Risk of gambling onset in youth who are younger than same-grade peers.
To assess whether a child's age relative to the median age of classmates in the same grade is associated with the onset of gambling. Grade 7 students (n = 647) from 10 Montreal secondary schools were followed for 8 years. Relative age was expressed as years above or below the school-specific grade 7 median age. Hazard ratios and 95% confidence intervals (CI) were estimated for the association between relative age and age of gambling onset, with adjustment for sex, ethnicity, parent education, and impulsivity. A greater proportion of students in the youngest quartile gambled compared with the oldest (85.8% vs 74.7%). Hazards of gambling onset for students younger than the median age were elevated after age 10.5 years, but hazards were protective beforehand. At age 17 years, for example, the hazard for gambling onset was 61% greater (95% CI 1.4-1.9) for youth who were 1 year younger, but at age 8 years the hazard was 23% lower (95% CI 0.7-0.9). Younger relative age may be a risk factor for gambling onset in older youth.


An ATP-sensitive phosphoketolase regulates carbon fixation in cyanobacteria.
Regulation of CO2 fixation in cyanobacteria is important both for the organism and global carbon balance. Here we show that phosphoketolase in Synechococcus elongatus PCC7942 (SeXPK) possesses a distinct ATP-sensing mechanism, where a drop in ATP level allows SeXPK to divert precursors of the RuBisCO substrate away from the Calvin-Benson-Bassham cycle. Deleting the SeXPK gene increased CO2 fixation particularly during light-dark transitions. In high-density cultures, the Δxpk strain showed a 60% increase in carbon fixation and unexpectedly resulted in sucrose secretion without any pathway engineering. Using cryo-EM analysis, we discovered that these functions were enabled by a unique allosteric regulatory site involving two subunits jointly binding two ATP, which constantly suppresses the activity of SeXPK until the ATP level drops. This magnesium-independent ATP allosteric site is present in many species across all three domains of life, where it may also play important regulatory functions.


Uterine torsion in pregnancy.
Torsion of the pregnant uterus is defined as rotation more than 45 degrees around the long axis of the uterus. Uterine torsion is observed in all age groups of the reproductive period, in all parity groups, and at all stages of pregnancy. Torsion from 60 degrees to 720 degrees has been described. It is not possible to clarify why uterine torsion occurs, but numerous abnormalities have appeared with uterine torsion; most often, abnormal fetal presentation, myoma uteri and uterine malformations. The most usual symptoms of uterine torsion are birth obstruction, abdominal pain, vaginal bleeding, shock, and urinary and intestinal symptoms. Eleven percent are asymptomatic. The treatment in the earlier months of pregnancy is immediate laparotomy and detorsion of the uterus and, if practicable, adjunct surgery to eliminate the possible etiologic factors. Near term or during labor cesarean section is carried out, and elimination of the possible etiologic factors. The fetal and maternal mortality rates since 1976 are 12% and 0% respectively.


Characterization of "oil on copper" paintings by energy dispersive X-ray fluorescence spectrometry.
Energy dispersive X-ray fluorescence is a common analytical tool for layer thickness measurements in quality control processes in the coating industry, but there are scarce microanalytical applications in order to ascertain semi-quantitative or quantitative information of painted layers. "Oil on copper" painting becomes a suitable material to be analysed by means of X-ray fluorescence spectrometry, due to the metallic nature of substrate and the possibility of applying layered models as used in coating industry. The aim of this work is to study the suitability of a quantitative energy dispersive X-ray fluorescence methodology for the assessment of the areal distribution of pigments and the characterization of painting methods on such kind of pictorial artworks. The method was calibrated using standard reference materials: dried droplets of monoelemental standard solutions laid on a metallic plate of copper. As an example of application, we estimated pigment mass distribution of two "oil on copper" paintings from the sixteenth and eighteenth centuries. Pictorial layers have been complementarily analysed by X-ray diffraction. Apart of the supporting media made of copper or brass, we could identify two different superimposed layers: (a) a preparation layer mainly composed by white lead and (b) the pictorial layer of variable composition depending on the pigments used by the artist on small areas of the painting surface. The areal mass distribution of the different elements identified in the painting pigments (Ca, Cr, Mn, Fe, Zn, Cd, Hg and Pb) have been determined by elemental mapping of some parts of the artworks.


Synthesis, structural investigations and biological evaluation of novel hexahydropyridazine-1-carboximidamides, -carbothioamides and -carbothioimidic acid esters as inducible nitric oxide synthase inhibitors.
Local excess of nitric oxide (NO) has been implicated in beta-cell damage, thus, a possible approach to the treatment of autoimmune IDDM is the selective inhibition of inducible nitric oxide synthase (iNOS). A series of variously substituted hexahydropyridazine-1-carbothioamides, -carbothioimidic acid esters and -carboximidamides was synthesized and dose-dependently evaluated as potential inhibitors of iNOS. The screening of the title compounds was performed with insulin-producing RIN-5AH cells and a combination of IL1-1 beta and IFN-gamma as inducers of cellular NO production. The structure-activity analysis revealed that the variation of substituents in the position 1 of the hexahydropyridazine strongly influences the inhibitory activity to iNOS as well as being critical for RIN cell survival. Among the compounds tested, the hexahydropyridazine-1-carbothioamides showed particularly significant inhibitory effects. However, for an efficient iNOS inhibition substitution at the nitrogen of the 1-carbothioamide group is important. Thus, the introduction of aliphatic chains such as propyl or butyl and of cyclic moieties such as cyclohexyl, 3-methoxyphenyl, and 4-methoxyphenyl (IC(50): 0.5-2.1 mM), respectively, provided compounds with similar inhibitory activity to aminoguanidine (IC(50): 0.3 mM), a common standard substance used for the selective inhibition of iNOS. However, the 1-carboximidamides, which represent more structurally related semicyclic derivatives of aminoguanidine, caused only incomplete iNOS inhibition. The hexahydropyridazine-1-carbothioimidic acid esters caused dose- and substituent-dependent damage of RIN-5AH cells. The toxicity of the synthesized compounds increased markedly if aliphatic substituents at the exocyclic N atom(s) were replaced by variously substituted aromatic rings.


An unreported mutation within protein Z gene is associated with very low protein levels in women with fetal loss.
Gene variant intron C G-42A of protein Z is significantly associated with the occurrence of fetal loss. A previously unreported sporadic missense mutation within exon 8 is described in a patient with very low protein Z levels.


Analyzing the interaction of human ACE2 and RBD of spike protein of SARS-CoV-2 in perspective of Omicron variant.
The newly identified Omicron (B.1.1.529) variant of Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) has steered concerns across the world due to the possession of a large number of mutations leading to high infectivity and vaccine escape potential. The Omicron variant houses 32 mutations in spike (S) protein alone. The viral infectivity is determined mainly by the ability of S protein Receptor Binding Domain (RBD) to bind to the human Angiotensin I Converting Enzyme 2 (hACE2) receptor. In this paper, the interaction of the RBDs of SARS-CoV-2 variants with hACE2 was analyzed by using protein-protein docking and compared with the novel Omicron variant. Our findings reveal that the Omicron RBD interacts strongly with hACE2 receptor via unique amino acid residues as compared to the Wuhan and many other variants. However, the interacting residues of RBD are found to be the same in Lamda (C.37) variant. This unique binding of Omicron RBD with hACE2 suggests an increased potential of infectivity and vaccine evasion potential of the new variant. The evolutionary drive of the SARS-CoV-2 may not be exclusively driven by RBD variants but surely provides for the platform for emergence of new variants.


Application of the distributed activation energy model to the kinetic study of pyrolysis of the fresh water algae Chlorococcum humicola.
Apart from capturing carbon dioxide, fresh water algae can be used to produce biofuel. To assess the energy potential of Chlorococcum humicola, the alga's pyrolytic behavior was studied at heating rates of 5-20K/min in a thermobalance. To model the weight loss characteristics, an algorithm was developed based on the distributed activation energy model and applied to experimental data to extract the kinetics of the decomposition process. When the kinetic parameters estimated by this method were applied to another set of experimental data which were not used to estimate the parameters, the model was capable of predicting the pyrolysis behavior, in the new set of data with a R(2) value of 0.999479. The slow weight loss, that took place at the end of the pyrolysis process, was also accounted for by the proposed algorithm which is capable of predicting the pyrolysis kinetics of C. humicola at different heating rates.


Herringbone Helical Foldamers from Aromatic Ether Derived ϵ-Amino Acid Peptides.
Oligomers based on an aromatic ether derived ϵ-amino acid peptides folded into herringbone helical structures, induced by successive NH-O-NH & O-NH-O bifurcated hydrogen bonding interactions and reinforced by π-π stacking between aryls from adjacent layers. The diaryl ether bonds -O- worked both as structural units to provide turn motifs for changing the amplitude of the slope along the axis of helix for herringbone formation, and also as acceptors for hydrogen bonding. Attachment of a single chiral carbon to the C-termini of the peptides induced excess of single-handed screw sense and amplification through the chain propagation as exemplified by chain length dependent circular dichroism (CD) investigations.


Interseasonal variation in blood concentrations of organochlorines in great black-backed gulls (Larus marinus).
In two subsequent breeding seasons (2001 and 2002), we measured 12 organochlorines (OCs), including hexachlorobenzene (HCB), beta-hexachlorocyclohexane (beta-HCH), p,p'-dichlorodiphenyldichloroethylene (DDE), oxychlordane, and eight polychlorinated biphenyl congeners (PCBs), in the blood of the same 25 great black-backed gulls (Larus marinus). The wet-weight concentrations of different OCs in the blood decreased between 45 and 60% from 2001 to 2002. The main reasons for this were lower blood-lipid concentrations and higher body condition in 2002 compared to 2001. The differences in blood lipids and body condition probably resulted from changes in the availability of different prey types between the years. Despite the variation in the blood concentrations of OCs, there was a high predictability of the relative relationship among individuals between the years, especially for the most-persistent compounds (persistent PCBs, oxychlordane, and DDE); that is, individuals with high levels in 2001 still had relatively high levels compared to other individuals in 2002. This suggests that a concentration obtained from a single blood sample is a relatively reliable measurement of OC burdens for individual great black-backed gulls compared to other individuals, independent of changes in mean OC levels within the population. However, by including information about the nutritional status of individuals, more precise interference from samples in different years and locations may be made. Moreover, the great seasonal variation in OC levels within individuals may have implications for how OC monitoring should be conducted in gull populations.


A Pipeline for PAR-CLIP Data Analysis.
Photo-activatable ribonucleoside cross-linking and immunoprecipitation (PAR-CLIP) is a method to detect binding sites of RNA-binding proteins (RBPs) transcriptome-wide. This chapter covers the computational analysis of the high-throughput sequencing reads generated from PAR-CLIP experiments. It explains how the reads are mutated due to UV cross-linking and how to appropriately pre-process and align them to a reference sequence. Aligned reads are then aggregated into clusters which represent putative RBP-binding sites. Mapping artifacts are a source of false positives, which can be controlled by means of a mapping decoy and adaptive quality filtering of the read clusters. A step-by-step explanation of this procedure is given. All necessary tools are open source, including the scripts presented and used in this chapter.


Diagnostic Accuracy of Clinical Tests for Assessing Greater Trochanteric Pain Syndrome: A Systematic Review With Meta-analysis.
OBJECTIVE: We aimed to evaluate the accuracy of clinical tests that are used to diagnose greater trochanteric pain syndrome (GTPS) in clinical practice. DESIGN: Diagnostic test accuracy systematic review with meta-analysis. LITERATURE SEARCH: MEDLINE, Embase, CINAHL, AMED, and SPORTDiscus were searched using key words mapped to diagnostic test accuracy for GTPS. STUDY SELECTION CRITERIA: Studies with published or derivable diagnostic accuracy data were included. DATA SYNTHESIS: Risk of bias was assessed using the QUADAS-2 tool, and certainty of evidence, via the Grading of Recommendations, Assessment, Development, and Evaluations (GRADE) framework. MetaDTA "R" random-effects models were used to summarize individual and pooled data including sensitivity, specificity, likelihood ratios, and pretest/posttest probabilities. RESULTS: From a database yield of 858 studies, 23 full texts were assessed. We included 6 studies for review, involving 15 tests and 272 participants (314 hips). Overall certainty of evidence ranged from very low to moderate. Meta-analysis of 6 tests revealed sequenced test clusters able to significantly shift pretest-posttest probability for or against a GTPS diagnosis. In people reporting lateral hip pain, a negative gluteal tendon (GT) palpation test followed by a negative resisted hip abduction test significantly reduced the posttest probability of GTPS from 59% to 14%. In those with a positive GT palpation test followed by a positive resisted hip abduction test, the posttest probability of GTPS significantly shifted from 59% to 96%. CONCLUSION: The value of magnetic resonance imaging for diagnosing GTPS is debated. We have identified a straightforward, clinically useful diagnostic test cluster to help confirm or refute the presence of GTPS in people reporting lateral hip pain. J Orthop Sports Phys Ther 2024;54(1):1-24. Epub 10 August 2023. doi:10.2519/jospt.2023.11890.


Assessment of dementia risk in aging adults using both FDG-PET and FDDNP-PET imaging.
In a previous study, positron emission tomography (PET) with 2-(1-{6-[(2-[F-18]fluoroethyl)(methyl)amino]-2-naphthyl}ethylidene)malononitrile (FDDNP), a molecule that binds to plaques and tangles in vitro, identified three subgroups of non-demented subjects according to FDDNP binding patterns: low global (LG) binding; high frontal, parietal, medial temporal binding (HF/PA); and high medial and lateral temporal and posterior cingulate (HT/PC) binding. In this follow-up investigation, we compared 2-deoxy-2-[F-18]fluoro- d-glucose (FDG)-PET cerebral metabolic patterns in the three FDDNP-PET binding subgroups. Fifty-four subjects with normal aging (N = 28) or amnestic forms of mild cognitive impairment (N = 26) underwent FDDNP-PET and FDG-PET scanning. Subjects in the LG, HF/PA, and HT/PC FDDNP subgroups were compared according to visual ratings, statistical parametric mapping, and automated region of interest analyses of their FDG-PET data. The FDDNP-PET subgroups demonstrated different glucose metabolic patterns according to visual ratings, region of interest, and statistical parametric mapping analyses of FDG-PET data. The LG FDDNP subgroup showed no areas of significant hypometabolism relative to the other subgroups and had low Alzheimer's disease risk by FDG-PET standards. The HF/PA FDDNP subgroup demonstrated hypometabolism in bilateral inferior parietal/parietotemporal, bilateral posterior cingulate, perisylvian, mid-temporal gyrus, and dorsolateral prefrontal regions, which is a pattern suggestive of high Alzheimer's disease risk. The HT/PC FDDNP subgroup demonstrated heterogeneous FDG-PET patterns with predominant anterior frontal and anterior temporal hypometabolism, suggestive of mixed etiologies, including fronto-temporal dementia risk. The FDG-PET data provided independent validation that different patterns of FDDNP-PET binding in non-demented individuals may be associated with differential dementia risk.


CT radiomics-based long-term survival prediction for locally advanced non-small cell lung cancer patients treated with concurrent chemoradiotherapy using features from tumor and tumor organismal environment.
Definitive concurrent chemoradiotherapy (CCRT) is the standard treatment for locally advanced non-small cell lung cancer (LANSCLC) patients, but the treatment response and survival outcomes varied among these patients. We aimed to identify pretreatment computed tomography-based radiomics features extracted from tumor and tumor organismal environment (TOE) for long-term survival prediction in these patients treated with CCRT. A total of 298 eligible patients were randomly assigned into the training cohort and validation cohort with a ratio 2:1. An integrated feature selection and model training approach using support vector machine combined with genetic algorithm was performed to predict 3-year overall survival (OS). Patients were stratified into the high-risk and low-risk group based on the predicted survival status. Pulmonary function test and blood gas analysis indicators were associated with radiomic features. Dynamic changes of peripheral blood lymphocytes counts before and after CCRT had been documented. Nine features including 5 tumor-related features and 4 pulmonary features were selected in the predictive model. The areas under the receiver operating characteristic curve for the training and validation cohort were 0.965 and 0.869, and were reduced by 0.179 and 0.223 when all pulmonary features were excluded. Based on radiomics-derived stratification, the low-risk group yielded better 3-year OS (68.4% vs. 3.3%, p < 0.001) than the high-risk group. Patients in the low-risk group had better baseline FEV1/FVC% (96.3% vs. 85.9%, p = 0.046), less Grade ≥ 3 lymphopenia during CCRT (63.2% vs. 83.3%, p = 0.031), better recovery of lymphopenia from CCRT (71.4% vs. 27.8%, p < 0.001), lower incidence of Grade ≥ 2 radiation-induced pneumonitis (31.6% vs. 53.3%, p = 0.040), superior tumor remission (84.2% vs. 66.7%, p = 0.003). Pretreatment radiomics features from tumor and TOE could boost the long-term survival forecast accuracy in LANSCLC patients, and the predictive results could be utilized as an effective indicator for survival risk stratification. Low-risk patients might benefit more from radical CCRT and further adjuvant immunotherapy. retrospectively registered.


The effect of dietary fish oil and long-term salt loading on blood pressure and eicosanoid metabolism in spontaneously hypertensive rats.
1. Dietary suppression of prostanoid synthesis with fish oils has had little effect on blood pressure in models of experimental hypertension in rats. However, a pressor effect of dietary fish oils was observed in spontaneously hypertensive rats (SHR) subject to 1 week of salt loading. 2. Animals were allocated to semisynthetic diets containing either 10% by weight Max EPA fish oil or a control diet of coconut oil, and studied after receiving 1.5% saline for 4 weeks. 3. Within the first week of salt loading, SHR-fed fish oil showed an increase in blood pressure (mean = 9 mmHg) relative to controls. This effect was transient, and after the first week of salt loading there was little difference in blood pressure between the two dietary groups. 4. Following dietary treatment there were substantial changes in plasma fatty acid composition with a 48% decrease in arachidonic acid content of fish oil-fed rats compared with control animals. Rats on the fish oil diet showed a threefold decrease in serum thromboxane generation. Prostacyclin production by incubated segments of aorta was reduced by more than 50% compared with the coconut oil-fed control group. 5. SHR on the fish oil diet showed increased urine volume and sodium excretion, presumably due to increased fluid and salt intake. 6. This study shows that dietary suppression of prostacyclin synthesis is associated with only a minor effect on blood pressure in long-term salt loading of SHR.


Rational design of a protein-based molecular device consisting of blue fluorescent protein and zinc protoporphyrin IX incorporated into a cytochrome b562 scaffold.
To make a single molecular photo-device, it is essential to control the exact orientation of two types of proteins. We made a chimeric protein in which cytochrome b562 was linked to the N-terminus of enhanced green fluorescent protein, cytb562-EGFP. Within cytb562-EGFP, the excitation energy of EGFP was transferred to the cytochrome b562 cofactor fixed proximally to EGFP. Cytb562-EGFP was engineered so that iron protoporphyrin IX was substituted by zinc protoporphyrin IX to make it a suitable cofactor for photo-induced electron transfer. The photosensitizer pigment was optimized and the EGFP was replaced by a blue fluorescent mutant that gave 15% higher energy transfer efficiency.


Is there an alternative explanation to the evolutionary account for financial and prosocial biases in favor of attractive individuals?
All three critical points of the evolutionary explanation proposed by Maestripieri et al. may not withstand close scrutiny. Instead, there should be an alternative explanation that has nothing to do with genetic continuity, but stresses the rewarding property of attractiveness that results mainly from sociocultural value assignment and sexual experience pursuit.


Erections and sexual function in post-sphincterotomy bladder neck patients.
A study of 131 patients who underwent sphincterotomy and bladder neck incision was done to determine changes in postoperative erectile and sexual function. A complete, permanent loss of erectile function was noted in 8.2 per cent of the patients and diminished erectile function was noted in 16.8 per cent. Unchanged or improved erections were noted in 74.8 per cent of the patients, while a complete loss of ability to engage in vaginal sexual intercourse, which had been present preoperatively, was sustained by 3.9 per cent of patients with diminished erections suffered no impairment of their preoperative sexual ability. Unaltered, improved or induced sexual function was present in 96.1 per cent of the patients postoperatively.


Relevance of asymptomatic spinal MRI lesions in patients with multiple sclerosis.
The impact of new asymptomatic spinal cord lesions (a-SL) in multiple sclerosis (MS) course is poorly characterized. The objective of this research paper is to assess the prognostic value of a-SL in predicting MS course. Relapsing-remitting MS patients who received serial MRI (brain and spinal) at baseline (t1) and within 12 to 36 months (t2) during clinical stability, and had a follow-up (t2-t3) ⩾24 months were included. Relapses and disability progression were evaluated between t2 and t3. Of 413 consecutive screened MS patients, 103 patients (65 females, median age 43 years) were included. After a median t1-t2 interval of 17 (IQR 13-26) months, 25.2% and 43.7% patients had ⩾1 new a-SL (a-SL+) and asymptomatic brain lesions (a-BL+), respectively. Relapse risk between t2 and t3 (median interval: 42 (IQR 32-57.5) months) was significantly increased in a-SL+ and/or a-BL+ vs a-BL- and a-SL- (HR = 2.31, 95% CI = 1.13-4.72, p = 0.02). No differences in the risk of disability progression were found in a-SL+ and/or a-BL+ vs a-SL- and a-BL-. a-SL occur in one-quarter of clinically stable RRMS, and combined with a-BL contribute significantly in predicting future disease course.


Downregulation of miR-223 and miR-153 mediates mechanical stretch-stimulated proliferation of venous smooth muscle cells via activation of the insulin-like growth factor-1 receptor.
Autologous venous grafts, used to circumvent occluded coronary arteries during coronary artery bypass, often develop thrombosis and neointimal hyperplasia. During neointimal hyperplasia, vascular smooth muscle cells (VSMCs), exposed to substantially higher pressure and hemodynamic forces, proliferate and extracellular matrix accumulate causing narrowing of the vessel lumen. Activation of insulin-like growth factor-1 receptor (IGF-1R) has been confirmed to be critically involved in mechanical stretch-stimulated VSMC proliferation. However, the comprehensive mechanisms responsible for activation of IGF-1R in VSMCs by mechanical stretch remain unclear. This study found that miR-223 and miR-153, targeted to IGF-1R, were down-regulated in VSMCs under stretch stress by miRNA microarray analysis in conjunction with Target Scan analysis. Overexpression of miR-223 or miR-153 down-regulated IGF-1R expression and activity in VSMCs under stretch stress. Specifically, overexpression of miR-223 and miR-153 inhibited stretch stress-enhanced VSMC proliferation and the activity of PI3K-AKT signaling. In conclusion, our study indicates that miR-153 and miR-223 are reduced in VSMCs by stretch stress, contributing to IGF-1R activation and resultant VSMC proliferation. Thus, miR-153 and miR-223 may be viable therapeutic targets for mechanical stretch-induced neointimal hyperplasia in vein grafts.


Impact of lifestyle on cytochrome P450 monooxygenase repertoire is clearly evident in the bacterial phylum Firmicutes.
Cytochrome P450 monooxygenases (CYPs/P450s), heme thiolate proteins, are well known for their role in organisms' primary and secondary metabolism. Research on eukaryotes such as animals, plants, oomycetes and fungi has shown that P450s profiles in these organisms are affected by their lifestyle. However, the impact of lifestyle on P450 profiling in bacteria is scarcely reported. This study is such an example where the impact of lifestyle seems to profoundly affect the P450 profiles in the bacterial species belonging to the phylum Firmicutes. Genome-wide analysis of P450s in 972 Firmicutes species belonging to 158 genera revealed that only 229 species belonging to 37 genera have P450s; 38% of Bacilli species, followed by 14% of Clostridia and 2.7% of other Firmicutes species, have P450s. The pathogenic or commensal lifestyle influences P450 content to such an extent that species belonging to the genera Streptococcus, Listeria, Staphylococcus, Lactobacillus, Lactococcus and Leuconostoc do not have P450s, with the exception of a handful of Staphylococcus species that have a single P450. Only 18% of P450s are found to be involved in secondary metabolism and 89 P450s that function in the synthesis of specific secondary metabolites are predicted. This study is the first report on comprehensive analysis of P450s in Firmicutes.


Clinical Outcome with Standard Regimen plus Clofazimine or Moxifloxacin in Cavitary Mycobacterium avium Complex Pulmonary Disease.
In this retrospective analysis including 173 patients in a tertiary referral center in South Korea, compared with the standard therapeutic regimen, clofazimine or moxifloxacin plus standard treatment regimen potentially did not induce a higher 1-year culture conversion rate in patients with Mycobacterium avium complex pulmonary disease who present with cavitary lesions (fibrocavitary or cavitary nodular bronchiectatic type).


Targeting ITGB4/SOX2-driven lung cancer stem cells using proteasome inhibitors.
This study investigates the role of integrin β4 (ITGB4) and stemness-associated factor SOX2 in platinum resistance in lung squamous cell carcinoma (LUSC). The expression of SOX2 and ITGB4 is found to be high in all LUSC subtypes, but the impact of ITGB4 expression on overall patient survival varies by subtype. Cancer stem cells (CSCs) isolated from LUSC patients were found to be resistant to cisplatin, but knocking down ITGB4 or SOX2 sensitized them to cisplatin. Carfilzomib (CFZ) synergized with cisplatin and suppressed CSC growth by inhibiting ITGB4 and SOX2 expression. Additionally, CFZ was found to inhibit SOX2 expression epigenetically by inhibiting histone acetylation at the SOX2 promoter site. CFZ also suppressed the growth of SOX2-dependent small cell lung cancer cells in vitro and in vivo. The study highlights the unique function of CFZ as a transcriptional suppressor of SOX2, independent of its proteasome inhibitory function.


Antibacterial activity of Terminalia pallida.
The methanol extract of the dried fruit powder of Terminalia pallida was evaluated for antimicrobial activity. The methanol extract showed a broad spectrum of antibacterial activity.


Liquid nitrogen storage of cultured T lymphocytes.
The conditions required for storing and recovering IL-2-dependent T cell clones from liquid nitrogen were investigated. For maximum cell recovery, cultured T lymphocytes were precooled at 4 degrees C for 15 min in medium containing 10% DMSO and 20% FCS before storage in liquid nitrogen. This method allowed adequate time for DMSO to penetrate the cells before freezing.


Expression of Claudins in Preneoplastic Conditions of the Gastrointestinal Tract: A Review.
Premalignant lesions of the gastrointestinal tract are a group of disorders which act as the harbinger of malignant tumors. They are the ground-zero of neoplastic transformation, and their identification and management offer patients the best opportunity of blocking the progress of cancer. However, diagnoses of some of these conditions are hard to make, and their clinical importance is difficult to assess. Recent reports indicated that several claudin proteins have altered expressions in many cancers, including esophageal, gastric, colon, liver, and pancreatic cancers. The early identification of the aberrant expression of these proteins could lead to the early diagnosis and management of gastrointestinal tumors. Specifically, claudins -1, -2, -3, -4, and -18 are frequently overexpressed in gastrointestinal preneoplastic lesions. These altered expressions have shown clinical value in several tumors, providing diagnostic and prognostic information. In this article, we review the literature on the aberrant expression of claudins in preneoplastic lesions of the gastrointestinal tract. Additionally, we summarize their diagnostic and prognostic implications.


A cross-sectional survey of self-rated health and its determinants in patients with hypertension.
The purpose of the study is to investigate the levels of self-rated health, blood pressure control, understand their relationships between the self-rated health and blood pressure control, and to identify the extent to which demographic, disease and psychosocial factors predict the self-rated health of hypertensive patients. The study adopted a cross-sectional design. Nine hundred forty-two subjects with essential hypertension were invited to join the study, 807 completed the survey. Self-report questionnaires were used to collect data. The hierarchical logistic regression was used to test the determinants of self-rated health status. Of all the subjects, 59.3% rated their health status as good, and 41.7% perceived their health status as poor. In terms of levels of blood pressure control, nurse-measured blood pressure showed that 40.2% of the subjects had good control levels, 59.8% for poor control levels. There were positive relationships between good self-rated health and controlled blood pressure of hypertensive patients (p<0.05). The logistic regression model showed that the determinants of subjects' self-rated health included income (OR=4.28; 95% CI=1.86-6.25), duration of hypertension diagnosis (OR=4.06; 95% CI=2.17-6.35), treatment adherence (OR=9.02; 95% CI=5.36-15.51), physical activity (OR=13.81; 95% CI=10.16-19.57) and social support (OR=8.63; 95% CI=7.17-11.35). The self-rated health status and blood pressure control for patients with hypertension is suboptimal, effective strategies should be developed to improve patients' general health.


Immediate but not long-term intranasal administration of insulin raises blood pressure in human beings.
Intranasal administration of insulin has been shown to influence neuroendocrine functions via an effect on central nervous mechanisms. Because insulin, in particular when infused into cerebral arteries, induces blood pressure (BP) elevation by an unknown mechanism, we investigated whether insulin exerts similar effects on BP after intranasal administration. To evaluate the immediate effects of insulin on BP, 20 IU of human insulin was intranasally administered every 10 minutes over a 2-hour period. Blood pressure, heart rate, and muscular sympathetic nervous activity (MSNA) were continuously monitored. For evaluating the effects of subchronic administration of insulin, changes during and after 8 weeks of treatment with 160 IU insulin/d on BP were monitored. Compared with placebo, the immediate nasal administration of insulin raised diastolic BP (12.21% +/- 5.10%; P < .05), mean arterial BP (10.81% +/- 4.32%; P < .04), and systolic BP (9.53% +/- 4.66%; P < .08), whereas MSNA and heart rate were unaffected. In contrast, prolonged intranasal insulin administration did not affect BP (P > .62 for all comparisons). The immediate increase in BP in the face of an unsuppressed MSNA after insulin suggests that intranasal insulin transiently changes the baroreflex set point. Thus, data suggest that intranasal insulin administration affects BP regulatory centers in the brain. However, the effect is not observed with prolonged administration of the hormone, suggesting the emergence of counterregulatory processes.


Anterior chamber maintainer for extracapsular cataract extraction and intraocular lens implantation.
An instrument for maintaining a deep anterior chamber during extracapsular cataract extraction is described. This anterior chamber maintainer makes the different stages of extracapsular technique safer and easier to perform.


In vitro reconstitution of the MHC class I peptide-loading complex.
The stability of the MHC (major histocompatibility complex) class I peptide repertoire is optimized during assembly in the endoplasmic reticulum (ER) and depends on the collective function of components of the peptide-loading complex (PLC). The chaperone-like molecule tapasin is the cornerstone of this complex and acts directly on the MHC class I molecule to promote high-affinity peptide loading. Optimal tapasin activity, however, relies on the ability of ERp57 and calreticulin, two proteins involved in general ER glycoprotein folding, to bridge and thereby stabilize its otherwise weak interaction with the MHC class I heavy chain. Here, we describe methods for the recombinant expression of soluble components of the PLC specifically tailored to generate the post-translational modifications required to support subcomplex assembly in vitro. Using recombinant MHC class I molecules bearing monoglucosylated N-linked glycans, calreticulin, and disulfide-linked tapasin/ERp57 heterodimers, this soluble PLC subcomplex can be employed to study the mechanism of peptide loading or the principles governing peptide selection for particular MHC class I alleles.


[ESC guidelines 2020: acute coronary syndrome without persistent ST-segment elevation : What is new?]
The European Society of Cardiology (ESC) guidelines for the management of acute coronary syndrome without persistent ST-segment elevation (NSTE-ACS) published in August 2020, replace the former NSTE-ACS guidelines published in 2015. These updated guidelines have some relevant changes for the clinical practice, which include the diagnostic work-up, risk stratification, antithrombotic therapy, invasive or noninvasive coronary diagnostics and also long-term treatment. New sections deal with spontaneous coronary artery dissection (SCAD), myocardial infarction with nonobstructive coronary arteries (MINOCA) and also newly introduced quality indicators for NSTE-ACS treatment. The diagnostic work-up using highly sensitive cardiac troponin (hs-cTn) assays is emphasized with the recommendation to use fast triage decisions that enable an early rule-in (no STEMI) or rule-out (NSTEMI probable) in the emergency room or chest pain unit. In antiplatelet therapy a greater individualization of the treatment concept is recommended based on the individual ischemic/thrombotic events and bleeding complications. Some new aspects were introduced for timing of invasive coronary angiography; however, principally the very high-risk group should still immediately undergo coronary angiography and the high-risk group should undergo an invasive angiography within 24 h. In risk stratification, the former intermediate risk group has been removed, instead it is now emphasized that low-risk patients should be treated similarly to patients with chronic coronary syndrome.


First Successful Liver-Alone Transplantation for TERT (Telomerase Reverse Transcriptase)-Telomeropathy-Related Hepatoportal Sclerosis Cirrhosis.
Hepatoportal sclerosis is a rare but well-described condition leading to end-stage liver disease. Telomeropathy is a rare genetic disorder which manifests as premature senescence of cells leading to multisystem disease involving bone marrow, lungs and skin. To the best of our knowledge, there is no report of telomeropathy precipitating end-stage liver disease. Our case presented hepatopulmonary syndrome. Herein, we report a successful liver transplantation in a patient who suffered hepatoportal cirrhosis from telomerase reverse transcriptase (TERT)-telomeropathy.


Impairment of cardiac function by moderate potassium depletion.
A previous study found that potassium depletion in dogs that resulted in a reduction in plasma potassium from 4.1 to 3.2 mmol/L was associated with impairment of many aspects of left ventricular mechanical function, including a 51% reduction in the peak rate of left ventricular filling. To determine if potassium depletion had similar effects in humans, cardiac function was assessed by Doppler and two-dimensional echocardiography in 10 normal volunteers following a 7-day period of potassium depletion, and again 7 days of potassium repletion. Potassium concentration for the group averaged 3.49 +/- 0.12 mmol/L after the depletion period, and 4.57 +/- 0.14 mmol/L after repletion. Early peak mitral flow velocity was significantly less during depletion than during repletion. The values at rest were 89.5 +/- 6.6 and 77.0 +/- 4.9 cm/s during repletion and depletion, respectively (P < .01). Isovolomic relaxation time and deceleration time of flow through the mitral valve were also significantly increased during potassium depletion. No other measured indices of cardiac function were affected by potassium depletion. The results suggest that in normal volunteers, moderate potassium depletion may impair active relaxation of the left ventricle to a degree that is clinically significant.


Fluoride-induced apoptosis in non-skeletal tissues of experimental animals: A systematic review and meta-analysis.
Different studies have suggested that fluoride can induce apoptosis in non-skeletal tissues, however, evidence from these experimental studies is still controversial. This meta-analysis aims to clarify the mechanism of fluoride-induced apoptosis in non-skeletal tissues of experimental animals. Primary studies which measured apoptosis were identified through exhaustive database searching in PubMed, Embase, Web of Science Core Collection, Scopus, and references of included studies. A random effects model with standardized mean difference (SMD) was used for meta-analyses. The heterogeneity of the studies was evaluated using Higgin's I2 statistics. The risk of bias and publication bias were assessed using the SYRCLE's risk of bias tool and Egger's test, respectively. There was an increase in total apoptotic cells, and the expression of Bax, Bax/Bcl-2 ratio, caspase-3, caspase-8, caspase-9, Cyt c, and p53, and a decrease in the expression of Bcl-2 in the fluoride-treated groups as compared to the control groups. However, there was no evidence of a difference in the expression of APAF-1 in the two groups. The subgroup analysis highlighted the role of the intervention period in modification of the apoptotic effect of fluoride and that the susceptibility and tolerance of different animal species and tissues vary. Meta-regression analysis indicated that the studies' effect size for total apoptotic cells was influenced by animal species and that of Bax by the sample source. The results of this meta-analysis revealed that fluoride causes apoptosis by up-regulating caspase-3, -8, and -9, Cyt c, p53, Bax, and down-regulating Bcl-2 with a concomitant up-regulation of the Bax/Bcl-2 ratio.


Biodeinking of waste papers using combinatorial fungal enzymes and subsequent production of butanol from effluent.
The present study aimed to enzymatic deinking of waste papers and to valorize the effluent for biobutanol production. Application of fungal enzymatic cocktail (cellulase, amylase, xylanase, pectinase, lipase, and ligninase) on office used paper, newspaper, and ballpen written paper leading to improvement in brightness (84.91, 72.51, 76.69 % ISO), InKd (82.89, 68.95, 76.49%), κ-number (12.9, 13.6, and 13.1), opacity (27.91, 30.07, and 2.85%), tensile strength (49.24, 45.31, and 46.98 Nm/g), respectively and indices were consistent with chemical treated pulps. The quality of effluent generated during enzymatic deinking in respect to BOD and COD level was eco-friendlier than the chemical process. The enzyme-treated effluent was employed as supporting substrate for butanol (18.4 g/l) production by Clostridium acetobutylicum ATCC824. Material balance and life cycle assessment of the whole processes were evaluated to validate its industrial and environmental relevance.


Artificial intelligence in the detection and classification of dental caries.
Automated detection of dental caries could enhance early detection, save clinician time, and enrich treatment decisions. However, a reliable system is lacking. The purpose of this study was to train a deep learning model and to assess its ability to detect and classify dental caries. Bitewings radiographs with a 1876×1402-pixel resolution were collected, segmented, and anonymized with a radiographic image analysis software program and were identified and classified according to the modified King Abdulaziz University (KAU) classification for dental caries. The method was based on supervised learning algorithms trained on semantic segmentation tasks. The mean score for the intersection-over-union of the model was 0.55 for proximal carious lesions on a 5-category segmentation assignment and a mean F1 score of 0.535 using 554 training samples. The study validated the high potential for developing an accurate caries detection model that will expedite caries identification, assess clinician decision-making, and improve the quality of patient care.


Emotional availability in the mother-child relationship for families of young children with autism spectrum disorder in Australia: A cross-sectional survey.
In families of children with autism spectrum disorder (ASD) the mother-child relationship can be affected by many factors; however, the impacts of maternal broad autism phenotype (BAP) and attachment styles are unknown. This study investigated predictors of emotional availability in the mother-child relationship in families of children with ASD. Mothers (N = 231) of children with ASD living in Australia completed questionnaires assessing emotional availability in the parent-child relationship (mutual attunement, child involvement, affect quality) and mothers' BAP, mental health, adult attachment style and parenting experiences. Hierarchical multiple regressions and a mediation analysis were conducted. Parent-reported positive parenting experiences was the greatest predictor of mutual attunement, child involvement and affect quality in the parent-child relationship. Maternal stress and anxiety predicted poorer mutual attunement, stress and depressive symptoms predicted less child involvement and anxiety predicted worse affect quality. Negative parenting experiences, maternal anxiety and stress mediated the relationship between BAP and mutual attunement. Interventions combining mental health and parenting support for mothers of children with ASD to bolster emotional availability within the mother-child relationship may be warranted.


Assessment of MRI image distortion based on 6 consecutive years of annual QAs and measurements on 14 MRI scanners used for radiation therapy.
To determine the magnitude of MRI image distortion based on 6 consecutive years of annual quality assurances/measurements on 14 MRI scanners used for radiation therapy and to provide evidence for the inclusion of additional margin for treatment planning. We used commercial MRI image phantoms to quantitatively study the MRI image distortion over period of 6 years for up to 14 1.5 and 3 T MRI scanners that could potentially be used to provide MRI images for treatment planning. With the phantom images collected from 2016 to 2022, we investigated the MRI image distortion, the dependence of distortion on the distance from the imaging isocenter, and the possible causes of large distortion discovered. MRI image distortion increases with the distance from the imaging isocenter. For a region of interest (ROI) with a radius of 100 mm centered at the isocenter, the mean magnitude of distortion for all MRI scanners is 0.44 ± 0.18 mm $0.44 \pm 0.18\;{\rm{mm}}$ , and the maximum distortion varies from 0.52 to 1.31 mm $0.52\;{\rm{to}}\;1.31\;{\rm{mm}}$ depending on MRI scanners. For an ROI with a radius of 200 mm centered at the isocenter, the mean magnitude of distortion increases to 0.84 ± 0.45 mm $0.84 \pm 0.45\;{\rm{mm}}$ , and the range of the maximum distortion increases to 1.92 - 5.03 mm $1.92 - 5.03\;{\rm{mm}}$ depending on MRI scanners. The distortion could reach 2 mm at 150 mm from the isocenter. An additional margin to accommodate image distortion should be considered for treatment planning. Imaging with proper patient alignment to the isocenter is vital to reducing image distortion. We recommend performing image distortion checks annually and after major upgrade on MRI scanners.


Safety and pharmacokinetic profiles of repeated-dose micafungin in children and adolescents treated for invasive candidiasis.
Micafungin is an echinocandin with proven efficacy against a broad range of fungal infections, including those caused by Candida spp. To evaluate the safety and pharmacokinetics of once-daily 3 mg/kg and 4.5 mg/kg micafungin in children with proven, probable or suspected invasive candidiasis. Micafungin safety and pharmacokinetics were assessed in 2 phase I, open-label, repeat-dose trials. In Study 2101, children aged 2-16 years were grouped by weight to receive 3 mg/kg (≥25 kg) or 4.5 mg/kg (<25 kg) intravenous micafungin for 10-14 days. In Study 2102, children aged 4 months to <2 years received 4.5 mg/kg micafungin. Study protocols were otherwise identical. Safety was analyzed in 78 and 9 children in Studies 2101 and 2102, respectively. Although adverse events (AEs) were experienced by most children (2101: n=62; 2102: n=9), micafungin-related AEs were less common (2101: n=28; 2102: n=1), and the number of patients discontinuing due to AEs was low (2101: n=4; 2102: n=1). The most common micafungin-related AEs were infusion-associated symptoms, pyrexia and hypomagnesemia (Study 2101), and liver function abnormalities (Study 2102). The micafungin pharmacokinetic profile was similar to that seen in other studies conducted in children, but different than that observed in adults. In this small cohort of children, once-daily doses of 3 mg/kg and 4.5 mg/kg micafungin were well tolerated. Pharmacokinetic data will be combined in a population pharmacokinetic analysis to support US dosing recommendations in children.


Physiology, pharmacology and pathophysiology of the pH regulatory transport proteins NHE1 and NBCn1: similarities, differences, and implications for cancer therapy.
The Na⁺/H⁺-exchanger 1, NHE1 (SLC9A1) and the electroneutral Na⁺,HCO₃⁻ cotransporter NBCn1 (SLC4A7) are coexpressed in a wide range of tissues. Under normal physiological conditions these transporters play an ostensibly similar role, namely that of net acid extrusion after cellular acidification. In addition, they have been implicated in multiple other cellular processes, including regulation of transepithelial transport, cell volume, cell death/survival balance, and cell motility. In spite of their apparent functional similarity, the two transporters also serve distinctly different functions and are differentially regulated. Here, we provide an update on the basic structure, function, regulation, physiology and pharmacology of NHE1 and NBCn1, with particular focus on the factors responsible for their functional similarities and differences. Finally, we highlight recent findings implicating these transporters in cancer development, and discuss issues relating to NHE1 and NBCn1 as potential targets in cancer treatment.


Navigating decisional conflict as a family when facing the decision of stem cell transplant for a child or adolescent with sickle cell disease.
Patients with sickle cell disease (SCD) face unpredictable disease, with stem cell transplant being a curative treatment option with risks. The aim of this study was to describe the level and source of decisional conflict in families of children/adolescents with SCD facing a transplant decision. A multiple-case study approach described decisional conflict in various SCD severity/donor risk decisional contexts. Cases included parents, child/adolescent with SCD, and sibling donor. The level and source of conflict was measured via O'Connor's Decisional Conflict Scale and analyzed using pattern-matching and cross-case synthesis. In-depth descriptions of conflict sources were obtained through thematic analysis of observation and interview data. Among 11 participants in four cases (i.e. family units) decisional conflict was not unique not to the decisional context. Conflict levels represented a level that can be linked with feeling unsure and decisional delay. The theme, 'navigating decisional conflict together', described how family units discussed uncertainties. Varying levels and sources of decisional conflict exist in pediatric patients with SCD and their families considering transplant. In our cases, decisional conflict and the transplant decision occurred at the family-level. Clinicians should encourage all family members to participate in discussions concerning transplant.


Nonpharmacological rehabilitation interventions for motor and cognitive outcomes following pediatric stroke: a systematic review.
The aim of this review was to evaluate the evidence for nonpharmacological rehabilitation interventions for motor and cognitive impairment following pediatric stroke. A literature search was conducted using multiple scientific databases. Studies were included if (1) the study population was > 50% pediatric (< 18 years) stroke, (2) a diagnosis of stroke was explicitly stated, (3) there were ≥ 3 pediatric stroke participants included in the study sample, and (4) motor or cognitive outcome measures were used to assess effect of treatment. Levels of evidence were assigned to each study to determine the strength of the evidence for each intervention. A total of 18 articles met inclusion criteria. Most studies (N = 14) examined rehabilitation of the upper limb, with constraint-induced movement therapy (CIMT) as the most common intervention. Overall, the evidence supports the use of CIMT, forced use therapy, repetitive transcranial magnetic stimulation, functional electrical stimulation, and robotics, but suggests no beneficial effect of transcranial direct current stimulation. Very few studies assessed interventions for the lower limb (N = 1) or cognitive impairment (N = 3).Conclusion: Effective rehabilitation approaches are important for optimizing outcomes in children who have had a stroke. Although the number of published clinical trials has increased in recent years, little evidence-based guidance exists for this clinical population. What is Known: • Pediatric stroke is a significant cause of disability in children that is often associated with long-term motor and cognitive sequelae. • There is a need to establish a knowledge base regarding available evidence-based rehabilitation therapies for this clinical population. What is New: • Most studies examining interventions for motor function focus on upper limb rehabilitation, whereas few studies have investigated interventions for improving lower limb or cognitive impairment. • An important gap exists regarding evidence-based rehabilitative treatment approaches for pediatric stroke.


Diverse RNAs in adipose-derived extracellular vesicles and their therapeutic potential.
Adipose tissue, which is considered an energy storage and active endocrine organ, produces and secretes a large amount of adipokines to regulate distant targets through blood circulation, especially extracellular vesicles (EVs). As cell-derived, membranous nanoparticles, EVs have recently garnered great attention as novel mediators in establishing intercellular communications as well as in accelerating interorgan crosstalk. Studies have revealed that the RNAs, including coding RNAs (messenger RNAs) and noncoding RNAs (long noncoding RNAs, microRNAs, and circular RNAs) are key bioactive cargoes of EV functions in various pathophysiological processes, such as cell differentiation, metabolic homeostasis, immune signal transduction, and cancer. Moreover, certain EV-contained RNAs have gradually been recognized as novel biomarkers, prognostic indicators, or even therapeutic nanodrugs of diseases. Therefore, in this review, we comprehensively summarize different classes of RNAs presented in adipose-derived EVs and discuss their therapeutic potential according to the latest research progress to provide valuable knowledge in this area.


A comparison of sexually abused and nonsexually abused children's behavioral responses to anatomically correct dolls.
Groups of 16 girls referred for evaluation and treatment of sexual abuse and 16 nonreferred girls between the ages of 5 and 8 years were compared on aggression, avoidance, private parts reference, and freeplay over two conditions: playing alone with anatomically correct dolls and telling a story about the dolls to an adult. Results indicated that sexually abused children displayed more sexually oriented behavior when alone but more avoidance of the dolls when interacting with an adult.


Cardioprotection by recombinant human erythropoietin following acute experimental myocardial infarction: dose response and therapeutic window.
Recombinant human erythropoietin (rhEPO) protects tissue from ischemic damage, but translation of this finding into useful guidelines with respect to human trials for myocardial infarction (MI) requires a determination of the minimum effective rhEPO dose and the therapeutic window following MI. Serial echocardiography revealed that during four weeks following MI, induced by a permanent coronary ligation in rats, the LV end-diastolic and end-systolic volumes in untreated rats expanded from 0.35 +/- 0.01 and 0.14 +/- 0.01 ml to 0.84 +/- 0.04 and 0.61 +/- 0.06 ml, respectively, and ejection fraction (EF) reduced by 50%. A single i.v. injection of rhEPO immediately following MI in a dose of 150 IU/kg was as effective as 3,000 IU/kg in causing a 2-fold reduction of the number of apoptotic nuclei in the AAR 24-h later, a 2-fold reduction of the MI size measured 4 weeks later, attenuation of progressive LV dilatation and fall in EF. A 3000 IU/kg dose had similar therapeutic effects when delayed by 4, 8, or 12 h following MI, but was not effective after a 24-h delay. A single dose of 150 IU/kg was effective within 4 h post-MI, but was without effect if administered after an 8-h delay. Cell death, final MI size, myocardial remodeling and functional decline are significantly reduced in rats by a single injection of rhEPO in a dose as low as 150 IU/kg if administered during the first 4 h after the ischemic event. Higher doses extend the therapeutic window up to 12 h.


The human fear paradox turns out to be less paradoxical when global changes in human aggression and language evolution are considered.
Our commentary focuses on the interaction between Grossmann's fearful ape hypothesis (FAH) and the human self-domestication hypothesis (HSDH), also taking into account language acquisition and evolution. Although there is considerable overlap between the two hypotheses, there are also some discrepancies, and our goal is to consider the extent to which HSDH can explain the phenomena identified by FAH without invoking fearfulness as directly adaptive.


A technique for determining individual fresh weights of live small animals, with special reference to Enchytraeidae.
A technique is presented in which desiccation as a source of error in fresh weight determinations of soft-bodied microfauna is avoided by weighing the animal in a drop of silica fluid.


Study of the efferent connections of the enkephalinergic magnocellular dorsal nucleus in the guinea-pig hypothalamus using lesions, retrograde tracing and immunohistochemistry: evidence for a projection to the lateral septum.
The efferents of enkephalin-immunoreactive neurons in the magnocellular dorsal nucleus of the guinea-pig were studied using different neuroanatomical methods and indirect immunocytochemical technique. Following unilateral implantation of the fluorescent dye 4',6-diamidino-2-phenylindole in the lateral septal nucleus, retrogradely-labeled perikarya were found in the magnocellular dorsal nucleus. These labeled perikarya reacted with antiserum against enkephalin, demonstrating that enkephalin-immunoreactive neurons in the magnocellular dorsal nucleus project to the lateral septal nucleus. In other experiments, complete bilateral lesions were produced in the magnocellular dorsal nucleus by electrocoagulation. Enkephalin-immunoreactive nerve fibers and terminals were totally depleted in the lateral septal nucleus. This confirms that septal enkephalin-immunoreactive terminals originate in the magnocellular dorsal nucleus and further suggests that this nucleus is the source of all the enkephalin-immunoreactive material found in the septum. Experiments utilizing two different fluorescent dyes, 4',6-diamidino-2-phenylindole and propidium iodide, injected in each side of the lateral septal nucleus, respectively, demonstrated that the magnocellular dorsal nucleus gives off axon collaterals to both sides of the septum, since double-labeling of individual cell bodies was detected in the nucleus. By relating this finding to the results obtained after unilateral destruction of the nucleus, which caused an incomplete loss of enkephalin- immunoreactive material in the lateral septal nucleus ipsilaterally, it is suggested that the enkephalinergic hypothalamo-septal pathway contains unbranching neurons projecting ipsilaterally and branching neurons distributing fibers ipsilaterally and contralaterally. Lesion experiments, and experiments based on the retrograde axonal transport of horseradish peroxidase after intravenous injections, demonstrated that the magnocellular dorsal nucleus contributes neither to the tubero-infundibular nor to the hypothalamo-neurohypophyseal tracts. The lateral septal nucleus receives numerous aminergic and peptidergic projections, indicating the potential importance of this region in physiological and behavioral events. In the guinea-pig, the well-demarcated enkephalinergic pathway demonstrated in this study provides a convenient model for the experimental study of the enkephalinergic innervation of the lateral septal nucleus.


Gastric cancer-related information on the Internet: incomplete, poorly accessible, and overly commercial.
Patients increasingly use the Internet for gastric cancer information. However, the quality of the information is questionable. We evaluated the accuracy, completeness, accessibility, reliability, and readability of gastric cancer websites. The Internet was searched for the terms "gastric cancer" or "stomach cancer" using general search engines. Websites were evaluated for completeness (CS) and accuracy (AS) using predefined quality appraisal instruments (QAIs), reliability using an integrity score (IS), readability using the Flesch-Kincaid (FK) grade level, and accessibility using automated accessibility appraisal tools. Site sponsor and the presence of quality labels were noted. Fifty-one websites were evaluated. The mean CS was 100.3 (SD ±44.9), AS was 107.22 (SD ±47.9), IS was 15.3 (SD ±3.7), and the mean readability grade level was 10.4 (SD ±2.5). Only 5 websites had the minimum mandatory basic accessibility. Commercial sites and sites with quality labels had significantly more accessibility violations. Internet gastric cancer information is overtly commercial, generally incomplete, and poorly accessible.


The Orphan G Protein-coupled Receptor Gpr175 (Tpra40) Enhances Hedgehog Signaling by Modulating cAMP Levels.
The Hedgehog (Hh) signaling pathway plays an essential role in vertebrate embryonic tissue patterning of many developing organs. Signaling occurs predominantly in primary cilia and is initiated by the entry of the G protein-coupled receptor (GPCR)-like protein Smoothened into cilia and culminates in gene transcription via the Gli family of transcription factors upon their nuclear entry. Here we identify an orphan GPCR, Gpr175 (also known as Tpra1 or Tpra40: transmembrane protein, adipocyte associated 1 or of 40 kDa), which also localizes to primary cilia upon Hh stimulation and positively regulates Hh signaling. Interaction experiments place Gpr175 at the level of PKA and upstream of the Gαi component of heterotrimeric G proteins, which itself localizes to cilia and can modulate Hh signaling. Gpr175 or Gαi1 depletion leads to increases in cellular cAMP levels and in Gli3 processing into its repressor form. Thus we propose that Gpr175 coupled to Gαi1 normally functions to inhibit the production of cAMP by adenylyl cyclase upon Hh stimulation, thus maximizing signaling by turning off PKA activity and hence Gli3 repressor formation. Taken together our data suggest that Gpr175 is a novel positive regulator of the Hh signaling pathway.


Self-identified barriers to rural mental health services in Iowa by older adults with multiple comorbidities: qualitative interview study.
Individuals in rural areas face critical health disparities, including limited access to mental healthcare services and elevated burden of chronic illnesses. While disease outcomes are often worse in individuals who have both physical and mental comorbidities, few studies have examined rural, chronically-ill older adults' experiences accessing mental health services. The aim of the study was to determine barriers to finding, receiving and adhering to mental health treatments in this population to inform future interventions delivering services. We conducted a qualitative study of barriers and facilitators to mental healthcare access. 19 interviews were analysed deductively for barriers using a modified version of Penchansky and Thomas's theory of access as an analytical framework. This study was conducted remotely using telephonic interviews. Patients were located in various rural Iowa towns and cities. 15 rural Iowan older adults with multiple physical comorbidities as well as anxiety and/or depression. We found that while patients in this study often felt that their mental health was important to address, they experienced multiple, but overlapping, barriers to services that delayed care or broke their continuity of receiving care, including limited knowledge of extant services and how to find them, difficulties obtaining referrals and unsatisfactory relationships with mental health service providers. Our findings indicate that intervention across multiple domains of access is necessary for successful long-term management of mental health disorders for patients with multiple chronic comorbidities in Iowa.


Hierarchical clustering analysis of pathologic and molecular data identifies prognostically and biologically distinct groups of colorectal carcinomas.
This work has evaluated the potential superiority of a morphomolecular classification based on the combination of clinicopathologic and molecular features of colorectal cancers. A cohort of 126 colorectal carcinomas was investigated by unsupervised hierarchical clustering analysis to combine 13 routinely assessed clinicopathologic features and all five molecular markers recently suggested by Jass' classification to distinguish four molecular subtypes of sporadic colorectal carcinomas. Survival analysis was assessed by a Cox proportional hazards model. A clear separation into three prognostically significant groups was identified: cluster A and cluster C were associated with good prognosis and cluster B with poor prognosis (P=0.006). Clinicopathologic and molecular features of cluster A and cluster B tumors were strongly concordant with colorectal cancer profiles characterized by microsatellite instability or by chromosomal instability, respectively. The clinicopathologic features of cluster C tumors were suggestive of a less aggressive disease than cluster B tumors. Genetically, they appeared intermediate between cluster A and cluster B tumors, as they were mainly microsatellite stable tumors showing high levels of both MGMT methylation and loss of heterozygosity. Chromosomal instability was significantly lower in cluster C than in cluster B tumors. A more accurate tumor classification should combine the prognostic power of clinicopathologic parameters with molecular biomarkers that provide information regarding the natural history of the cancer. Hierarchical clustering seems to be a useful, promising and powerful tool for further translational studies and should lead us to define a diagnostic and prognostic signature for different carcinomas.


A proposed mechanism relating the antitumor behavior of cis-platinum amine complexes to their inhibition of a model enzyme.
The twenty-four hour inhibition of m-malate dehydrogenase (E.C. 188.8.131.52) by various complexes of cis-platinum(II) and cis-platinum(IV) was measured as a function of the platinum concentration. It was observed that increased alkylation of the amine groups of Pt(II) and to a lesser degree of Pt(IV) decreased the activity consistently. It was also observed that the Pt(IV) analogues inhibit the enzyme to about an order of magnitude greater than the Pt(II) complexes. These phenomena will be interpreted.


Endometriosis is the independent prognostic factor for survival in Chinese patients with epithelial ovarian carcinoma.
Clinico-pathological characteristics and possible prognostic factors among women with epithelial ovarian carcinoma (EOC) with or without concurrent endometriosis were explored. We retrospectively identified 304 patients with EOC treated primarily at Peking Union Medical College Hospital with median follow-up time of 60 months. Of 304 patients with EOC, concurrent endometriosis was identified in 69 (22.7%). The patients with concurrent endometriosis were younger and more probably post-menopausal at onset, were less likely to have abdominal distension, with significantly lower level of pre-surgery serum Ca125 and less possibility of having the history of tubal ligation. The women with concurrent endometriosis group were more likely to have early stage tumors (88.41% versus 52.77%), receive optimal cytoreductive surgery (92.75% versus 71.06%), and less likely to have lymph node metastasis or to develop platinum resistance disease (7.25% versus 14.89%, and 7.35% versus 20%), when compared with women without coexisting endometriosis. The univariate analysis showed that concurrent endometriosis was a prognostic factor for overall survival (OS) and disease-free survival (DFS), but this association just remained in the DFS by multivariate analysis. Besides, multivariate analysis also showed that FIGO stage, residual disease, chemotherapy cycles, chemotherapy resistance and concomitant hypertension were the independent impact factors of OS for EOC patients; whereas FIGO stage, lymphadenectomy, residual disease, coexisting endometriosis and chemoresistance were independent impact factors of DFS for those patients. EOC patients with concurrent endometriosis showed distinct characteristics and had longer overall survival and disease-free survival when compared with those without endometriosis. Endometriosis was the independent prognostic factor for DFS for patients in this series.


Intraperitoneal radiolabeled OC 125 in patients with advanced ovarian cancer.
Twenty patients with recurrent or persistent epithelial ovarian cancer failing conventional therapies were treated with a single intraperitoneal injection of iodine-131-labeled OC 125 monoclonal antibody. Rare acute side effects were nausea and mild diarrhea. At doses up to 120 mCi of iodine-131, median white blood cell and platelet count nadirs were 3.6k/microliters and 187k/microliters, respectively. Two patients acquired thyroid toxicities despite thyroid blockage with "cold" iodine. One patient had transient TSH elevation while remaining clinically euthyroid, and 1 patient developed activation of a thyroid nodule and clinical hyperthyroidism. Dose-limiting toxicity has not yet been observed. Twelve of 20 patients are alive 3 to 17 months following therapy. Tumor progression was noted in the majority of patients, although 3 patients had documented decreases in tumor burden of short duration. We conclude that, at the doses examined, iodine-131 OC 125 can be safely administered intraperitoneally.


Patient-reported outcomes predict high readmission rates among patients with cardiac diagnoses. Findings from the DenHeart study.
High rates of readmission after myocardial infarction and cardiac surgery have been reported, indicating a heavy burden for both patients and society. Patient-reported outcomes are predictors of adverse outcomes such as morbidity and mortality and may also be useful in preventive risk assessment as predictors of readmission. To describe (i) the prevalence of cardiac readmissions one year after hospital discharge among cardiac patients, (ii) patient-reported outcomes at hospital discharge as predictors of readmission. The following patient-reported outcomes were measured across cardiac diagnoses at hospital discharge from the five heart centres, cardiology and thoracic surgery units, as a part of the national, cross-sectional DenHeart Study: Short-Form 12 (SF-12), Hospital Anxiety and Depression Scale (HADS), EuroQoL (EQ-5D-5L), HeartQoL and the Edmonton Symptom Assessment Scale (ESAS). One year readmissions were obtained from national registers. A total of 34,564 cardiac patients were discharged of whom 16,712 patients completed the questionnaire. A total of 11,693 (36%) patients were readmitted for cardiac reasons at least once during the first year after index admission. The risk of readmission was predicted by anxiety (HR = 1.36 (CI:1.26-1.46)) and depression (HR = 1.42 (CI:1.31-1.55)). Higher scores reflected lower readmission risk on the physical (HR = 0.98 (CI:0.98-0.98)) health component of the SF-12. A total of 36% of cardiac patients admitted to a national heart center were readmitted during the first year. Readmission was predicted by patient-reported anxiety, depression, perceived health, quality of life and symptom distress, which may be used in risk assessment in clinical practice.


Effect of chlordiazepoxide on the partial reinforcement extinction effect.
Rats were trained to run in a straight alley under conditions of partial or continuous reinforcement. Extinction was slower after partial reinforcement. Chlordiazepoxide, administered during acquisition only, had no effect on acquisition but abolished the partial reinforcement extinction effect. The results support the hypothesis that chlordiazepoxide acts by attenuating the effects of averisive stimuli.


Nucleus reuniens of the thalamus controls fear memory reconsolidation.
The nucleus reuniens has been shown to support the acquisition, consolidation, maintenance, destabilization upon retrieval, and extinction of aversive memories. However, the direct participation of this thalamic subregion in memory reconsolidation is yet to be examined. The present study addressed this question in contextually fear-conditioned rats. Post-reactivation infusion of the GABAA receptor agonist muscimol, the glutamate N2A-containing NMDA receptor antagonist TCN-201, or the protein synthesis inhibitor anisomycin into the NR induced significant impairments in memory reconsolidation. Administering muscimol or TCN-201 and anisomycin locally, or associating locally infused muscimol or TCN-201 with systemically administered clonidine, an α2-receptor adrenergic agonist that attenuates the noradrenergic tonus associated with memory reconsolidation, produced no further reduction in freezing times when compared with the muscimol-vehicle, TCN-201-vehicle, vehicle-anisomycin, and vehicle-clonidine groups. This pattern of results indicates that such treatment combinations produced no additive/synergistic effects on reconsolidation. It is plausible that NR inactivation and antagonism of glutamate N2A-containing NMDA receptors weakened/prevented the subsequent action of anisomycin and clonidine because they disrupted the early stages of signal transduction pathways involved in memory reconsolidation. It is noteworthy that these pharmacological interventions, either alone or combined, induced no contextual memory specificity changes, as assessed in a later test in a novel and unpaired context. Besides, omitting memory reactivation precluded the impairing effects of muscimol, TCN-201, anisomycin, and clonidine on reconsolidation. Together, the present findings demonstrate interacting mechanisms through which the NR can regulate contextual fear memory restabilization.


Evolution of Cell-Type-Specific RNA Aptamers via Live Cell-Based SELEX.
Live cell-based SELEX (Systematic Evolution of Ligand EXponential enrichment) is a promising approach for identifying aptamers that can selectively bind to a cell-surface receptor or recognize a particular target cell population. In particular, it offers a facile selection strategy for some special cell-surface proteins that are originally glycosylated or heavily posttranslationally modified and are unavailable in their native/active conformation after in vitro expression and purification. In this chapter, we describe a generalized procedure for evolution of cell type-specific RNA aptamers targeting a cell membrane bound target by combining the live cell-based SELEX strategy with high-throughput sequencing (HTS) and bioinformatics analysis.


International emergency medicine and the recent development of emergency medicine worldwide.
Emergency medicine is being established as a unique and independent specialty throughout the world. Two major models of emergency care delivery exist in the world today: the Anglo-American and the Franco-German model. Most countries developing new systems of emergency care are following the Anglo-American model and are recapitulating the sequence of steps taken to establish the systems of emergency medicine in the United States. The most important step in the development of emergency medicine in other countries is the recognition that emergency medicine incorporates a unique body of knowledge requiring specialized practitioners or emergency physicians. A global network of international emergency medicine is assisting the development of emergency medicine worldwide and now includes international organizations, academic institutions, and individuals in countries where emergency medicine is mature and their counterparts in countries where emergency medicine is developing. The multilevel exchange of information through various modalities, such as international conferences, physician exchange programs, and print or electronic media, is playing a vital role in the search for internationally applicable systems of emergency care.


Evaluation of the solvent black 3 fingermark enhancement reagent: part 2 - investigation of the optimum formulation and application parameters.
A comparison is reported of the relative effectiveness to two formulations of the solvent black 3 (Sudan Black) reagent used to enhance grease contaminated fingermarks. These experiments compared the currently recommended ethanol-based formulation with a lower flammability system based on 1-methoxy-2-propanol (PGME) using natural, deliberately sebaceous and grease contaminated marks across a range of surfaces. It is shown that overall the PGME-based formulation was significantly better at producing good ridge detail on most surfaces for both natural and deliberately sebaceous prints, and for contaminated prints the ridge detail obtained with the PGME-based formulation was as good or better than that obtained with the ethanol formulation. Several smaller experiments were also carried out in order to provide additional information on the solvent black 3 process. These showed that solutions of age up to 2 years can still develop good ridge detail, but the colour of the stained mark may vary. It was also demonstrated that the currently recommended 2 minute treatment time often resulted in very heavy background staining and in practice significantly reduced treatment times can be recommended according to the nature of the surface present.


Leukocyte activation primes fibrinogen for proteolysis by mitochondrial oxidative stress.
Critical illness leads to rapid fibrinogen consumption, hyperfibrinolysis, and coagulopathy that exacerbates bleeding and increases mortality. Immune cell activation and inflammation are associated with coagulopathy after injury but play an undetermined role. We performed high dimensional immunophenotyping and single-cell imaging flow cytometry to investigate for a pathophysiological mechanism governing the effects of leukocyte-associated inflammation on fibrinogen function. Fibrinogen was oxidized early, followed by its degradation after 3 hours of lipopolysaccharides (LPS)-induced sterile inflammation in a rat model in vivo. Fibrinogen incubated with human leukocytes activated by TNFα was similarly oxidized, and later proteolyzed after 3 hours in vitro. TNFα induced mitochondrial superoxide generation from neutrophils and monocytes, myeloperoxidase (MPO)-derived reactive oxygen species (ROS) from neutrophils, and nitric oxide from lymphocytes and monocytes. Inhibition of mitochondrial superoxide prevented oxidative modification and proteolysis of fibrinogen, whereas inhibition of MPO attenuated only fibrinogen proteolysis. Quenching of both mitochondrial superoxide and MPO-derived ROS prevented coagulopathy better than tranexamic acid. Collectively, these findings indicate that neutrophil and monocyte mitochondrial superoxide generation can rapidly oxidize fibrinogen as a priming step for fibrinogen proteolysis and coagulopathy during inflammation.


Joint impact of physical activity and family history on the development of diabetes among urban adults in Mainland China: a pooled analysis of community-based prospective cohort studies.
To examine the joint influences of physical activity (PA) and family history (FH) of diabetes on subsequent type 2 diabetes (T2D), the authors pooled and analyzed data from 2 community-based urban adult prospective cohort studies in 2011 in Nanjing, China. Among 4550 urban participants, the 3-year cumulative incidence of T2D was 5.1%. After adjustment for potential confounders, compared with those with FH+ and insufficient PA, the adjusted odds ratio (95% confidence interval) of developing T2D was 0.42 (0.18, 0.98) for participants with sufficient PA and FH+, 0.32 (0.22, 0.46) for participants with insufficient PA and FH-, and 0.15 (0.08, 0.28) for participants with sufficient PA and FH-. Such significant graduated associations between PA/FH and risk of developing T2D were also identified in either men or women, separately. Sufficient PA and FH- may jointly reduce the risk of developing T2D in urban Chinese adults.


Unraveling the orientation of phosphors doped in organic semiconducting layers.
Emitting dipole orientation is an important issue of emitting materials in organic light-emitting diodes for an increase of outcoupling efficiency of light. The origin of preferred orientation of emitting dipole of iridium-based heteroleptic phosphorescent dyes doped in organic layers is revealed by simulation of vacuum deposition using molecular dynamics along with quantum mechanical characterization of the phosphors. Consideration of both the electronic transitions in a molecular frame and the orientation of the molecules at the vacuum/molecular film interface allows quantitative analyses of the emitting dipole orientation depending on host molecules and dopant structures. Interactions between the phosphor and nearest host molecules on the surface, minimizing the non-bonded van der Waals and electrostatic interaction energies determines the molecular alignment during the vacuum deposition. Parallel alignment of the main cyclometalating ligands in the molecular complex due to host interactions rather than the ancillary ligand orienting to vacuum leads to the horizontal emitting dipole orientation.Iridium-based phosphors show high photoluminescence quantum yield in organic light-emitting diodes. Here, Moon et al. reveal the mechanism responsible for the preferred orientation of iridium complexes in an organic host and highlight the interaction between phosphor and host molecules at play.


[Hereditary neuropathy with liability to pressure palsy (HNPP): a diagnostic trap].
The authors report two clinical cases of a rarely observed pathology in orthopedic surgery daily practice: hereditary neuropathy with liability to pressure palsy (HNPP), which leads to dysesthesiae, hypoesthesiae and regressive palsies. Onset, clinical signs and electromyographic abnormalities are described. Forensic consequences can occur in early postoperative period. Knowledge of this familial pathology allows precautionary measures at surgery and avoids unnecessary surgical revisions.


Reconstructive Amputations of the Foot.
In the diabetic and peripheral vascular disease population there is a high risk of further amputation following a primary amputation. Amputation surgery is often approached negating the biomechanics of the lower extremity leading to complications or additional surgery. Implementing appropriate tendon balancing of stump and applying orthoplastic techniques will improve outcomes. This article introduces the basic techniques to a wider audience of foot and ankle surgeons. Specifically, this article is intended to be a descriptive guide for the use of tendon balancing and intrinsic muscle advancements in the various levels of foot amputations.


Investigation of combined CYP3A4 inductive/inhibitory properties by studying statin interactions: a model study with the renin inhibitor ACT-178882.
ACT-178882, a direct renin inhibitor, was used as a model compound in an elaborate drug-drug interaction study with atorvastatin and simvastatin to explore complex CYP3A4 inductive and inhibitory properties. Thirty-two healthy male subjects received single doses of 20 mg atorvastatin and 20 mg simvastatin on days 1, 9, 31, and 41. On days 6 to 33, 500 mg ACT-178882 was administered once daily. Plasma concentrations of ACT-178882, simvastatin, and atorvastatin were measured by LC-MS/MS. Routine safety assessments were performed throughout the study. Exposure (as based on area under the curve) to simvastatin and 6β-hydroxyacid simvastatin increased (90 % confidence interval) 4.63-fold (3.90, 5.50) and 3.71-fold (3.19, 4.32), respectively, when comparing day 9 and day 1. On day 9, exposure to atorvastatin was similar but Cmax decreased, while both variables decreased for ortho-hydroxy atorvastatin when compared to day 1. On day 31, after prolonged administration of ACT-178882, exposure to atorvastatin, ortho-hydroxy atorvastatin, simvastatin, and 6β-hydroxyacid simvastatin decreased by 14, 19, 21, and 27 %, respectively, when compared to day 9. However, on this day, exposure to simvastatin and its metabolite was still markedly higher when compared to day 1. Effects of ACT-178882 had largely dissipated on day 41. This design enabled the study of complex time-dependent effects on CYP3A4 activity with clinically relevant substrates.


Structure and dynamics of the Pf1 filamentous bacteriophage coat protein in micelles.
The major coat protein of filamentous bacteriophage adopts its membrane-bound conformation in detergent micelles. High-resolution 1H and 15N NMR experiments are used to characterize the structure and dynamics of residues 30-40 in the hydrophobic midsection of Pf1 coat protein in sodium dodecyl sulfate micelles. Uniform and specific-site 15N labels enable the immobile backbone sites to be identified by their 1H/15N heteronuclear nuclear Overhauser effect and allow the assignment of 1H and 15N resonances. About one-third of the amide N-H protons in the protein undergo very slow exchange with solvent deuterons, which is indicative of sites in highly structured environments. The combination of results from 1H/15N heteronuclear correlation, 1H homonuclear correlation, and 1H homonuclear Overhauser effect experiments assigns the resonances to specific residues and demonstrates that residues 30-40 of the coat protein have a helical secondary structure.


A pain in the neck: Salmonella spp. as an unusual cause of a thyroid abscess. A case report and review of the literature.
Thyroid gland infections are rare. Their incidence is estimated to be less than 1% in immunocompromised hosts. Most common pathogens isolated are Gram positive aerobic cocci. Infections with Gram negative facultative aerobes such as Salmonella are rare. A 55-year-old female with type II diabetes mellitus and a history of a colloid right thyroid lobe nodule presented with neck pain and fever. She was found to have a thyroid abscess 2 weeks following a non-specific diarrheal illness. A needle aspiration for symptomatic and diagnostic purposes was performed. Cultures grew Salmonella enterica serotype Heidelberg. She was treated with a 12-week course of oral antibiotics and serial aspiration. A thyroid abscess is a rare occurrence; however, a high index of suspicion is required to make the diagnosis. The management is directed at minimizing morbidity. The mainstay treatment is medical, but surgery is sometimes necessary to achieve adequate source control, particularly when complications arise.


Combined toxic effects of perfluorooctanoic acid and microcystin-LR on submerged macrophytes and biofilms.
Perfluorooctanoic acid (PFOA) and microcystin-LR (MCLR) are pervasive pollutants in surface waters that induce significant toxic effects on aquatic organisms. However, the combined environmental risk of PFOA and MCLR remains unclear. To assess the toxic effects of PFOA and MCLR on submerged macrophytes and biofilms, Vallisneria natans was exposed to different concentrations of PFOA and MCLR (0.01, 0.1, 1.0 and 10.0 μg L-1). Vallisneria natans was sensitive to high concentrations of MCLR (10 μg L-1): plants exposed to 10 μg L-1 of MCLR measured a biomass of 3.46 g, which was significantly lower than the 8.71 g of the control group. Additionally, antagonistic interactive effects were observed in plants exposed to combined PFOA and MCLR. Exposure to these pollutants adversely affected photosynthesis of the plants and triggered peroxidation that promoted peroxidase, superoxide dismutase and catalase activities, and increased malondialdehyde and glutathione concentrations. The total chlorophyll content was lower in the highest concentration of the combined treatment group (0.443 mg g-1) than in the control group (0.534 mg g-1). Peroxidase activity increased from 662.63 U mg-1 Pr to 1193.45 U mg-1 Pr with increasing PFOA concentrations. Metabolomics indicated that the stress tolerance of Vallisneria natans was improved via altered fatty acid metabolism, hormone metabolism and carbon metabolism. Furthermore, PFOA and MCLR influenced the abundance and structure of the microbial community in the biofilms of Vallisneria natans. The increased contents of autoinducer peptide and N-acylated homoserine lactone signaling molecules indicated that these pollutants altered the formation and function of the biofilm. These results expand our understanding of the combined effects of PFOA and MCLR in aquatic ecosystems.


G7063-2, a new nitrogen-containing antibiotic of the epoxydon group, isolated from the fermentation broth of a species of Streptomyces.
Antibiotic G7063-2, isolated from a Streptomyces species, is a new nitrogen-containing analogue of phyllostine and terreic acid. In vitro G7063-2 is moderately active against both Gram-positive and Gram-negative bacteria and weakly active against fungi. It is toxic to mice.


Humanized mice for human retrovirus infection.
Inbred mice with specific genetic defects have greatly facilitated the analysis of complex biological events. Several humanized mouse models using the C.B.-17 scid/scid mouse (referred to as the SCID mouse) have been created from two transplantation protocols, and these mice have been utilized for the investigation of human immunodeficiency virus type 1 (HIV-1) and human T-lymphotropic virus type I (HTLV-I) pathogenesis and the evaluation of antiviral compounds. To generate a more prominent small animal model for human retrovirus infection, especially for examination of the pathological process and the immune reaction, a novel immunodeficient mouse strain derived from the NOD SCID mouse was created by backcrossing with a common gamma chain (gamma(c))-knockout mouse. The NOD-SCID gamma(c)null (NOG) mouse has neither functional T and B cells nor NK cells and has been used as a recipient in humanized mouse models for transplantation of human immune cells particularly including hematopoietic stem cells (HSC). From recent advances in development of humanized mice, we are now able to provide a new version of the animal model for human retrovirus infection and human immunity.


Multi-omics data integration reveals the molecular network of dysregulation IQGAP2-mTOR promotes cell proliferation.
IQGAP2 as a tumor suppressor gene can influence cell proliferation in multiple tumor cell lines. However, the regulation network of cell proliferation resulting solely from the deficiency of IQGAP2 in cells was still unclear. Here, we integrated transcriptome, proteome, and phosphoproteome analyses to investigate the regulatory network of cell proliferation in IQGAP2 knockdown HaCaT and HEK293 cells. Our findings revealed that the dysregulation of the IQGAP2-mTOR molecular network led to increased cell proliferation. We demonstrated that IQGAP2 knockdown enhanced the phosphorylation levels of AKT and S6K, leading to increased cell proliferation. Additionally, we found that AKT and mTOR inhibitors partially rescued abnormal cell proliferation by reducing hyperphosphorylation. Our data suggest a potential connection between the mTOR signaling pathway and aberrant cell proliferation in IQGAP2 knockdown cells. These findings offer a new therapeutic strategy for patients with IQGAP2 deficiency.


Cytogenetic discrepancy between uncultured amniocytes and cultured amniocytes in mosaic trisomy 15 at amniocentesis.
We present mosaic trisomy 15 at amniocentesis. A 41-year-old woman underwent amniocentesis at 16 weeks of gestation because of an abnormal non-invasive prenatal testing (NIPT) result suspicious of trisomy 15. Amniocentesis revealed a karyotype of 46,XY. Array comparative genomic hybridization (aCGH) on uncultured amniocytes revealed 26% mosaicism for trisomy 15. She was referred for repeat amniocentesis. aCGH, interphase fluorescence in situ hybridization (FISH), quantitative fluorescent polymerase chain reaction (QF-PCR) assays and/or conventional cytogenetic analysis were applied on various cells and tissues including uncultured amniocytes, cultured amniocytes, cord blood, placenta, parental bloods and/or buccal mucosal cells. Repeat amniocentesis at 21 weeks of gestation revealed a karyotype of 46, XY in cultured amniocytes, and 30% mosaicism for trisomy 15 by aCGH and 32% mosaicism for trisomy 15 by FISH in uncultured amniocytes. Repeat amniocentesis at 29 weeks of gestation revealed a karyotype of 46, XY in cultured amniocytes, and 15% mosaicism for trisomy 15 by aCGH and 7.2% mosaicism for trisomy 15 by FISH in uncultured amniocytes. QF-PCR on cultured amniocytes excluded uniparental disomy (UPD) 15. A phenotypically normal baby was delivered subsequently with a karyotype of 46, XY in cord blood and 2% mosaicism for trisomy 15 by FISH in buccal mucosal cells. The aCGH analysis revealed trisomy 15 in placenta and no genomic imbalance in cord blood. QF-PCR assays determined a maternal origin of trisomy 15 in placenta. Cytogenetic discrepancy may occur between uncultured and cultured amniocytes in mosaic trisomy 15 at amniocentesis. The cells of trisomy 15 cell line in prenatally detected mosaic trisomy 15 may decrease in number as the fetus grows. Whenever NIPT suspects trisomy 15, a confirmatory amniocentesis should include genetic analysis on both uncultured and cultured amniocytes to exclude mosaic trisomy 15 and maternal UPD 15, especially when the cultured amniocytes have a normal karyotype.


Acute metabolic and cardiovascular effects of mirabegron in healthy individuals.
To quantify acute energy expenditure, supraclavicular skin temperature and cardiovascular responses to four doses of the β3-adrenoceptor agonist, mirabegron. A total of 17 individuals (11 men, six women) participated in this ascending-dose study, receiving single 50-, 100-, 150- and 200-mg doses of mirabegron on four separate days with 3 to 14 days wash-out between each dose. All variables were measured each visit from baseline to 180 minutes post mirabegron treatment. To determine brown adipose tissue (BAT) thermogenic efficacy at each dose, energy expenditure and supraclavicular skin temperature were compared from baseline to 180 minutes post mirabegron treatment. To examine safety, changes in cardiovascular variables at 100, 150 and 200 mg were compared with the standard clinical dose of 50 mg. Energy expenditure significantly increased after the 100- (35.6 ± 5.4 kJ/h) and 200-mg (35.6 ± 13.1 kJ/h) doses (P ≤ 0.05), and trended towards an increase after 150 mg (24.1 ± 13.6 kJ/h). Supraclavicular skin temperature increased after 50- (0.22 ± 0.1°C), 100- (0.30 ± 0.1°C) and 150-mg mirabegron doses (0.29 ± 0.1°C; P ≤ 0.05). The change in systolic blood pressure was greater after 150- (7.1 ± 1.3 mm Hg) and 200-mg doses (9.3 ± 1.9 mm Hg) than after the 50-mg dose (2.2 ± 1.3 mm Hg; P ≤ 0.05). The change in heart rate was greater after 200 mg (9.0 ± 2.2 bpm) compared with 50 mg (2.9 ± 1.4 bpm; P ≤ 0.05). A 100-mg dose of mirabegron increases energy expenditure and supraclavicular skin temperature in a β3-adrenoceptor-specific manner, without the off-target elevations in blood pressure or heart rate observed at higher doses.


Short-term effects of forced eccentric contractions on collagen synthesis and degradation in rat skeletal muscle.
Acute downhill running has been shown to activate matrix metalloproteinase- (MMP-) 2 and to change type IV collagen concentration in some muscle types. In order to study the influence of more intense exercise on total collagen and type IV collagen concentrations, molecules regulating their synthesis and degradation were investigated after forced lengthening contractions in rat skeletal muscle. Tibialis anterior (TA) muscle of 24 male Wistar rats was subjected to 240 forced lengthening contractions. TA muscle was excised at consecutive time points (0 and 6 h, 2, 4, and 7 days) after stimulation. With immunohistochemistry, types I, III and IV collagen were located in the swollen, necrotic and regenerated fibres in a similar manner as in intact undamaged skeletal muscle fibre. An increase in the activity of prolyl 4-hydroxylase was indicative of an overall elevated collagen biosynthesis. No change was demonstrated in total collagen concentration, whereas type IV collagen concentration increased after exercise. MMP-2 and MMP-9, which are the proteins that degrade type IV collagen, elevated after exercise. In conclusion, the increase in type IV collagen concentration seems to be the result of an increase in both the synthesis and activation of degrading enzymes and their inhibitors during recovery after forced lengthening contractions.


Tetraploidy and the striate cortex.
A tetraploid population of glial cell nuclei has been identified in layers one, two and three of the entire striate cortex. These have approximately twice the volume of diploid glial cell nuclei.


A short history of infant feeding and growth.
Our modern understanding of infant nutrition and feeding arose out of a constellation of scientific discoveries made more than 100 years ago. With the emergence of chemistry and physiology in the late 18th century, the analysis of foods, metabolic and energy balance studies, calorimetry, cell theory and measurements of growth and digestive function, became integrated to provide a coherent model of how organisms grow and are nourished. The interaction, with clinicians and public health professionals, of those working in these 'new' areas of the biological science, led to the application of safe and effective ways of feeding babies and of monitoring their growth and development, in the face of, and in response to, high infant mortality and morbidity.


4-[(E)-(4-Fluoro-benzyl-idene)amino]-benzoic acid.
In the title compound, C(14)H(10)FNO(2), the benzene rings make a dihedral angle of 57.50 (13)°, and the molecule has an E configuration about the C=N bond. In the crystal, molecules are linked via pairs of O-H⋯O hydrogen bonds, forming inversion dimers.