The Diabetes Disparity and Puerto Rican Identified Individuals.
Purpose The purpose of this systematic review was to describe what is known about the diabetes disparity affecting Puerto Rican identified adults living in the continental United States as well as illuminate areas that merit further investigation. Methods The CINAHL and PubMed databases were searched using the keywords Hispanic, Puerto Rican, and type 2 diabetes. Search limits included < 10-year-old, peer-reviewed, systematic reviews, available in the English language. The abstracts of 124 articles were reviewed, and 7 articles were reviewed in depth. Results The Puerto Rican identified Hispanic subgroup is disproportionately affected by diabetes-the diabetes disparity. Puerto Rican identified Hispanic adults are less affected by citizenship status, may be less affected by English proficiency, use health care services differently, and have contextually different fatalistic views of diabetes compared with other Hispanic identified people. Spiritual/religious influences, associated mental health problems, and general cultural practices related to diabetes self-care are understudied in this group. Conclusion Ambiguous use of the term Hispanic should be avoided when describing Hispanic subgroups. Stronger, more robust studies are needed to understand the unique cultural forces influencing the poor diabetes outcomes and individual behaviors that contribute to generally suboptimal diabetes self-care for Puerto Rican adults with type 2 diabetes.


Heart Rate Variability Responses to Visually Induced Motion Sickness.
Analysis of heart rate variability (HRV) can reveal a range of useful information regarding the dynamics of the autonomic nervous system (ANS). It is considered a robust and reliable tool to understand even some subtle changes in ANS activity. Here, we study the "hidden" characteristic changes in HRV during visually induced motion sickness; using nonlinear analytical methods, supplemented by conventional time- and frequency-domain analyses. We computed HRV from electrocardiograms (ECG) of 14 healthy participants measured at baseline and during nausea. Primarily hypothesizing evident differences in measures of physiologic complexity (SampEn; sample entropy, FuzzyEn; fuzzy entropy), chaos (LLE; largest Lyapunov exponent) and Poincaré/Lorenz (CSI; cardiac sympathetic activity, CVI; cardiac vagal index) between the two states. We found that during nausea, participants showed a markedly higher degree of regularity (SampEn, p = 0.0275; FuzzyEn, p = 0.0006), with a less chaotic ANS response (LLE, p = 0.0004). CSI significantly increased during nausea compared to baseline (p = 0.0005), whereas CVI did not appear to be statistically different between the two states (p = 0.182). Our findings suggest that motion sickness-induced ANS perturbations may be quantifiable via nonlinear HRV indices. These findings have implications for understanding the malaise of motion sickness and in turn, aid development of therapeutic interventions to relieve motion sickness symptoms.Clinical relevance- The study suggests potential indices of physiologic complexity and chaos that may be useful in monitoring motion sickness during clinical studies.


mGlu Receptors and Cancerous Growth.
G-protein coupled receptors (GPCR) represent a class of therapeutic targets that have been widely exploited for drug designs and development. Metabotropic glutamate receptors (mGluRs) belong to Class C GPCRs and are predominantly involved in maintaining cellular homeostasis in the central nervous system (CNS). The surprising accumulating evidence suggesting other functional roles of mGluRs in human malignancies in addition to synaptic transmission has presented intriguing possibilities to make mGluRs putative novel targets for human cancers. Since our group first described the aberrant expression of mGluR1 as the driving force in melanomagenesis in transgenic mouse models, other subtypes of mGluRs have been implicated in the pathogenesis of various cancer types such as malignant gliomas and medulloblastomas. As such, increased efforts have been generated to elucidate the mechanisms by which mGluRs confer oncogenic potentials. Current knowledge on the participation of various mGluRs in several human cancers suggests that mGluRs are "druggable" members of the GPCR superfamily and their oncogenic implications in cancer, so further understanding on anti-mGluR strategies will be beneficial.


Implementation of enhanced cognitive behaviour therapy (CBT-E) for adults with anorexia nervosa in an outpatient eating-disorder unit at a public hospital.
Anorexia nervosa (AN) in adults is difficult to treat, and no current treatment is supported by robust evidence. A few studies, most of which were performed by highly specialized research units, have indicated that enhanced cognitive behaviour therapy (CBT-E) for eating disorders can be effective. However, the dropout rate is high and the evidence from non-research clinical units is sparse. This quality assessment project implemented CBT-E in an outpatient setting at a public hospital. Forty-four patients with AN started therapy. Each patient received at least 40 sessions of CBT-E over a 12-month period. Their body mass index (BMI) was recorded at baseline and after 3, 6 and 12 months. Reasons for not starting therapy or for leaving therapy prematurely were recorded. Half (n = 22) of the 44 patients who started outpatient CBT-E did not complete the treatment. In the remaining sample there was a large (and statistically significant) weight gain after 12 months. The percentage of patients achieving the target BMI of > 18.5 kg/m2 was 36.4, 50.0 and 77.3% after 3, 6 and 12 months, respectively. This quality assessment project shows that it is possible to establish effective CBT-E in an outpatient eating-disorder unit at a public hospital. Although half of the patients did not complete CBT-E, the remaining patients achieved a significant increase in BMI at 1 year after the start of therapy.


Preventing recurrent ankle sprains: Is the use of an App more cost-effective than a printed Booklet? Results of a RCT.
Recurrent ankle sprains can be reduced by following a neuromuscular training (NMT) program via a printed Booklet or a mobile application. Regarding the high incidence of ankle sprains, cost-effectiveness regarding implementation can have a large effect on total societal costs. In this economic analysis, we evaluated whether the method of implementing a proven effective NMT program using an App or a Booklet resulted in differences in injury incidence rates leading to costs and hence to differences in cost-effectiveness. In total, 220 athletes with a previous ankle sprain were recruited for this randomized controlled trial with a follow-up of 12 months. Half of the athletes used the freely available "Strengthen your ankle" App and the other half received a printed Booklet. After the 8-week program, athletes were questioned monthly on their recurrent injuries. Primary outcome measures were incidence density of ankle injury and incremental cost-effectiveness ratio (ICER). During follow-up, 31 athletes suffered from a recurrent ankle sprain that led to costs resulting in a hazard ratio of 1.13 (95% CI: 0.56-2.27). The incremental cost-effectiveness ratio of the App group in comparison with the Booklet group was €361.52. The CE plane shows that there was neither a difference in effects nor in costs between both intervention methods. This study showed that the method of implementing the NMT program using an App or a Booklet led to similar cost-effectiveness ratios and the same occurrence of recurrent injuries leading to costs. Both the App and the Booklet can be used to prevent recurrent ankle injuries, showing no differences in (cost-) effectiveness at 12-month follow-up.


Obesity and Kidney Function: A Two-Sample Mendelian Randomization Study.
Obesity and type 2 diabetes (T2D) are correlated risk factors for chronic kidney disease (CKD). Using summary data from GIANT (Genetic Investigation of Anthropometric Traits), DIAGRAM (DIAbetes Genetics Replication And Meta-analysis), and CKDGen (CKD Genetics), we examined causality and directionality of the association between obesity and kidney function. Bidirectional 2-sample Mendelian randomization (MR) estimated the total causal effects of body mass index (BMI) and waist-to-hip ratio (WHR) on kidney function, and vice versa. Effects of adverse obesity and T2D were examined by stratifying BMI variants by their association with WHR and T2D. Multivariable MR estimated the direct causal effects of BMI and WHR on kidney function. The inverse variance weighted random-effects MR for Europeans was the main analysis, accompanied by several sensitivity MR analyses. One standard deviation (SD ≈ 4.8 kg/m2) genetically higher BMI was associated with decreased estimated glomerular filtration rate (eGFR) [β=-0.032 (95% confidence intervals: -0.036, -0.027) log[eGFR], P = 1 × 10-43], increased blood urea nitrogen (BUN) [β = 0.010 (0.005, 0.015) log[BUN], P = 3 × 10-6], increased urinary albumin-to-creatinine ratio [β = 0.199 (0.067, 0.332) log[urinary albumin-to-creatinine ratio (UACR)], P = 0.003] in individuals with diabetes, and increased risk of microalbuminuria [odds ratios (OR) = 1.15 [1.04-1.28], P = 0.009] and CKD [1.13 (1.07-1.19), P = 3 × 10-6]. Corresponding estimates for WHR and for trans-ethnic populations were overall similar. The associations were driven by adverse obesity, and for microalbuminuria additionally by T2D. While genetically high BMI, unlike WHR, was directly associated with eGFR, BUN, and CKD, the pathway to albuminuria was likely through T2D. Genetically predicted kidney function was not associated with BMI or WHR. Genetically high BMI is associated with impaired kidney function, driven by adverse obesity, and for albuminuria additionally by T2D.


Production and limbal lineage commitment of aniridia patient-derived induced pluripotent stem cells.
Congenital aniridia is caused by heterozygous mutations on the PAX6 gene leading to reduced amount of PAX6 protein (haploinsufficiency), abnormal eye development and aniridia-associated keratopathy (AAK). This progressive corneal opacification resembles late-onset limbal stem cell (LSC) deficiency, leading to disrupted corneal epithelial renewal. The factors leading to AAK are not known and defects in native LSC differentiation and/or features leading to ocular surface dysfunction like inflammation and loss of innervation could contribute to development of AAK. Here, we produced induced pluripotent stem cells (hiPSC) from three AAK patients and examined whether PAX6 haploinsufficiency affects LSC lineage commitment. During LSC differentiation, characterization of the AAK lines showed lowered PAX6 expression as compared to wild type (WT) controls and expression peak of PAX6 during early phase of differentiation was detected only in the WT hiPSC lines. Whether it reflects developmental regulation remains to be studied further. Nevertheless, the AAK-hiPSCs successfully differentiated towards LSC lineage, in line with the presence of LSCs in young patients before cell loss later in life. In addition, patient specific LSCs showed similar wound healing capacity as WT cells. However, extensive batch-related variation in the LSC marker expression and wound healing efficacy was detected without clear correlation to AAK. As development and maintenance of corneal epithelium involves an interplay between LSCs and their environment, the AAK-hiPSCs generated here can be further used to study the crosstalk between LSCs and limbal niche including e.g. corneal immune cells, stroma cells and neurons.


Death-Associated Protein Kinase 1 as a Promising Drug Target in Cancer and Alzheimer's Disease.
Death-Associated Protein Kinase 1 (DAPK1) plays an important role in apoptosis, tumor suppression and neurodegeneration including Alzheimer's Disease (AD). This review will describe the diverse roles of DAPK1 in the development of cancer and AD, and the current status of drug development targeting DAPK1-based therapies. Reports of DAPK1 regulation, function and substrates were analyzed using genetic DAPK1 manipulation and chemical DAPK1 modulators. DAPK1 expression and activity are deregulated in cancer and AD. It is down-regulated and/or inactivated by multiple mechanisms in many human cancers, and elicits a protective effect to counteract numerous death stimuli in cancer, including activation of the master regulator Pin1. Moreover, loss of DAPK1 expression has correlated strongly with tumor recurrence and metastasis, suggesting that lack of sufficient functional DAPK1 might contribute to cancer. In contrast, DAPK1 is highly expressed in the brains of most human AD patients and has been identified as one of the genetic factors affecting susceptibility to late-onset AD. The absence of DAPK1 promotes efficient learning and better memory in mice and prevents the development of AD by acting on many key proteins including Pin1 and its downstream targets tau and APP. Recent patents show that DAPK1 modulation might be used to treat both cancer and AD. DAPK1 plays a critical role in diverse physiological processes and importantly, its deregulation is implicated in the pathogenesis of either cancer or AD. Therefore, manipulating DAPK1 activity and/or expression may be a promising therapeutic option for cancer or AD.


Detection of JC virus-specific cytotoxic T lymphocytes in healthy individuals.
The polyomavirus JC (JCV) infects 85% of healthy individuals, and its reactivation in a limited number of immunosuppressed people causes progressive multifocal leukoencephalopathy (PML), a severe demyelinating disease of the central nervous system. We hypothesized that JCV-specific cytotoxic T lymphocytes (CTLs) might control JCV replication in healthy individuals, blocking the evolution of PML. Using 51Cr release and tetramer staining assays, we show that 8 of 11 HLA-A*0201+ healthy subjects (73%) harbor detectable JCV-specific CD8+ CTLs that recognize one or two epitopes of JCV VP1 protein, the HLA-A*0201-restricted VP1p36 and VPp1100 epitopes. We determined that the frequency of JCV VP1 epitope-specific CTLs varied from less than 1/100,000 to 1/2,494 peripheral blood mononuclear cells. More individuals had JCV VP1-specific than cytomegalovirus-specific CTLs (8 of 11 subjects [73%] versus 2 of 10 subjects [20%], respectively). These results show that a CD8+-T-cell response against JCV is commonly found in immunocompetent people and suggest that these cells might protect against the development of PML.


Evidence for the involvement of two different MHC class II regions in susceptibility or protection in allergic bronchopulmonary aspergillosis.
Allergic bronchopulmonary aspergillosis (ABPA) is a disease with uncertain pathology. Studies have suggested a pathogenic role for T(H)2 cells. Previously, we demonstrated, in a small group of patients, that T(H)2 reactivity to a major Aspergillus fumigatus antigen was restricted by HLA-DR2 or HLA-DR5 alleles. We sought to confirm whether susceptibility to ABPA is exclusively associated with HLA-DR locus and to investigate the involvement of HLA-DQ genes in the development of ABPA. Genomic DNA was extracted from patients with ABPA, patients without ABPA but with positive A fumigatus skin test responses and asthma or cystic fibrosis, and healthy control subjects. HLA-DR and HLA-DQ genes were detected by using low-resolution typing; high-resolution typing was done only on HLA-DR2- and HLA-DR5-positive individuals by using sequence-specific primers (PCR-SSP). A significantly higher frequency of HLA-DR2 was observed in patients with ABPA versus those without ABPA (corrected P <.01) or healthy control subjects (corrected P <.01). Genotype analysis revealed that susceptibility to ABPA is associated with HLA-DR2 alleles DRB1*1503 and DRB1*1501 and, to a lesser extent, with the HLA-DR5 allele DRB1*1104. The presence of DR4 or DR7 alleles in non-DR2/5 patients with ABPA suggests that these alleles may also be contributing factors in this disease. Another striking observation was the significantly high frequency of HLA-DQ2 in patients without ABPA (67. 4%) compared with patients with ABPA (20.5%) and normal control subjects (37.7%), suggesting that these alleles may confer protection in the population without ABPA. These genetic studies suggest that HLA-DR molecules DR2, DR5, and possibly DR4 or DR7 contribute to susceptibility while HLA-DQ2 contributes to resistance and that a combination of these genetic elements determines the outcome of ABPA in patients with cystic fibrosis and asthma.


Evaluation of Cellular Antioxidant and Antiproliferative Activities of Five Main Phyllanthus Emblica L. Cultivars in China.
The cell-based antioxidant activity assay as more biological relevant assay was considered to be more accurate to predict antioxidant activity in vivo than chemical activity assays. In the present study, the five main Phyllanthus emblica L. cultivars in China were subjected for cellular antioxidant activity based on HepG2 cells as well as antiproliferative activity. Total phenolics, total flavonoids and oxygen radical absorbance capacity were also measured. The results showed that Qingyougan, Binggan and Boligan (832±100, 774±52 and 704±28 μmol of quercetin equivalents/100 g) had higher cellular antioxidant activity than Tianyougan and Yougan (553±50 and 457±24 μmol of quercetin equivalents/100 g) in phosphate buffered saline wash protocol whereas, Boligan (3735±217 μmol of quercetin equivalents/100 g) had the highest cellular antioxidant activity and Tianyougan (2025±171 μmol of quercetin equivalents/100 g) had the lowest cellular antioxidant activity in no phosphate buffered saline wash protocol. The highest and lowest antiproliferative activities were observed in Binggan and Tianyougan (median effective dose: 6.95±0.11 and 14.03±0.10 mg/ml), respectively. The significant correlation was only observed between total flavonoids and cellular antioxidant activity from no phosphate buffered saline wash protocol (R(2) =0.908, P<0.05), and total flavonoids and antiproliferative activity (R(2) =0.887, P<0.05), suggesting the major contribution of flavonoids to the bioactivities of emblica. Overall, the data obtained revealed that different Phyllanthus emblica L. cultivars had strong cellular antioxidant and antiproliferative activities, thus should be recommended to increase consumption for health.


Dysregulated Neurovascular Control Underlies Declining Microvascular Functionality in People With Non-alcoholic Fatty Liver Disease (NAFLD) at Risk of Liver Fibrosis.
Increasing evidence shows that non-alcoholic fatty liver disease (NAFLD) is associated with dysregulation of microvascular perfusion independently of established cardio-metabolic risk factors. We investigated whether hepatic manifestations of NAFLD such as liver fibrosis and liver fat are associated with microvascular hemodynamics through dysregulation of neurovascular control. Microvascular dilator (post-occlusive reactive hyperemia) and sympathetically mediated constrictor (deep inspiratory breath-hold) responses were measured at the forearm and finger, respectively, using laser Doppler fluximetry. Non-linear complexity-based analysis was used to assess the information content and variability of the resting blood flux (BF) signals, attributable to oscillatory flow-motion activity, and over multiple sampling frequencies. Measurements were made in 189 adults (113 men) with NAFLD, with (n = 65) and without (n = 124) type 2 diabetes mellitus (T2DM), age = 50.9 ± 11.7 years (mean ± SD). Microvascular dilator and constrictor capacity were both negatively associated with age (r = -0.178, p = 0.014, and r = -0.201, p = 0.007, respectively) and enhanced liver fibrosis (ELF) score (r = -0.155, p = 0.038 and r = -0.418, p < 0.0001, respectively). There was no association with measures of liver fat, obesity or T2DM. Lempel-Ziv complexity (LZC) and sample entropy (SE) of the BF signal measured at the two skin sites were associated negatively with age (p < 0.01 and p < 0.001) and positively with ELF score (p < 0.05 and p < 0.0001). In individuals with an ELF score ≥7.8 the influence of both neurogenic and respiratory flow-motion activity on LZC was up-rated (p < 0.0001). Altered microvascular network functionality occurs in adults with NAFLD suggesting a mechanistic role for dysregulated neurovascular control in individuals at risk of severe liver fibrosis.


Systemic-Sclerosis-Related Interstitial Lung Disease: A Review of the Literature and Recommended Approach for Clinical Pharmacists.
To describe the efficacy, safety, and clinical utility of pharmacologic agents in the treatment of systemic sclerosis-related interstitial lung disease (SSc-ILD). A review of the literature was performed using the terms lung diseases, (interstitial/therapy) AND (scleroderma, systemic/therapy) OR (scleroderma, systemic) AND (lung diseases, interstitial/therapy) in PubMed, Ovid MEDLINE, CINAHL, and Web of Science. ClinicalTrials.gov was also searched to identify ongoing studies. The initial search was performed in October 2022, with follow-up searches performed in October 2023. Articles reviewed were limited to those written in the English language, human studies, and adult populations. A variety of therapeutic agents, including mycophenolate, azathioprine, cyclophosphamide (CYC), rituximab (RTX), nintedanib, and tocilizumab (TCZ) have slowed the rate of decline in forced vital capacity (FVC) and disease progression. Only nintedanib and TCZ have a labeled indication for SSc-ILD. Two agents, belimumab and pirfenidone, have shown encouraging results in smaller phase II and phase III studies, but have yet to be approved by the Food and Drug Administration. Patients with pulmonary manifestations of SSc-ILD have worse outcomes and lower survival rates compared with those without. It is imperative that disease management be individualized to achieve optimal patient-centered care. Pharmacists are uniquely suited to support this individualized management. Numerous pharmacologic agents have been studied and repurposed in the treatment of SSc-ILD, with nintedanib and TCZ gaining approval to slow the rate of decline in pulmonary function in SSc-ILD. Other agents, including belimumab and pirfenidone, are on the horizon as potential treatment options; but further studies are needed to compare their efficacy and safety with the current standard of care.


Phase I Clinical Pharmacology Study of F14512, a New Polyamine-Vectorized Anticancer Drug, in Naturally Occurring Canine Lymphoma.
F14512 is a new topoisomerase II inhibitor containing a spermine moiety that facilitates selective uptake by tumor cells and increases topoisomerase II poisoning. F14512 is currently in a phase I/II clinical trial in patients with acute myeloid leukemia. The aim of this study was to investigate F14512 potential in a new clinical indication. Because of the many similarities between human and dog lymphomas, we sought to determine the tolerance, efficacy, pharmacokinetic/pharmacodynamic (PK/PD) relationship of F14512 in this indication, and potential biomarkers that could be translated into human trials. Twenty-three dogs with stage III-IV naturally occurring lymphomas were enrolled in the phase I dose-escalation trial, which consisted of three cycles of F14512 i.v. injections. Endpoints included safety and therapeutic efficacy. Serial blood samples and tumor biopsies were obtained for PK/PD and biomarker studies. Five dose levels were evaluated to determine the recommended dose. F14512 was well tolerated, with the expected dose-dependent hematologic toxicity. F14512 induced an early decrease of tumoral lymph node cells, and a high response rate of 91% (21/23) with 10 complete responses, 11 partial responses, 1 stable disease, and 1 progressive disease. Phosphorylation of histone H2AX was studied as a potential PD biomarker of F14512. This trial demonstrated that F14512 can be safely administered to dogs with lymphoma resulting in strong therapeutic efficacy. Additional evaluation of F14512 is needed to compare its efficacy with standards of care in dogs, and to translate biomarker and efficacy findings into clinical trials in humans.


P53, bcl-2, and nm23 expressions in serous ovarian tumors: correlation with the clinical and histopathological parameters.
We studied p53, bcl-2, and nm23 expressions in serous benign, borderline and malignant tumors of the ovary. Our aim was to determine the association between these expressions and some clinical (patient age, tumor dimension, omenthal involvement, the presence of malignant cells in peritoneal fluid) and histopathological (grade, number of mitosis, nuclear pleomorphism, structural pattern) parameters in malignant serous tumors. A total of 71 tumors including 29 benign, 14 borderline, and 28 malignant ovarian serous tumors were included in the study, p53, bcl-2, and nm23 immunohistochemical staining was performed on the paraffin blocks. The results were scored as (+), (++) and (+++) according to the extent of staining. There was no staining for p53 in benign or borderline tumors. p53 was positive in 42.9% of malignant tumors. nm23 expression was revealed as 44.8%, 64.3% and 67.9% in benign, borderline and malignant tumors, respectively. Bcl-2 was positive in only 17.2% of benign, 35.7% of borderline and 25% of malignant tumors. The p53 positivity detected only in serous carcinomas shows its role in carcinogenesis. p53 was expressed at a significantly higher rate in advanced stage carcinomas (p = 0.031). nm23 expression in benign, borderline and malignant tumors was not significantly different. nm23 positivity was higher in advanced stage carcinomas (p = 0.032). This suggest that nm23 acts like an oncogene in ovarian carcinomas. There was no significant difference between the groups in terms of bcl-2 expression.


Strategies to prevent infections associated with cardiovascular implantable electronic devices.
Infections involving cardiovascular implantable electronic devices (CIED) are associated with high morbidity and mortality and substantial financial cost. In the past two decades, the rate of CIED infections has increased disproportionate to the number of devices implanted, likely due to aging patient population with multiple comorbidities. Microbial contamination of the generator pocket and or leads by skin flora at the time of implantation is a major mechanism for early CIED infections. Due to resistance to host immune cells and antibiotics caused by biofilm formation, complete removal of the device generator and leads is required to achieve cure. Areas covered: In this manuscript, we review the published literature regarding epidemiology, risk factors, and pathogenesis of CIED infections with primary focus on the preventative strategies to reduce the incidence of device infections. Expert commentary: Strict adherence to infection control measures at the time of CIED implantation is critical in reducing the risk of device infection while adjunctive strategies such as use of antimicrobial envelopes might help in certain high-risk individuals. Technological advances in device manufacturing with availability of subcutaneous devices without transvenous leads and self-contained intracardiac devices without leads and generator show promise with lower risk of infection.


Zoosporulation of a new Perkinsus species isolated from the gills of the softshell clam Mya arenaria.
A gill-associated Perkinsus sp. isolated from the softshell clam (Mya arenaria) is described as a new species, P. chesapeaki sp. nov. Examination of the parasite in seawater cultures revealed life cycle stages and zoosporulation processes similar to those described for other species of the genus Perkinsus. Prezoosporangia developed thickened cell walls upon contraction of the cytoplasm and development of a distinctive clear area between the cell wall and the protoplast. Successive bipartition of the protoplast led to the formation of hundred's of zoospores within mature sporangia. Zoospores were released into seawater through one or more discharge tubes. Ultrastructural studies revealed an oblong zoospore possessing two flagella that arose from a concave side located in the upper third of the zoospore body. The anterior flagellum possessed a unilateral array of hair-like structures. A large anterior vacuole and basolateral nucleus dominated the cytoplasm of the zoospore body. The presence of a rudimentary apical complex including an open-sided conoid, rhoptries, micronemes, and subpellicular microtubules were also discerned. Differences in zoospore morphology, and sequence analyses of two genes previously reported, support the designation of the gill-associated Perkinsus from the softshell clam as a new species.


Intramolecular Singlet Fission in Quinoidal Bi- and Tetrathiophenes: A Comparative Study of Low-Lying Excited Electronic States and Potential Energy Surfaces.
Quinoidal bithiophene has recently been introduced ( Varnavski, O. et al. J. Phys. Chem. Lett. 2015 , 6 , 1375 - 1384 ) as a very promising isolated organic compound for intramolecular singlet fission (iSF) with an outstanding SF quantum yield of ≈180%. In contrast, another recent study ( Ren, L. et al. J. Am. Chem. Soc. 2015 , 137 , 11294 - 11302 ) revealed that quinoidal tetrathiophenes have no activity in the iSF process and are strong fluorophores instead, with measured fluorescent quantum yields up to 53.1%. Using DFT and TD-DFT methods, the authors of the second contribution attributed the marked differences between these compounds to faster reverse T2 → S1 intersystem crossing processes in the tetrathiophenes. To address this unprecedented discrepancy, quinoidal bithiophene and tetrathiophene compounds and their derivatives are carefully examined using the CASPT2 technique. Theoretical evidence is provided through detailed investigation of CASPT2 potential energy surfaces of different singlet and triplet states involved in the iSF process. Through comparison of the CASPT2 results with the CASSCF and RAS-2SF data, it is found that the dynamic electron correlation present in the CASPT2 method plays a crucial role for correct description of the multiexciton nature of the triplet pair 1[TT] state in quinoidal bi- and tetrathiophenes. Effects of substitution and structural modification on iSF activity of these compounds are also examined using the CASPT2 method where the obtained results are in accordance with previous experimental predictions. These results contribute to a better understanding of the iSF mechanism in quinoidal systems which could be relevant for designing new iSF active compounds.


In Silico, Ex Vivo and In Vivo Studies of Roflumilast as a Potential Antidiarrheal and Antispasmodic agent: Inhibition of the PDE-4 Enzyme and Voltage-gated Ca++ ion Channels.
The aim of the present study was to evaluate the possible gut inhibitory role of the phosphodiesterase (PDE) inhibitor roflumilast. Increasing doses of roflumilast were tested against castor oil-induced diarrhea in mice, whereas the pharmacodynamics of the same effect was determined in isolated rabbit jejunum tissues. For in silico analysis, the identified PDE protein was docked with roflumilast and papaverine using the Autodock vina program from the PyRx virtual screening tool. Roflumilast protected against diarrhea significantly at 0.5 and 1.5 mg/kg doses, with 40% and 80% protection. Ex vivo findings from jejunum tissues show that roflumilast possesses an antispasmodic effect by inhibiting spontaneous contractions in a concentration-dependent manner. Roflumilast reversed carbachol (CCh, 1 µM)-mediated and potassium (K+, 80 mM)-mediated contractile responses with comparable efficacies but different potencies. The observed potency against K+ was significantly higher in comparison to CCh, similar to verapamil. Experiments were extended to further confirm the inhibitory effect on Ca++ channels. Interestingly, roflumilast deflected Ca++ concentration-response curves (CRCs) to the right with suppression of the maximum peak at both tested doses (0.001-0.003 mg/mL), similar to verapamil. The PDE-inhibitory effect was authenticated when pre-incubation of jejunum tissues with roflumilast (0.03-0.1 mg/mL) produced a leftward deflection of isoprenaline-mediated inhibitory CRCs and increased the tissue level of cAMP, similar to papaverine. This idea was further strengthened by molecular docking studies, where roflumilast exhibited a better binding affinity (-9.4 kcal/mol) with the PDE protein than the standard papaverine (-8.3 kcal/mol). In conclusion, inhibition of Ca++ channels and the PDE-4 enzyme explains the pharmacodynamics of the gut inhibitory effect of roflumilast.


Goal-directed arm movements in children with fetal alcohol syndrome: a kinematic approach.
Although many studies have documented deficits in general motor functioning in children with fetal alcohol syndrome (FAS), few have employed detailed measurements to explore the specific nature of such disabilities. This pilot study explores whether three-dimensional (3D) kinematic analysis may generate increased knowledge of the effect of intrauterine alcohol exposure on motor control processes by detecting atypical upper-limb movement pattern specificity in children with FAS relative to typically developing (TD) children. Left and right arm and head movements during a sequential unimanual goal-directed precision task in a sample of children with FAS and in TD children were registered by an optoelectronic tracking system (ProReflex, Qualisys Inc.). Children with FAS demonstrated evidently poorer task performance compared with TD children. Additionally, analyses of arm movement kinematics revealed atypical spatio-temporal organization in the children with FAS. In general, they exhibited longer arm movement trajectories at both the proximal and distal level, faster velocities at the proximal level but slower at the distal level, and more segmented distal movements. Children with FAS also showed atypically augmented and fast head movements during the task performance. Findings indicate neuromotor deficits and developmental delay in goal-directed arm movements because of prenatal alcohol exposure. It is suggested that 3D kinematic analysis is a valid technique for furthering the understanding of motor control processes in children with FAS/fetal alcohol spectrum disorders. A combination with relevant neuroimaging techniques in future studies would enable a more clear-cut interpretation of how atypical movement patterns relate to underlying brain abnormalities.


Quadratus Lumborum Block: Analgesic Effects and Chronological Ropivacaine Concentrations After Laparoscopic Surgery.
The quadratus lumborum block (QLB) is an abdominal truncal block, similar to transversus abdominis plane block (TAPB). However, the characteristics of QLB with regard to its duration and safety are not well known. The primary aim of this study was to determine the block duration and the cutaneous sensory block area. Our secondary analysis included assessment of the chronological change in arterial local anesthetic concentrations after QLB. This study included 11 patients scheduled for laparoscopic ovarian surgery under general anesthesia. The patients received bilateral single-injection QLBs (20 mL of 0.375% ropivacaine per side). Arterial blood was sampled at 10, 20, 30, 45, 60, 90, and 120 minutes after ropivacaine administration. The results were retrospectively compared with the results of our previous study on lateral TAPB. The median duration of analgesia after QLB exceeded 24 hours and was significantly longer than the duration of lateral TAPB (P = 0.003). Quadratus lumborum block affected the T7-T12 dermatomes, whereas TAPB affected T10-T12. Arterial ropivacaine levels after block peaked at comparable time in the QLB and lateral TAPB groups (Tmax: 35 [SD, 13] vs 35 [SD, 11] minutes; P = 0.93). Peak ropivacaine concentrations were significantly lower in QLB than in lateral TAPB (Cmax: 1.0 [SD, 0.5] vs 1.8 [SD, 0.4] μg/mL; P = 0.0003). Quadratus lumborum block resulted in a widespread and long-lasting analgesic effect after laparoscopic ovarian surgery and resulted in lower peak arterial ropivacaine concentrations as compared with those of lateral TAPB after 150 mg ropivacaine injection.


The Role of Epigenetic Regulation in Epstein-Barr Virus-Associated Gastric Cancer.
The Epstein-Barr virus (EBV) is detected in about 10% of gastric carcinoma cases throughout the world. In EBV-associated gastric carcinoma (EBVaGC), all tumor cells harbor the clonal EBV genome. The expression of latent EBV genes is strictly regulated through the methylation of EBV DNA. The methylation of viral DNA regulates the type of EBV latency, and methylation of the tumor suppressor genes is a key abnormality in EBVaGC. The methylation frequencies of several tumor suppressor genes and cell adhesion molecules are significantly higher in EBVaGC than in control cases. EBV-derived microRNAs repress translation from viral and host mRNAs. EBV regulates the expression of non-coding RNA in gastric carcinoma. With regard to the clinical application of demethylating agents against EBVaGC, we investigated the effects of decitabine against the EBVaGC cell lines. Decitabine inhibited the cell growth of EBVaGC cells. The promoter regions of p73 and Runt-related transcription factor 3(RUNX3) were demethylated, and their expression was upregulated by the treatment. We review the role of epigenetic regulation in the development and maintenance of EBVaGC and discuss the therapeutic application of DNA demethylating agents for EBVaGC.


Nitric oxide inhibits human and canine pulmonary vascular tone via a postjunctional, nonelectromechanical, cGMP-dependent pathway.
We examined nitric oxide mediated regulation of pulmonary arterial and venous smooth muscle (PASM and PVSM, respectively): whether this inhibition is mediated via prejunctional receptors on adrenergic nerve endings; whether NO is neuronally derived; the relationship between degree of inhibition and vessel size; and identification of the signalling mechanisms involved. Canine pulmonary vascular tissues were generally quiescent, while human PASM exhibited spontaneous phasic activity. The nitric oxide (NO) synthesis inhibitor Nomega-nitro-L-arginine (L-NNA; 10(-4) M) increased tone and enhanced phasic activity. Electrical field stimulation (EFS) evoked contractions were markedly enhanced by L-NNA in an endothelium-dependent fashion, and antagonized by the NO donor S-nitroso-N-acetylpenicillamine (SNAP; 10(-7) to 10(-5) M). 8-Bromo-cGMP mimicked the effects of SNAP on basal tone and EFS contractions, while an inhibitor of soluble guanylate cyclase mimicked those of L-NNA. While mechanical responses to exogenously added norepinephrine (10(-9)-10(-4) M) were also enhanced by L-NNA and suppressed by SNAP, EFS-evoked excitatory junction potentials were unaffected by SNAP. We conclude that, in human and canine PASM and PVSM, there is a tonic generation of NO originating within the endothelium that does not mediate a prejunctional effect, but which acts postjunctionally to activate a cGMP-dependent pathway within the smooth muscle.


Cryptic RNA-binding by PRC2 components EZH2 and SUZ12.
Polycomb repressive complex 2 (PRC2) is a histone-modifying complex that di/tri-methylates histone H3 lysine 27 (H3K27), a mark of transcriptionally repressed chromatin. However, how PRC2 is specifically recruited to its target loci remains controversial, although it has been postulated that long non-coding RNAs (lncRNAs) can function as guides. Here we purified individual components of PRC2 from human cultured cells and found that EZH2 and SUZ12 can directly bind to RNAs. In agreement with recent evidence, our results support the notion that these two PRC2 subunits have RNA-binding activity, with general preference for longer RNAs. However, the length alone does not explain their cryptic substrate preference. Our data highlight the difficulty of characterizing the RNA-binding activity of PRC2.


A minimal role for selectins in the recruitment of leukocytes into the inflamed liver microvasculature.
A two-step paradigm for leukocyte recruitment has been established in a number of tissues including the mesentery, skin, and muscle, and necessitates an initial rolling step via the selectins before firm leukocyte adhesion via the integrins. In view of the many inflammatory diseases that involve the liver, we investigated the importance of rolling and the selectins in the hepatic microvasculature and compared the responses to that of the commonly used mesentery or cremaster microvasculature. We visualized the liver microvasculature using intravital microscopy and we determined that within the liver the majority of leukocytes adhere within the sinusoids (80%) in response to a chemotactic stimulus such as FMLP (20% in postsinusoidal venules) whereas leukocytes adhere exclusively within postcapillary venules in tissue like the mouse cremaster. In the sinusoids, the adhesive response to FMLP is not dependent upon selectins inasmuch as adhesion was not reduced in the sinusoidal vessels of P-selectin-deficient mice or E-selectin/P-selectin- deficient animals in the presence or absence of L-selectin antibody. No rolling or adhesion was detected in response to FMLP in the selectin-deficient cremaster microvasculature. Immunoneutralization of selectins with fucoidan in wildtype mice eliminated rolling and adhesion in the cremaster but failed to affect adhesion in the liver sinusoids in response to FMLP. More long-term leukocyte recruitment with lipopolysaccharide (4 h) was also impaired in the cremaster but not the liver microvasculature in selectin-deficient animals. Leukocyte adhesion in the sinusoids was reduced in P-selectin-deficient mice also lacking intercellular adhesion molecule-1 (ICAM-1). This study for the first time demonstrates that selectins are not an essential step for leukocyte recruitment into the inflamed liver microvasculature.


Nailing versus plating in humerus shaft fractures: a prospective comparative study.
There is a debate about the choice of operative intervention in humerus shaft fractures requiring surgical intervention. A prospective, comparative study of management of acute humeral shaft fractures treated by antegrade interlocking nail fixation and dynamic compression plating was undertaken over a period of three years. Twenty patients of interlocking nailing and sixteen patients of plating were included after considering the inclusion and exclusion criteria. Functional scoring criteria were used for postoperative assessment and the average follow-up period was one year. A higher rate of excellent and good results and a tendency for earlier union was seen with the plating group in our series.


Aerosol Release by Healthy People during Speaking: Possible Contribution to the Transmission of SARS-CoV-2.
Our research aimed to review the potential risk of infection by SARS-CoV-2. We used an excerpt of a data set generated in May 2020 for reviewing the SARS-CoV-2 prevention concept of orchestras, singers and actors. People were sampled for droplet release for one-hour activities using a Grimm spectrometer covering a spectrum of 1 to 32 µm diameter. We estimated the number of "quanta" in the exhaled liquid from viral concentrations of 106 to 1011/mL, based on the Human Infective Dose 50 of 218 viral particles. We employed the Wells-Riley equation to estimate the risk of infection in typical meeting rooms for a one-hour meeting of 2, 4 and 6 people observing a 2 m distance. The four participating adults released a mean of 1.28 nLm3 while breathing, 1.68 nL/m3 while speaking normally, and two adults released a mean of 4.44 nL/m3 while talking with a raised voice. The combination of 50% breathing, 45% talking normally and 5% speaking with a raised voice increased the risk of infection above 5% for a one-hour meeting of two people. The result is based on 6 quanta released, corresponding to an initial virus concentration of 1000/nL (109/mL) in the fluid of the upper respiratory tract. Our data confirm the importance of using facemasks in combination with other measures to prevent transmission of SARS-CoV-2 at the workplace.


[New technique to determine graft length using the proximal anastomotic system during off-pump coronary artery bypass grafting].
For determining the graft length for an aortic connector, grafts to the circumflex (Cx) and the posterior descending (PD) regions often present problems. Difficulties in determining the appropriate distance between the aorta and coronary artery have been reported to be due to changes in the morphology of the heart following the evolution of Cx and PD. We set an intermediate point (IMP) in advance and then determine graft distance in 2 steps. When using the IMP method, determination of the graft length in the Cx region is not difficult. However, attention should be paid to determine the distance between the IMP and anastomosed site without deforming the heart, as the graft length becomes shorter if the heart as a whole is pulled up by traction of the diaphragm during evolution to the PD region.


[Liver resection in locally-spread and metastatic kidney cancer].
The postoperative outcome and survival were studied in patients operated for renal cancer with involvement of the liver. 9 patients have undergone radical nephrectomy and 12 patients--hepatic resections for direct hepatic involvement (2), synchronous (2) and metachronous (8) metastases of renal cell carcinoma. Right hemihepatectomy was performed in 2 and wedge resection in 10 cases. A complete resection was performed in 8 of 9 patients while one patient with direct hepatic invasion was found to have positive surgical margins. Postoperative lethality was absent but complications occurred in 6 patients: pancreatitis (1), pneumonia (3), hepatic abscess (1), hepatic and renal failure followed by GI bleeding (1). At follow-up, two patients died of progressive disease 4 and 68 months after the surgery and one was lost for follow-up. One patient with positive surgical margins is alive with pulmonary and liver metastases 16 months after surgery. Five patients are alive with no evidence of relapse 6, 10, 12, 19 and 56 months after the operation. Thus, the aggressive surgical approach is justified and should be considered in patients with renal cancer and hepatic involvement.


Improving Lifestyle Behaviors After Breast Cancer Treatment Among African American Women With and Without Diabetes: Role of Health Care Professionals.
Little is known about the effect of health professionals' advice on promoting healthy lifestyle behaviors (diet and exercise) among breast cancer patients. To identify predictors of receiving lifestyle advice from health professionals and its impact on healthy lifestyle behaviors. We used data from a randomized controlled trial of an interactive, cancer-communication video program using African American breast cancer survivor stories for newly diagnosed African American breast cancer patients (Stages 0-III). Participants completed five interviews over 2 years. This intervention did not significantly affect changes in quality-of-life outcomes. In secondary analysis, we examined differences in baseline variables between women with and without diabetes. Logistic regression models identified independent predictors of receiving advice from "a doctor or other health professional" to improve diet and exercise and of self-reported change in diet and exercise habits at 2 year follow-up. Of 193 patients included (85% of 228 enrolled), 53 (28%) had diabetes. At 2 year follow-up, a greater proportion of women with (vs. without) diabetes reported receiving advice by a doctor/health professional to improve their diet (73% vs. 57%, p = .04,). Predictors of receiving dietary advice were obesity, diabetes, and breast-conserving surgery (each p < .05). Women receiving dietary advice were 2.75 times more likely to report improving their diet (95% confidence interval: 1.17, 6.46) at follow-up, but receiving physical activity advice was not significantly associated with patients reporting an increase in exercise. Although receiving dietary advice predicted dietary improvements, receiving exercise advice did not lead to an increase in physical activity. Trial Number NCT00929084.


Physician perception of exercise electrocardiography as a prognostic test after acute myocardial infarction.
To determine how physicians interpret exercise electrocardiography with respect to prognosis after acute myocardial infarction (AMI), 29 cardiologists (all board certified) were presented a case history of a 50-year-old man with an uncomplicated AMI and asked to estimate the patient's risk of dying over the next year, the sensitivity and specificity of exercise electrocardiography with respect to 1-year mortality, and the patient's risk of dying given a positive and a negative test result. Each set of physician estimates did not differ from those derived from a review of the medical literature (difference not significant for each). Risk after the test was also calculated using the Bayes' theorem. Calculated versus estimated risks were compared after a negative (7 +/- 9 vs 11 +/- 11%) and a positive (27 +/- 22 vs 17 +/- 15%, differences not significant) test result. Estimated risks were more accurate for a negative result than for a positive one (89 +/- 10 vs 83 +/- 12%, p less than 0.001). Given a positive test result, 57% of the physicians recommended coronary angiography. However, their estimates of risk (30 +/- 23%) were not significantly different from the estimates of those physicians (14%) who recommended additional noninvasive testing (19 +/- 4%) or those (29%) who recommended medical therapy (28 +/- 26%) (difference not significant). Thus, cardiologists accurately estimated prognosis following AMI, but they were less accurate in assessing high risk than low risk, and their management decisions correlated poorly with their risk assessments.


SCooP: an accurate and fast predictor of protein stability curves as a function of temperature.
The molecular bases of protein stability remain far from elucidated even though substantial progress has been made through both computational and experimental investigations. One of the most challenging goals is the development of accurate prediction tools of the temperature dependence of the standard folding free energy ΔG(T). Such predictors have an enormous series of potential applications, which range from drug design in the biopharmaceutical sector to the optimization of enzyme activity for biofuel production. There is thus an important demand for novel, reliable and fast predictors. We present the SCooP algorithm, which is a significant step towards accurate temperature-dependent stability prediction. This automated tool uses the protein structure and the host organism as sole entries and predicts the full T-dependent stability curve of monomeric proteins assumed to follow a two-state folding transition. Equivalently, it predicts all the thermodynamic quantities associated to the folding transition, namely the melting temperature Tm, the standard folding enthalpy ΔHm measured at Tm, and the standard folding heat capacity ΔCp. The cross-validated performances are good, with correlation coefficients between predicted and experimental values equal to [0.80, 0.83, 0.72] for ΔHm, ΔCp and Tm, respectively, which increase up to [0.88, 0.90, 0.78] upon the removal of 10% outliers. Moreover, the stability curve prediction of a target protein is very fast: it takes less than a minute. SCooP can thus potentially be applied on a structurome scale. This opens new perspectives of large-scale analyses of protein stability, which is of considerable interest for protein engineering. The SCooP webserver is freely available at http://babylone.ulb.ac.be/SCooP. email@example.com, email@example.com or email@example.com. Supplementary data are available at Bioinformatics online.


[Verbal interaction between the nursing team and the AIDS patient].
3,336 verbal behaviors between 3 AIDS patients and a nursing team were analyzed. The pattern and priority areas of verbal behaviors which occur, according to the SAVI system, as well as the amount of information transmitted were determined. The results showed that the verbal behaviors ranged from relative ambiguity in terms of message clarity to clean and non-contradictory messages. The interaction tended to move away from stereotypy.


A computational multiscale agent-based model for simulating spatio-temporal tumour immune response to PD1 and PDL1 inhibition.
When the immune system responds to tumour development, patterns of immune infiltrates emerge, highlighted by the expression of immune checkpoint-related molecules such as PDL1 on the surface of cancer cells. Such spatial heterogeneity carries information on intrinsic characteristics of the tumour lesion for individual patients, and thus is a potential source for biomarkers for anti-tumour therapeutics. We developed a systems biology multiscale agent-based model to capture the interactions between immune cells and cancer cells, and analysed the emergent global behaviour during tumour development and immunotherapy. Using this model, we are able to reproduce temporal dynamics of cytotoxic T cells and cancer cells during tumour progression, as well as three-dimensional spatial distributions of these cells. By varying the characteristics of the neoantigen profile of individual patients, such as mutational burden and antigen strength, a spectrum of pretreatment spatial patterns of PDL1 expression is generated in our simulations, resembling immuno-architectures obtained via immunohistochemistry from patient biopsies. By correlating these spatial characteristics with in silico treatment results using immune checkpoint inhibitors, the model provides a framework for use to predict treatment/biomarker combinations in different cancer types based on cancer-specific experimental data.


ZTE imaging in humans.
Zero echo time (ZTE) imaging is a robust and silent 3D radial technique suitable for direct MRI of tissues with very rapid transverse relaxation. Given its successful application on micro- and animal MRI systems, the purpose of this work is to enable and demonstrate ZTE imaging in humans using a whole-body magnet. A commercial 7 T MRI scanner was complemented by rapid high-power transmit-receive switches, a custom-built spectrometer, and a proton-free detector coil. With this setup, transmit-receive switching is achieved within 1 µs, radiofrequency (RF) excitation is performed in 3 µs, and digital bandpass filtering takes 5.3 µs, resulting in an effective dead time of only 5 µs. ZTE imaging was performed at 250 and 500 kHz bandwidth with central k-space gaps of 1.2 and 2.5 Nyquist intervals and repetition times of 739 and 471 µs. The technique was applied for silent 3D imaging of the head and joints of human volunteers at an isotropic resolution down to 0.83 mm. A sound pressure level of 41 dB(A) was measured, which is a reduction of more than 40 dB(A) compared to gradient-switched MRI. ZTE imaging in humans was demonstrated for the first time, enabled by dedicated, high-performing RF hardware.


Optimization of trading physics models of markets.
We describe an end-to-end real-time S&P futures trading system. Inner-shell stochastic nonlinear dynamic models are developed, and canonical momenta indicators are derived from a fitted Lagrangian used by outer-shell trading models dependent on these indicators. Recursive and adaptive optimization using adaptive simulated annealing is used for fitting parameters shared across these shells of dynamics and trading models.


Allergic fungal sinusitis in the pediatric population.
To determine the optimal treatment in pediatric patients with allergic fungal sinusitis (AFS). A retrospective review of 10 patients diagnosed as having AFS. Academic tertiary medical center. Pediatric patients who fulfilled 5 criteria necessary for diagnosis of AFS: (1) type 1 hypersensitivity; (2) nasal polyposis; (3) characteristic computed tomographic scan; (4) histological evidence of eosinophilic mucus without evidence of fungal invasion into sinus tissue; and (5) a positive fungal stain or culture of sinus contents. All patients were treated with functional endoscopic sinus surgery with removal of fungal debris. Adjuvant therapy included nasal irrigations, postoperative endoscopic cleanings, and systemic corticosteroids in 9 of 10 patients. Clinical disease monitored endoscopically by means of an objective staging system. Five patients were without disease (stage 0), 1 had allergic mucin and mucosal edema (stage I), 1 had allergic mucin and polypoid edema (stage II), and 3 had polyps and/or fungal debris (stage III). The treatment and prognosis of pediatric AFS are similar to those of adult AFS. However, systemic corticosteroids should be weaned aggressively in children to minimize complications, particularly long-term growth retardation.


Prediction of lung tumor types based on protein attributes by machine learning algorithms.
Early diagnosis of lung cancers and distinction between the tumor types (Small Cell Lung Cancer (SCLC) and Non-Small Cell Lung Cancer (NSCLC) are very important to increase the survival rate of patients. Herein, we propose a diagnostic system based on sequence-derived structural and physicochemical attributes of proteins that involved in both types of tumors via feature extraction, feature selection and prediction models. 1497 proteins attributes computed and important features selected by 12 attribute weighting models and finally machine learning models consist of seven SVM models, three ANN models and two NB models applied on original database and newly created ones from attribute weighting models; models accuracies calculated through 10-fold cross and wrapper validation (just for SVM algorithms). In line with our previous findings, dipeptide composition, autocorrelation and distribution descriptor were the most important protein features selected by bioinformatics tools. The algorithms performances in lung cancer tumor type prediction increased when they applied on datasets created by attribute weighting models rather than original dataset. Wrapper-Validation performed better than X-Validation; the best cancer type prediction resulted from SVM and SVM Linear models (82%). The best accuracy of ANN gained when Neural Net model applied on SVM dataset (88%). This is the first report suggesting that the combination of protein features and attribute weighting models with machine learning algorithms can be effectively used to predict the type of lung cancer tumors (SCLC and NSCLC).


The involvement of WT1 in the regulation of GADD45a in response to genotoxic stress.
Expression of the human GADD45a gene is increased in TK6 cells exposed to mutagens, clastogens and aneugens. It is known to be regulated through both p53-dependent and p53-independent pathways and WT1 has been implicated in both cases. This article reports an investigation into the effect that mutations in the WT1 and p53 response elements of the gene have on GADD45a expression. This was conducted in both p53 wild-type (TK6) and mutant (WI-L2-NS) human B lymphoblastoid cell lines. Gene expression was monitored using a GADD45a-green fluorescent protein reporter assay. Mutant cell lines were exposed to the mechanistically diverse genotoxins methyl methanesulphonate, cisplatin and mitomycin C (direct acting), hydroxyurea, aphidicolin and 5'fluorouracil (inhibitors of nucleotide/DNA synthesis) and benomyl (aneugen). In all cases, the induction of the reporter was reduced in the mutants compared with wild-type. These results provide experimental evidence for the implied role of WT1 in both p53-dependent and p53-independent pathways of GADD45a regulation and further insight into the mechanism of GADD45a induction by genotoxins.


Lipopolysaccharide inhibits translation of iron chaperone PCBP1 to regulate inflammatory cytokine response in macrophage.
Macrophages play a key role in maintaining systemic iron homeostasis and immunity. During pro-inflammatory stage macrophages retain iron due to the decrease of the unique iron exporter ferroportin. Increased cellular iron is sequestered in to storage protein ferritin by iron chaperone poly(rC)-binding protein 1 (PCBP1). However, the fate of PCBP1 and its interaction with ferritin in pro-inflammatory macrophages has not been studied so far. Here we report that PCBP1 protein level is down-regulated in lipopolysaccharide (LPS) treated macrophages. LPS did not alter PCBP1 mRNA and protein stability suggesting inhibition of translation as a mechanism of PCBP1 down-regulation that was confirmed by 35S-methionine incorporation assay. PCBP1 interacts with ferritin-H (Ft-H) subunit to load iron into ferritin. We detected a decreased interaction between PCBP1 and Ft-H after LPS-stimulation. As a result iron loading in to ferritin was affected with simultaneous increase in labile iron pool (LIP). Pre-treatment of cells with iron chelator dampened LPS-induced expression of TNF-α, IL-1β and IL-6 mRNA. Silencing of PCBP1 increased the magnitude of expression of these cytokines compared to control siRNA transfected LPS-treated macrophages. In contrast, overexpression of PCBP1 resulted a decrease in expression of these cytokines compared to vector transfected macrophages. Our results reveal a novel regulation of PCBP1 and its role in expression of cytokines in LPS-induced pro-inflammatory macrophages.


Expression of UGA-containing Mycoplasma genes in Bacillus subtilis.
We used Bacillus subtilis to express UGA-containing Mycoplasma genes encoding the P30 adhesin (one UGA) of Mycoplasma pneumoniae and methionine sulfoxide reductase (two UGAs) of Mycoplasma genitalium. Due to natural UGA suppression, these Mycoplasma genes were expressed as full-length protein products, but at relatively low efficiency, in recombinant wild-type Bacillus. The B. subtilis-expressed Mycoplasma proteins appeared as single bands and not as multiple bands compared to expression in recombinant Escherichia coli. Bacillus mutants carrying mutations in the structural gene (prfB) for release factor 2 markedly enhanced the level of readthrough of UGA-containing Mycoplasma genes.


HMGB1/IL-1β complexes regulate neuroimmune responses in alcoholism.
Neuroimmune activation is a key feature of the pathologies of numerous psychiatric disorders including alcoholism, depression, and anxiety. Both HMGB1 and IL-1β have been implicated in brain disorders. Previous studies find HMGB1 andIL-1β form heterocomplexes in vitro with enhanced immune responses, lead to our hypothesis that HMGB1 and IL-1β heterocomplexes formed in vivo to contribute to the pathology of alcoholism. HMGB1/IL-1β heterocomplexes were prepared in vitro and found to potentiate IL-1β receptor proinflammatory gene induction compared to IL-1β alone in hippocampal brain slice culture. These HMGB1/IL-1β complexes were found to be increased in post-mortem human alcoholic hippocampus by co-immunoprecipiation. In mice, acute binge ethanol induced both HMGB1 and IL-1β in the brain and plasma. HMGB1 and IL-1β complexes were found only in mouse brain, with confocal microscopy revealing an ethanol-induced HMGB1 and IL-1β cytoplasmic co-localization. Surprisingly, IL-1β was found primarily in neurons. Studies in hippocampal brain slice culture found ethanol increased HMGB1/IL-1β complexes in the media. These studies suggest a novel neuroimmune mechanism in the pathology of alcoholism. Immunogenic HMGB1/IL-1β complexes represent a novel target for immune modulatory therapy in alcohol use disorders, and should be investigated in other psychiatric diseases that involve a neuroimmune component.


Viviparous1 alters global gene expression patterns through regulation of abscisic acid signaling.
Maize (Zea mays) Viviparous1 (VP1) and Arabidopsis ABI3 are orthologous transcription factors that regulate key aspects of plant seed development and ABA signaling. To understand VP1-regulated gene expression on a global scale, we have performed oligomicroarray analysis of transgenic Arabidopsis carrying 35S::VP1 in an abi3 null mutant background. We have identified 353 VP1/ABA-regulated genes by GeneChip analysis. Seventy-three percent of the genes were affected by both VP1 and ABA in vegetative tissues, indicating a tight coupling between ABA signaling and VP1 function. A large number of seed-specific genes were ectopically expressed in vegetative tissue of 35S::VP1 plants consistent with evidence that VP1 and ABI3 are key determinants of seed-specific expression. ABI5, a positive regulator of ABA signaling, was activated by VP1, indicating conservation of the feed-forward pathway mediated by ABI3. ABA induction of ABI1 and ABI2, negative regulators of ABA signaling, was strongly inhibited by VP1, revealing a second pathway of feed-forward regulation. These results indicate that VP1 strongly modifies ABA signaling through feed-forward regulation of ABI1/ABI5-related genes. Of the 32 bZIP transcription factors represented on the GeneChip, genes in the ABI5 clade were specifically coregulated by ABA and VP1. Statistical analysis of 5' upstream sequences of the VP1/ABA-regulated genes identified consensus abscisic responsive elements as an enriched element, indicating that many of the genes could be direct targets of the ABI5-related bZIPs. The Sph element is an enriched sequence motif in promoters of genes co-activated by ABA and VP1 but not in promoters of genes activated by ABA alone. This analysis reveals that distinct combinatorial patterns of promoter elements distinguish subclasses of VP1/ABA coregulated genes.


[Participation of the serotonin-reactive brain structure in certain forms of behavior in golden hamsters].
A viviacious play of young hamsters is shown to be accompanied by a drop of the serotonin level in the brain stem and the subsequent slumber - by its rise, while the corticosteroids content of the peripheral blood with the playful behavior experiences no changes. Iprazid and 5-oxytryptophan inhibit the playful activity, while dioxyphenylalanina (DOPA) does not influence it. A similar depression of the serotonin level in the brain stem was also noted in an aggressive behavior and stress conditions arising when adult male-hamsters are grouped together. A conclusion is drawn to the effect that changes in the content of serotonin in the brain stem are not associated with the emotional colouration of the condition, but rather reflect the transition from the somnolence to a highly active behavior.


Vanadium-Substituted Tunnel Structured Silver Hollandite (Ag1.2VxMn8-xO16): Impact on Morphology and Electrochemistry.
A series of tunnel structured V-substituted silver hollandite (Ag1.2VxMn8-xO16, x = 0-1.4) samples is prepared and characterized through a combination of synchrotron X-ray diffraction (XRD), synchrotron X-ray absorption spectroscopy (XAS), laboratory Raman spectroscopy, and electron microscopy measurements. The oxidation states of the individual transition metals are characterized using V and Mn K-edge XAS data indicating the vanadium centers exist as V5+, and the Mn oxidation state decreases with increased V substitution to balance the charge. Scanning transmission electron microscopy of reduced materials shows reduction-displacement of silver metal at high levels of lithiation. In lithium batteries, the V-substituted tunneled manganese oxide materials reveal previously unseen reversible nonaqueous Ag electrochemistry and exhibit up to 2.5× higher Li storage capacity relative to their unsubstituted counterparts. The highest capacity was observed for the Ag1.2(V0.8Mn7.2)O16·0.8H2O material with an intermediate level of V substitution, likely due to a combination of the atomic composition, the morphology of the particle, and the homogeneous distribution of the active material within the electrode structure where factors over multiple length scales contribute to the electrochemistry.


[Re-irradiation with hyperthermia in patients with recurrent breast cancer].
In the Daniel den Hoed Cancer Centre in Rotterdam, the Netherlands, patients with recurrent breast cancer within a previously irradiated area, are treated by application of hyperthermia in addition to reirradiation. In this development, the following issues are important: (a) the choice of an effective and tolerable reirradiation schedule; (b) the establishment of the limitations of the hyperthermia techniques available; (c) the finding that additional hyperthermia has to be applied to the total tissue volume at risk for tumour recurrence; (d) the assessment of the value of additional hyperthermia by a randomised study. With the reirradiation schedule of 8 x 4 Gy and the hyperthermia application technique at present available, local control is achieved in 76% of the patients for a median duration of 32 months. The probability of local control is related to tumour size. The treatment is tolerated well, with acceptable toxicity. In patients with recurrent breast cancer in a previously irradiated area, combined reirradiation and hyperthermia is very effective, well tolerated and little toxic.


A 5-(difluorenyl)-1,10-phenanthroline-based Ru(II) complex as a coating agent for potential multifunctional gold nanoparticles.
The synthesis and photophysical properties of small gold nanoparticles (NPs, AuNP-[Ru-PFF]) surface functionalized by 5-substituted-1,10-phenanthroline-ligand based Ru(II) complexes are described. Luminescence of the grafted and confined Ru(II) complexes is totally quenched on the gold surface. Nonlinear optical properties were determined via Z-scan measurements in the range 600-1300 nm for both the free Ru(II) complex and the related NPs. In the short wavelength range (around 600 nm) the behaviour switches from that of two-photon absorption (2PA) for the complex to saturable absorption for the NPs. 2PA applications such as optical power limiting or two-photon dioxygen sensitization can be anticipated for these nanoplatforms.


Osteogenesis imperfecta. The set point proposal (a possible causative mechanism).
The minimum effective strain (MES) constitutes a threshold that separates biomechanically acceptable from unacceptable strains on growing bone and fibrous tissues. Strains above that threshold affect modeling and remodeling activities in ways that change the size and configuration of growing bones, tendons, ligaments, and fascia to fit their new mechanical usage and return their strains to the threshold level. Were that threshold set too high from birth, the effects of normal function on remodeling and modeling should lead to thin fibrous tissue structures, to slender, osteopenic diaphyses and spongiosa, and to increased fragility. Those and other predictable set point effects fit so precisely many of the known hard and soft tissue abnormalities of osteogenesis imperfecta patients, that an elevated MES set point may be a heretofore unrecognized basic pathogenetic factor in that disease.


Is intraoperative calcitonin monitoring useful to modulate the extension of neck dissection in patients with medullary thyroid carcinoma?
The extension of the compartment-oriented neck dissection at primary surgery in medullary thyroid carcinoma (MTC) is controversial. Because a <50 % decrease in intraoperative calcitonin levels (IO-CT) after total thyroidectomy plus central neck dissection (TT-CND) has been associated with residual disease, IO-CT monitoring has been proposed to predict the completeness of surgery. The goal of the present prospective study was to verify the accuracy of IO-CT monitoring. All patients scheduled for primary surgery for suspected or proven MTC between November 2010 and January 2013 were included. Calcitonin was measured pre-incision (basal level), after tumor manipulation, at the time TT-CND was accomplished (ablation level), 10 and 30 min after ablation. A decrease >50 % with respect to the highest IO-CT level 30 min after ablation was considered predictive of cure. Twenty-six patients were included, and IO-CT monitoring identified 18 of 23 cured patients (true negative results) and 2 of 3 patients with persistent disease (true positive result). In 5 patients with normal basal and stimulated postoperative calcitonin levels, a decrease <50 % was observed (false positive results). In one of three patients with persistent disease a >50 % decrease in IO-CT was observed (false negative results). Specificity, sensitivity, and accuracy of IO-CT were 78.2, 66.6, and 76.9 %, respectively. Intraoperative calcitonin monitoring is not highly accurate in predicting the completeness of surgical resection. In the present series, relying on IO-CT would result in limited resection in about one third of the patients with residual neck disease and in unnecessary lateral neck dissection in about 20 % of the cured patients.


A pH-responsive carboxylic β-1,3-glucan polysaccharide for complexation with polymeric guests.
The helix-forming nature of β-1,3-glucan polysaccharides is a characteristic that has potential for producing gene carriers, bio-nanomaterials and other chiral nanowires. Herein, carboxylic curdlan (CurCOOH) bearing the β-1,3-polyglucuronic acid structure was successfully prepared from β-1,3-glucan polysaccharide curdlan (Cur) by one-step oxidation using a 4-acetamido-TEMPO/NaClO/NaClO(2) system as the oxidant. The resulting high-molecular-weight CurCOOH was proved to bear the 6-COOH group in 100% purity. The optical rotatory dispersion (ORD) spectra indicated that the obtained CurCOOH behaves as a water-soluble single-strand in various pH aqueous media. This advantage has allowed us to use CurCOOH as a polymeric host to form various macromolecular complexes. For example, complexation of CurCOOH with single-walled carbon nanotubes (SWNTs) resulted in a water-soluble one-dimensional architecture, which formed a dispersion in aqueous solution that was stable for several months, and much more stable than SWNTs complexes of the similar negatively-charged polyacrylic acid (PAA) and polymethacrylic acid (PMAA). It was shown that in the complex, SWNTs are effectively wrapped by a small amount of CurCOOH, enabling them to avoid electrostatic repulsion. This pH-responsive CurCOOH formed a very stable complex with cationic water-soluble polythiophenes (PT-1), which was stabilized not only by the hydrophobic interaction but also by the electrostatic attraction between trimethylammonium cations in PT-1 and dissociated anionic COO(-) groups in CurCOOH. The included PT-1 became CD-active only in the neutral to basic pH region, and the positive Cotton effect suggested that the conjugated main chain is twisted in the right-handed direction. We also found that CurCOOH can interact with polycytidylic acid (poly(C)) only under high NaCl concentrations, the binding and release of which could be controlled by a change in the salt concentration. We believe, therefore, that CurCOOH bearing a dissociable COOH group can act as a new potential polymeric host to construct novel polymeric complexes applicable for gene carriers, biosensors, chiral polymer assemblies, etc.


Current treatment of adult Duchenne muscular dystrophy.
Patients with Duchenne muscular dystrophy (DMD) are living longer into adulthood due to a variety of improvements in health care practices. This growing patient population presents new therapeutic challenges. In this article, we review the literature on current treatment of adult DMD as well as our own experience as a multidisciplinary team actively caring for 23 men ages 19-38 years of age. Approximately one quarter of our adult DMD patients have remained on moderate dose corticosteroids. Daily stretching exercises are recommended, particularly of the distal upper extremities. Cardiomyopathy is anticipated, detected, and treated early with afterload reduction. Oxygen saturation monitoring, noninvasive positive pressure ventilation and cough assist devices are routinely used. Other medical issues such as osteoporosis, gastrointestinal and urinary symptoms are addressed. Current and future therapies directed at prolonging the lifespan of those with DMD will result in further increases in this adult population with special needs and concerns. These needs are best addressed in a multidisciplinary clinic.


Jung's view on myth and post-modern psychology.
Post-modern psychology embodies two core themes, the social mind and the narrative self. Whereas the social-mind thesis seems diametrically opposed to Jung's position regarding human nature, the narrative-self thesis is associated with research and theorizing about personal myth and mythmaking in ways that could make contact with Jung's concerns. Jung's view is examined here with particular attention to McAdams' theory of narrative identity. It is suggested that the ostensible differences between Jung and post-modern psychology might reflect divergent interests, rather than necessarily irreconcilable worldviews.


Extracellular chloride and the maintenance of spontaneous epileptiform activity in rat hippocampal slices.
Previous studies showed that furosemide blocks spontaneous epileptiform activity without diminishing synaptic transmission or reducing hyperexcited field responses to electrical stimuli. We now test the hypothesis that the antiepileptic effects of furosemide are mediated through its blockade of the Na+,K+,2Cl- cotransporter and thus should be mimicked by a reduction of extracellular chloride ([Cl-]o). In the first set of experiments, field recordings from the CA1 cell body layer of hippocampal slices showed that spontaneous bursting developed within 10-20 min in slices perfused with low-[Cl-]o (7 mM) medium but that this spontaneous epileptiform activity ceased after a further 10-20 min. Intracellular recordings from CA1 pyramidal cells showed that normal action potential discharge could be elicited by membrane depolarization, even after the tissue was perfused with low-[Cl-]o medium for >2 h. In a second set of experiments, spontaneous bursting activity was induced in slices by perfusion with high-[K+]o (10 mM), bicuculline (100 microM), or 4-aminopyridine (100 microM). In each case, recordings from the CA1 region showed that reduction of [Cl-]o to 21 mM reversibly blocked the bursting within 1 h. Similar to previous observations with furosemide treatment, low-[Cl-]o medium blocked spontaneous hypersynchronous discharges without reducing synaptic hyperexcitability (i.e., hyperexcitable field responses evoked by electrical stimulation). In a third set of experiments, prolonged exposure (>1 h after spontaneous bursting ceased) of slices to systematically varied [Cl-]o and [K+]o resulted in one of three types of events: 1) spontaneous, long-lasting, and repetitive negative field potential shifts (7 mM [Cl-]o; 3 mM [K+]o); 2) oscillations consisting of 5- to 10-mV negative shifts in the field potential, with a period of approximately 1 cycle/40 s (16 mM [Cl-]o; 12 mM [K+]o); and 3) shorter, infrequently occurring negative field shifts lasting 20-40 s (21 mM [Cl-]o; 3 mM [K+]o). Our observations indicate that the effects of low [Cl-]o on neuronal synchronization and spontaneous discharge are time dependent. Similar effects were seen with furosemide and low [Cl-]o, consistent with the hypothesis that the antiepileptic effect of furosemide is mediated by the drug's effect on chloride transporters. Finally, the results of altering extracellular potassium along with chloride suggest that blockade of the Na+, K+,2Cl- cotransporter, which normally transports chloride from the extracellular space into glial cells, is key to these antiepileptic effects.


Efficacy of anti-sclerostin monoclonal antibody BPS804 in adult patients with hypophosphatasia.
Hypophosphatasia (HPP) is a rare genetic disorder resulting in variable alterations of bone formation and mineralization that are caused by mutations in the ALPL gene, encoding the tissue-nonspecific alkaline phosphatase (ALP) enzyme. In this phase IIA open-label, single-center, intra-patient, dose-escalating study, adult patients with HPP received 3 ascending intravenous doses of 5, 10, and 20 mg/kg BPS804, a fully human anti-sclerostin monoclonal antibody, on days 1, 15, and 29, respectively. Patients were followed for 16 weeks after the last dose. We assessed the pharmacodynamics, pharmacokinetics, preliminary efficacy, and safety of BPS804 administrations at specified intervals during treatment and follow-up. Eight patients (mean age 47.8 years) were enrolled in the study (6 females, 2 males). BPS804 treatment increased mean ALP and bone-specific ALP enzymatic activity between days 2 and 29. Transient increases in the bone formation markers procollagen type-I N-terminal propeptide (PINP), osteocalcin, and parathyroid hormone as well as a transient decrease in the bone resorption marker C-telopeptide of type I collagen (CTX-1) were observed. Lumbar spine bone mineral density showed a mean increase by day 85 and at end of study. Treatment-associated adverse events were mild and transient. BPS804 treatment was well tolerated and resulted in increases in bone formation biomarkers and bone mineral density, suggesting that sclerostin inhibition could be applied to enhance bone mineral density, stability, and regeneration in non-life-threatening clinical situations in adults with HPP. Clinicaltrials.gov NCT01406977. Novartis Institutes for BioMedical Research, Basel, Switzerland.


The human leukocyte antigen-presented ligandome of B lymphocytes.
Peptides presented by human leukocyte antigen (HLA) molecules on the cell surface play a crucial role in adaptive immunology, mediating the communication between T cells and antigen presenting cells. Knowledge of these peptides is of pivotal importance in fundamental studies of T cell action and in cellular immunotherapy and transplantation. In this paper we present the in-depth identification and relative quantification of 14,500 peptide ligands constituting the HLA ligandome of B cells. This large number of identified ligands provides general insight into the presented peptide repertoire and antigen presentation. Our uniquely large set of HLA ligands allowed us to characterize in detail the peptides constituting the ligandome in terms of relative abundance, peptide length distribution, physicochemical properties, binding affinity to the HLA molecule, and presence of post-translational modifications. The presented B-lymphocyte ligandome is shown to be a rich source of information by the presence of minor histocompatibility antigens, virus-derived epitopes, and post-translationally modified HLA ligands, and it can be a good starting point for solving a wealth of specific immunological questions. These HLA ligands can form the basis for reversed immunology approaches to identify T cell epitopes based not on in silico predictions but on the bona fide eluted HLA ligandome.


Long-term survival after cardiac retransplantation: a single-center experience.
Cardiac retransplantation is controversial therapy because of a chronic shortage of donor hearts. We retrospectively reviewed short- and long-term outcomes after cardiac retransplantation. Between February 1989 and December 2004, 28 cases of cardiac retransplantation were performed. Indications for retransplantation were primary graft failure (PGF) in 11 patients (39.3%), intractable acute cardiac rejection (IACR) in 4 (14.3%), and coronary allograft vasculopathy (CAV) in 13 (46.4%). The patients had been supported with prolonged cardiopulmonary bypass (CPB) (n = 3), IABP (n = 1), intravenous inotropic support (n = 7), ECMO (n = 3), and VAD (n = 4). Ten patients had no inotropic support. Eight patients died within 30 days postoperatively. The causes of early death were acute rejection (n = 3 ; 37%), MOF (n = 3 ; 37%), PGF (n = 1 ; 13%), and right ventricular failure (n = 1 ; 13%). The causes of late death in 8 other patients were acute rejection (n = 4 ; 50%), CAV (n = 2 ; 25%), MOF (n = 1 ; 13%), and infection (n = 1 ; 13%). The 1-, 5-, 10-, and 15-year survivals were 78.5, 68.4, 54.5, and 38.3%, respectively, for primary cardiac transplantation, and 46.4, 40.6, 32.5, and 32.5% for cardiac retransplantation (P = 0.003). Acute cardiac rejection was the most common cause of death (43.8%). Thirty-day and 1-year survivals of IACR, PGF, and CAV were 50.0/0, 63.6/45.5, and 84.6/68.4%, respectively. Long-term survival after retransplantation was acceptable for patients with CAV and PGF, however, we should select patients carefully if the indication for retransplantation is IACR because of the poor outcome.


Effects of single parenthood on mothers' behavior, morphology, and endocrine function in the biparental California mouse.
Motherhood is energetically costly for mammals and is associated with pronounced changes in mothers' physiology, morphology and behavior. In ~5% of mammals, fathers assist their mates with rearing offspring and can enhance offspring survival and development. Although these beneficial consequences of paternal care can be mediated by direct effects on offspring, they might also be mediated indirectly, through beneficial effects on mothers. We tested the hypothesis that fathers in the monogamous, biparental California mouse (Peromyscus californicus) reduce the burden of parental care on their mates, and therefore, that females rearing offspring with and without assistance from their mates will show differences in endocrinology, morphology and behavior, as well as in the survival and development of their pups. We found that pups' survival and development in the lab did not differ between those raised by a single mother and those reared by both mother and father. Single mothers spent more time in feeding behaviors than paired mothers. Both single and paired mothers had higher lean mass and/or lower fat mass and showed more anxiety-like behavior in open-field tests and tail-suspension tests, compared to non-breeding females. Single mothers had higher body-mass-corrected liver and heart masses, but lower ovarian and uterine masses, than paired mothers and/or non-breeding females. Mass of the gastrointestinal tract did not differ between single and paired mothers, but single mothers had heavier gastrointestinal tract compared to non-breeding females. Single motherhood also induced a flattened diel corticosterone rhythm and a blunted corticosterone response to stress, compared to non-breeding conditions. These findings suggest that the absence of a mate induces morphological and endocrine changes in mothers, which might result from increased energetic demands of pup care and could potentially help maintain normal survival and development of pups.


When smokers quit: exposure to nicotine and carcinogens persists from thirdhand smoke pollution.
Over a 6-month period, we examined tobacco smoke pollutants (also known as thirdhand smoke, THS) that remained in the homes of former smokers and the exposure to these pollutants. 90 smokers completed study measures at baseline (BL). Measures were repeated among verified quitters 1 week (W1), 1 month (M1), 3 months (M3) and 6 months (M6) following cessation. Measures were analysed for THS pollutants on household surfaces, fingers and in dust (ie, nicotine, tobacco-specific nitrosamines) and for urinary markers of exposure (ie, cotinine, 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanol (NNAL)). We observed significant short-term reduction of nicotine on surfaces (BL: 22.2 μg/m2, W1: 10.8 μg/m2) and on fingers of non-smoking residents (BL: 29.1 ng/wipe, W1: 9.1 ng/wipe) without further significant changes. Concentrations of nicotine and nicotine-derived nitrosamine ketone (NNK) in dust did not change and remained near BL levels after cessation. Dust nicotine and NNK loadings significantly increased immediately following cessation (nicotine BL: 5.0 μg/m2, W1: 9.3 μg/m2; NNK BL: 11.6 ng/m2, W1: 36.3 ng/m2) before returning to and remaining at near BL levels. Cotinine and NNAL showed significant initial declines (cotinine BL: 4.6 ng/mL, W1: 1.3 ng/mL; NNAL BL: 10.0 pg/mL, W1: 4.2 pg/mL) without further significant changes. Homes of smokers remained polluted with THS for up to 6 months after cessation. Residents continued to be exposed to THS toxicants that accumulated in settled house dust and on surfaces before smoking cessation. Further research is needed to better understand the consequences of continued THS exposure after cessation and the efforts necessary to remove THS.


Involvement of human internal globus pallidus in the early modulation of cortical error-related activity.
The detection and assessment of errors are a prerequisite to adapt behavior and improve future performance. Error monitoring is afforded by the interplay between cortical and subcortical neural systems. Ample evidence has pointed to a specific cortical error-related evoked potential, the error-related negativity (ERN), during the detection and evaluation of response errors. Recent models of reinforcement learning implicate the basal ganglia (BG) in early error detection following the learning of stimulus-response associations and in the modulation of the cortical ERN. To investigate the influence of the human BG motor output activity on the cortical ERN during response errors, we recorded local field potentials from the sensorimotor area of the internal globus pallidus and scalp electroencephalogram representing activity from the posterior medial frontal cortex in patients with idiopathic dystonia (hands not affected) during a flanker task. In error trials, a specific pallidal error-related potential arose 60 ms prior to the cortical ERN. The error-related changes in pallidal activity-characterized by theta oscillations-were predictive of the cortical error-related activity as assessed by Granger causality analysis. Our findings show an early modulation of error-related activity in the human pallidum, suggesting that pallidal output influences the cortex at an early stage of error detection.


Potential role of tocopherol in protecting crop plants against abiotic stresses.
The changing global climate have given rise to abiotic stresses that adversely affect the metabolic activities of plants, limit their growth, and agricultural output posing a serious threat to food production. The abiotic stresses commonly lead to production of reactive oxygen species (ROS) that results in cellular oxidation. Over the course of evolution, plants have devised efficient enzymatic and non-enzymatic anti-oxidative strategies to counteract harmful effects of ROS. Among the emerging non-enzymatic anti-oxidative technologies, the chloroplast lipophilic antioxidant vitamin A (Tocopherol) shows great promise. Working in coordination with the other cellular antioxidant machinery, it scavenges ROS, prevents lipid peroxidation, regulates stable cellular redox conditions, simulates signal cascades, improves membrane stability, confers photoprotection and enhances resistance against abiotic stresses. The amount of tocopherol production varies based on the severity of stress and its proposed mechanism of action involves arresting lipid peroxidation while quenching singlet oxygen species and lipid peroxyl radicals. Additionally, studies have demonstrated its coordination with other cellular antioxidants and phytohormones. Despite its significance, the precise mechanism of tocopherol action and signaling coordination are not yet fully understood. To bridge this knowledge gap, the present review aims to explore and understand the biosynthesis and antioxidant functions of Vitamin E, along with its signal transduction and stress regulation capacities and responses. Furthermore, the review delves into the light harvesting and photoprotection capabilities of tocopherol. By providing insights into these domains, this review offers new opportunities and avenues for using tocopherol in the management of abiotic stresses in agriculture.


Oxygen kinetics of frozen cytochrome oxidase. The capacity of the oxygen pocket.
Low-temperature kinetics of the reaction between O2 and cytochrome oxidase suggest the existence of an O2 pocket of limited capacity in membrane-bound cytochrome oxidase, and one of larger capacity in purified cytochrome oxidase. A model is proposed to explain the difference in capacity of the pockets.


Mobile Charge-Induced Fluorescence Intermittency in Methylammonium Lead Bromide Perovskite.
Organic-inorganic halide perovskite has emerged as a very promising material for solar cells due to its excellent photovoltaic enabling properties resulting in rapid increase in device efficiency over the last 3 years. Extensive knowledge and in-depth physical understanding in the excited state carrier dynamics are urgently required. Here we investigate the fluorescence intermittency (also known as blinking) in vapor-assisted fabricated CH3NH3PbBr3 perovskite. The evident fluorescence blinking is observed in a dense CH3NH3PbBr3 perovskite film that is composed of nanoparticles in close contact with each other. In the case of an isolated nanoparticle no fluorescence blinking is observed. The "ON" probability of fluorescence is dependent on the excitation intensity and exhibits a similar power rule to semiconductor quantum dots at higher excitation intensity. As the vapor-assisted fabricated CH3NH3PbBr3 perovskite film is a cluster of nanoparticles forming a dense film, it facilitates mobile charge migration between the nanoparticles and charge accumulation at the surface or at the boundary of the nanoparticles. This leads to enhanced Auger-like nonradiative recombination contributing to the fluorescence intermittency observed. This finding provides unique insight into the charge accumulation and migration and thus is of crucial importance for device design and improvement.


Aptamer engineering exosomes loaded on biomimetic periosteum to promote angiogenesis and bone regeneration by targeting injured nerves via JNK3 MAPK pathway.
Repairing critical bone defects is a complex problem in the clinic. The periosteum rich in nerve plays a vital role in initiating and regulating bone regeneration. However, current studies have paid little attention to repairing nerves in the periosteum to promote bone regeneration. Thus, it is essential to construct bionic periosteum with the targeted injured nerves in the periosteum. We coupled phosphatidylserine (PS) targeted aptamers with repair Schwann cell exosomes to construct exosome@aptamer (EA). Then through PEI, EA was successfully built on the surface of the electrospun fiber, which was PCL@PEI@exosome@aptamer (PPEA). Through SEM, TEM, and other technologies, PPEA was characterized. Experiments prove in vivo and in vitro that it has an excellent repair effect on damaged nerves and regeneration of vascular and bones. In vivo, we confirmed that biomimetic periosteum has an apparent ability to promote nerve and bone regeneration by using Microcomputer tomography, hematoxylin-eosin, Masson, and Immunofluorescence. In vitro, we used Immunofluorescence, Real-Time Quantitative PCR, Alkaline phosphatase staining, and other tests to confirm that it has central nerve, blood vessel, and bone regeneration ability. The PPEA biomimetic periosteum has apparent neurogenic, angiogenic, and osteogenic effects. The PPEA biomimetic periosteum will provide a promising method for treating bone defects.


Training-related changes in the maximal rate of torque development and EMG activity.
This study monitored the effects of a short-term elbow flexor training program on surface electromyographic (SEMG) spike activity. The experimental paradigm consisted of three test sessions separated by 2-week intervals. At the beginning of each session, participants (N=13) performed five maximal effort isometric contractions of the elbow flexors to serve as baseline. After 5 min of rest, the participants then engaged in a 30-trial isometric fatigue protocol during which maximal elbow flexion torque was measured with a load-cell, and the maximal rate of change in the torque (dtau/dt(max)) was obtained from the differentiated torque-time curve. Bipolar electrodes were used to monitor the SEMG spike activity of the biceps brachii. Mean spike amplitude (MSA) and mean spike frequency (MSF) were calculated for the torque development and constant-torque phases of the isometric contraction, termed Segment 1 and Segment 2, respectively. Mean power frequency (MPF) was also calculated for Segment 2. The five baseline contractions of the second and third sessions were compared with those of the first session and analyzed for training-related changes. Training increased dtau/dt(max) but failed to change maximal elbow flexion torque or MSA. However, there was an increase in the MSF during the torque development phase of the contraction (Segment 1). Both MSA and MSF were greatest during the constant-torque phase of the isometric contraction (Segment 2). There was a strong linear correlation (r=0.90, P<0.05) between MSF and MPF during (Segment 2). We hypothesize that the increase in dtau/dt(max) is due to enhanced motor-unit rate-coding. The demonstrated correlation between MSF and MPF measures will allow investigators to use spike analysis to examine the frequency content of the SEMG signal under non-stationary conditions.


Azimuthal modulation of electromagnetically induced transparency using structured light.
Recently a scheme has been proposed for detection of the structured light by measuring the transmission of a vortex beam through a cloud of cold rubidium atoms with energy levels of the Λ-type configuration [N. Radwell et al., Phys. Rev. Lett.114, 123603 (2015) ]. This enables observation of regions of spatially dependent electromagnetically induced transparency (EIT). Here we suggest another scenario for detection of the structured light by measuring the absorption profile of a weak nonvortex probe beam in a highly resonant five-level combined tripod and Λ (CTL) atom-light coupling setup. We demonstrate that due to the closed-loop structure of CTL scheme, the absorption of the probe beam depends on the azimuthal angle and orbital angular momentum (OAM) of the control vortex beams. This feature is missing in simple Λ or tripod schemes, as there is no loop in such atom-light couplings. One can identify different regions of spatially structured transparency through measuring the absorption of probe field under different configurations of structured control light.


Indwelling catheters: developing an integrated care pathway package.
Urinary catheterisation is a common nursing procedure in hospital and in the community, yet there are risks associated with it. Complications include urethral trauma, urinary tract infection, strictures, urethral perforation, encrustation, bladder calculi and neoplastic changes (Lowthian, 1998). The procedure is also linked to nosocomial infection and, in some cases, these catheter-related infections can prove fatal (Pratt et al, 2001). Due to the risks, catheterisation is indicated as a last resort after all other interventions have failed.