Miracle-dz/UniFAR-FTUs huggingface dataset:
Framework for microRNA variant annotation and prioritization using human population and disease datasets

MicroRNA (miRNA) expression is frequently deregulated in human disease, in contrast, disease‐associated miRNA mutations are understudied. We developed Annotative Database of miRNA Elements, ADmiRE, which combines multiple existing and new biological annotations to aid prioritization of causal miRNA variation. We annotated 10,206 mature (3,257 within seed region) miRNA variants from multiple large sequencing datasets including gnomAD (15,496 genomes; 123,136 exomes). The pattern of miRNA variation closely resembles protein‐coding exonic regions, with no difference between intragenic and intergenic miRNAs (P = 0.56), and high confidence miRNAs demonstrate higher sequence constraint (P < 0.001). Conservation analysis across 100 vertebrates identified 765 highly conserved miRNAs that also have limited genetic variation in gnomAD. We applied ADmiRE to the TCGA PanCancerAtlas WES dataset containing over 10,000 individuals across 33 adult cancers and annotated 1,267 germline (rare in gnomAD) and 1,492 somatic miRNA variants. Several miRNA families with deregulated gene expression in cancer have low levels of both somatic and germline variants, e.g., let‐7 and miR‐10. In addition to known somatic miR‐142 mutations in hematologic cancers, we describe novel somatic miR‐21 mutations in esophageal cancers impacting downstream miRNA targets. Through the development of ADmiRE, we present a framework for annotation and prioritization of miRNA variation in disease datasets.
The Outer Product Structure of Neural Network Derivatives

In this paper, we show that feedforward and recurrent neural networks exhibit an outer product derivative structure but that convolutional neural networks do not. This structure makes it possible to use higher-order information without needing approximations or infeasibly large amounts of memory, and it may also provide insights into the geometry of neural network optima. The ability to easily access these derivatives also suggests a new, geometric approach to regularization. We then discuss how this structure could be used to improve training methods, increase network robustness and generalizability, and inform network compression methods.
Intraspecific variation in lizard heat tolerance alters estimates of climate impact

Research addressing the effects of global warming on the distribution and persistence of species generally assumes that population variation in thermal tolerance is spatially constant or overridden by interspecific variation. Typically, this rationale is implicit in sourcing one critical thermal maximum (CTmax ) population estimate per species to model spatiotemporal cross-taxa variation in heat tolerance. Theory suggests that such an approach could result in biased or imprecise estimates and forecasts of impact from climate warming, but limited empirical evidence in support of those expectations exists. We experimentally quantify the magnitude of intraspecific variation in CTmax among lizard populations, and the extent to which incorporating such variability can alter estimates of climate impact through a biophysical model. To do so, we measured CTmax from 59 populations of 15 Iberian lizard species (304 individuals). The overall median CTmax across all individuals from all species was 42.8°C and ranged from 40.5 to 48.3°C, with species medians decreasing through xeric, climate-generalist and mesic taxa. We found strong statistical support for intraspecific differentiation in CTmax by up to a median of 3°C among populations. We show that annual restricted activity (operative temperature > CTmax ) over the Iberian distribution of our study species differs by a median of >80 hr per 25-km2 grid cell based on different population-level CTmax estimates. This discrepancy leads to predictions of spatial variation in annual restricted activity to change by more than 20 days for six of the study species. Considering that during restriction periods, reptiles should be unable to feed and reproduce, current projections of climate-change impacts on the fitness of ectotherm fauna could be under- or over-estimated depending on which population is chosen to represent the physiological spectra of the species in question. Mapping heat tolerance over the full geographical ranges of single species is thus critical to address cross-taxa patterns and drivers of heat tolerance in a biologically comprehensive way.
Short half‐life of HPV16 E6 and E7 mRNAs sensitizes HPV16‐positive tonsillar cancer cell line HN26 to DNA‐damaging drugs

Here we show that treatment of the HPV16‐positive tonsillar cancer cell line HN26 with DNA alkylating cancer drug melphalan‐induced p53 and activated apoptosis. Melphalan reduced the levels of RNA polymerase II and cellular transcription factor Sp1 that were associated with HPV16 DNA. The resulting inhibition of transcription caused a rapid loss of the HPV16 early mRNAs encoding E6 and E7 as a result of their inherent instability. As a consequence of HPV16 E6 and E7 down‐regulation, the DNA damage inflicted on the cells by melphalan caused induction of p53 and activation of apoptosis in the HN26 cells. The BARD1‐negative phenotype of the HN26 cells may have contributed to the failure to repair DNA damage caused by melphalan, as well as to the efficient apoptosis induction. Finally, nude mice carrying the HPV16 positive tonsillar cancer cells responded better to melphalan than to cisplatin, the chemotherapeutic drug of choice for tonsillar cancer. We concluded that the short half‐life of the HPV16 E6 and E7 mRNAs renders HPV16‐driven tonsillar cancer cells particularly sensitive to DNA damaging agents such as melphalan since melphalan both inhibits transcription and causes DNA damage.
Id1/NR2B Receptor Pathway Regulates Rat Cochlear Sensory Epithelial Cell Survival after Radiation

Survival of cochlear sensory epithelial cells may be regulated by inhibitor of differentiation-1 (Id1) and the N-methyl-D-aspartic acid (NMDA) receptor. However, it is unclear whether Id1 and the NMDA receptor are involved in the radiation-mediated survival of rat cochlear sensory epithelial cells. Here, we show that the percentage of apoptotic cells increased, the percentage of cells in the S phase decreased, Id1 mRNA and protein expression decreased and the NMDA receptor subtype 2B (NR2B) mRNA and protein level increased in OC1 cells after radiation. Cells infected with the Id1 gene exhibited higher Id1 mRNA and protein levels and lower NR2B mRNA and protein levels than the control cells. In contrast, after transfection of the Id1 siRNA into OC1 cells, Id1 mRNA and protein expression decreased and NR2B mRNA and protein expression increased relative to that of the control group. Additionally, treatment with ifenprodil for 24 h before radiation reduced apoptosis and increased the percentage of cells in the S phase. Our results suggest that Id1 and NR2B might regulate the survival of OC1 cells following radiation.
Upregulation of lincRNA‐p21 in thoracic aortic aneurysms is involved in the regulation of proliferation and apoptosis of vascular smooth muscle cells by activating TGF‐β1 signaling pathway

Long intergenic noncoding RNA‐p21 (lincRNA‐p21) has been proved in the pathogenesis of aortic aneurysms, while its functionality in thoracic aortic aneurysms (TAA) and the mechanism of function remains unclear. Therefore our study aimed to investigate the role of lincRNA‐p21 in TAA.
Cellular and Molecular Immune Response to Chikungunya Virus Infection

Chikungunya virus (CHIKV) is a re-emergent arthropod-borne virus (arbovirus) that causes a disease characterized primarily by fever, rash and severe persistent polyarthralgia. In the last decade, CHIKV has become a serious public health problem causing several outbreaks around the world. Despite the fact that CHIKV has been around since 1952, our knowledge about immunopathology, innate and adaptive immune response involved in this infectious disease is incomplete. In this review, we provide an updated summary of the current knowledge about immune response to CHIKV and about soluble immunological markers associated with the morbidity, prognosis and chronicity of this arbovirus disease. In addition, we discuss the progress in the research of new vaccines for preventing CHIKV infection and the use of monoclonal antibodies as a promising therapeutic strategy.
Why large icosahedral viruses need scaffolding proteins

Significance Despite a plethora of experimental data on the role of scaffolding proteins in the structure of viral shells, no theoretical/numerical explanations have been put forward to decipher the indisputable need of large shells for scaffolding proteins. This paper explains the underlying physical mechanisms for the formation of large viral shells and elucidates the “universal” role of scaffolding proteins in the formation of large spherical crystals. While small single-stranded viral shells encapsidate their genome spontaneously, many large viruses, such as the herpes simplex virus or infectious bursal disease virus (IBDV), typically require a template, consisting of either scaffolding proteins or an inner core. Despite the proliferation of large viruses in nature, the mechanisms by which hundreds or thousands of proteins assemble to form structures with icosahedral order (IO) is completely unknown. Using continuum elasticity theory, we study the growth of large viral shells (capsids) and show that a nonspecific template not only selects the radius of the capsid, but also leads to the error-free assembly of protein subunits into capsids with universal IO. We prove that as a spherical cap grows, there is a deep potential well at the locations of disclinations that later in the assembly process will become the vertices of an icosahedron. Furthermore, we introduce a minimal model and simulate the assembly of a viral shell around a template under nonequilibrium conditions and find a perfect match between the results of continuum elasticity theory and the numerical simulations. Besides explaining available experimental results, we provide a number of predictions. Implications for other problems in spherical crystals are also discussed.
Countering infanticide: Chimpanzee mothers are sensitive to the relative risks posed by males on differing rank trajectories.

OBJECTIVES Infanticide by males is common in mammals. According to the sexual selection hypothesis, the risk is inversely related to infant age because the older the infant, the less infanticide can shorten lactational amenorrhea; risk is also predicted to increase when an infanticidal male's chance of siring the replacement infant is high. Infanticide occurs in chimpanzees (Pan troglodytes), a species in which male dominance rank predicts paternity skew. Infanticidal male chimpanzees (if low-ranking) are unlikely to kill their own offspring, whereas those who are currently rising in rank, particularly when this rise is dramatic, have an increased likelihood of fathering potential future infants relative to any existing ones. Given that mothers should behave in ways that reduce infanticide risk, we predicted that female chimpanzees, and specifically those with younger, more vulnerable infants, would attempt to adjust the exposure of their infants to potentially infanticidal males. Specifically, mothers of young infants should reduce their association with adult males in general, and to a greater extent, with both low-ranking males and those rising in rank from a position where paternity of current infants was unlikely, to a rank where the probability of siring the next infant is significantly higher. We also investigated the alternative possibility that rather than avoiding all adult males, mothers would increase association with males of stable high rank on the basis that such males could offer protection against infanticide. MATERIALS AND METHODS We examined data on female association patterns collected from the Budongo Forest, Uganda, during a period encompassing both relative stability in the male hierarchy and a period of instability with a mid-ranking male rising rapidly in rank. RESULTS Using linear mixed models, we found that mothers reduced their association with the rank-rising male, contingent on infant age, during the period of instability. We also found evidence that females preferentially associated with a potential protector male during the high-risk period. DISCUSSION Our results support the sexually selected hypothesis for infanticide and demonstrate that female chimpanzees are sensitive to the relative risks posed by adult males.
Image Captioning as Neural Machine Translation Task in SOCKEYE

Image captioning is an interdisciplinary research problem that stands between computer vision and natural language processing. The task is to generate a textual description of the content of an image. The typical model used for image captioning is an encoder-decoder deep network, where the encoder captures the essence of an image while the decoder is responsible for generating a sentence describing the image. Attention mechanisms can be used to automatically focus the decoder on parts of the image which are relevant to predict the next word. In this paper, we explore different decoders and attentional models popular in neural machine translation, namely attentional recurrent neural networks, self-attentional transformers, and fully-convolutional networks, which represent the current state of the art of neural machine translation. The image captioning module is available as part of SOCKEYE at this https URL which tutorial can be found at this https URL .
Evaluation of the diet wide contribution to serum urate levels: meta-analysis of population based cohorts

Abstract Objective To systematically test dietary components for association with serum urate levels and to evaluate the relative contributions of estimates of diet pattern and inherited genetic variants to population variance in serum urate levels. Design Meta-analysis of cross sectional data from the United States. Data sources Five cohort studies. Review methods 16 760 individuals of European ancestry (8414 men and 8346 women) from the US were included in analyses. Eligible individuals were aged over 18, without kidney disease or gout, and not taking urate lowering or diuretic drugs. All participants had serum urate measurements, dietary survey data, information on potential confounders (sex, age, body mass index, average daily calorie intake, years of education, exercise levels, smoking status, and menopausal status), and genome wide genotypes. The main outcome measures were average serum urate levels and variance in serum urate levels. β values (95% confidence intervals) and Bonferroni corrected P values from multivariable linear regression analyses, along with regression partial R2 values, were used to quantitate associations. Results Seven foods were associated with raised serum urate levels (beer, liquor, wine, potato, poultry, soft drinks, and meat (beef, pork, or lamb)) and eight foods were associated with reduced serum urate levels (eggs, peanuts, cold cereal, skim milk, cheese, brown bread, margarine, and non-citrus fruits) in the male, female, or full cohorts. Three diet scores, constructed on the basis of healthy diet guidelines, were inversely associated with serum urate levels and a fourth, data driven diet pattern positively associated with raised serum urate levels, but each explained ≤0.3% of variance in serum urate. In comparison, 23.9% of variance in serum urate levels was explained by common, genome wide single nucleotide variation. Conclusion In contrast with genetic contributions, diet explains very little variation in serum urate levels in the general population.
Mitochondria reorganization upon proliferation arrest predicts individual yeast cell fate

Most cells spend the majority of their life in a non-proliferating state. When proliferation cessation is irreversible, cells are senescent. By contrast, if the arrest is only temporary, cells are defined as quiescent. These cellular states are hardly distinguishable without triggering proliferation resumption, hampering thus the study of quiescent cells properties. Here we show that quiescent and senescent yeast cells are recognizable based on their mitochondrial network morphology. Indeed, while quiescent yeast cells display numerous small vesicular mitochondria, senescent cells exhibit few globular mitochondria. This allowed us to reconsider at the individual-cell level, properties previously attributed to quiescent cells using population-based approaches. We demonstrate that cell’s propensity to enter quiescence is not influenced by replicative age, volume or density. Overall, our findings reveal that quiescent cells are not all identical but that their ability to survive is significantly improved when they exhibit the specific reorganization of several cellular machineries.
The enigma of atypical femoral fractures

Atypical femoral fractures (AFF) are stress or ‘insufficiency’ fractures, often complicated by the use of bisphosphonates or other bone turnover inhibitors. While these drugs are beneficial for the intact osteoporotic bone, they probably prevent a stress fracture from healing which thus progresses to a complete fracture. Key features of atypical femoral fractures, essential for the diagnosis, are: location in the subtrochanteric region and diaphysis; lack of trauma history and comminution; and a transverse or short oblique configuration. The relative risk of patients developing an atypical femoral fracture when taking bisphosphonates is high; however, the absolute risk of these fractures in patients on bisphosphonates is low, ranging from 3.2 to 50 cases per 100,000 person-years. Treatment strategy in patients with AFF involves: radiograph of the contralateral side (computed tomography and magnetic resonance imaging should also be considered); dietary calcium and vitamin D supplementation should be prescribed following assessment; bisphosphonates or other potent antiresorptive agents should be discontinued; prophylactic surgical treatment of incomplete AFF with cephalomedullary nail, unless pain free; cephalomedullary nailing for surgical fixation of complete fractures; avoidance of gaps in the lateral and anterior cortex; avoidance of varus malreduction. Cite this article: EFORT Open Rev 2018;3:494-500. DOI: 10.1302/2058-5241.3. 170070.
Information Geometry of Orthogonal Initializations and Training

Recently mean field theory has been successfully used to analyze properties of wide, random neural networks. It gave rise to a prescriptive theory for initializing feed-forward neural networks with orthogonal weights, which ensures that both the forward propagated activations and the backpropagated gradients are near $\ell_2$ isometries and as a consequence training is orders of magnitude faster. Despite strong empirical performance, the mechanisms by which critical initializations confer an advantage in the optimization of deep neural networks are poorly understood. Here we show a novel connection between the maximum curvature of the optimization landscape (gradient smoothness) as measured by the Fisher information matrix (FIM) and the spectral radius of the input-output Jacobian, which partially explains why more isometric networks can train much faster. Furthermore, given that orthogonal weights are necessary to ensure that gradient norms are approximately preserved at initialization, we experimentally investigate the benefits of maintaining orthogonality throughout training, from which we conclude that manifold optimization of weights performs well regardless of the smoothness of the gradients. Moreover, motivated by experimental results we show that a low condition number of the FIM is not predictive of faster learning.
Water-vapour measurements up to the lower stratosphere — the high power raman lidar at the schneefernerhaus

A high-power Raman lidar system has been developed at the high-altitude research station Schneefernerhaus (Garmisch-Partenkirchen, Germany) at 2675 m, at the side of an existing differential-absorption lidar. It is based on a 180-W single-line XeCl laser and on two Newtonian telescopes (up to 1.5-m-diameter). In this way a vertical range up to more than 20 km and an accuracy level of the order of 10 % can be achieved for a measurement time of 1 h. Temperature measurements have been demonstrated to altitudes up to 54 km with just 1 % of the full 308-nm backscatter signal. Significantly higher altitudes are expected when using a chopper that cuts off the first 10 km or for 353 nm.
Synthesizing stealthy reprogramming attacks on cardiac devices

An Implantable Cardioverter Defibrillator (ICD) is a medical device used for the detection of potentially fatal cardiac arrhythmias and their treatment through the delivery of electrical shocks intended to restore normal heart rhythm. An ICD reprogramming attack seeks to alter the device's parameters to induce unnecessary therapy or prevent required therapy. In this paper, we present a formal approach for the synthesis of ICD reprogramming attacks that are both effective, i.e., lead to fundamental changes in the required therapy, and stealthy, i.e., are hard to detect. We focus on the discrimination algorithm underlying Boston Scientific devices (one of the principal ICD manufacturers) and formulate the synthesis problem as one of multi-objective optimization. Our solution technique is based on an Optimization Modulo Theories encoding of the problem and allows us to derive device parameters that are optimal with respect to the effectiveness-stealthiness tradeoff. Our method can be tailored to the patient's current condition, and readily generalizes to new rhythms. To the best of our knowledge, our work is the first to derive systematic ICD reprogramming attacks designed to maximize therapy disruption while minimizing detection.
Rates of metachronous adenoma after curative resection for left-sided or right-sided colon cancer

Background/Aims We determined the rates of metachronous colorectal neoplasm in colorectal cancer (CRC) patients after resection for right (R)-sided or left (L)-sided cancer. Methods Consecutive CRC patients who had undergone surgical resection for curative intent in our hospital between 2001 and 2004 were identified. R-sided colonic cancers refer to cancer proximal to splenic flexure whereas L-sided cancers include rectal cancers. Patients were included only if they had a clearing colonoscopy performed either before or within 6 months after the operation. Findings of surveillance colonoscopy performed up to 5 years after colonic resection were included in the analysis. Results Eight hundred and sixty-three CRC patients underwent curative surgical resection during the study period. Three hundred and twenty-seven patients (107 R-sided and 220 L-sided) fulfilled the inclusion criteria and had at least 1 postoperative surveillance colonoscopy performed. The proportion of patients who had polyp and adenoma on surveillance colonoscopy was significantly higher among patients with L-sided than R-sided cancers (polyps: 30.9% vs. 19.6%, P=0.03; adenomas: 25.5% vs. 13.1%, P=0.01). The mean number of adenoma per patient on surveillance colonoscopy was also higher for patients with L-sided than R-sided tumors (0.52; 95% confidence interval [CI], 0.37–0.68 vs. 0.22; 95% CI, 0.08–0.35; P<0.01). Multivariate analysis showed that L-sided cancers, age, male gender and longer follow-up were independent predictors of adenoma detection on surveillance colonoscopy. Conclusions Patients with Lsided cancer had a higher rate of metachronous polyps and adenoma than those with R-sided cancer on surveillance colonoscopy.
Beyond Tube‐Feeding: Relationship‐Centered, Comfort Care for Individuals with Eating Challenges in Dementia

UCONN Health, Center on Aging, University of Connecticut, Farmington, CT Laura Hatchman, BA School of Medicine, University of Connecticut, Farmington, CT Zhaoyan Fan, PhD Oregon State University, Corvallis, OR Jack M. Guralnik, MD, PhD School of Medicine, University of Maryland, Baltimore, MD Robert X. Gao, PhD Case Western Reserve University, Cleveland, OH George A. Kuchel, MD UCONN Health, Center on Aging, University of Connecticut, Farmington, CT