Miracle-dz/UniFAR-FTUs huggingface dataset:
Cochlear Neurotrophin‐3 overexpression at mid‐life prevents age‐related inner hair cell synaptopathy and slows age‐related hearing loss

Age‐related hearing loss (ARHL) is the most prevalent sensory deficit in the elderly. This progressive pathology often has psychological and medical comorbidities, including social isolation, depression, and cognitive decline. Despite ARHL's enormous societal and economic impact, no therapies to prevent or slow its progression exist. Loss of synapses between inner hair cells (IHCs) and spiral ganglion neurons (SGNs), a.k. a. IHC synaptopathy, is an early event in cochlear aging, preceding neuronal and hair cell loss. To determine if age‐related IHC synaptopathy can be prevented, and if this impacts the time‐course of ARHL, we tested the effects of cochlear overexpression of neurotrophin‐3 (Ntf3) starting at middle age. We chose Ntf3 because this neurotrophin regulates the formation of IHC‐SGN synapses in the neonatal period. We now show that triggering Ntf3 overexpression by IHC supporting cells starting in middle age rapidly increases the amplitude of sound‐evoked neural potentials compared with age‐matched controls, indicating that Ntf3 produces a positive effect on cochlear function when the pathology is minimal. Furthermore, near the end of their lifespan, Ntf3‐overexpressing mice have milder ARHL, with larger sound‐evoked potentials along the ascending auditory pathway and reduced IHC synaptopathy compared with age‐matched controls. Our results also provide evidence that an age‐related decrease in cochlear Ntf3 expression contributes to ARHL and that Ntf3 supplementation could serve as a therapeutic for this prevalent disorder. Furthermore, these findings suggest that factors that regulate synaptogenesis during development could prevent age‐related synaptopathy in the brain, a process involved in several central nervous system degenerative disorders.
Fermi's golden rule applied to the gamma decay in the quasicontinuum of 46Ti

Particle-gamma coincidences from the 46Ti(p,p' gamma)46Ti inelastic scattering reaction with 15-MeV protons are utilized to obtain gamma-ray spectra as a function of excitation energy. The rich data set allows analyzing the coincidence data with various gates on excitation energy. This enables, for many independent data sets, a simultaneous extraction of level density and radiative strength function (RSF). The results are consistent with one common level density. The data seem to exhibit a universal RSF as the deduced RSFs from different excitation energies show only small fluctuations provided that only excitation energies above 3 MeV are taken into account. If transitions to well-separated low-energy levels are included, the deduced RSF may change by a factor of 2-3, which might be expected due to the involved Porter-Thomas fluctuations.
The emergent role of mitochondrial surveillance in cellular health

Mitochondrial dysfunction is one of the primary causatives for many pathologies, including neurodegenerative diseases, cancer, metabolic disorders, and aging. Decline in mitochondrial functions leads to the loss of proteostasis, accumulation of ROS, and mitochondrial DNA damage, which further exacerbates mitochondrial deterioration in a vicious cycle. Surveillance mechanisms, in which mitochondrial functions are closely monitored for any sign of perturbations, exist to anticipate possible havoc within these multifunctional organelles with primitive origin. Various indicators of unhealthy mitochondria, including halted protein import, dissipated membrane potential, and increased loads of oxidative damage, are on the top of the lists for close monitoring. Recent research also indicates a possibility of reductive stress being monitored as part of a mitochondrial surveillance program. Upon detection of mitochondrial stress, multiple mitochondrial stress‐responsive pathways are activated to promote the transcription of numerous nuclear genes to ameliorate mitochondrial damage and restore compromised cellular functions. Co‐expression occurs through functionalization of transcription factors, allowing their binding to promoter elements to initiate transcription of target genes. This review provides a comprehensive summary of the intricacy of mitochondrial surveillance programs and highlights their roles in our cellular life. Ultimately, a better understanding of these surveillance mechanisms is expected to improve healthspan.
Efficient Machine Translation Corpus Generation

This paper proposes an efficient and semi-automated method for human-in-the-loop post- editing for machine translation (MT) corpus generation. The method is based on online training of a custom MT quality estimation metric on-the-fly as linguists perform post-edits. The online estimator is used to prioritize worse hypotheses for post-editing, and auto-close best hypothe- ses without post-editing. This way, significant improvements can be achieved in the resulting quality of post-edits at a lower cost due to reduced human involvement. The trained estimator can also provide an online sanity check mechanism for post-edits and remove the need for ad- ditional linguists to review them or work on the same hypotheses. In this paper, the effect of prioritizing with the proposed method on the resulting MT corpus quality is presented versus scheduling hypotheses randomly. As demonstrated by experiments, the proposed method im- proves the lifecycle of MT models by focusing the linguist effort on production samples and hypotheses, which matter most for expanding MT corpora to be used for re-training them
Quantized Wasserstein Procrustes Alignment of Word Embedding Spaces

Motivated by the widespread interest in the cross-lingual transfer of NLP models from high resource to low resource languages, research on Cross-lingual word embeddings (CLWEs) has gained much popularity over the years. Among the most successful and attractive CLWE models are the unsupervised CLWE models. These unsupervised CLWE models pose the alignment task as a Wasserstein-Procrustes problem aiming to estimate a permutation matrix and an orthogonal matrix jointly. Most existing unsupervised CLWE models resort to Optimal Transport (OT) based methods to estimate the permutation matrix. However, linear programming algorithms and approximate OT solvers via Sinkhorn for computing the permutation matrix scale cubically and quadratically, respectively, in the input size. This makes it impractical and infeasible to compute OT distances exactly for larger sample size, resulting in a poor approximation quality of the permutation matrix and subsequently a less robust learned transfer function or mapper. This paper proposes an unsupervised projection-based CLWE model called quantized Wasserstein Procrustes (qWP) that jointly estimates a permutation matrix and an orthogonal matrix. qWP relies on a quantization step to estimate the permutation matrix between two probability distributions or measures. This approach substantially improves the approximation quality of empirical OT solvers given fixed computational cost. We demonstrate that qWP achieves state-of-the-art results on the Bilingual lexicon Induction (BLI) task.
On the Effectiveness of Quasi Character-Level Models for Machine Translation

Neural Machine Translation (NMT) models often use subword-level vocabularies to deal with rare or unknown words. Although some studies have shown the effectiveness of purely character-based models, these approaches have resulted in highly expensive models in computational terms. In this work, we explore the benefits of quasi-character-level models for very low-resource languages and their ability to mitigate the effects of the catastrophic forgetting problem. First, we conduct an empirical study on the efficacy of these models, as a function of the vocabulary and training set size, for a range of languages, domains, and architectures. Next, we study the ability of these models to mitigate the effects of catastrophic forgetting in machine translation. Our work suggests that quasi-character-level models have practically the same generalization capabilities as character-based models but at lower computational costs. Furthermore, they appear to help achieve greater consistency between domains than standard subword-level models, although the catastrophic forgetting problem is not mitigated.
A Comparison of Data Filtering Methods for Neural Machine Translation

With the increasing availability of large-scale parallel corpora derived from web crawling and bilingual text mining, data filtering is becoming an increasingly important step in neural machine translation (NMT) pipelines. This paper applies several available tools to the task of data filtration, and compares their performance in filtering out different types of noisy data. We also study the effect of filtration with each tool on model performance in the downstream task of NMT by creating a dataset containing a combination of clean and noisy data, filtering the data with each tool, and training NMT engines using the resulting filtered corpora. We evaluate the performance of each engine with a combination of direct assessment (DA) and automated metrics. Our best results are obtained by training for a short time on all available data then filtering the corpus with cross-entropy filtering and training until convergence.
Pharmacokinetics of Ascending Doses of Praziquantel in Adults Infected with Opisthorchis felineus in Western Siberia, Russian Federation

Opisthorchiasis due to the liver fluke Opisthorchis felineus is highly prevalent in rural regions of Western Siberia, causing severe liver and bile duct maladies. Praziquantel administered as a three-dose regimen is the only drug used to treat O. felineus-infected individuals. A simpler single-dose treatment might serve as an alternative. The aim of this study was to compare the pharmacokinetic (PK) properties of single, ascending doses of praziquantel compared to multiple dosing in patients infected with O. felineus to contribute to updated treatment guidelines. ABSTRACT Opisthorchiasis due to the liver fluke Opisthorchis felineus is highly prevalent in rural regions of Western Siberia, causing severe liver and bile duct maladies. Praziquantel administered as a three-dose regimen is the only drug used to treat O. felineus-infected individuals. A simpler single-dose treatment might serve as an alternative. The aim of this study was to compare the pharmacokinetic (PK) properties of single, ascending doses of praziquantel compared to multiple dosing in patients infected with O. felineus to contribute to updated treatment guidelines. Dried blood spots (DBSs) of 110 adults were collected at 11 time points post-drug administration at single oral doses of 20, 40, and 60 mg/kg, as well as 3× 20 mg/kg (4 h dosing interval). DBS samples were analyzed using a validated liquid chromatography-tandem mass spectrometry (LC-MS/MS) method, and PK parameters were obtained for R-, S-, and R-trans-4-OH-praziquantel employing noncompartmental analysis. We observed the highest drug exposure for all analytes when the triple-dose scheme was used; area under the concentration-time curve from 0 to 24 h (AUC0–24) values of 8.04, 27.75, and 36.38 μg/mL·h were obtained, respectively. Maximal plasma concentrations (Cmax) values of 1.72, 4.89, and 2.69 μg/mL were calculated for R-, S-, and R-trans-4-OH-praziquantel, respectively, when patients were given a single 60-mg/kg dose, and they peaked at 1.5 and 2 h for the enantiomers and at 3 h for the metabolite. The herein-generated PK data, together with results that will be obtained from the integrated efficacy study, lay the groundwork for a possibly optimized treatment scheme for O. felineus-infected patients.
Draft Genome Sequence of an Enterotoxigenic Escherichia coli Strain Carrying Genes for Colonization Surface Antigen 13 and a Heat-Labile Toxin

Here, we report the draft genome of ESEI_597, an enterotoxigenic Escherichia coli (ETEC) strain harboring genes encoding colonization surface antigen 13 (CS13) and a heat-labile toxin. The ESEI_597 strain was isolated from an 8-month-old child living in Korogocho, Kenya, in 2013. ABSTRACT Here, we report the draft genome of ESEI_597, an enterotoxigenic Escherichia coli (ETEC) strain harboring genes encoding colonization surface antigen 13 (CS13) and a heat-labile toxin. The ESEI_597 strain was isolated from an 8-month-old child living in Korogocho, Kenya, in 2013.
A Serotype-Specific and Multiplex PCR Method for Whole-Genome Sequencing of Dengue Virus Directly from Clinical Samples

Dengue virus (DENV) is becoming the most globally prevalent arbovirus. The number of people living under the threat of DENV is increasing year by year. ABSTRACT Dengue virus (DENV) is the most globally prevalent member of the genus Flavivirus in the family Flaviviridae, which can be classified into four serotypes. Historically, molecular epidemiological studies of DENV depended on E gene sequencing. The development of next-generation sequencing (NGS) allowed its application to viral whole-genome sequencing (WGS). In this study, we report the improvement of the existing WGS process for DENV by optimizing the primer design procedure, designing serotype-specific primer panels and reducing the sizes of amplicons. A total of 31 DENV-positive serum samples belonging to 4 serotypes and 9 genotypes of DENV were involved in the validation of the primer panels. The threshold cycle (CT) values of these samples ranged from 23.91 to 35.11. The validation results showed that the length of consensus sequences generated at a coverage depth of 20× or more ranged from 10,370 to 10,672 bp, with 100.00% coverage of the open reading frames and 97.34% to 99.52% coverage of the DENV genome. The amplification efficiency varied across amplicons, genotypes, and serotypes of DENVs. These results indicate that the serotype-specific primer panels allow users to obtain the whole genome of DENV directly from clinical samples, providing a universal, rapid, and effective tool for the integration of genomics with dengue surveillance. IMPORTANCE Dengue virus (DENV) is becoming the most globally prevalent arbovirus. The number of people living under the threat of DENV is increasing year by year. With the development of next-generation sequencing (NGS) technology, whole-genome sequencing (WGS) has been more and more widely used in infectious disease surveillance and molecular epidemiological studies. DENV population sequencing by NGS can increase our understanding of the changing epidemiology and evolution of the DENV genome at the molecular level, which demands universal primer panels and combination with NGS platforms. Multiplex PCR with a short-amplicon approach proved superior for amplifying viral genomes from clinical samples, particularly when the viral RNA was present at low concentrations. Additionally, DENV are known for their genetic diversity within serotype groups and geographical regions, so the primer panels we designed focused on universality, which would be useful in future local DENV outbreaks.
H/sup /spl infin// controller reduction for nonlinear systems

Sufficient conditions are proposed for the existence of reduced-order (fixed-order) controllers solving the standard nonlinear H/sup /spl infin// output feedback control problem. State-space formulas for such reduced-order H/sup /spl infin// controllers are also derived in terms of the solutions of two Hamilton-Jacobi inequalities. The development uses only elementary concepts of dissipativity and differential games, thus the proofs given are simple and clear.
Deep Brain Stimulation in Progressive Generalized Dystonia in Childhood Associated With ADAR1 Gene Variant

ADAR1 variants are associated with heterogeneous neurological conditions, including Aicardi – Goutières syndrome type 6 (AGS6). 1 Movement disorders are common in these patients, especially dystonia, which is often severe and refractory to medical treatment. 1,2 We report the case of a 10-year-old girl with progressive generalized dystonia who was treated with bilateral subthalamic nucleus (STN) deep brain stimulation (DBS). No signi ﬁ cant change in the Burke – Fahn – Marsden Dystonia Rating Scale (BFMDRS) score was observed after 15 months of DBS. Never-theless, the patient showed fewer dystonic crises and less need for medication than she had before treatment.
Paleogene forest fragmentation and out‐of‐Africa dispersal explain radiation of the Paleotropical dung beetle tribe Epactoidini trib. nov. (Coleoptera: Scarabaeinae)

Paleotropical clades with largely disjunct distributions are ideal models for biogeographic reconstructions. The dung beetle genera Grebennikovius Mlambo, Scholtz & Deschodt, Epactoides Olsouffief and Ochicanthon Vaz‐de‐Mello are distributed in Tanzania, Madagascar and Réunion, and the Oriental region, respectively. We combine morphology and molecular dataset to reconstruct the phylogenetic relationships between these taxa. Our analyses corroborate previous hypotheses of monophyly of the group, which is here described as new tribe Epactoidini trib. nov. Grebennikovius is recovered as sister to Epactoides, while Ochicanthon emerges as sister to them both. The disjunct distribution of our focal clade is unusual within the subfamily Scarabaeinae. Bayesian divergence time estimates and ancestral range reconstructions indicate an African origin of the crown group of the tribe Epactoidini trib. nov. in the early mid Eocene, ca. 46 Ma. The divergence between Epactoides and its sister is dated to 32.3 Ma, while the crown age for the genus Ochicanthon is dated to 27 Ma. We investigate the factors that may have shaped the current distribution of the tribe Epactoidini trib. nov. The formation of the Gomphotherium landbridge, along with favourable environmental conditions would have allowed dry‐intolerant organisms, such as Ochicanthon, to disperse out of Africa. Remarkable climatic stability of the Eastern Arc Mountains was critical for the retention of the monotypic genus Grebennikovius. We suggest two subsequent overwater dispersal events: the migration of the most recent common ancestor (MRCA) of Epactoides from Africa to Madagascar (32.3–29.5 Ma); the lately dispersal of the MRCA of the today's extinct Epactoides giganteus Rossini, Vaz‐de‐Mello & Montreuil to Réunion island from Madagascar (3.4 Ma). We suggest that the high potential of dispersal of Epactoidini trib. nov. dung beetles and the strict association to forest habitat might have triggered two major radiations, one in Madagascar and one in the Oriental Region.
A unifying Bayesian framework for merging X-ray diffraction data

Novel X-ray methods are transforming the study of the functional dynamics of biomolecules. Key to this revolution is detection of often subtle conformational changes from diffraction data. Diffraction data contain patterns of bright spots known as reflections. To compute the electron density of a molecule, the intensity of each reflection must be estimated, and redundant observations reduced to consensus intensities. Systematic effects, however, lead to the measurement of equivalent reflections on different scales, corrupting observation of changes in electron density. Here, we present a modern Bayesian solution to this problem, which uses deep learning and variational inference to simultaneously rescale and merge reflection observations. We successfully apply this method to monochromatic and polychromatic single-crystal diffraction data, as well as serial femtosecond crystallography data. We find that this approach is applicable to the analysis of many types of diffraction experiments, while accurately and sensitively detecting subtle dynamics and anomalous scattering.
Truncated RNA-binding protein production by DUX4-induced systemic inhibition of nonsense-mediated RNA decay

Nonsense-mediated RNA decay (NMD) is a surveillance mechanism that degrades both canonical and aberrant transcripts carrying premature translation termination codons. NMD is thought to have evolved to prevent the synthesis of toxic truncated proteins. However, whether global inhibition of NMD results in widespread production of truncated proteins is unknown. A human genetic disease, facioscapulohumeral muscular dystrophy (FSHD) features acute inhibition of NMD upon expression of the disease-causing transcription factor, DUX4. Here, using a cell-based model of FSHD, we show the production of hundreds of truncated proteins from physiological NMD targets. Using ribosome profiling, we map the precise C-terminal end of these aberrant truncated proteins and find that RNA-binding proteins are especially enriched for aberrant truncations. The stabilized NMD isoform of one RNA-binding protein, SRSF3, is robustly translated to produce a stable truncated protein, which can also be detected in FSHD patient-derived myotubes. Notably, ectopic expression of truncated SRSF3 alone confers toxicity and its downregulation is cytoprotective. Our results demonstrate the genome-scale impact of NMD inhibition. This widespread production of potentially deleterious truncated proteins has implications for FSHD biology as well as other genetic diseases where NMD is therapeutically modulated.
Bayesian optimization for demographic inference

Motivation Inference of demographic histories of species and populations is one of the central problems in population genetics. It is usually stated as an optimization problem: find a model’s parameters that maximize a certain log-likelihood. This log-likelihood is often expensive to evaluate in terms of time and hardware resources, critically more so for larger population counts. Although genetic algorithm based solution have proven efficient for demographic inference in the past, it struggles to deal with log-likelihoods in the setting of more than three populations. Different tools are therefore needed to handle such scenarios. Results We introduce a new specialized optimization pipeline for demographic inference with time-consuming log-likelihood evaluations. It is based on Bayesian optimization, a prominent technique for optimizing expensive black box functions. Comparing to the existing widely used genetic algorithm solution, we demonstrate new pipeline’s superiority in time limited conditions for demographic inference with four and five populations when using log-likelihoods provided by the moments tool. Moreover, we expect this behavior to generalize just as well to other expensive-to-evaluate log-likelihood functions in the field. Availability The proposed method was implemented as part of the GADMA software framework and is freely and openly available on GitHub: https://github.com/ctlab/GADMA. Contact ekaterina.e. noskova@gmail.com, viacheslav.borovitskiy@gmail.com Supplementary information Supplementary materials are available as a separate document.
Mechanical regulation of Titin N2B-us conformation and its binding to FHL2

The 572 amino acids unique sequence on titin N2B element (N2B-us) is known to regulate the passive elasticity of muscle as an elastic spring. It also serves as a hub for cardiac hypertrophic signaling by interacting with multiple proteins such as FHL1(Sheikh et al, 2008), FHL2(Lange et al, 2002), and Erk2(Perkin et al, 2015). N2B-us is thought to be an intrinsically disordered region. In addition, N2B-us bears force; therefore, the functions of N2B-us are likely regulated by mechanical stretching. In the work, we investigated the conformation of N2B-us as well as its force-dependent interaction with FHL2 using a combination of AlphaFold2 predictions and single-molecule experimental validation. Surprisingly, a stable alpha/beta structural domain (~115 a.a.) was predicted and confirmed in N2B-us, which can be mechanically unfolded at forces greater than 5 pN. More than twenty FHL2 LIM domain binding sites were predicted to spread throughout N2B-us including the regions cryptic in the structural domain. Mechanosensitive binding of FHL2 to N2B-us is revealed in single-molecule manipulation experiments. Together, the results unveil several previously unknown aspects of the N2B-us conformations and its force-dependent interactions with FHL2, which provides new insights into the physiological functions of the force-bearing N2B-us region.