age). Both short- and long-term FR restored the sensitivity to isoproterenol. In summary, FR profoundly affects many aspects of cardiac mechanics, enhancing some age-related changes (prolongation of the contraction and relaxation times), attenuating another (increasing the isoproterenol sensitivity), and, finally, inducing some unique changes unrelated to age (increased pressure development under low-calcium perfusate).


Oral health and pro-inflammatory status in end-stage renal disease patients.
The aim of the present study was to investigate the oro-facial health of patients with end stage renal disease, focusing on their periodontal conditions. A total of 51 patients (33 men) between the ages of 22 and 81 years with different types of chronic kidney disease that needed renal dialysis, underwent a full dental examination including a panoramic radiograph. A blood sample was collected from the subjects to investigate the levels of pro-inflammatory biomarkers. A large proportion of patients had oral health problems. A total of 35% claimed that they suffered problems of the oral cavity and 51% had periapical osteitis around one or more teeth. A high number of patients also suffered from gingivitis (46%), severe periodontitis (35%) and 37% had cavities due to caries. On average the patients had 22.9 (SD 7.3) teeth and 14% had complete or partial dentures. Although periodontitis influenced the C-reactive protein level and oral pathology was significant within this specific population, the correlation between inflammatory biomarkers and dental parameters was weak. This study indicates that a substantial number of patients who suffer from advanced chronic kidney disease, close to the start of dialysis treatment, have dental problems that require attention.


The role of shelf acetabuloplasty in early and late stages of Perthes disease: a meta-analysis of observational studies.
Perthes disease may result in deformity of the proximal femoral epiphysis and incongruity of the hip, and shelf acetabuloplasty has been frequently used for treatment. The aim of this study was to review the published articles about the outcome of shelf acetabuloplasty as a containment or reconstruction-salvage procedure in Perthes disease. We utilized the PubMed online database for peer review articles using the following search terms: shelf arthroplasty, acetabuloplasty, and Perthes. To be included in this meta-analysis, we isolated studies on children with Perthes disease who received shelf acetabuloplasty as a treatment, conducted in any geographic location with the Stulberg classification outcome. Twenty articles were identified for a qualitative systematic review. The fixed effect and random effect meta-analysis were performed as appropriate for the summary pool estimate following the heterogeneity test. The meta-analysis was performed on 11 articles in three categories: all articles, articles for shelf arthroplasty in the early stages of Perthes disease, and in the late stages. Overall, shelf acetabuloplasty provided 84 % good outcome of Stulberg classes I, II, and III. Shelf acetabuloplasty performed in early stages for containment provided good outcome in 85 %, while only 69 % good outcome was achieved when shelf acetabuloplasty was performed in late stages for reconstruction-salvage. Shelf acetabuloplasty provides a good or fair Stulberg outcome when performed in early Perthes stages (Waldenström stages I and II) as a containment surgery, but less favorable outcomes were observed when shelf surgery was used for reconstructive-salvage purposes in late Perthes disease stages (Waldenström stages III and IV). Caution is advised in performing the shelf procedure in children over 10-11 years of age.


Carbon opportunity cost increases carbon footprint advantage of grain-finished beef.
Beef production accounts for the largest share of global livestock greenhouse gas emissions and is an important target for climate mitigation efforts. Most life-cycle assessments comparing the carbon footprint of beef production systems have been limited to production emissions. None also consider potential carbon sequestration due to grazing and alternate uses of land used for production. We assess the carbon footprint of 100 beef production systems in 16 countries, including production emissions, soil carbon sequestration from grazing, and carbon opportunity cost-the potential carbon sequestration that could occur on land if it were not used for production. We conduct a pairwise comparison of pasture-finished operations in which cattle almost exclusively consume grasses and forage, and grain-finished operations in which cattle are first grazed and then fed a grain-based diet. We find that pasture-finished operations have 20% higher production emissions and 42% higher carbon footprint than grain-finished systems. We also find that more land-intensive operations generally have higher carbon footprints. Regression analysis indicates that a 10% increase in land-use intensity is associated with a 4.8% increase in production emissions, but a 9.0% increase in carbon footprint, including production emissions, soil carbon sequestration and carbon opportunity cost. The carbon opportunity cost of operations was, on average, 130% larger than production emissions. These results point to the importance of accounting for carbon opportunity cost in assessing the sustainability of beef production systems and developing climate mitigation strategies.


Effectiveness of transmural team-based palliative care in prevention of hospitalizations in patients at the end of life: A systematic review and meta-analysis.
Team-based palliative care interventions have shown positive results for patients at the end of life in both hospital and community settings. However, evidence on the effectiveness of transmural, that is, spanning hospital and home, team-based palliative care collaborations is limited. To systematically review whether transmural team-based palliative care interventions can prevent hospital admissions and increase death at home. Systematic review and meta-analysis. MEDLINE (Ovid), Embase (Ovid), CINAHL (Ebsco), PsychINFO (Ovid), and Cochrane Library (Wiley) were systematically searched until January 2021. Studies incorporating teams in which hospital and community professionals co-managed patients, hospital-based teams with community follow-up, and case-management interventions led by palliative care teams were included. Data was extracted by two researchers independently. About 19 studies were included involving 6614 patients, of whom 2202 received an intervention. The overall pooled odds ratio of at least one hospital (re)admissions was 0.46 (95% confidence interval (CI) 0.34-0.68) in favor of the intervention group. The highest reduction in admission was in the hospital-based teams with community follow-up: OR 0.21 (95% CI 0.07-0.66). The pooled effect on home deaths was 2.19 (95% CI 1.26-3.79), favoring the intervention, with also the highest in the hospital-based teams: OR 4.77 (95% CI 1.23-18.47). However, studies had high heterogeneity regarding intervention, study population, and follow-up time. Transmural team-based palliative care interventions, especially hospital-based teams that follow-up patients at home, show an overall effect on lowering hospital admissions and increasing the number of patients dying at home. However, broad clinical and statistical heterogeneity of included studies results in uncertainty about the effect size.


Myocardin-related transcription factor-a controls myofibroblast activation and fibrosis in response to myocardial infarction.
Myocardial infarction (MI) results in loss of cardiac myocytes in the ischemic zone of the heart, followed by fibrosis and scar formation, which diminish cardiac contractility and impede angiogenesis and repair. Myofibroblasts, a specialized cell type that switches from a fibroblast-like state to a contractile, smooth muscle-like state, are believed to be primarily responsible for fibrosis of the injured heart and other tissues, although the transcriptional mediators of fibrosis and myofibroblast activation remain poorly defined. Myocardin-related transcription factors (MRTFs) are serum response factor (SRF) cofactors that promote a smooth muscle phenotype and are emerging as components of stress-responsive signaling. We aimed to examine the effect of MRTF-A on cardiac remodeling and fibrosis. Here, we show that MRTF-A controls the expression of a fibrotic gene program that includes genes involved in extracellular matrix production and smooth muscle cell differentiation in the heart. In MRTF-A-null mice, fibrosis and scar formation following MI or angiotensin II treatment are dramatically diminished compared with wild-type littermates. This protective effect of MRTF-A deletion is associated with a reduction in expression of fibrosis-associated genes, including collagen 1a2, a direct transcriptional target of SRF/MRTF-A. We conclude that MRTF-A regulates myofibroblast activation and fibrosis in response to the renin-angiotensin system and post-MI remodeling.


[Use of neural network computer technology in the determination of therapeutic strategy in patients with stomach and duodenal ulcer].
The authors present the expert neural network programmed complex "Axon" allowing the prognosis of the course of ulcer disease of the stomach and duodenum to be made. On the basis of the prognosis obtained certain medical strategy can be recommended. The neural network in which the data of treatment of 909 patients with ulcer disease of the stomach and duodenum had been introduced was taken as a basis of the complex. The program is registered in the Russian copyright agency for PC programs, data base and topologies of integrated circuits. The authors consider that the approach proposed will allow the correct medical policy to be chosen which can lead to better results of treatment of patients with ulcer disease and thus the 100 years long contradictions between different specialists in determining medical policy for such category of patients will be overcome.


Sweet Orange Juice Processing By-Product Extracts: A Caries Management Alternative to Chlorhexidine.
Dental caries is one of the most prevalent chronic diseases globally in both children and adults. This study investigated the potential of industrial sweet orange waste extracts (ISOWE) as a substitute for chlorhexidine (CHX) in managing dental caries. First, the cytotoxicity of ISOWE (40, 80, 120 mg/mL) and CHX (0.1 and 0.2%) on buccal epithelial cells was determined. ISOWE exhibited no overall toxicity, whereas CHX strongly affected cell viability. The combination of ISOWE and CHX significantly enhanced cell proliferation compared to CHX alone. Next, the antimicrobial efficacy of ISOWE, CHX, and their combination was assessed against a 7-day complex biofilm model inoculated with oral samples from human volunteers. CHX exhibited indiscriminate antimicrobial action, affecting both pathogenic and health-associated oral microorganisms. ISOWE demonstrated lower antimicrobial efficacy than CHX but showed enhanced efficacy against pathogenic species while preserving the oral microbiome's balance. When applied to a cariogenic biofilm, the combined treatment of ISOWE with 0.1% CHX showed similar efficacy to 0.2% CHX treatment alone. Overall, the findings suggest that ISOWE is a promising natural anti-cariogenic agent with lower toxicity and enhanced selectivity for pathogenic species compared to CHX.


Suppressive effect of aspirin on aberrant crypt foci in patients with colorectal cancer.
and aims: Aspirin and other non-steroidal anti-inflammatory drugs have been shown to reduce the risk of colorectal cancer (CRC). Animal models have shown that aspirin is also effective in reducing the density of aberrant crypt foci (ACF). The aim of the study was to evaluate the effect of chronic administration of aspirin on the distribution pattern and histological characteristics of ACF in patients with CRC. Our study compared the distribution patterns and histomorphological characteristics of ACF between a group of CRC patients treated with low dose aspirin (n=59) and a control group without aspirin (n=135). ACF were visualised on methylene blue stained macroscopically normal mucosa, microdissected, and serially cut. ACF were found in 75.8% of mucosal samples from the control group and in 36% of mucosal samples from the aspirin treated group, indicating a 47% decline in prevalence of ACF in colonic samples of patients treated with aspirin. A significant reduction from 92.5% to 40% (p<0.0001) was found in distal large bowel samples containing one or more ACF. Similarly, the aspirin treated group showed a reduction in ACF density of 64% and 82%, respectively, in both proximal and distal parts of the colon, indicating a significant reduction in ACF/cm(2) in distal colon samples (p<0.01). The aspirin treated group displayed a 52% reduction in dysplastic ACF although this difference was not statistically significant. Our study has provided evidence of the effective chemopreventive action of low dose aspirin on ACF in humans.


Na+-K+ transport and volume of rat erythrocytes under dietary K+ deficiency.
Red cell Na+ and K+ content and transport were studied in Sprague-Dawley rats in the course of a dietary K+ depletion ranging 1-6 wk. Plasma K+ fell to below 2 mM, and red cell K+ decreased. Cellular Na+ rose due to an increase of the Na+ leak. Inward Rb+ and outward Na+ transport by the Na+-K+ pump (determined at 2 mM external Rb+) were accelerated by the rise in cell Na+ concentration. K+ depletion caused a cation deficit of up to 30% of total red cell Na+ plus K+ and a consecutive cell shrinkage with an increase in mean cellular hemoglobin content (MCHC). The cell shrinkage, in turn, was paralleled by up to a 10-fold increase in the maximum capacity of the furosemide-sensitive, chloride-dependent Na+-K+ cotransport system. This system participated with up to 50% of the total K+ movements across the red cell membrane in severe K+ deficiency. In normal cells shrunken by osmotic means, Na+-K+ cotransport was similarly accelerated severalfold, indicating that the cell shrinkage occurring during K+ depletion is a major factor inducing the changes in Na+-K+ cotransport. However, a second unknown factor is also involved. It is concluded that in the rat, not only genetic but also environmental parameters contribute in determining the actual activity of the red cell Na+-K+ cotransport system. The cell volume and MCHC must be considered when judging Na+ and K+ transport changes observed in rat erythrocytes under various pathophysiological conditions.


Malnutrition and the role of nutritional support in alcoholic liver disease.
Malnutrition adversely effects hepatic function and structure. In certain instances, histological changes indistinguishable from alcoholic liver disease may be seen. Alcohol is clearly a direct hepatic toxin and its results are not prevented by normal nutritional intake. The majority of patients admitted to the hospital with alcoholic liver disease are moderately to severely malnourished but find it difficult or impossible to resume an intake sufficient to repair and maintain a normal nutritional state. Malnutrition may be considered a complication of alcohol abuse which occurs simultaneously with liver damage. Repair of both nutrition and hepatic histology requires considerable time, more for the latter. Here we review the data which both incriminates and separates the effects of malnutrition and of alcohol on the liver, and review the current literature on the effect of intravenous or enteral protein-calorie supplementation on acute alcoholic liver disease. While the data suggest that improvement in conventional liver tests are accelerated somewhat by such treatment, there have been no major confirmed differences noted between treatment and control groups at 3 to 4 wk. More precise measures of liver function, as opposed to conventional tests of liver status, and longer follow-up periods will be required to substantiate the suggested beneficial effects of iv or enteral protein-calorie supplementation in acute alcoholic hepatitis.


Frontal asymmetry index in Williams syndrome: Evidence for altered emotional brain circuitry?
Asymmetrical frontal electroencephalography (EEG) activity is associated with motivational neural systems of approach/withdrawal behaviors. Greater left frontal EEG has been linked to increased appetitive tendencies whereas increased right frontal activity is related to the activation of avoidance mechanisms. Williams syndrome (WS) is a genetic condition characterized by a highly sociable personality manifested by a propensity to approach strangers and decreased social fear. Consequently, the current study was designed to investigate the frontal cortical activity during resting state, indexed by relative alpha power, in adults with WS as compared to typically developing (TD) controls, and a subgroup of TD extraverts. Results indicated that participants with WS produced attenuated left frontal activity relative to TD peers, or TD extraverts in particular; yet, no groups differed in their degree of right frontal activity. Finally, while both TD group and the extravert subset showed trends of greater left over right frontal activity, the WS participants demonstrated opposing effect of increased right over left frontal EEG. Importantly, individuals with WS produced deviating frontal activity patterns compared to TD extraverts despite exhibiting common social-affiliative tendencies, underscoring that neural mechanisms that give rise to extraversion in WS may not function similarly to those subserving this personality trait expressed in TD.


A full-spectrum-absorption from nickel sulphide nanoparticles for efficient NIR-II window photothermal therapy.
Near-infrared (NIR) light has been widely applied in the field of photothermal therapy (PTT). Recent advances in the light wavelength for efficient cancer PTT have gradually shifted from the first NIR (NIR-I) biowindow (700-1000 nm) to the second NIR (NIR-II) biowindow (1000-1350 nm) owing to its intrinsic deeper tissue penetration ability and a higher maximum permissible exposure (MPE) value. Herein, we have prepared nickel sulphide (Ni9S8) nanoparticles (NPs) with a full-spectrum-absorption (400 nm-1100 nm) in the NIR region. By a fair comparison, it is found that the PTT using the NPs upon irradiation from an NIR-II (i.e., 1064 nm) laser is more efficient than that from an NIR-I (i.e., 808, 915, and 976 nm) laser. The large mass extinction coefficient value (22.18 L g-1 cm-1) and high photothermal conversion efficiency (46%) at 1064 nm make these NPs promising candidates for NIR-II photo-thermal therapy. This study will benefit future exploration and optimization of nickel-based photoabsorbers utilizing NIR-II light for photothermal applications.


Early Life Exposure to Air Pollution and Autism Spectrum Disorder: Findings from a Multisite Case-Control Study.
Epidemiologic studies have reported associations between prenatal and early postnatal air pollution exposure and autism spectrum disorder (ASD); however, findings differ by pollutant and developmental window. We examined associations between early life exposure to particulate matter ≤2.5 µm in diameter (PM2.5) and ozone in association with ASD across multiple US regions. Our study participants included 674 children with confirmed ASD and 855 population controls from the Study to Explore Early Development, a multi-site case-control study of children born from 2003 to 2006 in the United States. We used a satellite-based model to assign air pollutant exposure averages during several critical periods of neurodevelopment: 3 months before pregnancy; each trimester of pregnancy; the entire pregnancy; and the first year of life. Logistic regression was used to estimate odds ratios (ORs) and 95% confidence intervals (CIs), adjusting for study site, maternal age, maternal education, maternal race/ethnicity, maternal smoking, and month and year of birth. The air pollution-ASD associations appeared to vary by exposure time period. Ozone exposure during the third trimester was associated with ASD, with an OR of 1.2 (95% CI: 1.1, 1.4) per 6.6 ppb increase in ozone. We additionally observed a positive association with PM2.5 exposure during the first year of life (OR = 1.3 [95% CI: 1.0, 1.6] per 1.6 µg/m increase in PM2.5). Our study corroborates previous findings of a positive association between early life air pollution exposure and ASD, and identifies a potential critical window of exposure during the late prenatal and early postnatal periods.


Age, Sex, and Blood Pressure-Related Influences on Reference Values of Left Atrial Deformation and Mechanics From a Large-Scale Asian Population.
Left atrial (LA) function is tightly linked to several cardiovascular diseases and confers key prognostic information. Speckle tracking-based deformation as a feasible and sensitive LA mechanical assessment has proven its clinical significance beyond volume measures; however, the reference values remain largely unknown. We studied 4042 participants undergoing annual cardiovascular survey. Among them, 2812 healthy participants (65% men; mean age, 47.4±9.9 years) were eligible for speckle tracking analysis. Peak atrial longitudinal systolic strain and strain rate (SR) at systolic (SRs), early diastolic (SRe), and late diastolic atrial contraction phases (SRa) were analyzed by dedicated software (EchoPAC, GE) and compared in terms of age, sex, and blood pressure. Overall, women demonstrated higher peak atrial longitudinal systolic strain (39.34±7.99% versus 37.95±7.96%; P<0.001) and showed age-dependent more pronounced peak atrial longitudinal systolic strain functional decay than those of men (P value for interaction, <0.05), with men showing higher SRs and SRa, although lower SRe (all P<0.001). Both increasing age and higher blood pressure were independently associated with deteriorated peak atrial longitudinal systolic strain, SRs, and SRe, although augmented LA SRa, even after accounting for baseline clinical covariates in multivariable models that incorporated LA volume, NT-proBNP (N-terminal pro-B-type natriuretic peptide), or left ventricular E/e' (all P<0.001). Our findings suggest LA mechanical functional decays in association with increasing age and higher blood pressure, which seem to be compensated for by augmentation of atrial pump function. We have also provided age- and sex-stratified reference values for strain and SR based on a large-scale Asian population.


Facial Spinulate Demodicosis.
Hyperkeratotic spicules are rare cutaneous lesions associated with underlying systemic illnesses. In more recent times, facial spinulate demodicosis has been suggested as an etiological factor. Demodicosis is a common dermatological condition characterized by the presence of Demodex mites in the pilocutaneous follicles. This report describes the case of a 40-year-old otherwise healthy woman who reported having undetected facial follicular spicules as a result of demodicosis. The diagnosis was confirmed by physical examination and skin punch biopsy. Initial treatment with 5% permethrin did not resolve the rash. As such, 1% Ivermectin was prescribed, after which the rash resolved completely within 3 weeks.


Selection of an anti-solvent for efficient and stable cesium-containing triple cation planar perovskite solar cells.
The perovskite layer is a crucial component influencing high-performance perovskite solar cells (PSCs). In the one-step solution method, anti-solvents are important for obtaining smooth and uniform perovskite active layers. This work explored the effect of various anti-solvents on the preparation of triple cation perovskite active layers. In general, anti-solvents with low dielectric constants, low polarity, and low boiling point are suitable for the preparation of perovskite films. Microstructural and elemental analyses of the perovskite films were systematically conducted by scanning electron microscopy, X-ray diffraction, and X-ray photoelectron spectroscopy. The photoelectric properties, carrier transfer, and recombination process in the PSCs were investigated using photocurrent-voltage characteristic curves and electrochemical impedance spectroscopy. Optimum performance was obtained when the anti-solvent was diethyl ether (DEE) and the ratio of the optimum amount of DEE to the volume of the precursor was 1 : 10. Meanwhile, we found that the partial replacement of formamidinium/methylammonium by cesium could increase the stability of the PSCs and enhance the power conversion efficiency from 15.49% to over 17.38%.


Rapid simultaneous cloning of drug targets from multiple mammalian species.
A method for the routine, rapid and simultaneous cloning of drug targets from multiple mammalian species is described. This expedites the generation of recombinant proteins and cell lines that can provide alternatives to animal experiments. This was achieved by the collection of RNA from a comprehensive range of tissues from a variety of species, and the optimisation of cDNA synthesis. This "zooplate" has been successfully used for the simultaneous amplification and cloning of drug targets from multiple species. These products have subsequently been used to develop in vitro assays that support efficacy and safety studies in new drug discovery programmes. Within the framework of the Three Rs, these reagents can reduce the number of animals required to provide material for ex vivo assays and can refine the in vivo studies that are still necessary.


The control of ribonucleic acid synthesis in bacteria. The synthesis and stability of ribonucleic acid in chloramphenicol-inhibited cultures of Escherichia coli.
The rate of polymerization of ribosomal ribonucleic acid chains was estimated for steadily growing cultures of Escherichia coli M.R.E.600, from the kinetics of incorporation of exogenous [5-(3)H]uracil into completed 23S rRNA molecules. The analytical method of Avery & Midgley (1971) was used. Measurements were made at 37 degrees C, in the presence or the absence of chloramphenicol, in each of three media; enriched broth, glucose-salts or sodium lactate-salts. The rate of chain elongation of 23S rRNA was virtually constant in all media at 37 degrees C, as 24+/-4 nucleotides added/s. Accelerations in the rate of biosynthesis of rRNA by chloramphenicol in growth-limiting media are due primarily to an increase in the rate of initiation of new RNA chains, up to the rates existing in cultures growing rapidly in broth. Thus, in poorer media, only a small fraction of the available DNA-dependent RNA polymerase molecules are active at any given instant, since the chain-initiation rate is limiting in these conditions. In cultures growing rapidly in enriched broth, antibiotic inhibition caused a rise of some 12% in the rate of incorporation of exogenous uracil into total RNA. This small acceleration was due entirely to the partial stabilization of the mRNA fraction, which accumulated as 14% of the RNA formed after the addition of chloramphenicol. In cultures growing more slowly in glucose-salts or lactate-salts media, chloramphenicol caused an immediate acceleration of two- to three-fold in the overall rate of RNA synthesis. Studies by DNA-RNA hybridization showed that the synthesis of mRNA was accelerated in harmony with the other affected species. However, just over half the mRNA formed after the addition of chloramphenicol quickly decayed to acid-soluble products, whereas the remainder was more stable and accumulated in the cells. The mRNA fraction constituted about 6% of the total cellular RNA after 3h inhibition. A model was suggested to explain the partial stabilization and accumulation of the mRNA fraction and the acceleration in the rate of synthesis of mRNA when chloramphenicol was added to cultures in growth-limiting media.


[Glomerular changes in the contralateral kidney in the rat with experimental hydronephrosis].
We have studied under optic and electronmicroscopes the alterations of glomeruli in contralateral kidneys of rats with experimental hydronephrosis. Forty-eight Wistar rats, divided into two groups (control and experimental) were used. They were sacrificed 3, 6, 9 and 12 days after ureteral obstruction. There was a slight hypertrophy of glomeruli and hiperplasia of other components accompanied by a increased development of podocytes.


Alginate for cardiac regeneration: From seaweed to clinical trials.
Heart failure is a growing endemic in the aging Western population with a prevalence of over 20 million people worldwide1. Existing heart failure therapies are unable to reverse heart failure and do not address its fundamental cause, the loss of cardiomyocytes2. In order to induce myocardial regeneration for the myocardium and the heart valve, facilitate self-repair, improve tissue salvage, reduce or reverse the adverse-remodeling and ultimately achieve long-term functional stabilization and improvement in the heart function, novel strategies for therapeutic regeneration are being developed which are aiming to compensate for the insufficient and low intrinsic regenerative ability of the adult heart3. Similarly, valve replacement with mechanical or biological substitutes meets numerous hurdles. New approaches using multicellular approaches and new material are extensively studied. Most of those strategies depend on biomaterials that help to achieve functional integrated vasculogenesis and myogenesis in the heart/tissue. Especially for failed heart valve function a number of therapeutic approaches are common from corrective intervention to complete replacement4. However the complexity of the heart valve tissue and its high physical exposure has led to a variety of approaches, however therapeutic regeneration needs to be established. Beside other approaches alginate has been identified as one building block to achieve therapeutic regeneration. Alginate is a versatile and adaptable biomaterial that has found numerous biomedical applications which include wound healing, drug delivery and tissue engineering. Due to its biologically favorable properties including the ease of gelation and its biocompatibility, alginate-based hydrogels have been considered a particularly attractive material for the application in cardiac regeneration and valve replacement techniques. Here, we review current applications of alginate in cardiac regeneration as well as perspectives for the alginate-dependent, cardiac regeneration strategies.