Miracle-dz/UniFAR-FTUs huggingface dataset:
Restoration of mitochondrial structure and function within Helicobacter pylori VacA intoxicated cells

The Helicobacter pylori vacuolating cytotoxin (VacA) is an intracellular, mitochondrial-targeting exotoxin that rapidly causes mitochondrial dysfunction and fragmentation. Although VacA targeting of mitochondria has been reported to alter overall cellular metabolism, there is little known about the consequences of extended exposure to the toxin. Here, we describe studies to address this gap in knowledge, which have revealed that mitochondrial dysfunction and fragmentation are followed by a time-dependent recovery of mitochondrial structure, mitochondrial transmembrane potential, and cellular ATP levels. Cells exposed to VacA also initially demonstrated a reduction in oxidative phosphorylation, as well as increase in compensatory aerobic glycolysis. These metabolic alterations were reversed in cells with limited toxin exposure, congruent with the recovery of mitochondrial transmembrane potential and the absence of cytochrome c release from the mitochondria. Taken together, these results are consistent with a model that mitochondrial structure and function are restored in VacA-intoxicated cells.
A Unifying Principle for the Functional Organization of Visual Cortex

A key feature of many cortical systems is functional organization: the arrangement of neurons with specific functional properties in characteristic spatial patterns across the cortical surface. However, the principles underlying the emergence and utility of functional organization are poorly understood. Here we develop the Topographic Deep Artificial Neural Network (TDANN), the first unified model to accurately predict the functional organization of multiple cortical areas in the primate visual system. We analyze the key factors responsible for the TDANN’s success and find that it strikes a balance between two specific objectives: achieving a task-general sensory representation that is self-supervised, and maximizing the smoothness of responses across the cortical sheet according to a metric that scales relative to cortical surface area. In turn, the representations learned by the TDANN are lower dimensional and more brain-like than those in models that lack a spatial smoothness constraint. Finally, we provide evidence that the TDANN’s functional organization balances performance with inter-area connection length, and use the resulting models for a proof-of-principle optimization of cortical prosthetic design. Our results thus offer a unified principle for understanding functional organization and a novel view of the functional role of the visual system in particular.
Estimation of brain tissue response by electrical stimulation in a subject-specific model implemented by conductivity tensor imaging

Electrical stimulation such as transcranial direct current stimulation (tDCS) is widely used to treat neuropsychiatric diseases and neurological disorders. Computational modeling is an important approach to understand the mechanisms underlying tDCS and optimize treatment planning. When applying computational modeling to treatment planning, uncertainties exist due to insufficient conductivity information inside the brain. In this feasibility study, we performed in vivo MR-based conductivity tensor imaging (CTI) experiments on the entire brain to precisely estimate the tissue response to the electrical stimulation. A recent CTI method was applied to obtain low-frequency conductivity tensor images. Subject-specific three-dimensional finite element models (FEMs) of the head were implemented by segmenting anatomical MR images and integrating a conductivity tensor distribution. The electric field and current density of brain tissues following electrical stimulation were calculated using a conductivity tensor-based model and compared to results using an isotropic conductivity model from literature values. The current density by the conductivity tensor was different from the isotropic conductivity model, with an average relative difference |rD| of 52 to 73%, respectively, across two normal volunteers. When applied to two tDCS electrode montages of C3-FP2 and F4-F3, the current density showed a focused distribution with high signal intensity which is consistent with the current flowing from the anode to the cathode electrodes through the white matter. The gray matter tended to carry larger amounts of current densities regardless of directional information. We suggest this CTI-based subject-specific model can provide detailed information on tissue responses for personalized tDCS treatment planning.
Reservoir classification and log prediction of gas hydrate occurrence in the Qiongdongnan Basin, South China Sea

Classifying natural gas hydrate reservoirs effectively and carrying out reservoir classification modelling is crucial, but to date, research on building artificial intelligence-assisted logging curve reservoir classification models is not abundant. As exploration and development have progressed, an increasing number of fine-grained reservoirs are being discovered, and their strong heterogeneity makes correct reservoir classification even more important. Two wells used for detecting hydrates in the Qiongdongnan (QDN) Basin are used to explore the relationship between logging response parameters and reservoir quality, as well as the method of building a logging-based reservoir classification model. Through K-means clustering and Adaboost methods, the K-means method is considered to be able to correspond to the hydrate enrichment degree, while the random forest method can establish an effective reservoir classification model (the recognition accuracy is 95%). In the different categories of reservoirs, the physical properties of the reservoirs are obviously poor, and the corresponding hydrate saturation is also low, which indicates that heterogeneity has indeed affected the enrichment of hydrates in fine-grained reservoirs. This reservoir classification research method can effectively recognize reservoirs.
Subject clustering by IF-PCA and several recent methods

Subject clustering (i.e., the use of measured features to cluster subjects, such as patients or cells, into multiple groups) is a problem of significant interest. In recent years, many approaches have been proposed, among which unsupervised deep learning (UDL) has received much attention. Two interesting questions are 1) how to combine the strengths of UDL and other approaches and 2) how these approaches compare to each other. We combine the variational auto-encoder (VAE), a popular UDL approach, with the recent idea of influential feature-principal component analysis (IF-PCA) and propose IF-VAE as a new method for subject clustering. We study IF-VAE and compare it with several other methods (including IF-PCA, VAE, Seurat, and SC3) on 10 gene microarray data sets and eight single-cell RNA-seq data sets. We find that IF-VAE shows significant improvement over VAE, but still underperforms compared to IF-PCA. We also find that IF-PCA is quite competitive, slightly outperforming Seurat and SC3 over the eight single-cell data sets. IF-PCA is conceptually simple and permits delicate analysis. We demonstrate that IF-PCA is capable of achieving phase transition in a rare/weak model. Comparatively, Seurat and SC3 are more complex and theoretically difficult to analyze (for these reasons, their optimality remains unclear).
Exploring the nature of the gender-congruency effect: implicit gender activation and social bias

The aim of the study was to explore the nature of the gender-congruency effect, characterized by a facilitation on the processing of congruent words in grammatical gender. Moreover, we explored whether resemblances between gender identities and gender attitudes with grammatical gender modulated lexical processing. We designed a gender-priming paradigm in Spanish, in which participants decided the gender of a masculine or feminine pronoun preceded by three different primes: biological gender nouns (mapping biological sex), stereotypical nouns (mapping biological and stereotypical information), and epicene nouns (arbitrary gender assignment). We found faster processing of gender congruent pronouns independently of the type of prime, showing that the grammatical gender feature is active even when processing bare nouns that are not conceptually related to gender. This indicates that the gender-congruency effect is driven by the activation of the gender information at the lexical level, which is transferred to the semantic level. Interestingly, the results showed an asymmetry for epicene primes: the gender-congruency effect was smaller for epicene primes when preceding the feminine pronoun, probably driven by the grammatical rule of the masculine being the generic gender. Furthermore, we found that masculine oriented attitudes can bias language processing diminishing the activation of feminine gender, which ultimately could overshadow the female figure.
The perception of pediatric sickle cell anemia patient's caregivers toward hematopoietic stem cell transplantation (single-center experience, Saudi Arabia)

Background Sickle cell disease (SCD) is a relatively common genetic disorder in Saudi Arabia characterized by the predominance of sickle hemoglobin (HbS). Although multiple supportive care options exist for patients with SCD, hematopoietic stem cell transplantation (HSCT) is the only cure available and has become highly successful, with an almost 91% overall survival rate. However, pursuing this procedure is still restrained as a curative treatment option. Therefore, this study aimed to evaluate the perception of parents' caregivers at the National Guard Hospital pediatric hematology clinic regarding using HSCT as a curative approach for their children with SCD. Methods This is a cross-sectional study of the interviewer-administered survey distributed utilizing electronic devices to caregivers of pediatric patients with SCD. Subjects were recruited from Pediatric Hematology & Oncology clinics at National Guard Hospital Affairs in King Abdulaziz Medical City, Jeddah, Saudi Arabia. An estimated sample size of 100 was initially calculated out of 140 pediatric SCD patients; 72 responses were collected from participants. All study participants gave informed consent. All results were analyzed using SPSS; moreover, statistics were set at a CI of 95% and a p < 0.05. In addition, inferential and descriptive statistics were done. Results Of all respondents, 42 (67.8%) would accept HSCT if their hematologist recommended it. However, approximately 7 (11.3%) were not interested in the procedure, and the rest, 13 (21%), were uncertain. The most reported reasons for HSCT rejection among all respondents were attributed to side effects 31 (50.8%), lack of knowledge 8 (13.1%), and misconception toward the procedure 22 (36.1%). Conclusion The results of this study were consistent with the fact that most caregivers would follow along with HSCT if it seemed to be fit and was recommended by their hematologists. However, to the best of our knowledge, our study being the first of its kind in the region, further research in the kingdom on the perception of HSCT is needed. Nonetheless, further patient education, an increase in caregivers' knowledge, and enlightenment of the medical team on HSCT as a curative option for sickle cell disease are vital.
Identification of transport systems involved in eflornithine delivery across the blood-brain barrier

Human African Trypanosomiasis (HAT) is a neglected parasitic disease that continues to persist in sub-Saharan Africa. It is fatal if untreated. The first stage of the disease is associated with the presence of the parasite in the periphery and the second stage with the presence of the parasites in the CNS. The treatment of CNS stage HAT requires the drugs to cross the blood-brain barrier (BBB). Eflornithine is an amino acid analogue that is used to treat second stage HAT gambiense both alone and in combination with nifurtimox. Recent studies have identified that accumulation of eflornithine into the parasites (trypanosomes) involves the amino acid transporter (Trypanosoma brucei AAT6). In this study we tested the hypothesis that eflornithine uses a cationic amino acid transport system to cross the BBB. We particularly focused on system y+ and system B0,+. To do this we utilized specialist databases to compare the physicochemical characteristics of relevant molecules and an in vitro model of the BBB to explore the mechanisms of eflornithine delivery into the CNS. Our results confirmed that eflornithine is related to the endogenous amino acid, ornithine. At pH 7.4, eflornithine is predominately (92.39%) a zwitterionic (dipolar) amino acid and ornithine is predominately (99.08%) a cationic (tripolar) amino acid. In addition, the gross charge distribution at pH 7.4 of eflornithine is much smaller (+0.073) than that of ornithine (+0.99). Further results indicated that eflornithine utilized a saturable transport mechanism(s) to cross the hCMEC/D3 cell membranes and that transport was inhibited by the presence of other amino acids including ornithine. Eflornithine transport was also sodium-independent and sensitive to a y+ system inhibitor, but not a B0,+ system inhibitor. Eflornithine transport was also inhibited by pentamidine, suggestive of transport by organic cation transporters (OCT) which are expressed in this cell line. We confirmed expression of the y+ system protein, CAT1, and the B0,+ system protein, ATB0,+, in the hCMEC/D3 cells. We conclude that eflornithine uses the cationic amino acid transporter, system y+, and OCT to cross the BBB. This research highlights the potential of system y+ to deliver drugs, including eflornithine, across the BBB to treat brain diseases.
Acute stress response of the HPA-axis in children with Prader-Willi syndrome: new insights and consequences for clinical practice

Background Prader-Willi syndrome (PWS) is associated with hypothalamic dysfunction. It has been reported that the HPA axis might show a delayed response during acute stress, and it is unknown whether the response of the HPA-axis during acute stress changes with age in children with PWS. Aim To investigate the HPA-axis response during an overnight single-dose metyrapone (MTP) test in children with PWS and to assess if the response changes with age, whether it is delayed and if it changes with repeated testing over time. In addition, we evaluated different cut-off points of ACTH and 11-DOC levels to assess stress-related central adrenal insufficiency (CAI). Methods An overnight single-dose MTP test was performed in 93 children with PWS. Over time, 30 children had a second test and 11 children a third one. Children were divided into age groups (0-2 years, 2-4 years, 4-8 years and > 8 years). Results Most children did not have their lowest cortisol level at 7.30h, but at 04.00h. Their ACTH and 11-DOC peaks appeared several hours later, suggesting a delayed response. When evaluated according to a subnormal ACTH peak (13-33 pmol/L) more children had an subnormal response compared to evaluation based on a subnormal 11-doc peak (< 200 nmol/L). The percentage of children with a subnormal ACTH response ranged from 22.2 to 70.0% between the age groups, while the percentage of a subnormal 11-DOC response ranged from 7.7 to 20.6%. When using the ACTH peak for diagnosing acute-stress-related CAI, differences between age groups and with repeated testing over time were found, whereas there was no age difference when using the 11-DOC peak. Conclusion Early morning ACTH or 11-DOC levels are not appropriate to determine acute stress-related CAI in children with PWS, thus multiple measurements throughout the night are needed for an accurate interpretation. Our data suggest a delayed response of the HPA-axis during acute stress. Using the 11-DOC peak for the test interpretation is less age-dependent than the ACTH peak. Repeated testing of the HPA-axis over time is not required, unless clinically indicated.
α-Synuclein is required for sperm exocytosis at a post-fusion stage

The sperm acrosome is a large dense-core granule whose contents are secreted by regulated exocytosis at fertilization through the opening of numerous fusion pores between the acrosomal and plasma membranes. In other cells, the nascent pore generated when the membrane surrounding a secretory vesicle fuses with the plasma membrane may have different fates. In sperm, pore dilation leads to the vesiculation and release of these membranes, together with the granule contents. α-Synuclein is a small cytosolic protein claimed to exhibit different roles in exocytic pathways in neurons and neuroendocrine cells. Here, we scrutinized its function in human sperm. Western blot revealed the presence of α-synuclein and indirect immunofluorescence its localization to the acrosomal domain of human sperm. Despite its small size, the protein was retained following permeabilization of the plasma membrane with streptolysin O. α-Synuclein was required for acrosomal release, as demonstrated by the inability of an inducer to elicit exocytosis when permeabilized human sperm were loaded with inhibitory antibodies to human α-synuclein. The antibodies halted calcium-induced secretion when introduced after the acrosome docked to the cell membrane. Two functional assays, fluorescence and transmission electron microscopies revealed that the stabilization of open fusion pores was responsible for the secretion blockage. Interestingly, synaptobrevin was insensitive to neurotoxin cleavage at this point, an indication of its engagement in cis SNARE complexes. The very existence of such complexes during AE reflects a new paradigm. Recombinant α-synuclein rescued the inhibitory effects of the anti-α-synuclein antibodies and of a chimeric Rab3A-22A protein that also inhibits AE after fusion pore opening. We applied restrained molecular dynamics simulations to compare the energy cost of expanding a nascent fusion pore between two model membranes and found it higher in the absence than in the presence of α-synuclein. Hence, our results suggest that α-synuclein is essential for expanding fusion pores.
Nocturnal melatonin increases glucose uptake via insulin-independent action in the goldfish brain

Melatonin, a neurohormone nocturnally produced by the pineal gland, is known to regulate the circadian rhythm. It has been recently reported that variants of melatonin receptors are associated with an increased risk of hyperglycemia and type 2 diabetes, suggesting that melatonin may be involved in the regulation of glucose homeostasis. Insulin is a key hormone that regulates circulating glucose levels and cellular metabolism after food intake in many tissues, including the brain. Although cells actively uptake glucose even during sleep and without food, little is known regarding the physiological effects of nocturnal melatonin on glucose homeostasis. Therefore, we presume the involvement of melatonin in the diurnal rhythm of glucose metabolism, independent of insulin action after food intake. In the present study, goldfish (Carassius auratus) was used as an animal model, since this species has no insulin-dependent glucose transporter type 4 (GLUT4). We found that in fasted individuals, plasma melatonin levels were significantly higher and insulin levels were significantly lower during the night. Furthermore, glucose uptake in the brain, liver, and muscle tissues also significantly increased at night. After intraperitoneal administration of melatonin, glucose uptake by the brain and liver showed significantly greater increases than in the control group. The administration of melatonin also significantly decreased plasma glucose levels in hyperglycemic goldfish, but failed to alter insulin mRNA expression in Brockmann body and plasma insulin levels. Using an insulin-free medium, we demonstrated that melatonin treatment increased glucose uptake in a dose-dependent manner in primary cell cultures of goldfish brain and liver cells. Moreover, the addition of a melatonin receptor antagonist decreased glucose uptake in hepatocytes, but not in brain cells. Next, treatment with N1-acetyl-5-methoxykynuramine (AMK), a melatonin metabolite in the brain, directly increased glucose uptake in cultured brain cells. Taken together, these findings suggest that melatonin is a possible circadian regulator of glucose homeostasis, whereas insulin acquires its effect on glucose metabolism following food intake.
All roads lead to Rome: inter-origin variation in metabolomics reprogramming of the northern shrimp exposed to global changes leads to a comparable physiological status

Impacts of global ocean changes on species have historically been investigated at the whole-organism level. However, acquiring an in-depth understanding of the organisms’ cellular metabolic responses is paramount to better define their sensitivity to environmental challenges. This is particularly relevant for species that experience highly different environmental conditions across their distribution range as local acclimatization or adaptation can influence their responses to rapid global ocean changes. We aimed at shedding light on the cellular mechanisms underpinning the sensitivity to combined ocean warming (OW) and acidification (OA) in the northern shrimp Pandalus borealis, from four different geographic origins defined by distinctive environmental regimes in the northwest Atlantic: i.e. St. Lawrence Estuary (SLE), Eastern Scotian Shelf (ESS), Esquiman Channel (EC) and Northeast Newfoundland Coast (NNC). We characterized targeted metabolomics profiles of the muscle of shrimp exposed to three temperatures (2, 6 or 10°C) and two pH levels (7.75 or 7.40). Overall, shrimp metabolomics profiles were modulated by a significant interaction between temperature, pH and origin. Temperature drove most of the metabolomics reprogramming, confirming that P. borealis is more sensitive to OW than OA. Inter-origin differences in metabolomics profiles were also observed, with temperature*pH interactions impacting only shrimp from SLE and ESS, pH affecting only shrimp from SLE and temperature impacting shrimp from all origins. Temperature influenced metabolomics pathways related to the tricarboxylic acid cycle (TCA) and amino acid metabolism, resulting mainly in an accumulation of TCA intermediates and tyrosine. Temperature*pH and pH in isolation only affected amino acid metabolism, leading to amino acids accumulation under low pH. However, the ratio of ATP : ADP remained constant across conditions in shrimp from all origins suggesting that their energetic status is not affected by OW and OA. Still, the accumulation of TCA intermediates and tyrosine suggests the possible enhancement of immune responses under future OW and OA conditions. Our findings suggest that shrimp from SLE are more sensitive at the molecular level, compared to others, to future complex environmental conditions. This underlines the importance of investigating intraspecific variation in mechanisms of responses to combined drivers when trying to define species’ sensitivity to global ocean changes. Graphical Abstract
IgA nephropathy: a review of existing and emerging therapies

IgA nephropathy (IgAN) is the most common form of primary glomerulonephritis worldwide. Recently, there have been multiple advances in the understanding of IgAN pathophysiology and therapeutic options. Despite the advent of new treatment options, individual risk stratification of the disease course and choosing the best treatment strategy for the patient remains challenging. A multitude of clinical trials is ongoing, opening multiple opportunities for enrollment. In this brief review we discuss the current approach to the management of IgAN and highlight the ongoing clinical trials.