bluuebunny/crossref_metadata_2025_split huggingface dataset:
Enhancing glycaemic control and promoting cardiovascular health: the therapeutic potential of Trigonella foenumgraecum in diabetic patients – a systematic review and meta-analysis
Authors: Shakil Saad , Akhtar Sareema E. , Ali Akhtar , Antony Meetty , Antony Ishan , Mansour Eyad , Khawar Farooqui Sabeeh , Akbar Absam , Alazazzi Hosam , Alsufyani Reema , Alsufyani Majid , Alawadhi Retaj , Ramtohul Rahul K. , Hadeed Sebastian , Tabassi Aysa , Tabassi Aylin , Almas Talal 
Published: January 2024

Background:
The antidiabetic potential of fenugreek has been highlighted in past literature, and various in-vitro and in-vivo studies have validated its glucose-lowering effects; however, very limited data are available on its effects on diabetic patients.

Objective:
An updated systematic review and meta-analysis of randomized control trials that assessed patients who were administered fenugreek.

Methods:
The PRISMA guidelines (Supplemental Digital Content 1, http://links.lww.com/MS9/A361) were followed when conducting this meta-analysis. PubMed, Scopus, Google Scholar and MEDLINE were searched from inception until June 2023, for randomized control trials that compared fenugreek with control in patients with type 2 diabetes mellitus (DM) and reported the following outcomes of interest: fasting blood glucose, glycated haemoglobin A1c (HbA1c) and postprandial glucose levels. The findings were presented as mean difference (MD) with 95% confidence intervals (CIs) and were pooled using a random effects model.

Results:
Fenugreek significantly (P<0.001) reduced the fasting blood sugar (FBS), HbA1c levels and postprandial glucose levels in diabetic patients when compared to the control.

Conclusion:
Among patients with type 2 DM, our comparisons demonstrated a reduction in FBS, HbA1c levels and postprandial glucose levels with the administration of fenugreek seed at 2–5 mg dose in powder form.
Suppression of soliton collapses, modulational instability and rogue-wave excitation in two-Lévy-index fractional Kerr media
Authors: Zhong Ming , Chen Yong , Yan Zhenya , Malomed Boris A. 
Published: January 2024

We introduce a generalized fractional nonlinear Schrödinger (FNLS) equation for the propagation of optical pulses in laser systems with two fractional-dispersion/diffraction terms, quantified by their Lévy indices,

α

1

α

2

∈
(
1
,
2
]

, and self-focusing or defocusing Kerr nonlinearity. Some fundamental solitons are obtained by means of the variational approximation, which are verified by comparison with numerical results. We find that the soliton collapse, exhibited by the one-dimensional cubic FNLS equation with only one Lévy index (LI)

α
=
1

, can be suppressed in the two-LI FNLS system. Stability of the solitons is also explored against collisions with Gaussian pulses and adiabatic variation of the system parameters. Modulation instability (MI) of continuous waves is investigated in the two-LI system too. In particular, the MI may occur in the case of the defocusing nonlinearity when two diffraction coefficients have opposite signs. Using results for the MI, we produce first- and second-order rogue waves on top of continuous waves, for both signs of the Kerr nonlinearity.
Altruism pays off in group-structured populations
Authors: Steiner Klaus F. 
Published: January 2024

AbstractThe evolution of altruistic traits is a Darwinian puzzle that has not yet been satisfactorily solved. Using cost-benefit analyses and multi-agent simulations, I show here that there is a clear fitness advantage for the altruists in a mixed population of altruists and egoists if the following conditions are met:(i) The population is segregated into groups that persist over time or several generations. (ii) The benefit achieved by altruists is only shared among the members of their own group. (iii) There is selection pressure on each individual, which is reduced by the benefit provided by altruists. (iv) The costs for an altruist are smaller than the total benefit achieved by him for all members of his group together. (v) There is already a high proportion of altruists in the population and/or the proportion of altruists varies greatly between groups.I refer this kind of population dynamics as the grouping effect, or G-effect for short. This effect is made up of two biases, which basically come about through simple individual selection: the tendency to increase the variance among the groups (variation bias) and the tendency to increase fitness for altruistic traits when this variance is high (fitness bias).In this context, selection only happens at the individual level. It does not require relationships between the group members, nor does it require competition among the groups. Extended multi-agent simulations with reproduction, mutation and migration also show that altruism can exist stably in a wide range of conditions due to this G-effect.
Haplotype phased genome of ‘Fairchild’ mandarin highlights influence of local chromatin state on gene expression
Authors: Diaz Isaac A. , Ostovar Talieh , Chen Jinfeng , Saddoris Sarah , Schmitz Robert J. , Wessler Susan R. , Stajich Jason , Seymour Danelle K. 
Published: January 2024

AbstractBackgroundCis-regulatory sequences control gene expression through the coordinated action of transcription factors and their associated partners. Both genetic and epigenetic perturbation of cis-regulatory sequences can lead to novel patterns of gene expression. Phased genome assemblies now enable the local dissection of linkages between cis-regulatory sequences, including their epigenetic state, and gene expression to further characterize gene regulation in heterozygous genomes.ResultsWe assembled a locally phased genome for a mandarin hybrid named ‘Fairchild’ to explore the molecular signatures of allele-specific gene expression. With genome phasing, genes with allele-specific expression were paired with haplotype-specific chromatin states, including levels of chromatin accessibility, histone modifications, and DNA methylation. We found that 30% of variation in allele-specific expression could be attributed to haplotype associated factors, with allelic levels of chromatin accessibility and three histone modifications in gene bodies having the most influence. Structural variants in promoter regions were also associated with allele-specific expression, including specific enrichments of hAT and MULE-MuDR DNA transposon sequences. Mining of cis-regulatory sequences underlying regions with allelic variation in chromatin accessibility revealed a paternally-associated sequence motif bound by ERF48, a target of the Polycomb repressive complex 2 (PRC2), and sequence similarity of this motif corresponded to local levels of H3K27me3, a signature of PRC2 activity.ConclusionsUsing a locally phased assembly of a heterozygous citrus cultivar, we dissected the interplay between genetic variants and molecular phenotypes with the goal of revealing functional cis-regulatory sequences and exploring the evolution of gene regulation.
The variation landscape ofCYP2D6in a multi-ethnic Asian population
Authors: Maulana Yusuf , Jimenez Rodrigo Toro , Twesigomwe David , Sani Levana , Irwanto Astrid , Bertin Nicolas , Gonzalez-Porta Mar 
Published: January 2024

AbstractCytochrome P450 2D6 (CYP2D6) plays a crucial role in metabolizing approximately 20% of medications prescribed clinically. This enzyme is encoded by theCYP2D6gene, known for its extensive polymorphism with over 170 catalogued haplotypes or star alleles, which can have a profound impact on drug efficacy and safety. Despite its importance, a gap exists in the global genomic databases, which are predominantly representative of European ancestries, thereby limiting comprehensive knowledge ofCYP2D6variation in ethnically diverse populations. In an effort to bridge this knowledge gap, we focused on elucidating theCYP2D6variation landscape within a multi-ethnic Asian cohort, encompassing individuals of Chinese, Malay, and Indian descent. Our study comprised data analysis of 1,850 whole genomes from the SG10K_Health dataset using an in-house consensus algorithm, which integrates the capabilities of Cyrius, Aldy, and StellarPGx. This analysis unveiled distinct population-specific star-allele distribution trends, highlighting the unique genetic makeup of the Singaporean population. Significantly, 46% of our cohort harbored actionableCYP2D6variants—those with direct implications for drug dosing and treatment strategies. Furthermore, we identified 14 potential novelCYP2D6star-alleles, of which 7 were observed in multiple individuals, suggesting their broader relevance. Overall, our study contributes novel data onCYP2D6genetic variations specific to the Southeast Asian context. The findings are instrumental for the advancement of pharmacogenomics and personalized medicine, not only in Southeast Asia but also in other regions with comparable genetic diversity.
Rewinding the ratchet: rare recombination locally rescues neo-W degeneration and generates plateaus of sex-chromosome divergence
Authors: Decroly Thomas , Vila Roger , Lohse Konrad , Mackintosh Alexander 
Published: January 2024

AbstractNatural selection is less efficient in the absence of recombination. As a result, non-recombining sequences, such as sex chromosomes, tend to degenerate over time. Although the outcomes of recombination arrest are typically observed after many millions of generations, recent neo-sex chromosomes can give insight into the early stages of this process. Here we investigate the evolution of neo-sex chromosomes in the Spanish marbled white butterfly,Melanargia ines, where a Z-autosome fusion has turned the homologous autosome into a non-recombining neo-W chromosome. We show that these neo-sex chromosomes are likely limited to the Iberian population ofM. ines, and that they arose around the time when populations in Iberia and North-Africa split, around 1.5 million years ago. Recombination arrest of the neo-W chromosome has led to an excess of premature stop codons and frameshift mutations, while levels of gene expression have remained similar for the neo-W and neo-Z chromosomes, even for genes with loss-of-function mutations. Surprisingly, we identified two regions of∼1 Mb at one end of the neo-W that are both less diverged from the neo-Z and less degraded than the rest of the chromosome, suggesting a history of rare but repeated genetic exchange between the two neo-sex chromosomes. These plateaus of neo-sex chromosome divergence suggest that neo-W degradation can be locally reversed by rare recombination between neo-W and neo-Z chromosomes.
SPT6L, a newly discovered ancestral component of the plant RNA-directed DNA methylation pathway
Authors: Čermák Vojtěch , Kašpar Tomáš , Fischer Lukáš 
Published: January 2024

AbstractRNA-directed DNA methylation (RdDM) is driven by small RNAs (sRNAs) complementary to the nascent transcript of RNA polymerase V (Pol V). sRNAs associated with ARGONAUTE (AGO) proteins are tethered to Pol V mainly by the AGO-hook domain of its subunit NRPE1. We found, byin silicoanalyses, that Pol V strongly colocalizes on chromatin with another AGO-hook protein, SPT6-like (SPT6L), which is a known essential transcription elongation factor of Pol II. Our phylogenetic analysis revealed that SPT6L acquired its AGO-binding capacity already in the most basal streptophyte algae, even before the emergence of Pol V, suggesting that SPT6L might be a driving force behind the RdDM evolution. Since its emergence, SPT6L with the AGO-hook represents the only conserved SPT6 homolog inViridiplantae, implying that the same protein is involved in both Pol II and Pol V complexes. To better understand the role of SPT6L in the Pol V complex, we characterized genomic loci where these two colocalize and uncovered that DNA methylation there is more dynamic, driven by higher levels of sRNAs often from non-canonical RdDM pathways and more dependent on chromatin modifying and remodeling proteins like MORC. Pol V loci with SPT6L are highly depleted in helitrons but enriched in gene promoters for which locally and temporally precise methylation is necessary. In view of these results, we discuss potential roles of multiple AGO-hook domains present in the Pol V complex and speculate that SPT6L mediatesde novomethylation of naïve loci by interconnecting Pol II and Pol V activities.
MoCHI: neural networks to fit interpretable models and quantify energies, energetic couplings, epistasis and allostery from deep mutational scanning data
Authors: Faure Andre J. , Lehner Ben 
Published: January 2024

AbstractThe massively parallel nature of deep mutational scanning (DMS) allows the quantification of the phenotypic effects of thousands of perturbations in a single experiment. We have developed MoCHI, a software tool that allows the parameterisation of arbitrarily complex models using DMS data. MoCHI simplifies the task of building custom models from measurements of mutant effects on any number of phenotypes. It allows the inference of free energy changes, as well as pairwise and higher-order interaction terms (energetic couplings) for specified biophysical models. When a suitable user-specified mechanistic model is not available, global nonlinearities (epistasis) can be estimated directly from the data. MoCHI also builds upon and leverages theory on ensemble (or background-averaged) epistasis to learn sparse predictive models that can incorporate higher-order epistatic terms and are informative of the genetic architecture of the underlying biological system. The combination of DMS and MoCHI allows biophysical measurements to be performed at scale, including the construction of complete allosteric maps of proteins. MoCHI is freely available (https://github.com/lehner-lab/MoCHI) and implemented as an easy-to-use python package relying on the PyTorch machine learning framework.
B-type plexins regulate mitosis via RanGTPase
Authors: Mukhwana Nicholus , Garg Ritu , Williamson Magali 
Published: January 2024

AbstractAberrant mitosis can result in aneuploidy and cancer. The small GTPase, Ran, is a key regulator of mitosis. B-type Plexins regulate Ran activity by acting as RanGTPase activating proteins (GAPs) and have been implicated in cancer progression. However, whether B-type plexins have a role in mitosis has not so far been investigated.We show here that PlexinB1 functions in the control of mitosis. Depletion of PlexinB1 resulted in defects in chromosomal segregation, increasing cells with multipolar spindles and prolonging metaphase, while activation of PlexinB1/B2 with Sema4D produced aberrant spindles.An increase in MAD1-positive kinetochores in PlexinB1/B2 depleted cells indicated application of spindle assembly checkpoint (SAC), possibly resulting from faulty spindle-microtubule assembly, and PlexinB1 depletion promoted regrowth of acentrosomal microtubules and defects in spindle pole refocussing. Depleted cells that had bypassed SAC possessed lagging chromosomes and chromosomal bridges.The mitotic defects observed upon PlexinB1 depletion were rescued by an RCC1 inhibitor, indicating that PlexinB1 signals, at least in part, via Ran to affect mitosis.These errors in mitosis generated multinucleate cells, and nuclei of altered morphology and abnormal karyotype. Furthermore, Sema4D-treatment increased the percentage of cells with micronuclei, precursors of chromothripsis. Defects in B-type plexins may contribute to the well-established role of plexins in cancer progression by inducing chromosomal instability.
Human IL-6 fosters long-term engraftment of patient derived disease-driving myeloma cells in immunodeficient mice
Authors: Hasanali Zainul S. , Garfall Alfred L. , Burzenski Lisa , Shultz Leonard D. , Tang Yan , Kadu Siddhant , Sheppard Neil C. , Dopkin Derek , Vogl Dan T. , Cohen Adam D. , Waxman Adam J. , Susanibar-Adaniya Sandra P. , Carroll Martin , Stadtmauer Edward A. , Allman David 
Published: January 2024

AbstractMultiple myeloma is a largely incurable and life-threatening malignancy of antibody-secreting plasma cells. An effective and widely available animal model that recapitulates human myeloma and related plasma cell disorders is lacking. We show that busulfan-conditioned hIL-6 transgenic NSG mice (NSG+hIL6) reliably support the engraftment of malignant and pre-malignant human plasma cells including from patients diagnosed with monoclonal gammopathy of undetermined significance, pre- and post-relapse myeloma, plasma cell leukemia, and AL amyloidosis. Consistent with human disease, NSG+hIL6 mice engrafted with patient-derived myeloma cells, developed serum M spikes, and a majority developed anemia, hypercalcemia, and/or bone lesions. Single cell RNA sequencing showed non-malignant and malignant cell engraftment, the latter expressing a wide array of mRNAs associated with myeloma cell survival and proliferation. Myeloma engrafted mice given CAR T-cells targeting plasma cells or bortezomib experienced reduced tumor burden. Our results establish NSG+hIL6 mice as an effective patient derived xenograft model for study and preclinical drug development of multiple myeloma and related plasma cell disorders.
Med12 cooperates with multiple differentiation signals to facilitate efficient lineage transitions in embryonic stem cells
Authors: Fernkorn Max , Schröter Christian 
Published: January 2024

AbstractCell differentiation results from coordinated changes in gene transcription in response to combinations of signals. FGF, Wnt, and mTOR signals regulate the differentiation of pluripotent mammalian cells towards embryonic and extraembryonic lineages, but how these signals cooperate with general transcriptional regulators is not fully resolved. Here, we report a genome-wide CRISPR screen that reveals both signaling components and general transcriptional regulators for differentiation-associated gene expression in mESCs. Focusing on the Mediator subunitMed12as one of the strongest hits in the screen, we show that it regulates gene expression in parallel to FGF and mTOR signals. Loss ofMed12is compatible with differentiation along both the embryonic epiblast and the extraembryonic primitive endoderm lineage, but impairs pluripotency gene expression and slows down transitions between pluripotency states. These findings suggest thatMed12helps pluripotent cells to efficiently execute transcriptional changes during differentiation, thereby modulating the effects of a broad range of signals.
An optimized live imaging and growth analysis approach for Arabidopsis Sepals
Authors: Yadav Avilash Singh , Roeder Adrienne H.K. 
Published: January 2024

AbstractBackgroundArabidopsis thalianasepals are excellent models for analyzing growth of entire organs due to their relatively small size, which can be captured at a cellular resolution under a confocal microscope [1]. To investigate how growth of different tissue layers generates unique organ morphologies, it is necessary to live-image deep into the tissue. However, imaging deep cell layers of the sepal is practically challenging, as it is hindered by the presence of extracellular air spaces between mesophyll cells, among other factors which causes optical aberrations. Image processing is also difficult due to the low signal-to-noise ratio of the deeper tissue layers, an issue mainly associated with live imaging datasets. Addressing some of these challenges, we provide an optimized methodology for live imaging sepals and subsequent image processing. This helps us track the growth of individual cells on the outer and inner epidermal layers, which are the key drivers of sepal morphogenesis.ResultsFor live imaging sepals across all tissue layers at early stages of development, we found that the use of a bright fluorescent membrane marker, coupled with increased laser intensity and an enhanced Z-resolution produces high-quality images suitable for downstream image processing. Our optimized parameters allowed us to image the bottommost cell layer of the sepal (inner epidermal layer) without compromising viability. We used a ‘voxel removal’ technique to visualize the inner epidermal layer in MorphoGraphX [2, 3] image processing software. Finally, we describe the process of optimizing the parameters for creating a 2.5D mesh surface for the inner epidermis. This allowed segmentation and parent tracking of individual cells through multiple time points, despite the weak signal of the inner epidermal cells.ConclusionWe provide a robust pipeline for imaging and analyzing growth across inner and outer epidermal layers during early sepal development. Our approach can potentially be employed for analyzing growth of other internal cell layers of the sepals as well. For each of the steps, approaches, and parameters we used, we have provided in-depth explanations to help researchers understand the rationale and replicate our pipeline.
Transcriptomic interplay betweenAcinetobacter baumannii, human macrophage and polymyxin
Authors: Kho Zhi Ying , Azad Mohammad Abul Kalam , Zhu Yan , Han Mei-Ling , Zhou Qi (Tony) , Velkov Tony , Naderer Thomas , Li Jian 
Published: January 2024

ABSTRACTOptimization of antibiotic therapy has been hindered by our dearth of understanding on the mechanism of the host-pathogen-drug interactions. Here, we employed dual RNA-sequencing to examine transcriptomic perturbations in response to polymyxin B in a co-culture infection model ofAcinetobacter baumanniiand human macrophages. Our findings revealed that polymyxin B treatment induced significant transcriptomic response in macrophage-interactingA. baumannii, exacerbating bacterial oxidative stress, disrupting metal homeostasis, affecting osmoadaptation, triggering stringent stress response, and influencing pathogenic factors. Moreover, infected macrophages adapt heme catabolism, coagulation cascade, and hypoxia-inducible signaling to confront bacterial invasion. DisruptingrcnB,ompW, andtraR/dksAgenes inA. baumanniiimpairs metal homeostasis, osmotic stress defense and stringent responses, thereby enhancing antibacterial killing by polymyxin. These findings shed light on the global stress adaptations at the network level during host-pathogen-drug interactions, revealing promising therapeutic targets for further investigation.IMPORTANCEIn the context of the development of bacterial resistance during the course of antibiotic therapy, the role of macrophages in shaping bacterial response to antibiotic killing remains enigmatic. Herein we employed dual RNA-sequencing and anin vitrotripartite model to delve into the unexplored transcriptional networks of theAcinetobacter baumannii-macrophage-polymyxin axis. Our findings uncovered the potential synergy between macrophages and polymyxin B which appear to act in co-operation to disrupt multiple stress tolerance mechanisms inA. baumannii. Notably, we discovered the critical roles of bacterial nickel/cobalt homeostasis (rcnBfamily), osmotic stress defense (ompWfamily), and stringent response regulator (traR/dksAC4-type zinc finger) in tolerating the last-line antibiotic polymyxin B. Our findings may lead to potential targets for the development of novel therapeutics against the problematic pathogenA. baumannii.