Miracle-dz/UniFAR-FTUs huggingface dataset:
ER stress-induced aggresome trafficking of HtrA1 protects against proteotoxicity.

High temperature requirement A1 (HtrA1) belongs to an ancient protein family that is linked to various human disorders. The precise role of exon 1-encoded N-terminal domains and how these influence the biological functions of human HtrA1 remain elusive. In this study, we traced the evolutionary origins of these N-terminal domains to a single gene fusion event in the most recent common ancestor of vertebrates. We hypothesized that human HtrA1 is implicated in unfolded protein response. In highly secretory cells of the retinal pigmented epithelia, endoplasmic reticulum (ER) stress upregulated HtrA1. HtrA1 co-localized with vimentin intermediate filaments in highly arborized fashion. Upon ER stress, HtrA1 tracked along intermediate filaments, which collapsed and bundled in an aggresome at the microtubule organizing center. Gene silencing of HtrA1 altered the schedule and amplitude of adaptive signaling and concomitantly resulted in apoptosis. Restoration of wild-type HtrA1, but not its protease inactive mutant, was necessary and sufficient to protect from apoptosis. A variant of HtrA1 that harbored exon 1 substitutions displayed reduced efficacy in rescuing cells from proteotoxicity. Our results illuminate
Simulation of Acoustic Wave Propagation in Aluminium Coatings for Material Characterization

Aluminium coatings and their characterization are of great interest in many fields of application, ranging from aircraft industries to microelectronics. Here, we present the simulation of acoustic wave propagation in aluminium coatings via the elastodynamic finite integration technique (EFIT) in comparison to experimental results. The simulations of intensity (I)–defocus (z) curves, obtained by scanning acoustic microscopy (SAM), were first carried out on an aluminium bulk sample, and secondly on a 1 μm aluminium coating deposited on a silicon substrate. The I(z) curves were used to determine the Rayleigh wave velocity of the aluminium bulk sample and the aluminium coating. The results of the simulations with respect to the Rayleigh velocity were corroborated by non-destructive SAM measurements and laser ultrasonic measurements (LUS).
gsSKAT: Rapid gene set analysis and multiple testing correction for rare‐variant association studies using weighted linear kernels

Next‐generation sequencing technologies have afforded unprecedented characterization of low‐frequency and rare genetic variation. Due to low power for single‐variant testing, aggregative methods are commonly used to combine observed rare variation within a single gene. Causal variation may also aggregate across multiple genes within relevant biomolecular pathways. Kernel‐machine regression and adaptive testing methods for aggregative rare‐variant association testing have been demonstrated to be powerful approaches for pathway‐level analysis, although these methods tend to be computationally intensive at high‐variant dimensionality and require access to complete data. An additional analytical issue in scans of large pathway definition sets is multiple testing correction. Gene set definitions may exhibit substantial genic overlap, and the impact of the resultant correlation in test statistics on Type I error rate control for large agnostic gene set scans has not been fully explored. Herein, we first outline a statistical strategy for aggregative rare‐variant analysis using component gene‐level linear kernel score test summary statistics as well as derive simple estimators of the effective number of tests for family‐wise error rate control. We then conduct extensive simulation studies to characterize the behavior of our approach relative to direct application of kernel and adaptive methods under a variety of conditions. We also apply our method to two case‐control studies, respectively, evaluating rare variation in hereditary prostate cancer and schizophrenia. Finally, we provide open‐source R code for public use to facilitate easy application of our methods to existing rare‐variant analysis results.
Relationship Between Emotions, Emotion Regulation, and Well-Being of Professional Caregivers of People With Dementia

So far, limited research has been carried out to better understand the interplay between the emotions, the use of emotion regulation strategies, and the well-being of professional caregivers of People with Dementia (PwD). This pilot study (N = 43 professional caregivers) aimed to (1) describe the type and frequency of emotions experienced at work; (2) analyze the associations between experienced emotions, emotion regulation strategies, and well-being; and (3) test whether the use of specific emotion regulation strategies moderates the relationship between experienced emotions and emotional exhaustion. In the challenging context of professionally caring for PwD, results suggest that (1) caregivers experience positive emotions more frequently than negative emotions; (2) caregivers using relatively inappropriate regulation strategies are more likely to experience negative emotions, less likely to experience positive emotions, and have poorer physical and mental health; and (3) expressive suppression significantly moderates the relationship between positive experienced emotions and emotional exhaustion.
Vitamin D in acute stress and critical illness

Purpose of reviewThe pleotropic effects of vitamin D on chronic diseases have received significant attention; however, its role in acute illness is less understood. The purpose of this review is to summarize the current evidence regarding the role of vitamin D in acute stress and critical illness. Recent findings25-Hydroxyvitamin D levels may affect risk of developing acute illnesses (e.g. respiratory infections), and low concentrations are associated with unfavorable outcomes during critical care. Inflammatory changes alone do not explain the observed deterioration in vitamin D status following acute stress. Hemodilution, interstitial extravasation, decreased synthesis of binding proteins, and renal wasting of 25-hydroxyvitamin D, all appear to play a more significant role in the regulation of vitamin D status during critical illness. SummarySingle-point assessments of 25-hydroxyvitamin D following acute stress may provide an inaccurate assessment of vitamin D status. In such cases, measurement of binding proteins and free vitamin D metabolites may be essential to create a more realistic approximation of vitamin D status. Variations in patient responses to acute stress and critical illness may depend not only on the degree of systemic vitamin D insufficiency, but also on the individual tissue requirements.
Does Facility Based Sexual and Reproductive Health Services Meet the Needs of Young Persons? Views from Cross Section of Ghanaian Youth

The focus on facility based health setting to provide sexual and reproductive health to the youth has been tested in several settings and achieved varying results. This study examined whether facility based sexual and reproductive health services met the needs of Ghanaian youth. Adopting the descriptive cross sectional design, 170 youths between the ages of 10 and 24 were sampled. A three-stage stratified random sampling technique was adopted. The results of the study are presented using descriptive statistics. The study established that a total of 55.8% (95/170) of the youth had utilized at least one or more of a sexual and reproductive health service in life time. However, only 45.2% (43/95) of youth used or accessed sexual and reproductive health services from a facility based setting. Facility based sexual and reproductive health service provided specifically for the youth is very limited. This calls for the provision of out-of health facility services located within the communities and at strategic places while ensuring confidentiality to the youth. More rigorous research is recommended on a national scale to examine youth preference for the type of facility based and out-of-facility based sexual and reproductive health services to meet the needs of young people.
Sensitivity Analysis Based on Markovian Integration by Parts Formula

Sensitivity analysis is widely applied in financial risk management and engineering; it describes the variations brought by the changes of parameters. Since the integration by parts technique for Markov chains is well developed in recent years, in this paper we apply it for computation of sensitivity and show the closed-form expressions for two commonly-used time-continuous Markovian models. By comparison, we conclude that our approach outperforms the existing technique of computing sensitivity on Markovian models.
Obesity and metabolic syndrome Lifetime risk : childhood obesity and cardiovascular risk

In a recent report, the worldwide prevalence of childhood obesity was estimated to have increased by 47% between 1980 and 2013. As a result, substantial concerns have been raised about the future burden of cardiovascular (CV) disease that could ensue. The purpose of this review is to summarize and interpret (i) the evidence linking early life obesity with adverse changes in CV structure and function in childhood, (ii) the lifetime risk for CV disease resulting from obesity in childhood, and (iii) the potential effects of lifestyle interventions in childhood to ameliorate these risks.
“Failure-to-Identify” Hunting Incidents: A Resilience Engineering Approach

Objective The objective was to develop an understanding, using the Functional Resonance Analysis Method (FRAM), of the factors that could cause a deer hunter to misidentify their intended target. Background Hunting is a popular activity in many communities. However, hunters vary considerably based on training, experience, and expertise. Surprisingly, safety in hunting has not received much attention, especially failure-to-identify hunting incidents. These are incidents in which the hunter, after spotting and targeting their quarry, discharge their firearm only to discover they have been spotting and targeting another human, an inanimate object, or flora by mistake. The hunter must consider environment, target, time of day, weather, and many other factors—continuously evaluating whether the hunt should continue. To understand how these factors can relate to one another is fundamental to begin to understand how incidents happen. Method Workshops with highly experienced and active hunters led to the development of a FRAM model detailing the functions of a “Hunting FRAM. ” The model was evaluated for correctness based on confidential and anonymous near-miss event submissions by hunters. Results A FRAM model presenting the functions of a hunt was produced, evaluated, and accepted. Using the model, potential sources of incidents or other unintended outcomes were identified, which in turn helped to improve the model. Conclusion Utilizing principles of understanding and visualization tools of the FRAM, the findings create a foundation for safety improvements potentially through training or safety messages based on an increased understanding of the complexity of hunting.
Prognostic significance of foetal‐like tyrosine kinase 3 mutation in Egyptian children with acute leukaemia

The foetal like tyrosine kinase 3 mutation (Flt3) gene encodes a tyrosine kinase receptor that regulates proliferation and differentiation of haematopoietic stem cells. In children with acute myelogenous leukaemia (AML), internal tandem duplication of the Flt3 gene (Flt3/ITD) was previously reported and correlated to poor prognosis. Limited data are available about childhood acute lymphoblastic leukaemia (ALL). We analysed bone marrow specimens from 55 newly diagnosed acute leukaemia cases including 30 AML and 25 ALL by genomic PCR for the presence of Flt3/ITD and correlated its presence with clinical outcome. Tandem duplication was found in 6/30(20%) AML cases: 2/8 M1, 1/8 M2, 2/6 M3, 1/6 M4 with loss of heterozygosity (LOH) in two cases. Four of the cases with duplication were males and the other two cases were females. Complete remission was achieved in 16.6% of cases with duplication vs. 45.8% in cases without duplication. Failure to achieve induction remission was noted in 50% of cases with duplication vs. 29.1% in cases without duplication. FLt3/ITD was not found in ALL cases. Lineage restriction analysis revealed that Flt3/ITD was not present in lymphocytes, suggesting a lack of stem cell involvement for this mutation. Flt3/ITD was the most significant prognostic factor as declared by multivariate analysis. Patients with Flt3/ITD appear to be refractory to primary induction therapy, and for those who achieve remission, there is a high rate of relapse and death so there may be an association between this type of mutation and patient outcome.
Maternal high fat diet during critical windows of development alters adrenal cortical and medullary enzyme expression in adult male rat offspring

We previously reported that a maternal high fat (HF) diet resulted in adult offspring with increased adiposity and hyperleptinemia. As leptin has an inhibitory effect on adrenal steroidogenesis and a stimulatory effect on epinephrine synthesis, we hypothesized that key adrenal steroidogenic and catecholaminergic enzymes would be altered in these offspring. Wistar rats were randomized into three groups at weaning: (1) control dams fed a standard control chow diet from weaning and throughout pregnancy and lactation (CON), (2) dams fed a HF diet from weaning and throughout pregnancy and lactation (MHF) and (3) dams fed standard control chow diet throughout life until conception, then fed a HF diet in pregnancy and lactation (PLHF). Dams were mated at day 100 (P100). After birth at P22 (weaning), male offspring were fed a standard control chow (con) or high fat (hf) diet. At P160, plasma samples and adrenal tissues were collected. Postweaning hf diet significantly elevated plasma corticosterone concentrations in PLHF-hf offspring compared to PLHF-con. MHF nutrition increased adrenal adrenocorticotrophic hormone receptor (ACTH-R) mRNA levels compared to CON-con. 3β-hydroxysteroid dehydrogenase (3βHSD) mRNA levels were decreased in MHF compared to PLHF offspring. Phenylethanolamine N-methyltransferase (PNMT) mRNA levels were increased in MHF-hf offspring compared to MHF-con. Plasma homocysteine (HCY) concentrations were significantly elevated in CON-hf and MHF-hf offspring compared to chow-fed offspring, associated with elevated intakes of methionine and reduced intakes of pyridoxine. Immunoreactive leptin receptor (ObRb) and PNMT were colocalized in medullary chromaffin cells. This study suggests that a postweaning HF diet in offspring induced changes in adrenal gene expression levels that are dependent upon the level of maternal nutrition.
"Experiments on the Development of Chick and Duck Embryos, Cultivated in vitro" (1932), by Conrad Hal Waddington

Conrad Hal Waddington’s “Experiments on the Development of Chick and Duck Embryos, Cultivated in vitro [5] ,” published in 1932 in Philosophical Transactions of the Royal Society of London, Series B , compares the differences in the development of birds [6] and amphibians [7] . Previous experiments focused on the self differentiation [8] of individual tissues in birds [6] , but Waddington wanted to study induction [9] in greater detail. The limit to these studies had been the amount of time an embryo could be successfully cultivated ex vivo . Waddington applied in vitro [5] cell culturing techniques to this experiment, as opposed to the chorio-allantoic technique used in many earlier studies. Culturing in vitro [5] consisted of placing the embryo on a clot of adult chicken [10] blood plasma and chick [11] embryo extract in a watch glass. Experiments reported in this paper were divided into three main sections: the development of the embryos in vitro [5] , induction [9] by the endoderm [12] , and induction [9] by the primitive streak [13] . The development of the embryos in vitro [5] was slower and less complete than normal development. Development also failed to continue beyond two days after cultivation. Waddington made no effort to improve the time of development or determine the degree of slowdown in this study because these limitations did not impact the results of this experiment. Another complication was that the endoderm [12] also had a tendency to form cysts during in vitro [5] cultivation. However, Waddington was able to cultivate the embryos long enough to observe primitive streak [13] formation, gastrulation [14] , and the induction [9] of neural tissue. This work provided the foundation for the experiments in this study.
Cushing’s Syndrome and Hypothalamic–Pituitary–Adrenal Axis Hyperactivity in Chronic Central Serous Chorioretinopathy

Objective Central serous chorioretinopathy (CSC), a specific form of macular degeneration, has been reported as presenting manifestation of Cushing’s syndrome. Furthermore, CSC has been associated with both exogenous hypercortisolism and endogenous Cushing’s syndrome. It is important to know whether CSC patients should be screened for Cushing’s syndrome. Although hypothalamic-pituitary-adrenal (HPA) axis hyperactivity in CSC has been suggested, no detailed evaluation of the HPA axis has been performed in a large cohort of CSC patients. This study aimed to investigate whether Cushing’s syndrome prevalence is increased among chronic CSC (cCSC) patients and whether detailed endocrinological phenotyping indicates hyperactivity of the HPA axis. Design Cross-sectional study. Patients 86 cCSC patients and 24 controls. Measurements Prevalence of Cushing’s syndrome, HPA axis activity. Results None of the cCSC patients met the clinical or biochemical criteria of Cushing’s syndrome. However, compared to controls, HPA axis activity was increased in cCSC patients, reflected by higher 24 h urinary free cortisol, and accompanying higher waist circumference and diastolic blood pressure, whereas circadian cortisol rhythm and feedback were not different. Chronic CSC patients did not report more stress or stress-related problems on questionnaires. Conclusion No case of Cushing’s syndrome was revealed in a large cohort of cCSC patients. Therefore, we advise against screening for Cushing’s syndrome in CSC patients, unless additional clinical features are present. However, our results indicate that cCSC is associated with hyperactivity of the HPA axis, albeit not accompanied with perception of more psychosocial stress.
Thermoplastic Composite Cylinders for Underwater Applications

A study of thermoplastic matrix composites has been performed to investigate their use in underwater applications such as oceanography, submarine, and sub-sea offshore structures. This article first presents six candidate materials. Results from simple mechanical and seawater aging screening tests on flat specimens are then described. Glass/epoxy and carbon/epoxy composites are used as reference materials. Two materials emerged from this process, glass/PEI and carbon/PEEK. Cylinders of both were manufactured and subjected to hydrostatic pressure tests, and results are compared to those for glass/epoxy and carbon/epoxy cylinders of similar geometry. The carbon/PEEK material appeared most promising. It resisted pressures in excess of 90 MPa and was retained for damage tolerance assessment studies. Drop weight impact damage zones were smaller in carbon/PEEK than carbon/epoxy for the same impact energies but the loss in residual collapse strength was more rapid in the thermoplastic composite. This was attributed to a change in failure mode, impact damage initiated a local buckling failure.
Alexithymia, anger, and interpersonal behavior.

BACKGROUND We explored the relationship between alexithymia and interpersonal behavior, particularly the expression of anger. METHODS Ninety-eight college students completed the Toronto Alexithymia Scale. A median split was used to divide participants into a low-alexithymia and a high-alexithymia group. The experimenter intentionally engaged in a series of anger-provoking behaviors. RESULTS Compared to individuals in the low-alexithymia group, individuals in the high-alexithymia group were more interpersonally avoidant and exhibited more nonverbal anger, yet there was a trend for them to describe their lab experience as more pleasant. Among individuals in the high-alexithymia group, the different measures of anger and interpersonal behavior were less strongly associated than they were among individuals in the low-alexithymia group. CONCLUSIONS The results provide evidence of a complex association between alexithymia and anger, and of the lack of coherence in the communication of individuals with high levels of alexithymia.
Unprecedented climate events: Historical changes, aspirational targets, and national commitments

UN aspirational targets reduce risk but still produce increases in probability of unprecedented extremes. The United Nations Paris Agreement creates a specific need to compare consequences of cumulative emissions for pledged national commitments and aspirational targets of 1.5° to 2°C global warming. We find that humans have already increased the probability of historically unprecedented hot, warm, wet, and dry extremes, including over 50 to 90% of North America, Europe, and East Asia. Emissions consistent with national commitments are likely to cause substantial and widespread additional increases, including more than fivefold for warmest night over ~50% of Europe and >25% of East Asia and more than threefold for wettest days over >35% of North America, Europe, and East Asia. In contrast, meeting aspirational targets to keep global warming below 2°C reduces the area experiencing more than threefold increases to <10% of most regions studied. However, large areas—including >90% of North America, Europe, East Asia, and much of the tropics—still exhibit sizable increases in the probability of record-setting hot, wet, and/or dry events.
Recent Advances in CNS P2X7 Physiology and Pharmacology: Focus on Neuropsychiatric Disorders

The ATP-gated P2X7 ion channel is an abundant microglial protein in the CNS that plays an important pathological role in executing ATP-driven danger signal transduction. Emerging data has generated scientific interest and excitement around targeting the P2X7 ion channel as a potential drug target for CNS disorders. Over the past years, a wealth of data has been published on CNS P2X7 biology, in particular the role of P2X7 in microglial cells, and in vivo effects of brain-penetrant P2X7 antagonists. Likewise, significant progress has been made around the medicinal chemistry of CNS P2X7 ligands, as antagonists for in vivo target validation in models of CNS diseases, to identification of two clinical compounds (JNJ-54175446 and JNJ-55308942) and finally, discovery of P2X7 PET ligands. This review is an attempt to bring together the current understanding of P2X7 in the CNS with a focus on P2X7 as a drug target in neuropsychiatric disorders.
Are Code Examples on an Online Q&A Forum Reliable?: A Study of API Misuse on Stack Overflow

Programmers often consult an online Q&A forum such as Stack Overflow to learn new APIs. This paper presents an empirical study on the prevalence and severity of API misuse on Stack Overflow. To reduce manual assessment effort, we design ExampleCheck, an API usage mining framework that extracts patterns from over 380K Java repositories on GitHub and subsequently reports potential API usage violations in Stack Overflow posts. We analyze 217,818 Stack Overflow posts using ExampleCheck and find that 31% may have potential API usage violations that could produce unexpected behavior such as program crashes and resource leaks. Such API misuse is caused by three main reasons—missing control constructs, missing or incorrect order of API calls, and incorrect guard conditions. Even the posts that are accepted as correct answers or upvoted by other programmers are not necessarily more reliable than other posts in terms of API misuse. This study result calls for a new approach to augment Stack Overflow with alternative API usage details that are not typically shown in curated examples.