Miracle-dz/UniFAR-FTUs huggingface dataset:
CERT1 mutations perturb human development by disrupting sphingolipid homeostasis

Neural differentiation, synaptic transmission, and action potential propagation depend on membrane sphingolipids, whose metabolism is tightly regulated. Mutations in the ceramide transporter CERT (CERT1), which is involved in sphingolipid biosynthesis, are associated with intellectual disability, but the pathogenic mechanism remains obscure. Here, we characterize 31 individuals with de novo missense variants in CERT1. Several variants fall into a previously uncharacterized dimeric helical domain that enables CERT homeostatic inactivation, without which sphingolipid production goes unchecked. The clinical severity reflects the degree to which CERT autoregulation is disrupted, and inhibiting CERT pharmacologically corrects morphological and motor abnormalities in a Drosophila model of the disease, which we call ceramide transporter (CerTra) syndrome. These findings uncover a central role for CERT autoregulation in the control of sphingolipid biosynthetic flux, provide unexpected insight into the structural organization of CERT, and suggest a possible therapeutic approach for patients with CerTra syndrome.
Space-time characteristics of wall-pressure and wall shear-stress fluctuations in wall-modeled large eddy simulation.

We report the space-time characteristics of the wall-pressure fluctuations and wall shear-stress fluctuations from wall-modeled large eddy simulation (WMLES) of a turbulent channel flow at Re τ = 2000. Two standard zonal wall models (equilibrium stress model and nonequilibrium model based on unsteady RANS) are employed, and it is shown that they yield similar results in predicting these quantities. The wall-pressure and wall shear-stress fields from WMLES are analyzed in terms of their r.m.s. fluctuations, spectra, two-point correlations, and convection velocities. It is demonstrated that the resolution requirement for predicting the wall-pressure fluctuations is more stringent than that for predicting the velocity. At least δ/Δx > 20 and δ/Δz > 30 are required to marginally resolve the integral length scales of the pressure-producing eddies near the wall. Otherwise, the pressure field is potentially aliased. Spurious high wave number modes dominate in the streamwise direction, and they contaminate the pressure spectra leading to significant overprediction of the second-order pressure statistics. When these conditions are met, the pressure statistics and spectra at low wave number or low frequency agree well with the DNS and experimental data. On the contrary, the wall shear-stress fluctuations, modeled entirely through the RANS-based wall models, are largely underpredicted and relatively insensitive to the grid resolution. The short-time, small-scale near-wall eddies, which are neither resolved nor modeled adequately in the wall models, seem to be important for accurate prediction of the wall shear-stress fluctuations.
Effects of Controlled Supramaximal High-Intensity Interval Training on Cardiorespiratory Fitness and Global Cognitive Function in Older Adults: The Umeå HIT Study—A Randomized Controlled Trial

Abstract Background This study examined the effects of regulated and controlled supramaximal high-intensity interval training (HIT) adapted for older adults, compared to moderate-intensity training (MIT), on cardiorespiratory fitness; cognitive, cardiovascular, and muscular function; and quality of life. Methods Sixty-eight nonexercising older adults (66–79 years, 44% males) were randomized to 3 months of twice-weekly HIT (20-minute session including 10 × 6-second intervals) or MIT (40-minute session including 3 × 8-minute intervals) on stationary bicycles in an ordinary gym setting. Individualized target intensity was watt controlled with a standardized pedaling cadence and individual adjustment of the resistance load. Primary outcomes were cardiorespiratory fitness (V̇o2peak) and global cognitive function (unit-weighted composite). Results V̇o2peak increased significantly (mean 1.38 mL/kg/min, 95% CI [0.77, 1.98]), with no between-group difference (mean difference 0.05 [−1.17, 1.25]). Global cognition did not improve (0.02 [−0.05, 0.09]), nor differed between groups (0.11 [−0.03, 0.24]). Significant between-group differences in change were observed for working memory (0.32 [0.01, 0.64]), and maximal isometric knee extensor muscle strength (0.07 N·m/kg [0.003, 0.137]), both in favor of HIT. Irrespective of the group, there was a negative change in episodic memory (−0.15 [−0.28, −0.02]), a positive change in visuospatial ability (0.26 [0.08, 0.44]), and a decrease in systolic (−2.09 mmHg [−3.54, −0.64]) and diastolic (−1.27 mmHg [−2.31, −0.25]) blood pressure. Conclusions In nonexercising older adults, 3 months of watt-controlled supramaximal HIT improved cardiorespiratory fitness and cardiovascular function to a similar extent as MIT, despite half the training time. In favor of HIT, there was an improvement in muscular function and a potential domain-specific effect on working memory. Clinical Trial Registration NCT03765385
Socio-Cultural Influencers of Disclosure of HIV Status to Children on Antiretroviral Therapy in the Masaka Region, Uganda: A Qualitative Study

This study explored sociocultural influencers of disclosure of HIV status to children taking daily antiretroviral therapy (ART) in the Masaka region, Uganda using data collected from 26 key informant interviews with caregivers between October 2020 and July 2021. The findings revealed both positive and negative sociocultural influencers of disclosure. Beliefs that disclosure cultivates responsibility in the child to improve ART adherence and the culture of routine sexual health education conversations with children were positive socio-cultural influencers. Beliefs that disclosure increases children's loss of hope in life and breaks confidentiality with children inadvertently disclosing their HIV status to others leading to discrimination and social rejection, were key negative sociocultural influencers. These findings suggest a need for socio-culturally informed interventions that target caregiver negative socio-cultural disclosure influencers in this setting through contextualized sensitization and training to prepare children taking daily ART to receive disclosure progressively.
A polypyrrole-cotton pad sorbent as micro-solid phase extractor enclosed in tea bag envelope for determination of synthetic antioxidants in non-alcoholic beverage products

Abstract A polypyrrole (PPy)-cotton pad sorbent enclosed in tea bag envelope was developed and used in micro-solid phase extraction (µ-SPE) for the determination of butylated hydroxyanisole (BHA) and butylated hydroxytoluene (BHT). After extraction, the extract was qualified and quantified by a gas chromatograph equipped with a flame ionization detector (GC-FID). Parameters influencing this developed method and the efficiency of µ-SPE were studied and optimized. Under the optimal conditions, the developed method provided good linearity in a concentration range of 0.100–100 µg L−1 for BHA and 0.050–50 µg L−1 for BHT, respectively. The limits of detection were 39.27 ± 0.52 ng L−1 for BHA and 16.96 ± 0.17 ng L−1 for BHT. Satisfactory relative recoveries of BHA and BHT were achieved in the range from 86.8 ± 1.9 to 117.1 ± 2.3% with acceptable relative standard deviation (RSD) below 8.1%. Good reproducibility was obtained with RSDs < 3.1%, for n = 6. The developed adsorbent is easy to operate, low cost, eco-friendly, reusable, with high extraction efficiency, and was successfully applied in the simultaneous synthetic antioxidant determination of non-alcoholic beverage samples.
Predictive Utility of Irritability "In Context": Proof-of-Principle for an Early Childhood Mental Health Risk Calculator.

OBJECTIVE We provide proof-of-principle for a mental health risk calculator advancing clinical utility of the irritability construct for identification of young children at high risk for common, early onsetting syndromes. METHOD Data were harmonized from two longitudinal early childhood subsamples (total N = 403; 50.1% Male; 66.7% Nonwhite; Mage = 4.3 years). The independent subsamples were clinically enriched via disruptive behavior and violence (Subsample 1) and depression (Subsample 2). In longitudinal models, epidemiologic risk prediction methods for risk calculators were applied to test the utility of the transdiagnostic indicator, early childhood irritability, in the context of other developmental and social-ecological indicators to predict risk of internalizing/externalizing disorders at preadolescence (Mage = 9.9 years). Predictors were retained when they improved model discrimination (area under the receiver operating characteristic curve [AUC] and integrated discrimination index [IDI]) beyond the base demographic model. RESULTS Compared to the base model, the addition of early childhood irritability and adverse childhood experiences significantly improved the AUC (0.765) and IDI slope (0.192). Overall, 23% of preschoolers went on to develop a preadolescent internalizing/externalizing disorder. For preschoolers with both elevated irritability and adverse childhood experiences, the likelihood of an internalizing/externalizing disorder was 39-66%. CONCLUSIONS Predictive analytic tools enable personalized prediction of psychopathological risk for irritable young children, holding transformative potential for clinical translation.
Sequence-Based Characterization of Microalgal Microbiomes: Impact of DNA Extraction Protocol on Yield and Community Composition

Microalgae are very important as primary producers in the ocean, but also as forthcoming sustainable producers of biotechnologically interesting compounds. Accordingly, the bacterial microbiomes associated with microalgae are attracting increasing attention due to their effects on the growth and health of microalgae. ABSTRACT The bacterial communities associated with microalgae are vital for the growth and health of the host, and engineering algal microbiomes can enhance the fitness of the algae. Characterization of these microbiomes mostly relies on sequencing of DNA, which can be extracted with an array of protocols that potentially impact DNA quantity and quality and thus potentially affect subsequent analyses of microbiome composition. Here, we extracted DNA from Isochrysis galbana, Tetraselmis suecica, and Conticribra weissflogii microbiomes using four different protocols. DNA yield and quality was greatly impacted by the choice of extraction protocol, whereas microbiome composition determined by 16S rRNA gene amplicon sequencing was only impacted to a minor degree, with microalgal host species being the main determinant of microbiome composition. The I. galbana microbiome was dominated by the genus Alteromonas, whereas the microbiome associated with T. suecica was dominated by Marinobacteraceae and Rhodobacteraceae family members. While these two families were also prevalent in the microbiome associated with C. weissflogii, Flavobacteriaceae and Cryomorphaceae were also highly dominant. Phenol-chloroform extraction resulted in higher DNA quality and quantity compared to commercial kits; however, because they have other advantages such as high throughput and low toxicity, commercial kits can be employed to great benefit for the characterization of microalgal microbiomes. IMPORTANCE Microalgae are very important as primary producers in the ocean, but also as forthcoming sustainable producers of biotechnologically interesting compounds. Accordingly, the bacterial microbiomes associated with microalgae are attracting increasing attention due to their effects on the growth and health of microalgae. Since most members of these microbiomes cannot be cultured, knowledge about community composition is best obtained using sequencing-based methods. This study evaluates the impact of DNA extraction methods on DNA quantity and quality along with sequence-based characterization of the bacterial microbiome composition of three microalgae: Isochrysis galbana, Tetraselmis suecica, and Conticribra weissflogii.
Central and peripheral α‐synuclein in Parkinson disease detected by seed amplification assay

Detection of α‐synuclein aggregates by seed amplification is a promising Parkinson disease biomarker assay. Understanding intraindividual relationships of α‐synuclein measures could inform optimal biomarker development. The objectives were to test accuracy of α‐synuclein seed amplification assay in central (cerebrospinal fluid) and peripheral (submandibular gland) sources, compare to total α‐synuclein measures, and investigate within‐subject relationships.
Extraction of Curved Fibers from 3D Data

A segmentation algorithm is proposed which automatically extracts single fibers from tomographic 3D data of fiber-based materials. As an example, the algorithm is applied to a non-woven material used in the gas diffusion layer of polymer electrolyte membrane fuel cells. This porous material consists of a densely packed system of strongly curved carbon fibers. Our algorithm works as follows. In a first step, we focus on the extraction of skeletons, i.e., center lines of fibers. Due to irregularities like noise or other data artefacts, it is only possible to extract fragments of center lines. Thus, in a second step, we consider a stochastic algorithm to adequately connect these parts of center lines to each other, with the general aim to reconstruct the complete fibers such that the curvature properties of real fibers are reflected correctly. The quality of the segmentation algorithm is validated by applying it to simulated test data.
The Economic Design of Control Charts: A Unified Approach

The choice of control chart parameters—sample size, sampling interval, and control limits—is considered from an economic point of view. A general process model is considered, and the hourly cost function is derived. This cost function simplifies when the recorded statistics are independent. Numerical techniques to minimize this cost function are discussed, and sensitivity analyses are performed. An example illustrates the potential savings of this technique of designing control charts.
Artificial versus natural crystals: effective wave impedance of printed photonic bandgap materials

Printed metallo-dielectric photonic bandgap (PBG) materials are analyzed using an analytical approach based on multipole expansions for the scattered fields of individual scatterers and a transfer-matrix method for reconstructing the total scattered fields created by successive lattice planes of the artificial crystal. An effective description of the PBG medium is derived and its correspondence with natural crystals is further advanced through an analysis based on Lorentzian response functions, which characterize natural crystals. The effective wave impedance and bulk reflection coefficient of the medium are provided and their properties inside and outside the bandgaps are examined. The presented treatment for these effective response functions extends far beyond the traditional effective medium theory (EMT) limits.
Evolution of Local Circuit Neurons in Two Sensory Thalamic Nuclei in Amniotes

Local circuit neurons are present in the thalamus of all vertebrates where they are considered inhibitory. They play an important role in computation and influence the transmission of information from the thalamus to the telencephalon. In mammals, the percentage of local circuit neurons in the dorsal lateral geniculate nucleus remains relatively constant across a variety of species. In contrast, the numbers of local circuit neurons in the ventral division of the medial geniculate body in mammals vary significantly depending on the species examined. To explain these observations, the numbers of local circuit neurons were investigated by reviewing the literature on this subject in these two nuclei in mammals and their respective homologs in sauropsids and by providing additional data on a crocodilian. Local circuit neurons are present in the dorsal geniculate nucleus of sauropsids just as is the case for this nucleus in mammals. However, sauropsids lack local circuits neurons in the auditory thalamic nuclei homologous to the ventral division of the medial geniculate body. A cladistic analysis of these results suggests that differences in the numbers of local circuit neurons in the dorsal lateral geniculate nucleus of amniotes reflect an elaboration of these local circuit neurons as a result of evolution from a common ancestor. In contrast, the numbers of local circuit neurons in the ventral division of the medial geniculate body changed independently in several mammalian lineages.
Sequence mining yields 18 phloretin C‐glycosyltransferases from plants for the efficient biocatalytic synthesis of nothofagin and phloretin‐di‐C‐glycoside

C‐glycosyltransferases (C‐GTs) offer selective and efficient synthesis of natural product C‐glycosides under mild reaction conditions. In contrast, the chemical synthesis of these C‐glycosides is challenging and environmentally harmful. The rare occurrence of C‐glycosylated compounds in Nature, despite their stability, suggests that their biosynthetic enzymes, C‐GTs, might be scarce. Indeed, the number of characterized C‐GTs is remarkably lower than O‐GTs. Therefore, discovery efforts are crucial for expanding our knowledge of these enzymes and their efficient application in biocatalytic processes. This study aimed to identify new C‐GTs based on their primary sequence. 18 new C‐GTs were discovered, 10 of which yielded full conversion of phloretin to its glucosides. Phloretin is a dihydrochalcone natural product, with its mono‐C‐glucoside, nothofagin, having various health‐promoting effects. Several of these enzymes enabled highly selective production of either nothofagin (UGT708A60 and UGT708F2) or phloretin‐di‐C‐glycoside (UGT708D9 and UGT708B8). Molecular docking simulations, based on structural models of selected enzymes, showed productive binding modes for the best phloretin C‐GTs, UGT708F2 and UGT708A60. Moreover, we characterized UGT708A60 as a highly efficient phloretin mono‐C glycosyltransferase (kcat = 2.97 s‒1, KM = 0.1 μM) active in non‐buffered, dilute sodium hydroxide (0.1–1 mM). We further investigated UGT708A60 as an efficient biocatalyst for the bioproduction of nothofagin.
Unique Tandem Repeats in the Inverted Terminal Repeat Regions of Monkeypox Viruses

The different groups of MPXVs contain unique tandem repeats with different copy numbers in the ITR regions, and these repeats may be likely to play a role in the genetic diversity of the virus. Clade IIb (B) MPXV contains 38 and 32 repeats similar to the Tandem repeats reported in the human and rodent genome, respectively. ABSTRACT The genetic diversity, especially in noncoding regions between clade I, clade IIa, and clade IIb monkeypox viruses (MPXVs), is still not fully understood. Here, we report that unique 16-nucleotide-length tandem repeats in MPXVs viruses are located in the noncoding regions of inverted terminal repeats (ITR), and the copy number of this repeat is different among clade I, clade IIa, and clade IIb viruses. It is noteworthy that tandem repeats containing these specific sequences (AACTAACTTATGACTT) are only present in MPXVs and are not found in other poxviruses. Also, the tandem repeats containing these specific sequences (AACTAACTTATGACTT) do not correspond to the tandem repeats present in the human and rodent (mice and rat) genomes. On the other hand, some of the reported tandem repeats in the human and rodent (mice and rat) genomes are present in the clade IIb-B.1 lineage of MPXV. In addition, it is noteworthy that the genes flanking these tandem repeats are lost and gained compared between clade I, clade IIa, and clade IIb MPXV. IMPORTANCE The different groups of MPXVs contain unique tandem repeats with different copy numbers in the ITR regions, and these repeats may be likely to play a role in the genetic diversity of the virus. Clade IIb (B) MPXV contains 38 and 32 repeats similar to the Tandem repeats reported in the human and rodent genome, respectively. However, none of these 38 (human) and 32 (rodent) tandem repeats matched the tandem repeats (AACTAACTTATGACTT) found in the present study. Finally, when developing attenuated or modified MPXV vaccine strains, these repeats in noncoding genomic regions can be exploited to incorporate foreign proteins (adjuvants/other virus proteins/racking fluorescent proteins such as green fluorescent protein) to carry out studies such as vaccine production and virus pathogenesis.
Cheminformatics identification of phenolics as modulators of penicillin-binding protein-3 of Pseudomonas aeruginosa towards interventive antibacterial therapy

Abstract Antibacterial resistance to β-lactams in microorganisms has been attributed majorly to alterations in penicillin-binding proteins (PBPs) coupled with β-lactams’ inactivation by β-lactamase. Consequently, the identification of a novel class of therapeutics with improved modulatory action on the PBPs is imperative and plant secondary metabolites, including phenolics, have found relevance in this regard. For the first time in this study, the over 10,000 phenolics currently known were computationally evaluated against PBP3 of Pseudomonas aeruginosa, a superbug implicated in several nosocomial infections. In doing this, a library of phenolics with an affinity for PBP3 of P. aeruginosa was screened using structure-activity relationship-based pharmacophore and molecular docking approaches. Subsequent thermodynamic screening of the top five phenolics with higher docking scores, more drug-likeness attributes, and feasible synthetic accessibility was achieved through a 120 ns molecular dynamic (MD) simulation. Four of the top five hits had higher binding free energy than cefotaxime (−18.72 kcal/mol), with catechin-3-rhamside having the highest affinity (−28.99 kcal/mol). All the hits were stable at the active site of the PBP3, with catechin-3-rhamside being the most stable (2.14 Å), and established important interactions with Ser294, implicated in the catalytic activity of PBP3. Also, PBP3 became more compact with less fluctuation of the active site amino acid residues following the binding of the hits. These observations are indicative of the potential of the test compounds as PBP3 inhibitors, with catechin-3-rhamside being the most prominent of the compounds that could be further improved for enhanced druggability against PBP3 in vitro and in vivo. Communicated by Ramaswamy H. Sarma