bluuebunny/crossref_metadata_2025 huggingface dataset:
Overexpression of cytochrome P450 gene CYP6K1 is associated with pyrethroid resistance in German cockroaches (Blattodea: Ectobiidae) from California
Authors: Tseng Shu-Ping , Lee Shao-Hung , Choe Dong-Hwan , Lee Chow-Yang
Published: March 2024

We investigated the expression of 4 cytochrome P450 genes (CYP4G19, CYP6J1, CYP6K1, and CYP4C21) in 4 field-collected strains (WM, RG386, CDR, and Ryan) of the German cockroach, Blattella germanica (L.), collected from California. The UCR susceptible strain was used as a comparison. Topical assays using a diagnostic dose (3× LD95) of deltamethrin revealed decreased sensitivity in all field-collected strains with mortality ranging from 0% to 58%, and the addition of PBO before deltamethrin treatment increased mortality to 52.5%–87.5%. Using qPCR to investigate the expression levels of CYP4G19, CYP4C21, CYP6J1, and CYP6K1, we found that only CYP6K1 was significantly overexpressed (2.1–5.8× higher) in all field-collected strains when compared to the UCR strain. Next, we investigated the role of the CYP6K1 gene by performing gene knockdown using RNAi. After dsCYP6K1 treatment, the expression levels of CYP6K1 in WM and Ryan strains were significantly reduced (P < 0.01) by 91%–94% vs. those treated with dsEGFP (control) on the third and sixth day posttreatment. RG386, CDR, and Ryan strains were more susceptible compared to their respective controls to topically applied deltamethrin 6 days after treatment with dsCYP6K1. This study provides evidence of the involvement of the P450 CYP6K1 gene in pyrethroid resistance in some populations of German cockroaches.
Adaptive graph Laplacian MTL L1, L2 and LS-SVMs
Authors: Ruiz Carlos , Alaíz Carlos M , Dorronsoro José R
Published: March 2024

Multi-Task Learning tries to improve the learning process of different tasks by solving them simultaneously. A popular Multi-Task Learning formulation for SVM is to combine common and task-specific parts. Other approaches rely on using a Graph Laplacian regularizer. Here we propose a combination of these two approaches that can be applied to L1, L2 and LS-SVMs. We also propose an algorithm to iteratively learn the graph adjacency matrix used in the Laplacian regularization. We test our proposal with synthetic and real problems, both in regression and classification settings. When the task structure is present, we show that our model is able to detect it, which leads to better results, and we also show it to be competitive even when this structure is not present.
A comparison of time series lags and non-lags in Spanish electricity price forecasting using data science models
Authors: Vega-Márquez Belén , Solís-García Javier , Nepomuceno-Chamorro Isabel A , Rubio-Escudero Cristina
Published: March 2024

Electricity is an indicator that shows the progress of a civilization; it is a product that has greatly changed the way we think about the world. Electricity price forecasting became a fundamental task in all countries due to the deregulation of the electricity market in the 1990s. This work examines the effectiveness of using multiple variables for price prediction given the large number of factors that could influence the price of the electricity market. The tests were carried out over four periods using data from Spain and deep learning models. Two different attribute selection methods based on Pearson’s correlation coefficient have been used to improve the efficiency of the training process. The variables used as input to the different prediction models were chosen, considering those most commonly used previously in the literature. This study attempts to test whether using time series lags improves the non-use of lags. The results obtained have shown that lags improve the results compared to a previous work in which no lags were used.
In vitro effect of diazoxon on cell signaling and second messengers in Nile tilapia (Oreochromis niloticus) leukocytes
Authors: Camacho-Pérez Milton Rafael , Díaz-Resendiz Karina Janice Guadalupe , Ortiz-Butrón Rocío , Covantes-Rosales Carlos Eduardo , Benitez-Trinidad Alma Betsaida , Girón-Pérez Daniel Alberto , Toledo-Ibarra Gladys Alejandra , Pavón Lenin , Girón-Pérez Manuel Iván
Published: March 2024

The physiological and molecular responses of leukocytes are altered by organophosphate pesticides. Some reports have shown that diazinon causes immunotoxic effects; diazoxon, the oxon metabolite of diazinon, is attributed to influence the immune response by affecting the leukocyte cholinergic system. In this study, the in vitro effects of diazoxon on molecules involved in cell signaling (cAMP, IP3, DAG, JAK1, and STAT3), which play a crucial role in the activation, differentiation, and survival of leukocytes, were evaluated. Data indicate that diazoxon leads to a decrease in cAMP concentration and an increase in basal IP3 levels. However, diazoxon does not affect basal levels of JAK1 and STAT3 phosphorylation. Instead, diazoxon inhibits leukocyte responsiveness to phorbol myristate acetate and ionomycin, substances that, under normal conditions, enhance JAK/STAT signaling. These findings demonstrate that diazoxon significantly affects key molecular parameters related to cell signaling.
Exploration of anti-diabetic activity and metabolite profiling of Bruguiera cylindrica (l.) Bl.—in vivo anti-diabetic activity, exploration of molecular mechanism, and network pharmacological analysis
Authors: Gayen Srijon , Jana Sandipan , Das Gupta Barun , Ghosh Avijit , Kar Amit , Bala Asis , Mukherjee Pulok Kumar , Haldar Pallab Kanti
Published: March 2024

Introduction

The Bruguiera cylindrica L. is a mangrove plant that is typically found in coastal areas of Asia, including India. It has been known for its medicinal properties, which have been utilized for generations. For example, in Thailand, it has been used to treat wounds and diarrhoea, while in India, it has been effective in addressing diabetes, ulcers, and other health issues. This particular study sought to investigate the potential of B. cylindrica bark extract in reducing the symptoms of diabetes in rats.

Methods

In this study, we examined the potential of B. cylindrica bark extract as an inhibitor of α-amylase and α-glucosidase enzymes in vitro. We also evaluated the effects of the extract and Metformin on rats fed high-fat diets and measured their lipid profiles and biochemical parameters. Furthermore, we conducted a network pharmacology analysis to identify proteins and pathways involved in the amelioration of diabetes.

Results

Through metabolite profiling, we identified 58 compounds in B. cylindrica hydroalcoholic extract. These compounds include alkaloids, phenolics, flavonoids, and fatty acids. The extract was found to have a dose-dependent inhibition activity against α-amylase and α-glucosidase, with IC50 values similar to acarbose. In rats, oral administration of 200–400 mg/kg of B. cylindrica led to reduced blood glucose levels and normalized serum biochemical parameters.

Conclusions

Bruguiera cylindrica bark may reduce blood sugar levels in rats with diabetes. The study found metabolites that interact with protein targets associated with different types of diabetes.
Joint analysis of multivariate longitudinal, imaging, and time-to-event data
Authors: Zhou Xiaoxiao , Song Xinyuan
Published: March 2024

Alzheimer’s (AD) is a progressive neurodegenerative disease frequently associated with memory deficits and cognitive decline. Despite its irreversible once onset, some discoveries revealed the existence of a certain percentage of people who are non-susceptible to AD. This study proposes a joint analysis of multivariate longitudinal data, survival data with a non-susceptible fraction, and ultrahigh-dimensional imaging data. The proposed model comprises three major components. The first component is a mixture proportional hazards cure model with images to examine the potential predictors of the non-susceptible probability and hazards of interest. The second component is a dynamic factor analysis model with images to characterize group-specific latent factors through multiple observed variables. The last component is a semiparametric trajectory model to reveal the change patterns of the dynamic latent factors in the ‘non-susceptible’ and ‘susceptible’ groups. A two-stage approach is developed for statistical inference. The first stage manages the imaging data through high-dimensional functional principal component analysis. The second stage develops a Bayesian approach coupled with penalized splines, data augmentation, and Markov chain Monte Carlo techniques to perform estimation. The application to the Alzheimer’s Disease Neuroimaging Initiative dataset sheds new insight into the pathology of AD.
A rare case of a cholecysto-duodenocolonic fistula secondary to cholelithiasis
Authors: Sidhu Tejminder S , Jhamb Shaurya , Ben David Matan M
Published: March 2024

Internal biliary fistula is a rare but well-known complication of cholelithiasis. It is a notoriously challenging entity to diagnose and manage. Gallstones are often the causative factor in the formation of a cholecystoenteric fistula, with the most common internal biliary fistula being a cholecystoduodenal fistula followed by a cholecystocolonic fistula. Rarely, do these fistulae exist simultaneously. Here, we present an uncommon case of cholecysto-duodenocolonic fistula.
‘English in taste, Indian in blood’: caste hegemony in the making of British international legal thought
Authors: Memon Ahmed
Published: March 2024

In this article, I argue that caste was a central factor in the development of British international legal thought in the subcontinent. Specifically, I contend that British international legal thought entrenched caste hegemony into the broader racial civilisation hierarchy of international law in the nineteenth century.
Predicting the XRISM dark matter decay signal in the Milky Way halo
Authors: Lovell M R
Published: March 2024

Dark matter may be detected in X-ray decay, including from the decay of the dark matter particles that make up the Milky Way (MW) halo. We use a range of density profiles to compute X-ray line intensity profiles, with a focus on the resonantly produced sterile neutrino dark matter candidate. Compared to the Navarro–Frenk–White density profile, we show that using an adiabatically contracted halo profile suppresses the line intensity in the halo outskirts and enhances it in the Galactic Centre (GC), although this enhancement is eliminated by the likely presence of a core within 3 kpc. Comparing our results to MW halo observations, other X-ray observations, and structure formation constraints implies a sterile neutrino mixing angle parameter s11 ≡ sin 2(2θ) × 1011 ∼ [3, 4] (particle lifetime $\tau _{28}\equiv \tau /(10^{28}\rm {s})\sim [1.0,1.3]$), which is nevertheless is strong tension with some reported non-detections. We make predictions for the likely decay flux that the X-Ray Imaging and Spectroscopy Mission (XRISM) satellite would measure in the GC, plus the Virgo and Perseus clusters, and outline further steps to determine whether the dark matter is indeed resonantly produced sterile neutrinos as detected in X-ray decay.
Constraining a relativistic mean field model using neutron star mass–radius measurements I: nucleonic models
Authors: Huang Chun , Raaijmakers Geert , Watts Anna L , Tolos Laura , Providência Constança
Published: March 2024

Measurements of neutron star mass and radius or tidal deformability deliver unique insight into the equation of state (EOS) of cold dense matter. EOS inference is very often done using generalized parametric or non-parametric models, which deliver no information on composition. In this paper, we consider a microscopic nuclear EOS model based on a field theoretical approach. We show that current measurements from NICER and gravitational wave observations constrain primarily the symmetric nuclear matter EOS. We then explore what could be delivered by measurements of mass and radius at the level anticipated for future large-area X-ray timing telescopes. These should be able to place very strong limits on the symmetric nuclear matter EOS, in addition to constraining the nuclear symmetry energy that determines the proton fraction inside the neutron star.
Geometry-driven and dark-matter-sustained Milky Way rotation curves with Gaia DR3
Authors: Beordo William , Crosta Mariateresa , Lattanzi Mario G , Re Fiorentin Paola , Spagna Alessandro
Published: March 2024

Thanks to Gaia DR2, we proved for the first time that a general relativistic Milky Way rotation curve is statistically indistinguishable from its state-of-the-art dark matter analogue. Those results supported the ansatz that gravitational dragging can explain the observed flatness of the Milky Way rotation curve with a consistent radial matter density profile. To challenge again such a scenario, we select 719 143 young disc stars within |z| < 1 kpc and up to R ≃ 19 kpc from Gaia DR3 providing a much larger sample of high-quality astrometric and spectrophotometric data of unprecedented homogeneity. This sample comprises 241 918 OBA stars, 475 520 RGB giants, and 1705 Cepheides that we use to fit, as with DR2, both a classical velocity profile model, i.e. with a dark matter halo, and a general relativistic analogue derived from a dust disc-scale metric. Once more, further corroborating our earlier findings, both models are found to explain, with similar statistical quality, the new observed rotational velocities derived from different combinations of the selected sets of stars belonging to the disc of our Galaxy. The geometrical effect is found to drive the velocity profile from 10 kpc outwards, while being responsible for ∼30–37 per cent of this profile already at the Sun distance, similarly to the halo contribution in the classical model. This confirms our previous results on the contribution of Einstein’s geometry and pushes to further investigate the role of General Relativity in tracing the Milky Way rotation curve; notably, the origin of this gravitational dragging remains undetermined, necessitating a dedicated in-depth exploration.
Overabundance of orphan galaxies in the UniverseMachine empirical galaxy formation model
Authors: Kumar Amit , More Surhud , Sunayama Tomomi
Published: March 2024

Orphan galaxies that have lost a large fraction of the dark matter subhaloes have often been invoked in semi-analytical as well as empirical models of galaxy formation. However, observations have not yet constrained the distribution of orphan galaxies in such models so far. We run a mock cluster finder that mimics the optical cluster finding technique of the redMaPPer algorithm on a catalogue of galaxies with quenched star formation from one such empirical model, the UniverseMachine, and obtain the prevalence of orphan galaxies in these clusters as a function of their cluster-centric distance. We compare the fraction of orphan galaxies with the upper limits derived based on our prior observations of the weak lensing signals around satellite galaxies from SDSS redMaPPer clusters. Although the orphan fraction from the UniverseMachine is marginally consistent with the upper limits in the innermost regions of galaxy clusters spanning $[0.1, 0.3]\, {h^{-1}\,\rm Mpc}$, we observe that the orphan fractions substantially violate the upper limits in the outer regions of galaxy clusters beyond $0.3\,{h^{-1}\,\rm Mpc}$. We discuss the reasons, plausible improvements to the model, and how observations can be used to constrain such models further.
Effects of remimazolam tosilate on gastrointestinal hormones and gastrointestinal motility in patients undergoing gastrointestinal endoscopy with sedation: a randomized control trial
Authors: Yang Tianyi , Zhou Yinji , Wang Mingshan , Zhang Lina , Liu Bing , Sun Lixin , Shi Fei , Yuan Yang , Zhang Gaofeng
Published: March 2024

Purpose

To investigate the impacts of remimazolam tosilate on gastrointestinal hormones and motility in patients undergoing gastrointestinal endoscopy with sedation.

Methods

A total of 262 American Society of Anesthesiologists Physical Status I or II patients, aged 18–65 years, scheduled for gastrointestinal endoscopy with sedation, were randomly allocated into two groups (n = 131 each): the remimazolam tosilate group (Group R) and the propofol group (Group P). Patients in Group R received 0.2–0.25 mg/Kg remimazolam tosilate intravenously, while those in Group P received 1.5–2.0 mg/kg propofol intravenously. The gastrointestinal endoscopy was performed when the Modified Observer’s Assessment of Alertness/Sedation scores were ≤3. The primary endpoints included the endoscopic intestinal peristalsis rating by the endoscopist; serum motilin and gastrin levels at fasting without gastrointestinal preparation (T0), before gastrointestinal endoscopy (T1), and before leaving the Post Anesthesia Care Unit (T2); and the incidences of abdominal distension during Post Anesthesia Care Unit.

Results

Compared with Group P, intestinal peristalsis rating was higher in Group R (P < .001); Group R showed increased motilin and gastrin levels at T2 compared with Group P (P < .01). There was a rise in motilin and gastrin levels at T1 and T2 compared with T0 and at T2 compared with T1 in both groups (P < .01). The incidence of abdominal distension was lower in Group R (P < .05).

Conclusion

Compared with propofol used during gastrointestinal endoscopy with sedation, remimazolam tosilate mildly inhibits the serum motilin and gastrin levels, potentially facilitating the recovery of gastrointestinal motility.
Identification and validation of new fatty acid metabolism–related mechanisms and biomarkers for erectile dysfunction
Authors: He Yanfeng , Liu Changyi , Zheng Zhongjie , Gao Rui , Lin Haocheng , Zhou Huiliang
Published: March 2024

Background

Erectile dysfunction (ED) is a common condition affecting middle-aged and elderly men.

Aim

The study sought to investigate differentially expressed fatty acid metabolism–related genes and the molecular mechanisms of ED.

Methods

The expression profiles of GSE2457 and GSE31247 were downloaded from the Gene Expression Omnibus database and merged. Differentially expressed genes (DEGs) between ED and normal samples were obtained using the R package limma. Gene Ontology and Kyoto Encyclopedia of Genes and Genomes enrichment analyses of DEGs were conducted using the R package clusterProfiler. Fatty acid metabolism–related DEGs (FAMDEGs) were further identified and analyzed. Machine learning algorithms, including Lasso (least absolute shrinkage and selection operator), support vector machine, and random forest algorithms, were utilized to identify hub FAMDEGs with the ability to predict ED occurrence. Coexpression analysis and gene set enrichment analysis of hub FAMDEGs were performed.

Outcome

Fatty acid metabolism–related functions (such as fatty acid metabolism and degradation) may play a vital role in ED.

Results

In total, 5 hub FAMDEGs (Aldh2, Eci2, Acat1, Acadl, and Hadha) were identified and found to be differentially expressed between ED and normal samples. Gene set enrichment analysis identified key pathways associated with these genes. The area under the curve values of the 5 hub FAMDEGs for predicting ED occurrence were all >0.8.

Clinical Translation

Our results suggest that these 5 key FAMDEGs may serve as biomarkers for the diagnosis and treatment of ED.

Strengths and Limitations

The strengths of our study include the use of multiple datasets and machine learning algorithms to identify key FAMDEGs. However, limitations include the lack of validation in animal models and human tissues, as well as research on the mechanisms of these FAMDEGs.

Conclusion

Five hub FAMDEGs were identified as potential biomarkers for ED progression. Our work may prove that fatty acid metabolism–related genes are worth further investigation in ED.
Impact of FDA’s HCT/P ZIKV Recommendations on Cord Blood Unit Eligibility and Utilization in a Large Public Cord Blood Bank
Authors: Guggenheim Dana S , Kurtzberg Joanne , Shaz Beth H
Published: March 2024

Background

Cord blood units (CBUs) that are ineligible for licensure due to incomplete compliance with FDA recommendations may be used for hematopoietic stem cell transplantation under urgent medical need and an Investigational Drug Application. The largest reason for CBU donor ineligibility is Zika virus (ZIKV) risk. The study’s objective was to analyze the impact of current FDA recommendations for ZIKA risk on a large public cord blood bank and propose updated recommendations.

Methods

We performed a retrospective analysis of Carolinas Cord Blood Bank (CCBB), an FDA licensed public CBB, using data from January 1, 2016 to November 21, 2023 and compared FDA recommendations for transfusion transmitted infections (TTI) for blood products and relevant communicable disease agents or diseases for human cell, tissue, or cellular or tissue-based products (HCT/Ps).

Results

CCBB: 9057 (84.3% licensed) CBUs were banked. 984/1682 (58.5%) of unlicensed CBUs had ZIKV risk. 22.0% of CBUs with ZIKV risk were from Hispanic parents, compared to 16.1% of all units. 31 of IND CBUs (11 due to ZIKV risk without reported ZIKV transmission) were safely infused. FDA Guidance: HCT/P ZIKV, HIV, and vCJD recommendations have not been updated since 2018 in contrast to FDA removal of ZIKV as a relevant TTI in 2021 and updating HIV and vCJD guidance related to TTI in 2023 and 2022, respectively.

Discussion

The FDA should consider new data to revise the HCT/P donor eligibility recommendations, which will increase the number of eligible HCT/P donors, and potentially improve access to therapies for a more diverse patient population.
A role for TGFβ signaling in Gli1+ tendon and enthesis cells
Authors: Song Lee , Golman Mikhail , Abraham Adam C. , Zelzer Elazar , Thomopoulos Stavros
Published: March 2024

The development of musculoskeletal tissues such as tendon, enthesis, and bone relies on proliferation and differentiation of mesenchymal progenitor cells. Gli1+ cells have been described as putative stem cells in several tissues and are presumed to play critical roles in tissue formation and maintenance. For example, the enthesis, a fibrocartilage tissue that connects tendon to bone, is mineralized postnatally by a pool of Gli1+ progenitor cells. These cells are regulated by hedgehog signaling, but it is unclear if TGFβ signaling, necessary for tenogenesis, also plays a role in their behavior. To examine the role of TGFβ signaling in Gli1+ cell function, the receptor for TGFβ, TbR2, was deleted in Gli1‐lineage cells in mice at P5. Decreased TGFβ signaling in these cells led to defects in tendon enthesis formation by P56, including defective bone morphometry underlying the enthesis and decreased mechanical properties. Immunohistochemical staining of these Gli1+ cells showed that loss of TGFβ signaling reduced proliferation and increased apoptosis. In vitro experiments using Gli1+ cells isolated from mouse tail tendons demonstrated that TGFβ controls cell proliferation and differentiation through canonical and non‐canonical pathways and that TGFβ directly controls the tendon transcription factor scleraxis by binding to its distant enhancer. These results have implications in the development of treatments for tendon and enthesis pathologies.
EcologicalNetworksDynamics.jl A Julia package to simulate the temporal dynamics of complex ecological networks
Authors: Lajaaiti Ismaël , Bonnici Iago , Kéfi Sonia , Mayall Hana , Danet Alain , Beckerman Andrew P , Malpas Thomas , Delmas Eva
Published: March 2024

Species interactions play a crucial role in shaping biodiversity, species coexistence, population dynamics, community stability and ecosystem functioning. Our understanding of the role of the diversity of species interactions driving these species, community and ecosystem features is limited because current approaches often focus only on trophic interactions. This is why a new modelling framework that includes a greater diversity of interactions between species is crucially needed.

We developed a modular, user-friendly, and extensible Julia package that delivers the core functionality of the bio-energetic food web model. Moreover, it embeds several ecological interaction types alongside the capacity to manipulate external drivers of ecological dynamics like temperature. These new features represent important processes known to influence biodiversity, coexistence, functioning and stability in natural communities. Specifically, they include: a) an explicit multiple nutrient intake model for producers, b) competition among producers, c) temperature dependence implemented via the Boltzmann-Arhennius rule, and d) the ability to model several non-trophic interactions including competition for space, plant facilitation, predator interference and refuge provisioning.

The inclusion of the various features provides users with the ability to ask questions about multiple simultaneous processes and stressor impacts, and thus develop theory relevant to real world scenarios facing complex ecological communities in the Anthropocene. It will allow researchers to quantify the relative importance of different mechanisms to stability and functioning of complex communities.

The package was build for theoreticians seeking to explore the effects of different types of species interactions on the dynamics of complex ecological communities, but also for empiricists seeking to confront their empirical findings with theoretical expectations. The package provides a straightforward framework to model explicitly complex ecological communities or provide tools to generate those communities from few parameters.
Low-intensity vibration does not induce changes in microtubule dynamics in vitro
Authors: Crandall Chase A. , Nikitina Nina N. , Zavala Anamaria G. , Howard Sean M. , Uzer Gunes
Published: March 2024

Microtubules (MTs) are cytoskeletal filaments responsible for many vital cellular processes including intracellular organelle organization and enabling the movement of intracellular components. While MTs were shown to respond to low frequency and large mechanical signals like substrate strain, how MTs may respond to a high frequency mechanical signal like low-intensity vibrations (LIV) is unknown. Here we quantified the polymerization dynamics of MTs under an acute 1-day LIV protocol applied at 90 Hz and 0.7 xg, a signal we have shown to be effective for altering F-actin dynamics and nuclear stiffness. LIV treatments were compared against Taxol, a potent regulator of MT acetylation. Using mouse mesenchymal stem cells (MSCs)in vitro, we quantified tubulin polymerization via centrifugal fractionation and western blots as well as alpha-tubulin acetylation via immunostaining. Finally, MT growth dynamics were quantified using machine learning-assisted analysis of live cell fluorescence microscopy of MT plus end binding protein EB1. Our results were not able to detect differences between LIV and control groups while Taxol treatment was effective in all measured outcomes. Our findings indicate that LIV applied at 90 Hz and 0.7 xg does not affect MT dynamics in MSCs, suggesting a higher mechanical threshold of MTs when compared to F-actin cytoskeleton.
A frosty genetic screen unmasks a major regulatory role for SHORT VEGETATIVE PHASE of flowering in response to a cold snap
Authors: Edwards Ashleigh , Thordal-Christensen Hans , Wenkel Stephan
Published: March 2024

The control of flowering in plants is intricately governed by a combination of internal and environmental signals, with temperature playing a critical role. Thus,Arabidopsis thalianaplants display temperature-dependent variations in flowering time. As unexpected periods of cold temperatures can occur at any time, plants have evolved mechanisms to detect such cold snaps and to respond by delaying flowering. Plants are more tolerant to cold temperatures in the vegetative stage, while flowers are more sensitive and have reduced reproductive success due to damage to floral structures and gametes. At the molecular level, delayed flowering can be caused by repressing theFLOWERING LOCUS T(FT) gene, and several MADS box transcription factors have been shown to repressFTexpression in response to cold and in this way prevent flowering. Here, we employed a forward genetic screen aimed at understanding the effect of a cold snap on the transition to flowering. We germinated a population ofA. thalianaEMS M2 plants at 20°C and then gradually lowered the temperature to 10°C and selected early flowering mutants. Using whole-genome sequencing, we identified seven mutant alleles of theSHORT VEGETATIVE PHASE(SVP) gene. This finding establishes a central role forSVPin repressing flowering in response to a cold snap and provides novel alleles, several of which affect splice junctions. Our research thus presents valuable insights into the nuanced molecular mechanisms governing temperature-responsive flowering in Arabidopsis and sheds light on the dynamic interplay betweenSVPand environmental cues.
ProtAlign-ARG: Antibiotic Resistance Gene Characterization Integrating Protein Language Models and Alignment-Based Scoring
Authors: Ahmed Shafayat , Emon Muhit Islam , Moumi Nazifa Ahmed , Huang Lifu , Zhou Dawei , Vikesland Peter , Pruden Amy , Zhang Liqing
Published: March 2024

The evolution and spread of antibiotic resistance pose a global health challenge. Whole genome and metagenomic sequencing pose a promising approach to monitoring the spread, but typical alignment-based approaches for antibiotic resistance gene (ARG) detection are inherently limited in the ability to detect new variants. Large protein language models could present a powerful alternative but are limited by databases available for training. Here we introduce ProtAlign-ARG, a novel hybrid model combining a pre-trained protein language model and an alignment scoring-based model to expand the capacity for ARG detection from DNA sequencing data. ProtAlign-ARG learns from vast unannotated protein sequences, utilizing raw protein language model embeddings to improve the accuracy of ARG classification. In instances where the model lacks confidence, ProtAlign-ARG employs an alignment-based scoring method, incorporating bit scores and e-values to classify ARGs according to their corresponding classes of antibiotics. ProtAlign-ARG demonstrated remarkable accuracy in identifying and classifying ARGs, particularly excelling in recall compared to existing ARG identification and classification tools. We also extended ProtAlign-ARG to predict the functionality and mobility of ARGs, highlighting the model’s robustness in various predictive tasks. A comprehensive comparison of ProtAlign-ARG with both the alignment-based scoring model and the pre-trained protein language model demonstrated the superior performance of ProtAlign-ARG.
Retrieval of an ethanol-conditioned taste aversion promotes GABAergic plasticity in the insular cortex
Authors: Taxier Lisa R. , Flanigan Meghan E , Haun Harold L. , Kash Thomas L.
Published: March 2024

Blunted sensitivity to ethanol’s aversive effects can increase motivation to consume ethanol; yet, the neurobiological circuits responsible for encoding these aversive properties are not fully understood. Plasticity in cells projecting from the insular cortex (IC) to the basolateral amygdala (BLA) is critical for taste aversion learning and retrieval, suggesting this circuit’s potential involvement in modulating the aversive properties of ethanol. Here, we tested the hypothesis that GABAergic activity onto IC-BLA projections would be facilitated following the retrieval of an ethanol-conditioned taste aversion (CTA). Consistent with this hypothesis, frequency of mIPSCs was increased following retrieval of an ethanol-CTA across cell layers in IC-BLA projection neurons. This increase in GABAergic plasticity occurred in both a circuit-specific and learning-dependent manner. Additionally, local inhibitory inputs onto layer 2/3 IC-BLA projection neurons were greater in number and strength following ethanol-CTA. Finally, DREADD-mediated inhibition of IC parvalbumin-expressing cells blunted the retrieval of ethanol-CTA in male, but not female, mice. Collectively, this work implicates a circuit-specific and learning-dependent increase in GABAergic tone following retrieval of an ethanol-CTA, thereby advancing our understanding of how the aversive effects of ethanol are encoded in the brain.

Significance statement

Sensitivity to the aversive properties of ethanol contributes to motivation to consume alcohol. However, the plasticity-associated mechanisms through which ethanol’s aversive effects are represented within neural circuits are largely unidentified. In the present study, we used whole-cell patch clamp electrophysiology combined with synaptic input mapping to identify alterations in GABAergic plasticity within the insula, and within cells projecting from the insula to the basolateral amygdala. We demonstrate learning and circuit-specific alterations in GABAergic tone following retrieval of an ethanol-conditioned taste aversion, as well as a male-specific role for Parvalbumin-expressing interneurons in modulating the strength of an ethanol-conditioned taste aversion. Combined, these findings provide novel insights into how the aversive properties of ethanol are encoded within brain circuitry.
Rapid evolution of recombination landscapes during the divergence of cichlid ecotypes in Lake Masoko
Authors: Talbi Marion , Turner George F. , Malinsky Milan
Published: March 2024

Variation of recombination rate along the genome is of crucial importance to rapid adaptation and organismal diversification. Many unknowns remain regarding how and why recombination landscapes evolve in nature. Here, we reconstruct recombination maps based on linkage disequilibrium and use subsampling and simulations to derive a new measure of recombination landscape evolution: the Population Recombination Divergence Index (PRDI). Using PRDI, we show that fine-scale recombination landscapes differ substantially between two cichlid fish ecotypes ofAstatotilapia callipterathat diverged only ∼2,500 generations ago. Perhaps surprisingly, recombination landscape differences are not driven by divergence in terms of allele frequency (FST) and nucleotide diversity (Δ(π)): although there is some association, we observe positive PRDI in regions whereFSTandΔ(π) are zero. We found a stronger association between evolution of recombination and 47 large haplotype blocks that are polymorphic in Lake Masoko, cover 21% of the genome, and appear to include multiple inversions. Among haplotype blocks, there is a strong and clear association between the degree of recombination divergence and differences between ecotypes in heterozygosity, consistent with recombination suppression in heterozygotes. Overall, our work provides a holistic view of changes in population recombination landscapes during early stages of speciation with gene flow.
Ecogeographic signals of local adaptation in a wild relative help to identify variants associated with improved wheat performance under drought stress
Authors: Nyine Moses , Davidson Dwight , Adhikari Elina , Clinesmith Marshall , Wang Huan , Akhunova Alina , Fritz Allan , Akhunov Eduard
Published: March 2024

Prioritizing wild relative diversity for improving crop adaptation to emerging drought-prone environments is challenging. Here, we combined the genome-wide environmental scans (GWES) in wheat diploid ancestorAegilops tauschiiwith allele testing in the genetic backgrounds of adapted cultivars to identify new diversity for improving wheat adaptation to water-limiting conditions. Evaluation of adaptive allele effects was carried out inAe. tauschii-wheat introgression lines (ILs) phenotyped for multiple agronomic traits under irrigated and water-limiting conditions using both UAS-based imaging and conventional approaches. The GWES showed that climatic gradients alone explain most (57.8%) of genomic variation inAe. tauschii, with many alleles associated with climatic factors inAe. tauschiibeing linked with improved performance of ILs under water-limiting conditions. The most significant GWES SNP located on chromosome 4D and associated with temperature annual range was linked with reduced canopy temperature in ILs. Our results suggest that (i) introgression of climate-adaptive alleles fromAe. tauschiihave potential to improve wheat performance under water-limiting conditions, (ii) variants controlling physiological processes responsible for maintaining leaf temperature are likely among the targets of adaptive selection in a wild relative, and (iii) adaptive variation uncovered by GWES in wild relatives has potential to improve climate resilience of crop varieties.
The priming phosphorylation of KaiC is activated by the release of its autokinase autoinhibition
Authors: Furuike Yoshihiko , Onoue Yasuhiro , Saito Shinji , Mori Toshifumi , Akiyama Shuji
Published: March 2024

KaiC, a cyanobacterial circadian clock protein with autokinase activity, catalyzes the dual phosphorylation of its own S431 and T432 residues in a circadian manner in the presence of KaiA and KaiB. Priming phosphorylation at T432 is a key step that promotes secondary phosphorylation at S431. Although KaiA binding is considered essential for KaiC phosphorylation, the mechanisms underlying the activation and inactivation of priming phosphorylation remain elusive. We found that the priming phosphorylation proceeds even in the absence of KaiA, but is autoinhibited within KaiC, which decreases the rate constant to 0.019 h-1. The autoinhibition of KaiC and the mechanism underlying the release from autoinhibition by KaiA were examined by KaiC structural analysis, and by classical molecular dynamics and quantum mechanics / molecular mechanics simulations. We found that the side chain of T432 adopts two rotamers in dephosphorylated KaiC, one of which places T432 in a position suitable for a nucleophilic attack on the terminal phosphate of adenosine triphosphate (ATP). However, the nucleophilicity of T432 was insufficient to overcome an energy barrier of approximately 22 kcal mol-1because the catalytic function of a nearby base, E318, was self-suppressed by hydrogen bonding to positively charged R385. Biochemical assays of KaiC mutants showed that the autoinhibition of KaiC autokinase activity is attenuated by conferring T432 high nucleophilicity through the KaiA-assisted release of R385 from E318 to E352. During the circadian cycle, R385 switches interacting partners to inactivate/activate the autokinase function and to ensure the unidirectionality of the KaiC phosphorylation cycle.

Significance Statement

KaiC, a central player in the circadian clock system of cyanobacteria, undergoes an ordered phosphorylation cycle in the presence of KaiA and KaiB. To elucidate the mechanism underlying the rhythmic regulation of the KaiC autokinase, we performed structural analyses, computational simulations, and biochemical assays of KaiC and its mutants. The results indicate that KaiC is essentially an autoinhibited autokinase, and the autoinhibition of primary phosphorylation at its T432 residue is attenuated by conferring it high nucleophilicity against the terminal phosphate of adenosine triphosphate. KaiA contributes to releasing the autoinhibition of KaiC in a morning phase by switching the interacting partners of R385 from a catalytic glutamate E318 to E352, as well as ensuring unidirectionality of the KaiC phosphorylation cycle.
Trace Amines are Essential Metabolites for the Autocrine Regulation ofβ-Cell Signaling and Insulin Secretion
Authors: Hauke Sebastian , Keutler Kaya , Laguerre Aurelien , Carbo Mireia A. , Rada Jona , Grandy David , Yushchenko Dmytro A. , Schultz Carsten
Published: March 2024

Secretion of insulin in response to extracellular stimuli, such as elevated glucose levels and small molecules that act on G-protein coupled receptors (GPCRs), is the hallmark ofβ-cell physiology. Trace amines (TAs) are small aromatic metabolites that were identified as low-abundant ligands of the trace amine-associated receptor 1 (TAAR1) in the central nervous system (CNS), a GPCR that is also expressed by pancreaticβ-cells. In the present work, we identify TAs as essential autocrine signaling factors forβ-cell activity and insulin secretion. We find thatβ-cells are producing TAs in significant amounts and that the modulation of endogenous TA levels by the selective inhibition of TA biosynthetic pathways directly translated into changes of oscillations of the intracellular Ca2+concentration ([Ca2+]ioscillations) and insulin secretion. Selective TAAR1 agonists or inhibitors of monoamine oxidases increased [Ca2+]ioscillations and insulin secretion. Opposite effects were mediated by selective TAAR1 antagonists, by recombinant monoamine oxidase action and by the inhibition of amino acid decarboxylase. As the modulation of TA biochemical pathways immediately translated into changes of [Ca2+]ioscillations, we inferred high metabolic turnover rates of TAs and autocrine feedback. We found that psychotropic drugs modulate [Ca2+]ioscillations and insulin secretion, either directly acting on TAAR1 or by altering endogenous TA levels. Our combined data support the hypothesis of TAs as essential autocrine signaling factors forβ-cell activity and insulin secretion as well as TAAR1 as an important mediator of amine-modulated insulin secretion.
Floral phenotypic divergence and genomic insights in anOphrysorchid: Unraveling early speciation processes
Authors: Gibert Anaïs , Schatz Bertrand , Buscail Roselyne , Nguyen Dominique , Baguette Michel , Barthes Nicolas , Bertrand Joris A.M.
Published: March 2024

Summary

Adaptive radiation inOphrysorchids leads to complex floral phenotypes that vary in scent, color and shape.

Using a novel pipeline to quantify these phenotypes, we investigated trait divergence at early stages of speciation in six populations ofOphrys aveyronensisexperiencing recent allopatry. By integrating different genetic/genomic techniques, we investigated: (i) variation and integration of floral components (scent, color and shape), (ii) phenotypes and genomic regions under divergent selection, and (iii) the genomic bases of trait variation.

We identified a large genomic island of divergence, associated with phenotypic variation in particular in floral odor. We detected potential divergent selection on macular color, while convergent selection was suspected on floral morphology and for several volatile olfactive compounds. We also identify candidate genes involved in anthocyanin and in steroid biosynthesis pathways associated with standing genetic variation in color and odor.

This study sheds light on early differentiation inOphrys, revealing patterns that often become invisible over time, i.e., the geographic mosaic of traits under selection and the early appearance of strong genomic divergence. It also supports a crucial genomic region for future investigation and highlights the value of a multifaceted approach in unraveling speciation within taxa with large genomes.
CD4+ T cells facilitate replication of primary HIV-1 strains in macrophages and formation of macrophage internal virus-containing compartments
Authors: Montero Sabina Victoria , Leyens Johanna , Meckes Lea Marie , Turk Gabriela , Schindler Michael
Published: March 2024

HIV-1 infects CD4+ T cells and macrophages. However, replication of HIV-1 in these cell types is highly variable and may depend on the use of CCR5 as a co-receptor. In addition, there is internal accumulation of infectious HIV-1 in so-called virus-containing compartments of macrophages (VCCs). VCCs are thought to represent a persistent viral reservoir that is shielded from the antiviral immune response. To date, VCC formation has only been studied in lab-adapted HIV-1 and it is unknown whether VCCs play a role in the replication of primary HIV-1 strains. Furthermore, although macrophages transmit HIV-1 from VCCs to CD4+ T cells, it is unknown whether T cells have an impact on VCC formation. We analyzed the ability of primary and lab-adapted HIV-1 to replicate in macrophages, the effect of coculture with non-infected CD4+ T cells and the extent of VCC formation. Although differentially, all HIV-1 strains replicated in CD4+ T cells, whereas only lab-adapted HIV-1 replicated in macrophages. Strikingly, replication of patient-derived HIV-1 in macrophages was enhanced by coculture with non-infected CD4+ T cells and correlated with VCC formation. In conclusion, non-infected CD4+ T cells facilitate the replication of primary HIV-1 strains in macrophages and the formation of VCCs appears to be a proxy for this phenotype. Our study suggests an essential role for VCCs in the replication of patient-derived HIV-1 in macrophages, which is fueled by non-infected CD4+ T cells. Furthermore, our findings call for strategies to specifically disrupt VCC formation in order to eliminate the HIV-1 reservoir in macrophages.

IMPORTANCE

Here we focus on the intimate interplay between HIV-1 infected macrophages and CD4+ T cells. Specifically, we analyzed whether primary HIV-1 strains induce virus-containing compartments (VCCs) within macrophages, which are thought to serve as viral sanctuaries and macrophage reservoirs. Notably, primary HIV-1 strains were unable to replicate in macrophages and induce VCCs unless they were cocultured with non-infected CD4+ T cells, leading to increased VCC formation and viral replication. This suggests an essential role for non-infected CD4+ T cells in facilitating primary HIV-1 replication in macrophages. Our data highlight the importance of not only targeting the latent HIV-1 T-cell reservoir, but also targeting VCC formation in macrophages to achieve the ultimate goal of functional HIV-1 cure.
Specialization in Molecular Functions and Secondary Metabolite Production Potential in Cyanobacterial Symbionts
Authors: Cameron Ellen S , Sanchez Santiago , Goldman Nick , Blaxter Mark , Finn Robert D.
Published: March 2024

Cyanobacteria are globally occurring photosynthetic bacteria notable for their contribution to primary production and their production of toxins which have detrimental impacts on ecosystems. Beyond this, cyanobacteria can form mutualistic symbiotic relationships with a diverse set of eukaryotes, ranging from land plants to fungi. Nevertheless, not all cyanobacteria are found in symbiotic associations suggesting symbiotic cyanobacteria have evolved specializations that facilitate host-interactions. Photosynthetic capabilities, nitrogen fixation, and the production of complex biochemicals are key functions provided by host-associated cyanobacterial symbionts. To explore if additional specializations are associated with such lifestyles in cyanobacteria, we have conducted comparative phylogenomics of molecular functions and of biosynthetic gene clusters (BGCs) in 977 cyanobacterial genomes. Cyanobacteria with host-associated and symbiotic lifestyles were concentrated in the family Nostocaceae, where eight monophyletic clades correspond to specific host taxa. In agreement with previous studies, symbionts are likely to provide fixed nitrogen to their eukaryotic partners. Additionally, our analyses identified chitin metabolising pathways in cyanobacteria associated with specific host groups, while obligate symbionts had fewer BGCs. The conservation of molecular functions and BGCs between closely related symbiotic and free-living cyanobacteria suggests that there is the potential for additional cyanobacteria to form symbiotic relationships than is currently known.