Miracle-dz/UniFAR-FTUs huggingface dataset:
Review: Lessons Learned From Clinical Trials Using Antimicrobial Peptides (AMPs)

Antimicrobial peptides (AMPs) or host defense peptides protect the host against various pathogens such as yeast, fungi, viruses and bacteria. AMPs also display immunomodulatory properties ranging from the modulation of inflammatory responses to the promotion of wound healing. More interestingly, AMPs cause cell disruption through non-specific interactions with the membrane surface of pathogens. This is most likely responsible for the low or limited emergence of bacterial resistance against many AMPs. Despite the increasing number of antibiotic-resistant bacteria and the potency of novel AMPs to combat such pathogens, only a few AMPs are in clinical use. Therefore, the current review describes (i) the potential of AMPs as alternatives to antibiotics, (ii) the challenges toward clinical implementation of AMPs and (iii) strategies to improve the success rate of AMPs in clinical trials, emphasizing the lessons we could learn from these trials.
Differential contributions of M1 and pre-M1 to ion selectivity in ASICs and ENaCs Running title: Ion selectivity in ASICs and ENaCs

1Department of Drug Design and Pharmacology, University of Copenhagen, Jagtvej 160, 2100 Copenhagen, Denmark 2 Nanion Technologies, Ganghoferstrasse 70a, 80339 Munich, Germany 3 School of Natural and Environmental Sciences, Newcastle University, Newcastle upon Tyne, UK #Current address: Department of Natural Sciences, Institute for Functional Gene Analytics, BonnRhein-Sieg University of Applied Sciences, Rheinbach, Germany §Current address: Sars International Centre for Marine Molecular Biology, University of Bergen, Thormøhlensgate 55, 5006 Bergen, Norway
Scheduling and Rescheduling Operations Using Decision Support Systems: Insights From Emotional Influences on Decision-Making

For many years, manufacturers have focused on improving their productivity. Production scheduling operations are critical for this objective. However, in modern manufacturing systems, the original schedule must be regularly updated as it takes places in a dynamic and uncertain environment. The modern manufacturing environment is therefore very stressful for the managers in charge of the production process because they have to cope with many disruptions and uncertainties. To help them in their decision-making process, several decision support systems (DSSs) have been developed. A recent and enormous challenge is the implementation of DSSs to efficiently manage the aforementioned issues. Nowadays, these DSSs are assumed to reduce the users' stress and workload because they automatically (re)schedule the production by applying algorithms. However, to the best of our knowledge, the reciprocal influence of users' mental state (i.e., cognitive and affective states) and the use of these DSSs have received limited attention in the literature. Particularly, the influence of users' unrelated emotions has received even less attention. However, these influences are of particular interest because they can account for explaining the efficiency of DSSs, especially in modulating DSS feedback processing. As a result, we assumed that investigating the reciprocal influences of DSSs and users' mental states could provide useful avenues of investigation. The intention of this article is then to provide recommendations for future research on scheduling and rescheduling operations by suggesting the investigation of users' mental state and encouraging to conduct such research within the neuroergonomic approach.
Fast A-type currents shape a rapidly adapting form of delayed short latency firing of excitatory superficial dorsal horn neurons that express the NPY Y1 receptor

Neuroanatomical and behavioral evidence indicates that neuropeptide Y Y1 receptor-expressing interneurons (Y1-INs) in the superficial dorsal horn (SDH) are predominantly excitatory and contribute to chronic pain. Using an adult ex vivo spinal cord slice preparation from Y1eGFP reporter mice, we characterized firing patterns in response to steady state depolarizing current injection of GFP-positive cells in lamina II, the great majority of which expressed Y1 mRNA (88%). Randomly sampled and Y1eGFP neurons exhibited five firing patterns: tonic (TF), initial burst (IBF), phasic (PF), delayed short-latency <180 ms (DSLF), and delayed long-latency >180 ms (DLLF). When studied at resting membrane potential, most RS neurons exhibited delayed firing, while most Y1eGFP neurons exhibited phasic firing and not delayed firing. A preconditioning membrane hyperpolarization produced only subtle changes in the firing patterns of randomly sampled neurons, but dramatically shifted Y1eGFP neurons to DSLF (46%) and DLLF (24%). In contrast to randomly sampled DSLF neurons which rarely exhibited spike frequency adaptation, Y1eGFP DSLF neurons were almost always rapidly adapting, a characteristic of nociceptive-responsive SDH neurons. Rebound spiking was more prevalent in Y1eGFP neurons (6% RS vs 32% Y1eGFP), indicating enrichment of T-type calcium currents. Y1eGFP DSLF neurons exhibited fast A-type potassium currents that are known to delay or limit action potential firing, and these were of smaller current density as compared to randomly sampled DSLF neurons. Our results inspire future studies to determine whether tissue or nerve injury downregulates channels that contribute to A-currents, thus potentially unmasking T-type calcium channel activity and membrane hyperexcitability in Y1-INs, leading to persistent pain. KEYPOINTS Neuropeptide Y Y1 receptor-expressing neurons in the dorsal horn of the spinal cord contribute to chronic pain. For the first time, we characterized the firing patterns of Y1-expressing neurons in Y1eGFP reporter mice. Under hyperpolarized conditions, most Y1eGFP neurons exhibited fast A-type potassium currents and delayed, short-latency firing (DSLF). Y1eGFP DSLF neurons were almost always rapidly adapting and often exhibited rebound spiking, characteristics of spinal pain neurons under the control of T-type calcium channels. These results inspire future studies to determine whether tissue or nerve injury downregulates the channels that underlie A-currents, thus unmasking membrane hyperexcitability in Y1- expressing dorsal horn neurons, leading to persistent pain
In vitro efficacy of Artemisia extracts against SARS-CoV-2

Background Traditional medicines based on herbal extracts have been proposed as affordable treatments for patients suffering from coronavirus disease 2019 (COVID-19) caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Teas and drinks containing extracts of Artemisia annua and Artemisia afra have been widely used in Africa in efforts to prevent SARS-CoV-2 infection and fight COVID-19. Methods The plant extracts and Covid-Organics drink produced in Madagascar were tested for plaque reduction using both feline coronavirus and SARS-CoV-2 in vitro. Their cytotoxicities were also investigated. Results Several extracts as well as Covid-Organics inhibited SARS-CoV-2 and FCoV infection at concentrations that did not affect cell viability. Conclusions Some plant extracts show inhibitory activity against FCoV and SARS-CoV-2. However, it remains unclear whether peak plasma concentrations in humans can reach levels needed to inhibit viral infection following consumption of teas or Covid-Organics. Clinical studies are required to evaluate the utility of these drinks for COVID-19 prevention or treatment of patients.
Frequent origins of traumatic insemination involve convergent shifts in sperm and genital morphology

Traumatic insemination is a mating behaviour during which the (sperm) donor uses a traumatic intromittent organ to inject an ejaculate through the epidermis of the (sperm) recipient, thereby frequently circumventing the female genitalia. Traumatic insemination occurs widely across animals, but the frequency of its evolution, the intermediate stages via which it originates, and the morphological changes that such shifts involve remain poorly understood. Based on observations in 145 species of the free-living flatworm genus Macrostomum, we identify at least nine independent evolutionary origins of traumatic insemination from reciprocal copulation, but no clear indication of reversals. These origins involve convergent shifts in multivariate morphospace of male and female reproductive traits, suggesting that traumatic insemination has a canalising effect on morphology. Signatures of male-female coevolution across the genus indicate that sexual selection and sexual conflict drive the evolution of traumatic insemination, because it allows donors to bypass postcopulatory control mechanisms of recipients.
PhylEx: Accurate reconstruction of clonal structure via integrated analysis of bulk DNA-seq and single cell RNA-seq data

We propose PhylEx: a clonal-tree reconstruction method that integrates bulk genomics and single-cell transcriptomics data. In addition to the clonal-tree, PhylEx also assigns single-cells to clones, which effectively produce clonal expression profiles, and generates clonal genotypes. By analyzing scRNA-seq integrated with bulk DNA-seq, PhylEx can take advantage of co-occurrences of the mutations found in the cells. In the probabilistic model underlying PhylEx, the raw read counts from scRNA-seq follow a mixture of Beta-Binomial distributions, which accounts for the sparse nature of single-cell gene expression data; the mixture lessens the penalty caused by mutations not observed due to mono-allelic expression. We rigorously evaluated PhylEx on simulated datasets as well as a biological dataset consisting of a previously well-characterized high-grade serous ovarian cancer (HGSOC) cell line. PhylEx outperformed the state-of-the-art methods by a wide margin both when comparing capacity for clonal-tree reconstruction and capacity for correctly clustering mutations. By analyzing HGSOC and HER2+ breast cancer data, we also show that PhylEx clears the way for phylo-phenotypic analysis of cancer, i.e., that the clonal expression profiles, induced by the cell-to-clone assignments, can be exploited in a manner beyond what is possible with only expression-based clustering.
Potential of fungicides, botanicals and biocontrol agents to induce physio-biochemical tolerance on Curcuma longa impaired by Colletotrichum gloeosporioides

Necrotic leaf spot of Curcuma longa (turmeric) limits the chief physio-biochemical activity for maintaining the plant health and productivity. In the present study, polyhouse and open field trials were conducted to estimate the pathogenicity of C. gloeosporioides on turmeric and to evaluate the foliar efficiency of propiconazole @ RD and copper oxychloride, extracts of A. indica, A. sativum and O. sanctum @ 40%, and culture filtrates of T. viride, T. harzianum and T. virens @ 4×106 cfu/ml in inducing physio-biochemical tolerance of pathogen inoculated and non-inoculated plants. In both the trials, these three agents yielded the highest efficiency to enhance the physio-biochemical traits. The induced physio-biochemical tolerance in treated turmeric plants showed variation in the elevation of plant health and immunity in response to pathogen aggressiveness or disease severity. However, phytophenol content was quite higher in infected plants than non-infected plants due to initiation of defense reaction in response of pathogenic elicitors. Thus, the present study demonstrated the novelty of physio-biochemical tolerance induction on turmeric plants by using fungicides, biocontrol agents and phytoextracts. Highlights Foliar treatments improve desirable plant physio-biochemical traits against pathogen. Physio-biochemical variation induces the innate plant defense system. High phytophenol accumulation counteracts the pathogenic stress. Turmeric plant’s health and yield enhance by the reduction of disease intensity.
The Anna Karenina Model of β-Cell Maturation in Development and Their Dedifferentiation in Type 1 and Type 2 Diabetes

Loss of mature β-cell function and identity, or β-cell dedifferentiation, is seen in both type 1 and type 2 diabetes. Two competing models explain β-cell dedifferentiation in diabetes. In the first model, β-cells dedifferentiate in the reverse order of their developmental ontogeny. This model predicts that dedifferentiated β-cells resemble β-cell progenitors. In the second model, β-cell dedifferentiation depends on the type of diabetogenic stress. This model, which we call the “Anna Karenina” model, predicts that in each type of diabetes, β-cells dedifferentiate in their own way, depending on how their mature identity is disrupted by any particular diabetogenic stress. We directly tested the two models using a β-cell–specific lineage-tracing system coupled with RNA sequencing in mice. We constructed a multidimensional map of β-cell transcriptional trajectories during the normal course of β-cell postnatal development and during their dedifferentiation in models of both type 1 diabetes (NOD) and type 2 diabetes (BTBR-Lepob/ob). Using this unbiased approach, we show here that despite some similarities between immature and dedifferentiated β-cells, β-cell dedifferentiation in the two mouse models is not a reversal of developmental ontogeny and is different between different types of diabetes.
Probe the effect of clustering on EphA2 receptor signaling efficiency by subcellular control of ligand-receptor mobility

Clustering of ligand:receptor complexes on the cell membrane is widely presumed to have functional consequences for subsequent signal transduction. However, it is experimentally challenging to selectively manipulate receptor clustering without altering other biochemical aspects of the cellular system. Here, we develop a microfabrication strategy to produce substrates displaying mobile and immobile ligands that are separated by roughly one micron and thus experience an identical cytoplasmic signaling state, enabling precision comparison of downstream signaling reactions. Applying this approach to characterize the ephrinA1:EphA2 signaling system reveals that EphA2 clustering enhances receptor phosphorylation. Single molecule imaging clearly resolves increased molecular binding dwell time at EphA2 clusters for both Grb2:SOS and NCK:NWASP signaling modules. This type of intracellular comparison enables a substantially higher degree of quantitative analysis than is possible when comparisons must be made between different cells and essentially eliminates the effects of cellular response to ligand manipulation.
Robust clustering and interpretation of scRNA-seq data using reference component analysis

Motivation The transcriptomic diversity of the hundreds of cell types in the human body can be analysed in unprecedented detail using single cell (SC) technologies. Though clustering of cellular transcriptomes is the default technique for defining cell types and subtypes, single cell clustering can be strongly influenced by technical variation. In fact, the prevalent unsupervised clustering algorithms can cluster cells by technical, rather than biological, variation. Results Compared to de novo (unsupervised) clustering methods, we demonstrate using multiple benchmarks that supervised clustering, which uses reference transcriptomes as a guide, is robust to batch effects. To leverage the advantages of supervised clustering, we present RCA2, a new, scalable, and broadly applicable version of our RCA algorithm. RCA2 provides a user-friendly framework for supervised clustering and downstream analysis of large scRNA-seq data sets. RCA2 can be seamlessly incorporated into existing algorithmic pipelines. It incorporates various new reference panels for human and mouse, supports generation of custom panels and uses efficient graph-based clustering and sparse data structures to ensure scalability. We demonstrate the applicability of RCA2 on SC data from human bone marrow, healthy PBMCs and PBMCs from COVID-19 patients. Importantly, RCA2 facilitates cell-type-specific QC, which we show is essential for accurate clustering of SC data from heterogeneous tissues. In the era of cohort-scale SC analysis, supervised clustering methods such as RCA2 will facilitate unified analysis of diverse SC datasets. Availability RCA2 is implemented in R and is available at github.com/prabhakarlab/RCAv2
Overexpression of ELOVL6 has been associated with poor prognosis in patients with head and neck squamous cell carcinoma

Head and neck squamous cell carcinoma (HNSCC) is a high mortality disease. Extension of long-chain fatty acid family member 6 (ELOVL6) is a key enzyme involved in fat formation that catalyzes the elongation of saturated and monounsaturated fatty acids. Overexpression of ELOVL6 has been associated with obesity-related malignancies, including hepatocellular carcinoma, breast, colon, prostate, and pancreatic cancer. The following study investigated the role of ELOVL6 in HNSCC patients. Gene expression and clinicopathological analysis, enrichment analysis, and immune infiltration analysis were based on the Gene Expression Omnibus (GEO) and the Cancer Genome Atlas (TCGA), with additional bioinformatics analyses. The statistical analysis was conducted in R, and TIMER was used to analyze the immune response of ELOVL6 expression in HNSCC. The expression of ELOVL6 was related to tumor grade. Survival analysis showed that patients with high expression of ELOVL6 had a poor prognosis. Moreover, the results of GSEA enrichment analysis showed that ELOVL6 affects the occurrence of HNSCC through fatty acid metabolism, biosynthesis of unsaturated fatty acids, and other pathways. Finally, ELOVL6 verified by the Human Protein Atlas (HPA) database were consistent with the mRNA levels in HNSCC samples. ELOVL6 is a new biomarker for HNSCC that may be used as a potential predictor of the prognosis of human HNSCC.
Generalization of motor learning in psychological space

To generate adaptive movements, we must generalize what we have previously learned to novel situations. The generalization of learned movements has typically been framed as a consequence of neural tuning functions that overlap for similar movement kinematics. However, as is true in many domains of human behavior, situations that require generalization can also be framed as inference problems. Here, we attempt to broaden the scope of theories about motor generalization, hypothesizing that part of the typical motor generalization function can be characterized as a consequence of top-down decisions about different movement contexts. We tested this proposal by having participants make explicit similarity ratings over traditional contextual dimensions (movement directions) and abstract contextual dimensions (target shape), and perform a visuomotor adaptation generalization task where trials varied over those dimensions. We found support for our predictions across five experiments, which revealed a tight link between subjective similarity and motor generalization. Our findings suggest that the generalization of learned motor behaviors is influenced by both low-level kinematic features and high-level inferences.
Distinct metabolic flux modes through the tricarboxylic acid cycle in mesophyll and guard cells revealed by GC-MS-based 13C-positional isotopomer analysis

13C-Metabolic flux analysis (13C-MFA) have greatly contributed to revealing the regulation of plant metabolism. However, mass spectrometry (MS) approaches have hitherto been limited in their power to deduce flux information due to lack of positional information. Here we established an MS-based 13C-positional isotopomer labelling approach and performed a multi-species/cell-types analysis based on previous 13C-MFA to compare flux modes through the tricarboxylic acid (TCA) cycle and associated pathways in mesophyll (MCs) and guard cells (GCs). Both cell types showed high 13C-enrichment in pyruvate. However, GCs and sink MCs, but not source MCs showed high 13C-incorporation into Glu/Gln following provision of 13C-sucrose. Only GCs showed higher 13C-enrichment in the carbon 1 atom of Gln, which is derived from PEPc-mediated CO2 fixation. Increased 13C-enrichment in the carbon 1 of Glu was also observed in both trxo1 and ntra ntrb mutants, but not in wild type Arabidopsis plants, following provision of 13C-glucose. Our results suggest that the mitochondrial thioredoxin system restricts the fluxes from PEPc and glycolysis to Glu in illuminated MCs and reveal that fluxes throughout the TCA cycle of GCs resemble those of sink MCs but operate different non-cyclic flux modes to support Gln synthesis in the light.
Human pluripotent stem cell-derived cardiomyocytes align under cyclic strain when guided by cardiac fibroblasts

The human myocardium is a mechanically active tissue typified by anisotropic organization of the resident cells (cardiomyocytes (CMs) and cardiac fibroblasts (cFBs)) and the extracellular matrix (ECM). Upon ischemic injury, the anisotropic tissue is replaced by disorganized scar tissue, eventually resulting in loss of coordinated contraction. Efforts to re-establish tissue anisotropy in the injured myocardium are hampered by a lack of understanding on how CM and/or cFB structural organization is affected by the two major physical cues inherent in the myocardium: ECM organization and cyclic mechanical strain. Herein, we investigate the singular and combined effect of ECM (dis)organization and cyclic strain in a 2D human in vitro co-culture model of the myocardial microenvironment. We show that (an)isotropic ECM protein patterning can guide the orientation of CMs and cFBs, both in mono- and co-culture. Subsequent application of uniaxial cyclic strain – mimicking the local anisotropic deformation of beating myocardium – causes no effect when applied parallel to the anisotropic ECM. However, when cultured on isotropic substrates, cFBs, but not CMs, orient away from the direction of cyclic uniaxial strain (strain avoidance). In contrast, CMs show strain avoidance via active remodeling of their sarcomeres only when co-cultured with at least 30% cFBs. Paracrine signaling or N-cadherin-mediated communication between CMs and cFBs were no contributing factors, but our findings suggest that the mechanoresponsive cFBs provide structural guidance for CM orientation and elongation. Our study therefore highlights a synergistic mechanobiological interplay between CMs and cFBs in shaping tissue organization, which is of relevance for regenerating functionally organized myocardium.