bluuebunny/crossref_metadata_2025 huggingface dataset:
The invasion pore induced byToxoplasma gondii
Authors: Kegawa Y. , Male F. , Jiménez-Munguía I. , Blank P. S. , Mekhedov E. , Ward G. , Zimmerberg J.
Published: October 2024

Obligate intracellular parasites invade host cells to survive. Following host cell contact, the apicomplexanToxoplasma gondiiinjects proteins required for invasion into the host cell. Here, electrophysiological recordings of host cells acquired at sub- 200 ms resolution allowed detection and analysis of a transient increase in host membrane conductance following exposure toToxoplasma gondii. Transients always preceded invasion but parasites depleted of the moving junction protein RON2 generated transients without invading, ruling out a direct structural role for RON2 in generating the conductance pathway or restricting the diffusion of its components. Time-series analysis developed for transients and applied to the entire transient dataset (910,000 data points) revealed multiple quantal conductance changes in the parasite-induced transient, consistent with a rapid insertion, then slower removal, blocking, or inactivation of pore-like conductance steps. Quantal steps for RH had a principal mode with Gaussian mean of 0.26 nS, similar in step size to the apicomplexan protein translocon EXP2. Without RON2 the quantal mean was significantly different (0.19 nS). Because no invasion occurs without poration, the term ‘invasion pore’ is proposed.
Glycyl-tRNA sequestration is a unifying mechanism underlyingGARS1-associated peripheral neuropathy
Authors: Mora Natalia , Slot Erik F.J. , Lewandowski Vanessa , Menafra Maria P. , Mallik Moushami , Lith Pascal van , Sijlmans Céline , van Bakel Nick , Ignatova Zoya , Storkebaum Erik
Published: October 2024

Dominantly inherited mutations in eight cytosolic aminoacyl-tRNA synthetase genes cause hereditary motor and sensory neuropathy, characterized by degeneration of peripheral motor and sensory axons. We previously identified a pathogenic gain-of-toxic function mechanism underlying peripheral neuropathy (PN) caused by heterozygous mutations in theGARS1gene, encoding glycyl-tRNA synthetase (GlyRS). Specifically, PN-mutant GlyRS variants sequester tRNAGly, which depletes the cellular tRNAGlypool, leading to insufficient glycyl-tRNAGlyavailable to the ribosome and consequently ribosome stalling at glycine codons. Given that GlyRS functions as a homodimer, a subset of PN-GlyRS mutations might alternatively cause peripheral neuropathy through a dominant negative loss-of-function mechanism. To explore this possibility, we here generated three novel PN-GlyRSDrosophilamodels expressing human PN-GlyRS (hGlyRS) variants that do not alter the overall GlyRS protein charge (S211F and H418R) or the single reported PN-GlyRS variant that renders the GlyRS protein charge more negative (K456Q). High-level expression of hGlyRS-K456Q did not induce peripheral neuropathy and the K456Q variant does not affect aminoacylation activity, suggesting that K456Q is not a pathogenic mutation. Expression of hGlyRS-S211F or hGlyRS-H418R inDrosophiladid induce peripheral neuropathy andde novoprotein synthesis defects. Genetic and biochemical evidence indicates that these phenotypes were attributable to tRNAGlysequestration rather than a dominant negative mechanism. Our data identify tRNAGlysequestration as a unifying pathogenic mechanism underlying PN-GlyRS. Thus, elevating tRNAGlylevels may constitute a therapeutic approach for all PN-GlyRS patients, irrespective of their disease-causing mutation.
Unravelling the Enantioselective Mechanism of Benzylsuccinate Synthase: Insights into Anaerobic Hydrocarbon Degradation Through Multiscale Modelling and Kinetics
Authors: Szaleniec Maciej , Oleksy Gabriela , Aleksic Ivana , Krämer Kai , Heider Johann
Published: October 2024

Fumarate-adding enzymes (FAE) are a subset of the glycyl radical enzyme superfamily involved in anaerobic hydrocarbon degradation. Benzylsuccinate synthase (BSS) catalyzes the enantiospecific formation ofR-benzylsuccinate from toluene and fumarate, initiating anaerobic toluene degradation. In this paper, we present a detailed theoretical study of the reaction mechanism using classical molecular dynamics and multiscale modelling (QM:MM). We describe the potential energy surface of the reaction, confirming the previously postulated mechanism. However, the multiscale character of our model allowed to elucidate the origins of several experimentally observed catalytic phenomena, such as the inversion of the configuration of the benzylic atom upon C-C bond formation,synaddition of the abstracted H atom back to the benzylsuccinyl radical, or kinetic isotope effects in the range of 1.7-2.1. The obtained model is supported by microkinetic analysis and was able to explain and quantitatively predict the strictR-enantioselectivity of BSS, which is not enforced by the binding orientation of the fumarate, but by dynamic kinetic behaviour of toluene in the active site leading to faster production of theR-enantiomer. We were also able to explain the experimentally observed slow H/D exchange in the product during incubation with BSS in D2O, confirming the partial reversibility of the reaction. Our study contributes to the elucidation of the catalytic processes catalyzed by BSS and its role in the bioremediation of hydrocarbon pollutants.
Defining the alpha domain of K1-like killer toxins
Authors: Coss Sarah A. , Ytreberg F. Marty , Rowley Paul A.
Published: October 2024

Antifungal killer toxins produced by yeasts undergo post-translational processing to enable the formation of mature and active toxins. The preprocessed, immature K1 killer toxin fromSaccharomyces cerevisiaehas four different domains (delta, alpha, gamma, and beta) that are cleaved to produce a mature toxin consisting of a disulfide-linked alpha and beta heterodimer. K1 homologs from various yeast species of the Saccharomycotina have been previously identified by primary sequence homology. Primary sequence analysis has identified putative cleavage sites across all homologs, with some conservation with cleavage sites identified in K1 and the likely importance of the conserved carboxypeptidases Kex1 and Kex2. The identification of sites of proteolytic processing has enabled an accurate definition of the domain boundaries of delta, alpha, gamma, and beta domains in all K1 homologs. Functional assays revealed that many K1 homologs contain cytotoxic alpha domains. Interestingly, several killer toxins that lacked measurable antifungal activity still exhibited toxic alpha domains when expressed independently. These findings suggest that alpha domain toxicity is conserved across K1 homologs, and that variations in post-translational processing and domain interactions may influence full-length toxin functionality. This work provides insights into the evolutionary conservation and diversity of yeast killer toxins.
Unraveling the Associations Between Voice Pitch and Major Depressive Disorder: A Multisite Genetic Study
Authors: Di Yazheng , Rahmani Elior , Mefford Joel , Wang Jinhan , Ravi Vijay , Gorla Aditya , Alwan Abeer , Kendler Kenneth S. , Zhu Tingshao , Flint Jonathan
Published: October 2024

Major depressive disorder (MDD) often goes undiagnosed due to the absence of clear biomarkers. We sought to identify voice biomarkers for MDD and separate biomarkers indicative of MDD predisposition from biomarkers reflecting current depressive symptoms. Using a two-stage meta-analytic design to remove confounds, we tested the association between features representing vocal pitch and MDD in a multisite case-control cohort study of Chinese women with recurrent depression. Sixteen features were replicated in an independent cohort, with absolute association coefficients (beta values) from the combined analysis ranging from 0.24 to 1.07, indicating moderate to large effects. The statistical significance of these associations remained robust, with P-values ranging from 7.2 × 10−6to 6.8 × 10−58. Eleven features were significantly associated with current depressive symptoms. Using genotype data, we found that this association was driven in part by a genetic correlation with MDD. Significant voice features, reflecting a slower pitch change and a lower pitch, achieved an AUC-ROC of 0.90 (sensitivity of 0.85 and specificity of 0.81) in MDD classification. Our results return vocal features to a more central position in clinical and research work on MDD.
A survey investigating United States federal grant submissions proposing to investigate therapeutic applications of psychedelics
Authors: Barnett Brian S.
Published: October 2024

This study surveyed researchers to assess the contents and funding success of federal grant applications for research into therapeutic applications of psychedelics in the United States. The author emailed an anonymous survey to the corresponding authors of the 50 most-cited articles on psychedelics published after 2000 and disseminated it via Twitter. Ten researchers responded, reporting on 24 grant submissions for psilocybin, ibogaine, LSD, MDMA, and other psychedelics, all to the National Institutes of Health (NIH), from the early 1990s onward. The number of grant applications rose noticeably starting in 2006. Of all grant applications assessed,16.7% were funded, lower than the NIH’s 23.4% average funding rate for R-01 equivalent grants between 1998-2023. More specifically, while no relevant grant applications submitted prior to 2006-2010 were funded by NIH, the funding rate of applications since then, estimated at 19.05% to 22.2%, is close to the average annual NIH funding rate of 20.6 ± 1.9% for R-01 equivalent grant applications from 2006 to early 2023. Respondents generally believed applications for this line of research had a lower chance of success compared to other lines of research, although they felt the funding landscape has improved in recent years, in line with this study’s other findings.
Analyzing greedy vaccine allocation algorithms for metapopulation disease models
Authors: Keithley Jeffrey , Choudhuri Akash , Adhikari Bijaya , Pemmaraju Sriram V.
Published: October 2024

As observed in the case of COVID-19, effective vaccines for an emerging pandemic tend to be in limited supply initially and must be allocated strategically. The allocation of vaccines can be modeled as a discrete optimization problem that prior research has shown to be computationally difficult (i.e., NP-hard) to solve even approximately.

Using a combination of theoretical and experimental results, we show that this hardness result may be circumvented. We present our results in the context of a metapopulation model, which views a population as composed of geographically dispersed heterogeneous subpopulations, with arbitrary travel patterns between them. In this setting, vaccine bundles are allocated at a subpopulation level, and so the vaccine allocation problem can be formulated as a problem of maximizing an integer lattice functionsubject to a budget constraint ∥x∥1≤D. We consider a variety of simple, well-known greedy algorithms for this problem and show the effectiveness of these algorithms for three problem instances at different scales: New Hampshire (10 counties, population 1.4 million), Iowa (99 counties, population 3.2 million), and Texas (254 counties, population 30.03 million). We provide a theoretical explanation for this effectiveness by showing that the approximation factor of these algorithms depends on thesubmodularity ratioof objective functiong, a measure of how distantgis from being submodular.

Author summary

Strategic and timely allocation of vaccines is crucial in combating epidemic outbreaks. Developing strategies to allocate vaccines over sub-populations rather than to individuals leads to policy recommendations that are more feasible in practice. Despite this, vaccine allocation over sub-populations has only received limited research interest, and the associated computational challenges are relatively unknown. To address this gap, we study vaccine allocation problems over geographically distinct subpopulations in this paper. We formulate our problems to reduce eitheri)the total infections orii)the sum of peak infections over meta-population disease models. We first demonstrate that these problems are computationally challenging even to approximate and then show that a family of simple, well-known greedy algorithms exhibit provable guarantees. We conduct realistic experiments on state-level mobility networks derived from real-world data in three states of distinct population levels: New Hampshire, Iowa, and Texas. Our results show that the greedy algorithms we consider arei)scalable andii)outperform both state-of-the-art and natural baselines in a majority of settings.
High-dimensional confounding in causal mediation: a comparison study of double machine learning and regularized partial correlation network
Authors: Chen Ming , Nguyen Tanya T. , Liu Jinyuan
Published: October 2024

In causal mediation analyses, of interest are the direct or indirect pathways from exposure to an outcome variable. For observation studies, massive baseline characteristics are collected as potential confounders to mitigate selection bias, possibly approaching or exceeding the sample size. Accordingly, flexible machine learning approaches are promising in filtering a subset of relevant confounders, along with estimation using the efficient influence function to avoid overfitting. Among various confounding selection strategies, two attract growing attention. One is the popular debiased, or double machine learning (DML), and another is the penalized partial correlation via fitting a Gaussian graphical network model between the confounders and the response variable. Nonetheless, for causal mediation analyses when encountering high-dimensional confounders, there is a gap in determining the best strategy for confounding selection. Therefore, we exemplify a motivating study on the human microbiome, where the dimensions of mediator and confounders approach or exceed the sample size to compare possible combinations of confounding selection methods. By deriving the multiply robust causal direct and indirect effects across various hypotheses, our comprehensive illustrations offer methodological implications on how the confounding selection impacts the final causal target parameter estimation while generating causality insights in demystifying the “gut-brain axis”. Our results highlighted the practicality and necessity of the discussed methods, which not only guide real-world applications for practitioners but also motivate future advancements for this crucial topic in the era of big data.
ExoSloNano: Multi-Modal Nanogold Tags for identification of Macromolecules in Live Cells & Cryo-Electron Tomograms
Authors: Young Lindsey N. , Sherrard Alice , Zhou Huabin , Shaikh Farhaz , Hutchings Joshua , Riggi Margot , Rosen Michael K. , Giraldez Antonio J. , Villa Elizabeth
Published: October 2024

In situ cryo-Electron Microscopy (cryo-EM) enables the direct interrogation of structure-function relationships by resolving macromolecular structures in their native cellular environment. Tremendous progress in sample preparation, imaging and data processing over the past decade has contributed to the identification and determination of large biomolecular complexes. However, the majority of proteins are of a size that still eludes identification in cellular cryo-EM data, and most proteins exist in low copy numbers. Therefore, novel tools are needed for cryo-EM to identify the vast majority of macromolecules across multiple size scales (from microns to nanometers). Here, we introduce and validate novel nanogold probes that enable the detection of specific proteins using cryo-ET (cryo-Electron Tomography) and resin-embedded correlated light and electron microscopy (CLEM). We demonstrate that these nanogold probes can be introduced into live cells, in a manner that preserves intact molecular networks and cell viability. We use this system to identify both cytoplasmic and nuclear proteins by room temperature EM, and resolve associated structures by cryo-ET. We further employ gold particles of different sizes to enable future multiplexed labeling and structural analysis. By providing high efficiency protein labeling in live cells and molecular specificity within cryo-ET tomograms, we establish a broadly enabling tool that significantly expands the proteome available to electron microscopy.
The Growing Little Brain: Cerebellar Functional Development from Cradle to School
Authors: Lyu Wenjiao , Thung Kim-Han , Huynh Khoi Minh , Wang Li , Lin Weili , Ahmad Sahar , Yap Pew-Thian
Published: October 2024

Despite the cerebellum’s crucial role in brain functions, its early development, particularly in relation to the cerebrum, remains poorly understood. Here, we examine cerebellocortical connectivity using over 1,000 high-quality resting-state functional MRI scans of children from birth to 60 months. By mapping cerebellar topography with fine temporal detail for the first time, we show the hierarchical and contralateral organization of cerebellocortical connectivity from birth. We observe dynamic shifts in cerebellar network gradients, which become more focal with age while maintaining stable anchor points similar to adults, highlighting the cerebellum’s evolving yet stable role in functional integration during early development. Our findings provide the first evidence of cerebellar connections to higher-order networks at birth, which generally strengthen with age, emphasizing the cerebellum’s early role in cognitive processing beyond sensory and motor functions. Our study provides insights into early cerebellocortical interactions, reveals functional asymmetry and sexual dimorphism in cerebellar development, and lays the groundwork for future research on cerebellum-related disorders in children.
Predicting and phase targeting brain oscillations in real-time
Authors: Jongejan Stefan L. , van der Heijden Christa , Patriota Joao , Talamini Lucia M.
Published: October 2024

Objective: Closed-loop neurostimulation (CLNS) procedures, aligning stimuli with electrical brain activity, are quickly gaining popularity in neuroscience. They have been employed to reveal causal links between neural activity patterns and function, and to explore therapeutic effects of electroencephalography (EEG-)guided stimulations during sleep. Most CLNS procedures are developed for a single purpose, detecting one specific pattern of interest in the EEG. Furthermore, most procedures have limited, if any, flexibility to adapt to temporal or interindividual variance in the signal, which means they wouldn't work optimally across the full physiological phenomenology. Approach: Here we present a new approach to CLNS, based on real-time signal modelling to predict brain activity, allowing targeting of a broad variety of oscillatory dynamics. Intrinsic to the modelling approach is adaptation to signal variance, such that no personalization steps prior to use are necessary. We systematically assess stimulus targeting performance of modelling-based CLNS (M-CLNS), across a wide range of brain oscillation frequencies and phases in human and rodent neurophysiological signals. Main results: Our results show high performance for all target phases and frequency bands, including slow oscillations, theta and alpha waves. Significance: These findings highlight the general applicability and adaptability of M-CLNS, which also favors its application in populations with an atypical oscillatory signature, like clinical or elderly populations. In conclusion, M-CLNS provides a promising new tool for neural activity-dependent stimulation in both experimental research and therapeutic applications, such as enhancing deep sleep in patients with sleep disorders.
Asymmetric spin echo multi-echo echo planar imaging (ASEME-EPI) sequence for pre-clinical high-field fMRI
Authors: Johnson Kyle A. , Pawela Christopher P. , Nencka Andrew S. , Sidabras Jason W.
Published: October 2024

In functional magnetic resonance imaging (fMRI) of the blood oxygen level-dependent (BOLD) contrast, gradient-recalled echo (GRE) acquisitions offer high sensitivity but suffer from susceptibility-induced signal loss and lack specificity to microvasculature. In contrast, spin echo (SE) acquisitions provide improved specificity at the cost of reduced sensitivity. This study introduces Asymmetric Spin Echo Multi-Echo Echo Planar Imaging (ASEME-EPI), a technique designed to combine the benefits of both GRE and SE for high-field preclinical fMRI. ASEME-EPI employs a spin echo readout followed by two asymmetric spin echo (ASE) GRE readouts, providing an initial T2-weighted SE image and subsequent T2*-weighted ASE images. A feasibility study for the technique was implemented on a 9.4 T pre-clinical MRI system and tested using a visual stimulation in northern tree shrews. Comparing ASEME-EPI with conventional GRE echo planar imaging (GRE-EPI) and SE echo planar imaging (SE-EPI) acquisitions, results showed that ASEME-EPI achieved BOLD contrast-to-noise ratio (CNR) comparable to GRE-EPI while offering improved specificity in activation maps. ASEME-EPI activation was more confined to the primary visual cortex (V1), unlike GRE-EPI which showed activation extending beyond anatomical boundaries. Additionally, ASEME-EPI demonstrated the ability to recover signal in areas of severe field inhomogeneity where GRE-EPI suffered from signal loss. The performance of ASEME-EPI is attributed to its multi-echo nature, allowing for SNR-optimized combination of echoes, effectively denoising the data. The inclusion of the initial SE also contributes to signal recovery in areas prone to susceptibility artifacts. This feasibility study demonstrates the potential of ASEME-EPI for high-field pre-clinical fMRI, offering a promising compromise between GRE sensitivity and SE specificity while addressing challenges of T2*decay at high field strengths.
Quantitative measurements of shear stress-dependent adhesion and motion ofDictyostelium discoideumcells in a microfluidic device
Authors: Fakhari Sepideh , Belleannée Clémence , Charrette Steve J. , Greener Jesse
Published: October 2024

Shear stress plays a crucial role in modulating cell adhesion and signaling. We present a microfluidic shear stress generator used to investigate the adhesion dynamics ofDictyostelium discoideum, an amoeba cell model organism with well-characterized adhesion properties. We applied shear stress and tracked cell adhesion, motility, and detachment using time-lapse videomicroscopy. In the precise shear conditions generated on-chip, our results show cell migration patterns influenced by shear stress, with cells displaying an adaptive response to shear forces as they alter their adhesion and motility behavior in reaction to shear stress. Additionally, we observed that DH1-10 wild-typeD. discoideumcells exhibit stronger adhesion and resistance to shear-induced detachment compared tophg2adhesion-defective mutant cells and also highlighted the influence of initial cell density on detachment behavior.
Structured stabilization in recurrent neural circuits through inhibitory synaptic plasticity
Authors: Festa Dylan , Cusseddu Claudia , Gjorgjieva Julijana
Published: October 2024

Inhibitory interneurons play a dual role in recurrently connected biological circuits: they regulate global neural activity to prevent runaway excitation, and contribute to complex neural computations. While the first role can be achieved through unstructured connections tuned for homeostatic rate stabilization, computational tasks often require structured excitatory-inhibitory (E/I) connectivity. Here, we consider a broad class of pairwise inhibitory spike-timing dependent plasticity (iSTDP) rules, demonstrating how inhibitory synapses can self-organize to both stabilize excitation and generate functionally relevant connectivity structures — a process we call “structured stabilization”. We show that in both E/I circuit motifs and large spiking recurrent neural networks the choice of iSTDP rule can lead to either mutually connected E/I pairs, or to lateral inhibition, where an inhibitory neuron connects to an excitatory neuron that does not directly connect back to it. In a one-dimensional ring network, if two inhibitory populations follow these distinct forms of iSTDP, the effective connectivity within the excitatory population self-organizes into a Mexican-hat-like profile with excitatory influence in the center and inhibitory influence away from the center. This leads to emergent dynamical properties such as surround suppression and modular spontaneous activity. Our theoretical work introduces a family of rules that retains the broad applicability and simplicity of spike-timing-based plasticity, while promoting structured, self-organized stabilization. These findings highlight the rich interplay between iSTDP rules, circuit structure, and neuronal dynamics, offering a framework for understanding how inhibitory plasticity shapes network function.
Impacts of sequence and structure on pyrrolocytosine fluorescence in RNA
Authors: Coulson Taylor L. , Widom Julia R.
Published: October 2024

Fluorescence spectroscopy encompasses many useful methods for studying the structures and dynamics of biopolymers. Applications to nucleic acids require the use of extrinsic fluorophores such as fluorescent base analogues (FBAs), which mimic the native bases but have enhanced fluorescence quantum yields. In this work, we use multiple complementary methods to systematically investigate the sequence- and structure-dependence of the fluorescence of the FBA pyrrolocytosine (pC) within RNA. We demonstrate that pC is typically brightest in conformations in which it is base-stacked but not base-paired, properties that distinguish it from more widely used FBAs. This effect is strongly sequence-dependent, with adjacent adenosine and cytidine residues conferring the greatest contrast between stacked and unstacked structures. Structural heterogeneity was resolved in single-stranded RNA and fully complementary and mismatched double-stranded RNA using time-resolved fluorescence measurements and fluorescence-detected circular dichroism spectroscopy. Double-stranded contexts are distinguished from single-stranded contexts by the presence of inter-strand energy transfer from opposing bases, while base-paired pC is distinguished by its short excited state lifetime. This work will enhance the value of pC as a structural probe for biologically and medicinally significant RNAs by guiding the selection of labeling sites and interpretation of the resulting data.

GRAPHICAL ABSTRACT
A computational principle of habit formation
Authors: Lakshminarasimhan Kaushik
Published: October 2024

1

Actions are influenced by multiple decision-making systems – including a goal-directed system that favors rewarded actions and a habit system that repeats past actions – but precisely when one system prevails is not known. We show that when competition between these systems is resolved by a winner-take-all mechanism, the precise condition for the emergence of habits can be cast in terms of the well-known probability matching principle. The theory embodies a trade-off in which exploitation, or overmatching, maximizes reward but strengthens habits, while paradoxically, exploration preserves goal-directed behavior by sacrificing rewards. This tradeoff can be averted if learning operates on abstract latent state representations whereby knowing the broader context allows for switching between two habits instead of avoiding one, thus maximizing rewards without forfeiting flexibility. The theory explains a range of animal behaviors as well as task-dependent effects of striatal manipulation, and suggests that neural mechanisms governing exploration implicitly control arbitration between decision-making systems.
Integration of distinct cortical inputs to primary and higher order inhibitory cells of the thalamus
Authors: Puzzo Christian D. , Martinez-Garcia Rosa I. , Liu Hero , Dyson Levi F. , Gilbert William O. , Cruikshank Scott J.
Published: October 2024

The neocortex controls its own sensory input in part through top-down inhibitory mechanisms. Descending corticothalamic projections drive GABAergic neurons of the thalamic reticular nucleus (TRN), which govern thalamocortical cell activity via inhibition. Neurons in sensory TRN are organized into primary and higher order (HO) subpopulations, with separate intrathalamic connections and distinct genetic and functional properties. Here, we investigated top-down neocortical control over primary and HO neurons of somatosensory TRN. Projections from layer 6 of somatosensory cortex evoked stronger and more state-dependent activity in primary than in HO TRN, driven by more robust synaptic inputs and potent T-type calcium currents. However, HO TRN received additional, physiologically distinct, inputs from motor cortex and layer 5 of S1. Thus, in a departure from the canonical focused sensory layer 6 innervation characteristic of primary TRN, HO TRN integrates broadly from multiple corticothalamic systems, with unique state-dependence, extending the range of mechanisms for top-down control.
MMP21 behaves as a fluid flow transported morphogen to impart laterality during development
Authors: Ott Tim , Brugger Amelie , Szenker-Ravi Emmanuelle , Kurrle Yvonne , Aberle Olivia , Tisler Matthias , Blum Martin , Whalen Sandra , Bouvagnet Patrice , Reversade Bruno , Schweickert Axel
Published: October 2024

Heterotaxy (HTX) is frequently caused by deleterious variants in the gene encoding Matrix metallopeptidase 21 (MMP21). However, the underlying pathomechanism has not been ascertained. In this study, we report on a novel HTX-associatedMMP21knockout allele in humans and investigate the peptidase’s role during laterality development usingXenopusembryos as animal model. The targeted inactivation ofmmp21in f0 mutantXenopussuccessfully phenocopied the human HTX condition, yet the cilia-driven leftward fluid flow, which initiates asymmetric gene activity at the left-right organizer (LRO), was unaltered inmmp21null frogs. Instead, our analysis of downstream events revealed that flow response, the left-sided repression ofdand5, could not take place. Remarkably, gain-of-function experiments demonstrated that Mmp21 spreads over LRO cells and triggers flow response. Additionally, Mmp21 functions upstream of Cirop, another metallopeptidase, which we found specifically localized to LRO cilia. Thus, our findings suggest that Mmp21 may be the long-sought morphogen, which is actively transported by the leftward fluid flow to Cirop-laden cilia, in order to specify the left side of the embryo.
Potent Anti-Influenza Synergistic Activity of Theobromine and Arainosine
Authors: Lahiri Hiya , Israeli Eitan , Krugliak Miriam , Basu Kingshuk , Britan-Rosich Yelena , Yaish Tamar Ravins , Arkin Isaiah T.
Published: October 2024

Influenza represents one of the biggest health threats facing humanity. Seasonal epidemics can transition to global pandemics, with cross-species infection presenting a continuous challenge. Although vaccines and several anti-viral options are available, constant genetic drifts and shifts vitiate any of the aforementioned prevention and treatment options. Therefore, we describe an approach targeted at the virus’s channel to derive new anti-viral options. Specifically, Influenza A’s M2 protein is a well-characterized channel targeted for a long time by aminoadamantane blockers. However, widespread mutations in the protein render the drugs ineffective. Consequently, we started by screening a repurposed drug library against aminoadamantane-sensitive and resistant M2 channels using bacteria-based genetic assays. Subsequentin cellulotesting and structure-activity relationship studies yielded a combination of Theobromine and Arainosine, which exhibits stark anti-viral activity by inhibiting the virus’s channel. The drug duo was potent against H1N1 pandemic swine flu, H5N1 pandemic avian flu, aminoadamantane-resistant and sensitive strains alike, exhibiting activity that surpassed Oseltamivir, the leading anti-flu drug on the market. When this drug duo was tested in an animal model, it once more outperformed Oseltamivir, considerably reducing disease symptoms and viral RNA progeny. In conclusion, the outcome of this study represents a new potential treatment option for influenza alongside an approach that is sufficiently general and readily applicable to other viral targets.
Cryo-electron tomography reveals coupled flavivirus replication, budding and maturation
Authors: Dahmane Selma , Schexnaydre Erin , Zhang Jianguo , Rosendal Ebba , Chotiwan Nunya , Kumari Singh Bina , Yau Wai-Lok , Lundmark Richard , Barad Benjamin , Grotjahn Danielle A. , Liese Susanne , Carlson Andreas , Överby Anna K. , Carlson Lars-Anders
Published: October 2024

Flaviviruses replicate their genomes in replication organelles (ROs) formed as bud-like invaginations on the endoplasmic reticulum (ER) membrane, which also functions as the site for virion assembly. While this localization is well established, it is not known to what extent viral membrane remodeling, genome replication, virion assembly, and maturation are coordinated. Here, we imaged tick-borne flavivirus replication in human cells using cryo-electron tomography. We find that the RO membrane bud is shaped by a combination of a curvature-establishing coat and the pressure from intraluminal template RNA. A protein complex at the RO base extends to an adjacent membrane, where immature virions bud. Naturally occurring furin site variants determine whether virions mature in the immediate vicinity of ROs. We further visualize replication in mouse brain tissue by cryo-electron tomography. Taken together, these findings reveal a close spatial coupling of flavivirus genome replication, budding, and maturation.
Ventral Striatum is Preferentially Correlated with the Salience Network Including Regions in Dorsolateral Prefrontal Cortex
Authors: Kosakowski Heather L. , Eldaief Mark C. , Buckner Randy L.
Published: October 2024

The ventral striatum (VS) receives input from the cerebral cortex and is modulated by midbrain dopaminergic projections in support of processing reward and motivation. Here we explored the organization of cortical regions linked to the human VS using within-individual functional connectivity MRI in intensively scanned participants. In two initial participants (scanned 31 sessions each), seed regions in the VS were preferentially correlated with distributed cortical regions that are part of the Salience (SAL) network. The VS seed region recapitulated SAL network topography in each individual including anterior and posterior midline regions, anterior insula, and dorsolateral prefrontal cortex (DLPFC) – a topography that was distinct from a nearby striatal seed region. The region of DLPFC linked to the VS is positioned adjacent to regions associated with domain-flexible cognitive control. The full pattern was replicated in independent data from the same two individuals and generalized to 15 novel participants (scanned 8 or more sessions each). These results suggest that the VS forms a cortico-basal ganglia loop as part of the SAL network. The DLPFC is a neuromodulatory target to treat major depressive disorder. The present results raise the possibility that the DLPFC may be an effective neuromodulatory target because of its preferential coupling to the VS and suggests a path toward further personalization.
PEPITEM Tripeptides and Peptidomimetics: Next-Generation Modulators of Inflammation in Immune-Mediated Conditions
Authors: Saviano Anella , Apta Bonita , Tull Samantha , Pezhman Laleh , Fatima Areeba , Mete Antonio , Sevim Mustafa , Chimen Myriam , Schettino Anna , Marigliano Noemi , McGettrick Helen M. , Iqbal Asif J. , Maione Francesco , Ed Rainger G.
Published: October 2024

PEPITEM is an immune-modulatory peptide that effectively regulates inflammation and mitigates immune-mediated inflammatory diseases (IMIDs). Here we identify two independently active tripeptide pharmacophores within PEPITEM and engineered peptidomimetics with enhanced pharmacodynamic properties. These peptidomimetics regulate T-cell traffickingin vitroand reduce T-cell, neutrophil and macrophage numbers in the inflamed peritoneal cavity in vivo. In a plaque psoriasis model, topical administration reduced disease severity, inflammation and immune cell infiltration, while regulating cytokine release in macrophages and fibroblasts, as well as keratinocyte proliferation. Th1 and Th17 cell abundance, along with their cytokines, was reduced in secondary lymphoid organs. This expanded functional repertoire of PEPITEM and its derivatives provides innovative tools for countering immune and stromal cell-induced pathology in IMIDs, paving the way for a novel class of anti-inflammatory agents.
The Dynamic Genetic Atlas of 122 Gestational Phenotypes
Authors: Liu Siyang , Zheng Hao , Gu Yuqin , Yang Zijing , Liu Yanhong , Wei Yuandan , Guo Xinxin , Chen Yanchao , Hu Liang , Chen Xiaohang , Zhang Fuquan , Chen Guo-Bo , Qiu Xiu , Huang Shujia , Zhen Jianxin , Wei Fengxiang
Published: October 2024

The gestational period, spanning approximately 40 weeks from fertilization to birth, is pivotal in human reproduction. Monitoring the health of pregnant women and newborns during this period involves systematic prenatal and postpartum examinations, guided by indicators established under the national medical insurance system, collectively termed gestational phenotypes. However, our understanding of the genetic basis of these phenotypes and their intricate relationship with maternal long-term health outcomes remain markedly limited. We conducted comprehensive genetic investigations into 122 gestational phenotypes among 121,579 Chinese pregnancies. These phenotypes included anthropometric metrics, comprehensive blood biomarker measurements, and common gestational complications and outcomes. We identified 3,845 genetic loci, 1,385 of which are novel. Our analyses revealed gestation-specific genetic effects, ranging from proportion 0% to 100% for 23 phenotypes, highlighting genes and pathways predominantly enriched in response to hormones, growth and immune function. Longitudinal trajectory genome-wide association study (GWAS) analyses of repeated measures across 24 complete blood cell phenotypes revealed that 17.8% of the genetic variants exhibited significant interactions with gestational timing across five gestational and postpartum periods. Two-sample univariable and multivariable Mendelian Randomization (MR) analyses of 220 mid- and old-age phenotypes suggested causal associations between gestational phenotypes and the risk of chronic diseases in later life. These findings provide initial insights into the genetic foundations of human gestational phenotypes and their relationship with long-term health, laying a basis for advanced population health during gestation.
Protocol for developing the reporting guidelines for the use CHatbots and other gEnerative AI tools in mEdical Research (CHEER)
Authors: Luo Xufei , Tham Yih Chung , Daher Mohammad , Bian Zhaoxiang , Chen Yaolong , Estill Janne
Published: October 2024

Background

The integration of artificial intelligence (AI) has revolutionized medical research, offering innovative solutions for data collection, patient engagement, and information dissemination. Powerful generative AI (GAI) tools like ChatGPT and other similar chatbots have emerged, facilitating user interactions with virtual conversational agents. However, the increasing use of GAI tools in medical research presents challenges, including ethical concerns, data privacy issues, and the potential for generating false content. These issues necessitate standardization of reporting to ensure transparency and scientific rigor.

Objective

The development of the CHatbots and other gEnerative AI tools in mEdical Research (CHEER) reporting guidelines aims to establish a comprehensive, standardized guideline for reporting the use of GAI tools in medical research.

Methods

The CHEER guidelines are being developed following the methodology recommended by the Enhancing the QUAlity and Transparency Of health Research (EQUATOR) network, involving scoping reviews and expert Delphi consensus. The process consists of three stages: preparatory work, Delphi survey, and testing and dissemination. The study is approved by the Ethics Committee of the Institute of Health Data Science at Lanzhou University (approval number: HDS-202406-01).

Expected results

The CHEER project was launched in July 2023 by the Evidence-Based Medicine Center of Lanzhou University and the WHO Collaborating Centre for Guideline Implementation and Knowledge Translation, and is scheduled to conclude in July 2024. The expected outcome of the CHEER project is a reporting checklist, accompanied by relevant terminology, examples, and explanations, to guide stakeholders in better reporting the use of GAI tools.

Conclusion

CHEER aims to guide researchers, reviewers, and editors in the transparent and scientific application of GAI tools in medical research. By providing a standardized reporting framework, CHEER seeks to enhance the clarity, completeness, and integrity of research involving GAI tools, promoting collaboration, comparability, and cumulative knowledge generation in AI-driven healthcare technologies.

Trial Registration

We registered this protocol on the EQUATOR Network (https://www.equator-network.org/library/reporting-guidelines-under-development/reporting-guidelines-under-development-for-other-study-designs/#CHEER).
The dual role of blockchain in mediating credence attributes and moderating sensing capabilities in the wine sector
Authors: Kramer Michael Paul , Adamashvili Nino , Vrontis Demetris , Hanf Jon H. , Galati Antonino
Published: October 2024

Purpose

This study aims to investigate the dynamic capabilities of wineries, focusing on sensing and its role in enabling digital innovation. Furthermore, it explores the role of blockchain technology (BCT) in validating credence attributes of wine, emphasising blockchain as a strategic asset that enhances the ability of wineries to innovate and respond to changing market conditions.

Design/methodology/approach

The study adopts an exploratory approach based on a longitudinal, single-case study of the Argentinian Costaflores Organic Winery.

Findings

Findings reveal that integrating digital disruptive innovations such as blockchain can strategically position wineries to better meet emerging consumer preferences and market trends. Blockchain simultaneously acts as both a mediator and a moderator. As a mediator, it facilitates the validation of credence attributes of wine such as authenticity and sustainability, enhancing customer trust and loyalty. As a moderator, it influences the strength and effectiveness of the relationship between sensing and innovation capabilities. This enables wineries to more effectively respond to changing consumer requirements and market trends and improve operational performance.

Research limitations/implications

The study was limited by its focus on a single case study of the Argentinian Costaflores Organic Winery, which may affect the generalisability of the findings. However, the study provides valuable insights into the strategic adaptation and competitive positioning of wineries in response to the continuing market challenges. It significantly contributes to the understanding of integrating digital disruptive innovations as strategic assets in the agri-food sector, particularly in the wine sector.

Originality/value

This study addresses a significant research gap by exploring how BCT facilitates the organisation of sensing capabilities. It contributes to the understanding of how the wineries’ sensing capabilities both influence and are influenced by the adoption of BCT, particularly in the context of innovation enabling and improved operational performance.
Does digital finance improve welfare effects of maize farmers’ productivity gains?
Authors: Traoré Salimata , Moussa Richard K.
Published: October 2024

Purpose

In Burkina Faso, maize is a key component in farm households’ food security and welfare. However, maize productivity in the country is low and productivity improvements do not necessarily result in better living conditions. This paper aims to establish linkages between maize productivity and welfare by considering the context of digital finance adoption for farmers in Burkina Faso.

Design/methodology/approach

For this purpose, we use an endogenous switching regression approach on the Burkina Faso’s Living Standard Measurement Survey of 2018.

Findings

Our estimates show that digital finance adoption enhances the transmission of productivity gains to farm households’ welfare, with the welfare elasticity of maize productivity almost twice higher for digital finance adopters.

Social implications

Our findings highlight the importance of increasing the access to digital finance to improve farm household welfare.

Originality/value

This manuscript makes the valuable contribution of analysing the heterogeneity of the transmission of agricultural productivity to welfare, with a focus on the identification of the role of digital finance.

Peer review

The peer review history for this article is available at: https://publons.com/publon/10.1108/IJSE-01-2024-0077
The nexus of political connections and corporate tax strategies in Pakistan
Authors: Ahmad Fawad , Houqe Muhammad , van Zijl Tony
Published: October 2024

Purpose

Extant literature investigating the tax payment behaviour of politically connected firms largely supports the notion that politically connected firms have tax sheltering incentives, i.e. politically connected firms pay significantly less tax. Our paper adds to this stream of literature by considering the tax payment behaviour of two different groups of politically connected firms in Pakistan, viz. civil connected firms and military connected firms.

Design/methodology/approach

The paper sheds light on the tax payment behaviour of politically connected firms and provides evidence that the tax incentives of politically connected firms are shaped by the institutional structure and contextual factors.

Findings

The results indicate that civil (military) connected firms pay significantly lower (higher) tax than non-connected firms. The findings hold in the face of a number of robustness tests, including the use of alternative proxies for the tax variable and endogeneity concerns.

Originality/value

These results make a significant contribution to the existing literature examining the tax payment behaviour of politically connected firms by providing evidence suggesting that tax sheltering is not the only viable option for politically connected firms; rather, some groups of connected firms have tax under-sheltering incentives. Our findings add to the political cost hypothesis and the signalling hypothesis in relation to tax payment incentives of politically connected firms.
The future of tourism: interview with emeritus professor Pauline Sheldon on regenerative tourism
Authors: Yeoman Ian Seymour , Sheldon Pauline Joy
Published: October 2024

Purpose

As the Journal of Tourism Futures (JTF) celebrates its 10th Anniversary, Dr Ian Yeoman (Hotel Management School Leeuwarden) interviews Emeritus Professor Pauline Sheldon (University of Hawaiʻi) about transformation and the regenerative future of tourism, a special issue published by the journal in 2022.

Design/methodology/approach

A personal interview.

Findings

Emeritus Professor Pauline Sheldon highlights the importance of regenerative tourism for the future and the role the JTF plays in this field. In particular, Sheldon highlights the pioneering research and practice of Dr Dianne Dredge, who has championed a pathway on regenerative tourism.

Originality/value

The interview provides insights into the directions of regenerative tourism and research about the future of tourism.