Miracle-dz/UniFAR-FTUs huggingface dataset:
The Effects of Dual GLP-1/GIP Receptor Agonism on Glucagon Secretion—A Review

The gut-derived incretin hormones glucagon-like peptide 1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP) are secreted after meal ingestion and work in concert to promote postprandial insulin secretion. Furthermore, GLP-1 inhibits glucagon secretion when plasma glucose concentrations are above normal fasting concentrations while GIP acts glucagonotropically at low glucose levels. A dual incretin receptor agonist designed to co-activate GLP-1 and GIP receptors was recently shown to elicit robust improvements of glycemic control (mean haemoglobin A1c reduction of 1.94%) and massive body weight loss (mean weight loss of 11.3 kg) after 26 weeks of treatment with the highest dose (15 mg once weekly) in a clinical trial including overweight/obese patients with type 2 diabetes. Here, we describe the mechanisms by which the two incretins modulate alpha cell secretion of glucagon, review the effects of co-administration of GLP-1 and GIP on glucagon secretion, and discuss the potential role of glucagon in the therapeutic effects observed with novel unimolecular dual GLP-1/GIP receptor agonists. For clinicians and researchers, this manuscript offers an understanding of incretin physiology and pharmacology, and provides mechanistic insight into future antidiabetic and obesity treatments.
Slice-Based Online Convolutional Dictionary Learning

Convolutional dictionary learning (CDL) aims to learn a structured and shift-invariant dictionary to decompose signals into sparse representations. While yielding superior results compared to traditional sparse coding methods on various signal and image processing tasks, most CDL methods have difficulties handling large data, because they have to process all images in the dataset in a single pass. Therefore, recent research has focused on online CDL (OCDL) which updates the dictionary with sequentially incoming signals. In this article, a novel OCDL algorithm is proposed based on a local, slice-based representation of sparse codes. Such representation has been found useful in batch CDL problems, where the convolutional sparse coding and dictionary learning problem could be handled in a local way similar to traditional sparse coding problems, but it has never been explored under online scenarios before. We show, in this article, that the proposed algorithm is a natural extension of the traditional patch-based online dictionary learning algorithm, and the dictionary is updated in a similar memory efficient way too. On the other hand, it can be viewed as an improvement of existing second-order OCDL algorithms. Theoretical analysis shows that our algorithm converges and has lower time complexity than existing counterpart that yields exactly the same output. Extensive experiments are performed on various benchmarking datasets, which show that our algorithm outperforms state-of-the-art batch and OCDL algorithms in terms of reconstruction objectives.
Transcriptional autoregulation of zebrafish tbx6 is required for somite segmentation

ABSTRACT The presumptive somite boundary in the presomitic mesoderm (PSM) is defined by the anterior border of the expression domain of Tbx6 protein. During somite segmentation, the expression domain of Tbx6 is regressed by Ripply-meditated degradation of Tbx6 protein. Although the expression of zebrafish tbx6 remains restricted to the PSM, the transcriptional regulation of tbx6 remains poorly understood. Here, we show that the expression of zebrafish tbx6 is maintained by transcriptional autoregulation. We find that a proximal-located cis-regulatory module, TR1, which contains two putative T-box sites, is required for somite segmentation in the intermediate body and for proper expression of segmentation genes. Embryos with deletion of TR1 exhibit significant reduction of tbx6 expression at the 12-somite stage, although its expression is initially observed. Additionally, Tbx6 is associated with TR1 and activates its own expression in the anterior PSM. Furthermore, the anterior expansion of tbx6 expression in ripply gene mutants is suppressed in a TR1-dependent manner. The results suggest that the autoregulatory loop of zebrafish tbx6 facilitates immediate removal of Tbx6 protein through termination of its own transcription at the anterior PSM. Summary: Genetic studies reveal that transcriptional autoregulation maintains the expression of tbx6 in the presomitic mesoderm of zebrafish embryos.
Dynamic functional connectivity states characterize NREM sleep and wakefulness

According to recent neuroimaging studies, temporal fluctuations in functional connectivity patterns can be clustered into dynamic functional connectivity (DFC) states and correspond to fluctuations in vigilance. However, whether there consistently exist DFC states associated with wakefulness and sleep stages and what are the characteristics and electrophysiological origin of these states remain unclear. The aims of the current study were to investigate the properties of DFC in different sleep stages and to explore the relationship between the characteristics of DFC and slow‐wave activity. We collected both eyes‐closed wakefulness and sleep data from 48 healthy young volunteers with simultaneous electroencephalography (EEG) and functional magnetic resonance imaging (fMRI) recordings. EEG data were employed as the gold standard of sleep stage scoring, and DFC states were estimated based on fMRI data. The results demonstrated that DFC states of the fMRI signals consistently corresponded to wakefulness and nonrapid eye movement sleep stages independent of the number of clusters. Furthermore, the mean dwell time of these states significantly correlated with slow‐wave activity. The inclusion or omission of regression of the global signal and the selection of parcellation schemes exerted minimal effects on the current findings. These results provide strong evidence that DFC states underlying fMRI signals match the fluctuations of vigilance and suggest a possible electrophysiological source of DFC states corresponding to vigilance states.
Understanding the effects of culture conditions in bacterial growth: A biochemical perspective using Raman microscopy

Rapid, sensitive and label‐free methods to probe bacterial growth irrespective of the culture conditions can shed light on the mechanisms by which bacteria adapt to different environmental stimuli. Raman spectroscopy can rapidly and continuously monitor the growth of bacteria under varied conditions. In this study, the growth of Escherichia coli in Luria broth (nutrient rich conditions) and minimal media with either glucose or glycerol as carbon source (nutrient limiting conditions) is profiled using Raman spectroscopy. Moreover, the study also gives insights into the altered bacterial biochemistry upon exposure to low‐ (25°C) and high‐temperature (45°C) stress. Raman spectral measurement was performed on bulk bacteria cultured under laboratory conditions. A detailed analysis of the spectra as a function of bacterial growth reveals changes in Raman band intensities/area of biomolecules such as DNA, proteins and lipids. We also report five novel ratiometric markers (I830/I810, I1126/I1100, I1340/I1440, I1207/I1240 and I1580/I1440) that can identify the phase of growth, independent of the culture condition. Unsupervised multivariate methods like Principal Component Analysis also corroborate the aforementioned markers of growth. Altogether, our findings highlight the potential of Raman spectroscopy in yielding universal biochemical signatures that may be indicative of stress and aging in a growth milieu.
A Collection of Bioactive Nitrogen-Containing Molecules from the Marine Sponge Acanthostrongylophora ingens

Thirteen nitrogen-containing molecules (1a/1b and 2–12) were isolated from the Indonesian sponge Acanthostrongylophora ingens, highlighting the richness of this organism as a source of alkaloids. Their structures were elucidated using one- and two-dimensional NMR spectroscopy and HR-ESI-MS, while the stereochemistry of the diketopiperazines was established using Marfey’s method. All compounds were screened in our standard bioactivity assays, including antibacterial, antikinases, and amyloid β-42 assays. The most interesting bioactivity result was obtained with the known acanthocyclamine A (3), which revealed for the first time a specific Escherichia coli antimicrobial activity and an inhibitory effect on amyloid β-42 production induced by aftin-5 and no cytotoxicity at the dose of 26 µM. These results highlight the potentiality of a bipiperidine scaffold as a promising skeleton for preventing or reducing the production of amyloid β-42, a key player in the initiation of Alzheimer’s disease.
VceC Mediated IRE1 Pathway and Inhibited CHOP-induced Apoptosis to Support Brucella Replication in Goat Trophoblast Cells

The effectors of the type IV secretion system (T4SS) of bacteria play important roles in mediating bacterial intracellular proliferation and manipulating host-related pathway responses to bacterial infection. Brucella Spp. inhibit the apoptosis of host cells to benefit their own intracellular proliferation. However, the underlying mechanisms between T4SS effectors and Brucella-inhibited apoptosis in goat trophoblast cells remain unclear. Here, based on Brucella suis vaccine strain 2, the VceC was deleted by allelic exchange. We show that ΔVceC was able to infect and proliferate to high titers in goat trophoblast cells (GTCs) and increase C/EBP-homologous protein (CHOP)-mediated apoptosis. GRP78 expression decreased upon ΔVceC infection. In addition, we discovered that the inositolrequiring enzyme 1 (IRE1) pathway was inhibited in this process. Changing endoplasmic reticulum (ER) stress affected Brucella intracellular replication in GTCs. The replication of ΔVceC was more sensitive under the different ERstress conditions in the GTC line after treatment with ER stress inhibitors 4 phenyl butyric acid (4-PBA) or ER stress activator Tm. Together, our findings show that VceC has a protective effect on the intracellular persistence of Brucella infection, and inhibits ER stress-induced apoptosis in the CHOP pathway. The present work provides new insights for understanding the mechanism of VceC in the establishment of chronic Brucella infection.
Myelin status and oligodendrocyte lineage cells over time after spinal cord injury: What do we know and what still needs to be unwrapped?

Spinal cord injury (SCI) affects over 17,000 individuals in the United States per year, resulting in sudden motor, sensory and autonomic impairments below the level of injury. These deficits may be due at least in part to the loss of oligodendrocytes and demyelination of spared axons as it leads to slowed or blocked conduction through the lesion site. It has long been accepted that progenitor cells form new oligodendrocytes after SCI, resulting in the acute formation of new myelin on demyelinated axons. However, the chronicity of demyelination and the functional significance of remyelination remain contentious. Here we review work examining demyelination and remyelination after SCI as well as the current understanding of oligodendrocyte lineage cell responses to spinal trauma, including the surprisingly long‐lasting response of NG2+ oligodendrocyte progenitor cells (OPCs) to proliferate and differentiate into new myelinating oligodendrocytes for months after SCI. OPCs are highly sensitive to microenvironmental changes, and therefore respond to the ever‐changing post‐SCI milieu, including influx of blood, monocytes and neutrophils; activation of microglia and macrophages; changes in cytokines, chemokines and growth factors such as ciliary neurotrophic factor and fibroblast growth factor‐2; glutamate excitotoxicity; and axon degeneration and sprouting. We discuss how these changes relate to spontaneous oligodendrogenesis and remyelination, the evidence for and against demyelination being an important clinical problem and if remyelination contributes to motor recovery.
Widespread antimicrobial resistance among bacterial infections in a Rwandan referral hospital

Background Resistance among bacterial infections is increasingly well-documented in high-income countries; however, relatively little is known about bacterial antimicrobial resistance in low-income countries, where the burden of infections is high. Methods We prospectively screened all adult inpatients at a referral hospital in Rwanda for suspected infection for seven months. Blood, urine, wound and sputum samples were cultured and tested for antibiotic susceptibility. We examined factors associated with resistance and compared hospital outcomes for participants with and without resistant isolates. Results We screened 19,178 patient-days, and enrolled 647 unique participants with suspected infection. We obtained 942 culture specimens, of which 357 were culture-positive specimens. Of these positive specimens, 155 (43.4%) were wound, 83 (23.2%) urine, 64 (17.9%) blood, and 55 (15.4%) sputum. Gram-negative bacteria comprised 323 (88.7%) of all isolates. Of 241 Gram-negative isolates tested for ceftriaxone, 183 (75.9%) were resistant. Of 92 Gram-negative isolates tested for the extended spectrum beta-lactamase (ESBL) positive phenotype, 66 (71.7%) were ESBL positive phenotype. Transfer from another facility, recent surgery or antibiotic exposure, and hospital-acquired infection were each associated with resistance. Mortality was 19.6% for all enrolled participants. Conclusions This is the first published prospective hospital-wide antibiogram of multiple specimen types from East Africa with ESBL testing. Our study suggests that low-resource settings with limited and inconsistent access to the full range of antibiotic classes may bear the highest burden of resistant infections. Hospital-acquired infections and recent antibiotic exposure are associated with a high proportion of resistant infections. Efforts to slow the development of resistance and supply effective antibiotics are urgently needed.
Role of miRNAs in Alzheimer’s Disease and Possible Fields of Application

miRNAs (or microRNAs) are a class of single-stranded RNA molecules, responsible for post-transcriptional gene silencing through binding to the coding region as well as 3′ and 5′ untranslated region of target genes. About 70% of experimentally detectable miRNAs are expressed in the brain and some studies suggest that miRNAs are intimately involved in synaptic function and in specific signals during memory formation. More and more evidence demonstrates the possible involvement of miRNAs in Alzheimer’s disease (AD). AD is the most common form of senile dementia, a disease that affects memory and cognitive functions. It is a neurodegenerative disorder characterized by loss of synapses, extracellular amyloid plaques composed of the amyloid-β peptide (Aβ), and intracellular aggregates of hyperphosphorylated TAU protein. This review aims to provide an overview of the in vivo studies of the last 5 years in the literature describing the role of the different miRNAs involved in AD. miRNAs hold huge potential as diagnostic and prognostic biomarkers and, at the same time, their modulation could be a potential therapeutic strategy against AD.
Analysis of caecal mucosal inflammation and immune modulation during Anoplocephala perfoliata infection of horses

Anoplocephala perfoliata is the commonest equine tapeworm, the adult parasites are attached in groups close to the ileocaecal valve causing marked inflammatory pathology. This work aimed to characterize the nature of the in vivo mucosal immune response to A perfoliata, and to investigate the role of A perfoliata excretory‐secretory components in modulating in vitro immune responses. Real‐time PCR detected elevation of IL13 and TGFβ transcription in early‐stage A perfoliata infection. In late‐stage infection, IL‐13, IL4 and Ifn transcripts were reduced while the regulatory cytokines, TGFβ, IL10 and the transcription factor FOXP3 were increased in tissue close to the site of A perfoliata attachment; indicating downregulation of T‐cell responses to A perfoliata. In vitro, A perfoliata excretory‐secretory products induced apoptosis of the Jurkat T‐cell line and premature cell death of ConA stimulated equine peripheral blood leucocytes. Analysis of cytokine transcription patterns in the leucocyte cultures showed a marked inhibition of IL‐1 and IL‐2 suggesting that a lack of T‐cell growth factor transcription underlies the mechanism of the induced equine T‐cell death. These preliminary findings suggest A perfoliata may have the ability to down‐regulate host T‐cell responses.
Lactoferrin protects against iron dysregulation, oxidative stress, and apoptosis in 1‐methyl‐4‐phenyl‐1,2,3,6‐tetrahydropyridine (MPTP)‐induced Parkinson’s disease in mice

Parkinson's disease (PD) is the second most common neurodegenerative disease after Alzheimer's disease. Its pathological features are dopaminergic neuronal death in the substantia nigra (SN), and significant reduction in dopamine (DA) content in the striatum. A large number of studies have found an increase in iron levels in PD patients and animal models, which suggested that brain iron metabolism dysfunction played a key role in the pathogenesis of PD. Lactoferrin (Lf) is a non‐heme iron‐binding glycoprotein belonging to the transferrin family, entering the cell membrane via a lactoferrin receptor‐mediated pathway. Lf exists mainly in two forms: iron‐free‐lactoferrin (apo‐Lf) and iron‐saturated‐lactoferrin (holo‐Lf). Our previous studies found thatapo‐Lf and holo‐Lf exert neuroprotective effects against 1‐methyl‐4‐phenylpyridinium toxicity in ventral mesencephalon neurons in vitro. This study aimed to further investigate whether two different forms of Lf have neuroprotective effects in vivo, and to examine their mechanisms, so as to provide an experimental basis for finding new therapeutic strategies against PD. In the central nervous system, Lf antagonized 1‐methyl‐4‐phenyl‐1,2,3,6‐tetrahydropyridine (MPTP)‐induced DA depletion in the striatum, iron deposition, oxidative, and apoptotic processes in the SN. Lf treatment down‐regulated iron import protein divalent metal transporter1 and up‐regulated iron export protein ferroportin1, attenuating MPTP‐induced accumulation of nigral iron level. In the peripheral system, Lf alleviated MPTP‐induced increases in serum iron and ferritin, and decreases in serum total iron‐binding capacity, loss of spleen weight, and reduction in spleen iron content. The results indicate that Lf has a neuroprotective effect on MPTP‐induced PD model mice, and its mechanism may be related to anti‐iron dysregulation, anti‐oxidative stress, and anti‐apoptosis, with apo‐Lf showing greater efficacy. Therefore, Lf might be a promising therapeutic substance for PD.
Catalyst State Diagnosis of Three-Way Catalytic Converters Using Different Resonance Parameters—A Microwave Cavity Perturbation Study

Recently, radio frequency (RF) technology was introduced as a tool to determine the oxygen storage level of a three-way catalyst (TWC) for gasoline vehicles. Previous studies on the investigation of commercial catalysts mostly use only the resonant frequency to describe the correlation of oxygen storage level and RF signal. For the first time this study presents a comparison under defined laboratory conditions considering both, resonance frequency and also the quality factor as measurands. Furthermore, various advantages over the sole use of the resonant frequency in the technical application are discussed. Experiments with Ø4. 66’’ catalysts and Ø1. 66’’ catalyst cores with alternating (rich/lean) gas compositions showed that the relative change in signal amplitude due to a change in oxygen storage is about 100 times higher for the inverse quality factor compared to the resonant frequency. In addition, the quality factor reacts more sensitively to the onset of the oxygen-storage ability, and delivers precise information about the necessary temperature, which is not possible when evaluating the resonant frequency due to the low signal amplitude. As investigations on aged catalysts confirm, the quality factor also provides a new approach to determine operando the ageing state of a TWC.
Predicting Drug-Target Interaction Using a Novel Graph Neural Network with 3D Structure-Embedded Graph Representation

We propose a novel deep learning approach for predicting drug-target interaction using a graph neural network. We introduce a distance-aware graph attention algorithm to differentiate various types of intermolecular interactions. Furthermore, we extract the graph feature of intermolecular interactions directly from the 3D structural information on the protein-ligand binding pose. Thus, the model can learn key features for accurate predictions of drug-target interaction rather than just memorize certain patterns of ligand molecules. As a result, our model shows better performance than docking and other deep learning methods for both virtual screening (AUROC of 0.968 for the DUD-E test set) and pose prediction (AUROC of 0.935 for the PDBbind test set). In addition, it can reproduce the natural population distribution of active molecules and inactive molecules.
Trends and determinants of perinatal mortality in Bangladesh

Background Although the perinatal mortality rate (PNMR) has been reduced over time in Bangladesh, the rate is still very high. Only a few studies explored the determinants of high PNMR in Bangladesh, yet most of them were small-scale or conducted for stillbirths and early neonatal deaths separately. The objective of this study was to explore the trends in and determinants of perinatal deaths in Bangladesh which would be an advanced step in effective policies to tackle the issue. Methods The data used for this study was extracted from four rounds of Bangladesh Demographic and Health Surveys (BDHSs) 2004, 2007, 2011 and 2014. We considered the outcome of the 26604 pregnancies reaching seven months of their gestation. The trends of perinatal mortality was assessed using the Cochran–Armitage test, while the logistic regression with generalized estimating equation (GEE) to account for the clustering effect was implemented to explore the association between perinatal mortality and its risk factors. Results The PNMR was significantly reduced from 64 (95% CI: 57–73) to 41 (95% CI: 35–48) per 1000 pregnancies between 2004 and 2014 (stillbirths: 34 to 19 and early neonatal deaths: 30 to 22). After adjusting for potential covariates in the model, we found that administrative division, type of cooking fuel, child’s gender, maternal occupation, body mass index, birth interval, history of miscarriage, previous deaths of children, total number of under 5 children, mode of delivery, type of delivery, access to participation in decision making, paternal education and occupation were significantly associated with perinatal deaths. Conclusion The study highlights the importance of strengthening proper postnatal care services in the healthcare facilities. Alongside this, effort should also be stressed to ensure proper pregnancy care and to improve the socio-economic condition of the households to address the issue.