Miracle-dz/UniFAR-FTUs huggingface dataset:
In Silico Analysis of Missense Mutations as a First Step in Functional Studies: Examples from Two Sphingolipidoses

In order to delineate a better approach to functional studies, we have selected 23 missense mutations distributed in different domains of two lysosomal enzymes, to be studied by in silico analysis. In silico analysis of mutations relies on computational modeling to predict their effects. Various computational platforms are currently available to check the probable causality of mutations encountered in patients at the protein and at the RNA levels. In this work we used four different platforms freely available online (Protein Variation Effect Analyzer- PROVEAN, PolyPhen-2, Swiss-model Expert Protein Analysis System—ExPASy, and SNAP2) to check amino acid substitutions and their effect at the protein level. The existence of functional studies, regarding the amino acid substitutions, led to the selection of the distinct protein mutants. Functional data were used to compare the results obtained with different bioinformatics tools. With the advent of next-generation sequencing, it is not feasible to carry out functional tests in all the variants detected. In silico analysis seems to be useful for the delineation of which mutants are worth studying through functional studies. Therefore, prediction of the mutation impact at the protein level, applying computational analysis, confers the means to rapidly provide a prognosis value to genotyping results, making it potentially valuable for patient care as well as research purposes. The present work points to the need to carry out functional studies in mutations that might look neutral. Moreover, it should be noted that single nucleotide polymorphisms (SNPs), occurring in coding and non-coding regions, may lead to RNA alterations and should be systematically verified. Functional studies can gain from a preliminary multi-step approach, such as the one proposed here.
Design and Development of a Portable Exoskeleton for Hand Rehabilitation

Improvement in hand function to promote functional recovery is one of the major goals of stroke rehabilitation. This paper introduces a newly developed exoskeleton for hand rehabilitation with a user-centered design concept, which integrates the requirements of practical use, mechanical structure, and control system. The paper also evaluated the function with two prototypes in a local hospital. Results of functional evaluation showed that significant improvements were found in ARAT (P = 0.014), WMFT (P = 0.020), and FMA_WH (P = 0.021). Increase in the mean values of FMA_SE was observed but without significant difference (P = 0.071). The improvement in ARAT score reflects the motor recovery in hand and finger functions. The increased FMA scores suggest there is a motor improvement in the whole upper limb, and especially in the hand after the training. The product met patients’ requirements and has practical significance. It is portable, cost-effective, easy to use and supports multiple control modes to adapt to different rehabilitation phases.
Collaborative remembering reduces suggestibility: A study with the Gudjonsson Suggestibility Scale

ABSTRACT Collaboration during the retrieval phase can have both negative and positive effects (referred to as collaborative inhibition and error pruning, respectively) on emotional and eyewitness memory. To further elucidate these issues, the present experiment used the Gudjonsson Suggestibility Scale to investigate the question of whether collaborative remembering reduced post-event suggestibility. Collaborative and nominal pairs listened to the GSS2, provided immediate and delayed (after 30 min) free recalls, and answered a series of leading questions before or after receiving a negative feedback about their performance. We found no evidence of collaborative inhibition in the immediate and delayed free recall tasks. Importantly, however, collaborative pairs produced less confabulated elements in the free recall tasks, were considerably less prone to give in to leading questions (both before and after receiving the negative feedback), and exhibited lower levels of Total Suggestibility, compared to both nominal and individual dyads. Taken together, these results support the conclusion that collaboration can have a beneficial influence on eyewitnesses’ accuracy, by strengthening their resistance to post-event suggestibility.
Timing of Prenatal Androgen Exposure: Anatomical and Endocrine Effects on Juvenile Male and Female Rhesus Monkeys

Prenatal androgen shapes genital differentiation. In humans, genital anatomy determines sex of rearing and subsequent behavioral development. Rhesus monkey genital anatomy and neuroendocrine function are sexually differentiated, and behavioral development occurs in a complex social environment. We investigated prenatal hormonal influences on sexual differentiation by suppressing or increasing androgens in male and female rhesus monkeys. Pregnant multiparous female rhesus monkeys received 35-40 days of testosterone enanthate (TE) treatment, androgen antagonist (flutamide, FL) treatment, or vehicle starting on gestation day (GD) 35 or 40 (early) or GD 110 or 115 (late). Exogenous androgen increased neonatal LH secretion in females when given early and altered female genital differentiation when administered either early or late. TE treatment, early or late in gestation, had no measurable effects on male genital differentiation or neuroendocrine function. Early FL treatment, however, radically altered male genital differentiation, producing in two cases males with a urethral opening separate from the glans. In females, early FL treatment produced detectable alterations in genitalia consistent with a reduced exposure to prenatal androgen, suggesting that female rhesus monkeys are naturally exposed prenatally to meaningful levels of T. Late FL treatment reduced male penis size and increased neonatal T secretion, but had no effect in females. This is the first study to block endogenous prenatal testosterone in rhesus monkeys, thereby altering sexual differentiation. These findings illustrate the complexity of prenatal influences on anatomical and neuroendocrine development. The relationship between the anatomical changes reported here and sex differences in behavior is currently under investigation.
A Novel Pathogenic UGT1A1 Variant in a Sudanese Child with Type 1 Crigler-Najjar Syndrome

Uridine diphosphate glucuronosyltransferases (UGTs) are key enzymes responsible for the body’s ability to process a variety of endogenous and exogenous compounds. Significant gains in understanding UGT function have come from the analysis of variants seen in patients. We cared for a Sudanese child who showed clinical features of type 1 Crigler-Najjar syndrome (CN-1), namely severe unconjugated hyperbilirubinemia leading to liver transplantation. CN-1 is an autosomal recessive disorder caused by damaging mutations in the gene for UGT1A1, the hepatic enzyme responsible for bilirubin conjugation in humans. Clinical genetic testing was unable to identify a known pathogenic UGT1A1 mutation in this child. Instead, a novel homozygous variant resulting in an in-frame deletion, p.Val275del, was noted. Sanger sequencing demonstrated that this variant segregated with the disease phenotype in this family. We further performed functional testing using recombinantly expressed UGT1A1 with and without the patient variant, demonstrating that p.Val275del results in a complete lack of glucuronidation activity, a hallmark of CN-1. Sequence analysis of this region shows a high degree of conservation across all known catalytically active human UGTs, further suggesting that it plays a key role in the enzymatic function of UGTs. Finally, we note that the patient’s ethnicity likely played a role in his variant being previously undescribed and advocate for greater diversity and inclusion in genomic medicine.
Compensation of Susceptibility-Induced BOLD Sensitivity Losses in Echo-Planar fMRI Imaging

Gradient-echo echo-planar imaging is a standard technique in functional magnetic resonance imaging (fMRI) experiments based on the blood oxygenation level-dependent (BOLD) effect. A major problem is the occurrence of susceptibility gradients near air/tissue interfaces. As a consequence, the detection of neuronal activation may be greatly compromised in certain brain areas, especially in the temporal lobes and in the orbitofrontal cortex. Common approaches to overcome this problem, such as z-shimming or the use of tailored radio frequency pulses, usually compensate only for susceptibility gradients in the slice selection direction. In the present study, the influence of susceptibility gradients in the phase encoding direction is investigated both theoretically and experimentally. It is shown that these gradients influence the effective echo time TE and may reduce considerably the local BOLD sensitivity, even in the case of acceptable image intensities. A compensation method is proposed and tested in an fMRI experiment based on a hypercapnic challenge. The results suggest that the compensation method allows for the detection of activation in brain areas which are usually unavailable for BOLD studies.
Application of Power Method and Dominant Eigenvector/Eigenvalue Concept for Approximate Eigenspace Solutions to Mechanical Engineering Algebraic Systems

This paper shows how the concept of dominant eigenvector/eigenvalue and the power method can be used for understanding the solution to practical problems in a broad class of mechanical engineering systems described by linear algebraic equations. An analytical mathematical procedure is developed to obtain a reasonably accurate approximate eigenspace solution to the system Ax=b by transforming the non-symmetric system matrix into a form where the power method is used several times to compute the contribution of only one or two eigenvector/eigenvalue pairs that dominate the solution. The complete set of eigenvalues and eigenvectors is not required. The intent is to provide a novel application of and show the importance of the significance of dominant eigenvector/eigenvalue pairs and to use the power method in the analysis and understanding of mechanical engineering systems for both education and practice. Typically, the concepts of both eigenvector expansion and dominant contribution are not included in mechanical engineering education. The scope of application is a broad area of six practical mechanical engineering problems including translational and rotational dynamics, statics of structures, thermal energy balance, fluid continuity, and feedback control. These general mechanical engineering systems naturally contain numerical A and b matrices that fit the scope suitable for providing feasible accuracy. The systems range from fourth order to two hundredth order. Results indicate that accuracy greatly improves as the A matrix contains elements of the same order of numerical magnitude, either naturally from the physics of the problem, or through a transformation to dimensionless parameters. Motivation for using the power method for dominant eigenvector/eigenvalue calculation comes from methods used in web page rank algorithms and a desire to expand mechanical engineering students’ education in understanding the role of the eigenstate expansion method for the solution of algebraic equations without computing all of its eigenvalues and eigenvectors. An in depth quantitative assessment of the approximate dominant eigenspace method accuracy is obtained by testing the mechanical engineering examples against a near exact solution via a software solver. This error assessment is based on parameters useful in the design and understanding of mechanical systems. The accuracy achieved is feasible for education and for other uses of the method by practicing mechanical engineers such as when a simple analytical based approximate model may be more suited for inclusion into larger system based models.
A Molecular Biophysical Approach to Diclofenac Topical Gastrointestinal Damage

Diclofenac (DCF), the most widely consumed non-steroidal anti-inflammatory drug (NSAID) worldwide, is associated with adverse typical effects, including gastrointestinal (GI) complications. The present study aims to better understand the topical toxicity induced by DCF using membrane models that mimic the physiological, biophysical, and chemical environments of GI mucosa segments. For this purpose, phospholipidic model systems that mimic the GI protective lining and lipid models of the inner mitochondrial membrane were used together with a wide set of techniques: derivative spectrophotometry to evaluate drug distribution at the membrane; steady-state and time-resolved fluorescence to predict drug location at the membrane; fluorescence anisotropy, differential scanning calorimetry (DSC), dynamic light scattering (DLS), and calcein leakage studies to evaluate the drug-induced disturbance on membrane microviscosity and permeability; and small- and wide-angle X-ray scattering studies (SAXS and WAXS, respectively), to evaluate the effects of DCF at the membrane structure. Results demonstrated that DCF interacts chemically with the phospholipids of the GI protective barrier in a pH-dependent manner and confirmed the DCF location at the lipid headgroup region, as well as DCF’s higher distribution at mitochondrial membrane contact points where the impairment of biophysical properties is consistent with the uncoupling effects reported for this drug.
Neuer Frühindikator für die Entwicklung der Arbeitslosigkeit: Startschuss für das IAB-Arbeitsmarktbarometer

von Christian Hutter, Enzo Weber, Katrin Schmidt und Silke Delfs  Wir stellen das IAB-Arbeitsmarktbarometer vor, einen neuen Frühindikator, der die Entwicklung der saisonbereinigten Arbeitslosenzahl Deutschlands in der kurzen Frist anzeigt.  Künftig wird das IAB-Arbeitsmarktbarometer immer zum Ende eines Monats veröffentlicht.  Der aktuelle Oktober-Wert von 99,6 signalisiert eine Seitwärtsbewegung der saisonbereinigten Arbeitslosigkeit in den nächsten drei Monaten. Im Sommer hatte sich der Barometerstand verbessert, bewegt sich seitdem aber im neutralen Bereich.  Als Basis für den neuen Indikator dient eine monatliche Umfrage der Bundesagentur für Arbeit unter allen lokalen Arbeitsagenturen.  Das IAB-Arbeitsmarktbarometer geht über ein einfaches gewichtetes Mittel der Antworten hinaus. Insbesondere berücksichtigt es, dass die Einschätzungen der Befragten im Zeitablauf unterschiedlich gut zutreffen.  Die Verwendung des neuen Indikators führt zu einer signifikanten Verbesserung der Prognosegüte gegenüber verschiedenen BenchmarkAnsätzen. Auch im Vergleich mit anderen potenziellen Frühindikatoren kann das neue IAB-Arbeitsmarktbarometer überzeugen. Die kurzfristige Prognose von Beschäftigung und Arbeitslosigkeit in Deutschland ist eine zentrale Leistung des IAB. Geeignete Frühindikatoren können hierzu wesentlich beitragen. Auch wenn für den deutschen Arbeitsmarkt bereits einige solcher Indikatoren existieren, so besteht aktuell noch Bedarf an einem Frühindikator, der die Entwicklung der Arbeitslosigkeit direkt signalisiert. Wir stellen hier einen neuen, umfragebasierten Arbeitslosigkeitsindikator vor, der diese Lücke schließt: das IAB-Arbeitsmarktbarometer.
Cryo-EM structure of the NLRC4CARD filament provides insights into how symmetric and asymmetric supramolecular structures drive inflammasome assembly

Inflammasomes are supramolecular signaling platforms integral to innate immune defense against invading pathogens. The NOD-like receptor (NLR) family apoptosis inhibitory protein (NAIP)·NLR family caspase-recruiting domain (CARD) domain-containing 4 (NLRC4) inflammasome recognizes intracellular bacteria and induces the polymerization of the caspase-1 protease, which in turn executes maturation of interleukin-1β (IL-1β) and pyroptosis. Several high-resolution structures of the fully assembled NAIP·NLRC4 complex are available, but these structures do not resolve the architecture of the CARD filament in atomic detail. Here, we present the cryo-EM structure of the filament assembled by the CARD of human NLRC4 (NLRC4CARD) at 3.4 Å resolution. The structure revealed that the helical architecture of the NLRC4CARD filament is essentially identical to that of the downstream filament assembled by the CARD of caspase-1 (casp1CARD), but deviates from the split washer-like assembly of the NAIP·NLRC4 oligomer. Our results suggest that architectural complementarity is a major driver for the recognition between upstream and downstream CARD assemblies in inflammasomes. Furthermore, a Monte Carlo simulation of the NLRC4CARD filament assembly rationalized why an (un)decameric NLRC4 oligomer is optimal for assembling the helical base of the NLRC4CARD filament. Together, our results explain how symmetric and asymmetric supramolecular assemblies enable high-fidelity signaling in inflammasomes.
Generalized multifactor dimensionality reduction approaches to identification of genetic interactions underlying ordinal traits

The manifestation of complex traits is influenced by gene–gene and gene–environment interactions, and the identification of multifactor interactions is an important but challenging undertaking for genetic studies. Many complex phenotypes such as disease severity are measured on an ordinal scale with more than two categories. A proportional odds model can improve statistical power for these outcomes, when compared to a logit model either collapsing the categories into two mutually exclusive groups or limiting the analysis to pairs of categories. In this study, we propose a proportional odds model‐based generalized multifactor dimensionality reduction (GMDR) method for detection of interactions underlying polytomous ordinal phenotypes. Computer simulations demonstrated that this new GMDR method has a higher power and more accurate predictive ability than the GMDR methods based on a logit model and a multinomial logit model. We applied this new method to the genetic analysis of low‐density lipoprotein (LDL) cholesterol, a causal risk factor for coronary artery disease, in the Multi‐Ethnic Study of Atherosclerosis, and identified a significant joint action of the CELSR2, SERPINA12, HPGD, and APOB genes. This finding provides new information to advance the limited knowledge about genetic regulation and gene interactions in metabolic pathways of LDL cholesterol. In conclusion, the proportional odds model‐based GMDR is a useful tool that can boost statistical power and prediction accuracy in studying multifactor interactions underlying ordinal traits.
The specificity of the individual professional practice of midwives with regard to home births. Analysis of the ‘relationship field’

Abstract Introduction. By virtue of the Act of 5 July 1996 on the occupation of nurses and midwives, a midwife in Poland has full professional autonomy. The Act does not forbid conduct of individual practice outside of a hospital. Aim. The purpose of the article is to present practical execution of individual practice of assisting during home birth with regard to relations between the midwife and the woman giving birth. Materials and methods. The issues presented in the article are a part of broader research concerning home births in Poland. The research was commenced in 2014 and finalized in 2018. The analysis concerned statements of women who decided not to give birth in a hospital. I obtained the empirical material through in-depth interviews and I referred to data existing in the form of e.g. blog entries. Finally, I collected 40 descriptions of home births. They underwent a qualitative analysis with the use of the grounded theory methodology and the social world theory. Results. The outcome of the research is a multifaceted “sociological portrait” of the world of women, which implement an alternative to the hospital birth scenario. In the article, I limit myself to the presentation of mechanisms of transformation of midwife-birthing woman relations from professionally neutral to emotionally involved: mutual appreciation, balancing of positions, comprehensive qualification, systematic maintenance of relations, and feminization of birth. I also presented the principles of cooperation with the birthing woman during home birth: constant and imperceptible presence, following a woman, patient accompaniment, support, animation of bonds, and respect for the ceremony. The whole discussion depicts the special character of the individual practice of midwives with regard to the field of relations. Conclusion. Reference to childbirth experiences allowed for identifying potential expectations of women planning to have children towards the midwife’s profession, as well as the possible paths of professional development of representatives of this profession, especially in the face of the growing awareness and autonomy of people using health care services. These issues may also be treated as an element of a broader discussion on the shape of an optimum pre- and post-natal care.
A further examination of a pre-existing bias favouring a sword in the genus
 Xiphophorus
 


Models of sexual selection have recently been broadened to include the pre-existing bias model. This model suggests that female preferences that result in the evolution of male traits can be established prior to the appearance of a male trait. Previous work suggests that in the genus Xiphophorus, which consists of swordless platyfish and sworded swordtails, female southern platyfish, X. maculatus, prefer conspecific males with surgically attached swords, despite phylogenetic evidence that the common ancestor of platyfish and swordtails was swordless. In the present study, female X. maculatuswere found to prefer conspecific males with a naturally occurring component of the sword, an abbreviated lower caudal stripe. To investigate the possibility that the previously suggested pre-existing bias favouring a sword was merely an extension of a preference for this stripe specific to X. maculatus, whether female variable platyfish, X. variatus, also demonstrate a preference for males with swords was tested; this species has neither a sword nor any component of the sword. Female X. variatuswere found to prefer conspecific males with swords to those without. This work suggests that X. variatus and X. maculatus share a preference favouring a sword, despite the lack of a sword in these species. 1995 The Association for the Study of Animal Behaviour
Word and sentence embedding tools to measure semantic similarity of Gene Ontology terms by their definitions

The Gene Ontology (GO) database contains GO terms that describe biological functions of genes. Previous methods for comparing GO terms have relied on the fact that GO terms are organized into a tree structure. In this paradigm, the locations of two GO terms in the tree dictate their similarity score. In this paper, we introduce two new solutions for this problem, by focusing instead on the definitions of the GO terms. We apply neural network based techniques from the natural language processing (NLP) domain. The first method does not rely on the GO tree, whereas the second indirectly depends on the GO tree. In our first approach, we compare two GO definitions by treating them as two unordered sets of words. The word similarity is estimated by a word embedding model that maps words into an N-dimensional space. In our second approach, we account for the word-ordering within a sentence. We use a sentence encoder to embed GO definitions into vectors and estimate how likely one definition entails another. We validate our methods in two ways. In the first experiment, we test the model’s ability to differentiate a true protein-protein network from a randomly generated network. In the second experiment, we test the model in identifying orthologs from randomly-matched genes in human, mouse, and fly. In both experiments, a hybrid of NLP and GO-tree based method achieves the best classification accuracy. Availability github.com/datduong/NLPMethods2CompareGOterms