Functional analysis of BARD1 missense variants in homology-directed repair and damage sensitivity

The BARD1 protein, which heterodimerizes with BRCA1, is encoded by a known breast cancer susceptibility gene. While several BARD1 variants have been identified as pathogenic, many more missense variants exist that do not occur frequently enough to assign a clinical risk. In this paper, whole exome sequencing of over 10,000 cancer samples from 33 cancer types identified from somatic mutations and loss of heterozygosity in tumors 76 potentially cancer-associated BARD1 missense and truncation variants. These variants were tested in a functional assay for homology-directed repair (HDR), as HDR deficiencies have been shown to correlate with clinical pathogenicity for BRCA1 variants. From these 76 variants, 4 in the ankyrin repeat domain and 5 in the BRCT domain were found to be non-functional in HDR. Two known benign variants were found to be functional in HDR, and three known pathogenic variants were non-functional, supporting the notion that the HDR assay can be used to predict the clinical risk of BARD1 variants. The identification of HDR-deficient variants in the ankyrin repeat domain indicates there are DNA repair functions associated with this domain that have not been closely examined. In order to examine whether BARD1-associated loss of HDR function results in DNA damage sensitivity, cells expressing non-functional BARD1 variants were treated with ionizing radiation or cisplatin. These cells were found to be more sensitive to DNA damage, and variations in the residual HDR function of non-functional variants did not correlate with variations in sensitivity. These findings improve the understanding of BARD1 functional domains in DNA repair and support that this functional assay is useful for predicting the cancer association of BARD1 variants.</div

On the Existence of H1H^1 solutions for Stationary Linearized Boltzmann Equations in a Small Convex Domain

In this article, we investigate the incoming boundary value problem for the stationary linearized Boltzmann equations in $\Omega \subseteq \mathbb{R}^{3}$. For a $C^2$ bounded domain with boundary of positive Gaussian curvature, the existence theory is established in $H^{1}(\Omega \times \mathbb{R}^{3})$ provided that the diameter of the domain $\Omega$ is small enough.Comment: 19 pages, 1 figur

A Study of Learning Pressure, Learning Attitudes, and Achievement among Macau Undergraduates

The purpose of this study was to examine the relationships among learning pressure, learning attitudes, and academic achievement of university students; specifically, Chinese undergraduates from three universities in Macau. Convenience sampling was used in the current study, and a total of 135 questionnaires were retrieved. We found a significant, moderate, and positive correlation between learning pressure and learning attitudes. We also found a negative correlation between learning pressure and academic achievement. The last correlation we found, between learning attitude and academic achievement, was positive and significant. When we regressed learning pressure and learning attitudes on academic achievement, the results showed that both variables were effective predictors of achievement

“I can’t see an end in sight.” How the COVID-19 pandemic may influence suicide risk: a qualitative study

&lt;jats:p&gt; Zusammenfassung: Theoretischer Hintergrund: Das Ziel der vorliegenden Studie war es, eine deutschsprachige Adaptation der Bergen Study Addiction Scale (BStAS), einer Skala zur Erfassung von exzessivem Studierverhalten, zu entwickeln und zu validieren. Methode: Die Daten von 615 Studierenden wurden analysiert. Die Dimensionalität der BStAS wurde mittels konfirmatorischer Faktorenanalyse überprüft. Außerdem wurden Korrelations- und hierarchische Regressionsanalysen durchgeführt, um Zusammenhänge von exzessivem Studierverhalten mit Persönlichkeit und Gesundheit zu untersuchen. Ergebnisse: Der Vergleich mit Dynamic Fit Index Cutoffs deutete auf eine moderate Missspezifikation des einfaktoriellen Modells hin. Wie erwartet war exzessives Studierverhalten positiv mit wöchentlichen Lernstunden, Neurotizismus, wahrgenommenem Stress, psychosomatischen Beschwerden und Schlafproblemen assoziiert und hing negativ mit Lebenszufriedenheit zusammen. Schlussfolgerung: Es ist fraglich, ob alle Items der BStAS Aspekte einer Verhaltenssucht erfassen. Die Ergebnisse legen dennoch nahe, dass die BStAS ein Studierverhalten misst, das in Bezug auf physische und psychische Gesundheit von Relevanz ist. &lt;/jats:p&gt

Serum leptin is associated with cardiometabolic risk and predicts metabolic syndrome in Taiwanese adults

<p>Abstract</p> <p>Background</p> <p>Leptin is associated with cardiovascular disease (CVD); however, few studies have assessed its relationship with metabolic syndrome, especially in an Asian population. Therefore, the aim of the present study was to assess leptin levels and evaluate its association with CVD and metabolic syndrome.</p> <p>Methods</p> <p>In 2009, 957 subjects, who underwent a routine physical examination and choose leptin examination, were selected to participate. Participants (269 females and 688 males) were stratified according to leptin level quartiles. Metabolic syndrome was defined by NCEP ATP III using waist circumference cutoffs modified for Asian populations, and CVD risk was determined using the Framingham Heart Study profile.</p> <p>Results</p> <p>Leptin levels were correlated with CVD risk in men and women. With the exception of fasting plasma glucose, increased leptin levels were observed as factors associated with metabolic syndrome increased in both males and females. After adjusting for age, an association between leptin levels and metabolic syndrome was observed. After adjusting for age alone or with tobacco use, subjects in the highest leptin quartile had a higher risk of having metabolic syndrome than those in the lowest quartile (OR = 6.14 and 2.94 for men and women, respectively). After further adjustment for BMI, metabolic syndrome risk remained significantly increased with increasing leptin quartiles in men. Finally, increased leptin levels were a predictor of metabolic syndrome in men and women.</p> <p>Conclusions</p> <p>Serum leptin levels are correlated with CVD risk and metabolic syndrome. Analysis of leptin as part of routine physical examinations may prove beneficial for early diagnosis of metabolic syndrome.</p

D2ADA: Dynamic Density-aware Active Domain Adaptation for Semantic Segmentation

In the field of domain adaptation, a trade-off exists between the model performance and the number of target domain annotations. Active learning, maximizing model performance with few informative labeled data, comes in handy for such a scenario. In this work, we present D2ADA, a general active domain adaptation framework for semantic segmentation. To adapt the model to the target domain with minimum queried labels, we propose acquiring labels of the samples with high probability density in the target domain yet with low probability density in the source domain, complementary to the existing source domain labeled data. To further facilitate labeling efficiency, we design a dynamic scheduling policy to adjust the labeling budgets between domain exploration and model uncertainty over time. Extensive experiments show that our method outperforms existing active learning and domain adaptation baselines on two benchmarks, GTA5 -> Cityscapes and SYNTHIA -> Cityscapes. With less than 5% target domain annotations, our method reaches comparable results with that of full supervision.Comment: 14 pages, 5 figure

Early utilization of hypertonic peritoneal dialysate and subsequent risks of non-traumatic amputation among peritoneal dialysis patients: a nationwide retrospective longitudinal study

BACKGROUND: The hemodialysis (HD) population has a particularly high incidence of amputation, which is likely associated with decreased tissue oxygenation during HD. However, information about the risk factors leading to amputation in peritoneal dialysis (PD) patients is limited. Here, we have investigated the association between the use of hypertonic peritoneal dialysate (HPD) and subsequent amputation in PD patients. METHODS: Based on the data from the Taiwan National Health Insurance research database, this observational cohort study enrolled 203 PD patients who had received HPD early during treatment and had not undergone amputation and 296 PD controls who had not undergone amputation. Subjects were followed through until the end of 2009 and the event rates of new non-traumatic amputation were compared between groups. RESULTS: The incidence of amputation was 3 times higher for the HPD cohort than for the comparison cohort (23.68 vs. 8.01 per 1000 person-years). The hazard ratio (HR) for this group, estimated using a multivariable Cox model, was 2.48 (95% confidence interval [CI] = 1.06–5.79). The HR for patients with both diabetes and early adoption of HPD increased to 44.34 (95% CI = 5.51-357.03), compared to non-HPD non-diabetic PD controls. CONCLUSION: Early utilization of HPD in PD patients is associated with increasing risk of amputation; this risk considerably increases for those with concomitant diabetes

Using Capacitance Sensor to Extract Characteristic Signals of Dozing from Skin Surface

Skin is the largest organ of the human body and a physiological structure that is directly exposed to the environment. From a theoretical perspective, numerous physiological and psychological signals use the skin as a medium for input and output with the outside world. Therefore, the skin is considered an optimal signal interception point when developing noninvasive, direct, and rapid signal exploration devices. To date, skin signal interceptions are predominantly performed by measuring skin impedance. However, this method is prone to interference such as sweat secretion, salt accumulation on the skin, and muscle contractions, which may result in a substantial amount of interference and erroneous results. The present study proposes novel and effective methods for skin signal interception, such as using a nested probe as a sensor to measure capacitance to be further processed as physiological and psychological signals. The experimental results indicate that the capacitance curve for the transition between wakefulness and dozing exhibits significant changes. This change in the curve can be analyzed by computer programs to clearly and rapidly determine whether the subject has entered the initial phases of sleep

Fak56 functions downstream of integrin alphaPS3betanu and suppresses MAPK activation in neuromuscular junction growth

Background: Focal adhesion kinase (FAK) functions in cell migration and signaling through activation of the mitogen-activated protein kinase (MAPK) signaling cascade. Neuronal function of FAK has been suggested to control axonal branching; however, the underlying mechanism in this process is not clear. Results: We have generated mutants for the Drosophila FAK gene, Fak56. Null Fak56 mutants display overgrowth of larval neuromuscular junctions (NMJs). Localization of phospho-FAK and rescue experiments suggest that Fak56 is required in presynapses to restrict NMJ growth. Genetic analyses imply that FAK mediates the signaling pathway of the integrin αPS3βν heterodimer and functions redundantly with Src. At NMJs, Fak56 downregulates ERK activity, as shown by diphospho-ERK accumulation in Fak56 mutants, and suppression of Fak56 mutant NMJ phenotypes by reducing ERK activity. Conclusion: We conclude that Fak56 is required to restrict NMJ growth during NMJ development. Fak56 mediates an extracellular signal through the integrin receptor. Unlike its conventional role in activating MAPK/ERK, Fak56 suppresses ERK activation in this process. These results suggest that Fak56 mediates a specific neuronal signaling pathway distinct from that in other cellular processes