bluuebunny/crossref_metadata_2025 huggingface dataset:
Seedless fruit inAnnona squamosaL. is monogenic and conferred byINOlocus deletion in multiple accessions
Authors: Rodrigues Bruno Rafael Alves , Gasser Charles S. , Pimenta Samy , Pereira Marlon Cristian Toledo , Nietsche Silvia
Published: October 2022

Understanding the genetic basis and inheritance of a trait facilitates the planning of breeding and development programs of new cultivars. In the sugar apple tree (Annona squamosaL.), the mechanism of the desirable seedless trait in the Thai seedless (Ts) and Brazilian seedless (Bs) accessions was associated with a deletion of theINNER NO OUTER(INO) locus. Genetic analysis of F1, F2and backcross descendants of crosses of Bs to fertile wild-type varieties showed that seedlessness was recessive and monogenic. Whole genome sequencing of a third accession, Hawaiian seedless (Hs), identified a 16 kilobase deletion includingINO. The finding of an identical deletion in Ts and Bs indicated a common origin among genotypes, from a single deletion event. Analysis of microsatellite markers could not preclude the possibility that all three accessions are vegetatively propagated clones. The sequence of the deletion site enabled formulation of a codominant assay for the wild-type and mutant genes that validated theINOgene deletion as the cause of seedless trait, and can be used in the selection of new seedless varieties. The study findings and obtained progenies should be useful in breeding and introgression programs of the trait into elite sugar apple lines and into otherAnnonasby means of interspecific crossings.
Disrupting peroxisomes alters lipid metabolism in melanoma and uncovers a novel therapeutic vulnerability in combination with MAPK-targeted therapies
Authors: Huang Fan , Cai Feiyang , Dahabieh Michael S. , Gunawardena Kshemaka , Talebi Ali , Dehairs Jonas , El-Turk Farah , Park Jae Yeon , Goncalves Christophe , Gagnon Natascha , Su Jie , Gaub Perrine , Joyal Jean-Sébastien , Mitchell John J , Swinnen Johannes V , Miller Wilson H. , del Rincón Sonia V.
Published: October 2022

Melanomas reprogram their metabolism to rapidly adapt to therapy-induced stress conditions, allowing them to persist and ultimately develop resistance. We report that a subpopulation of melanoma cells tolerate MAPK pathway inhibitors (MAPKi) through a concerted metabolic reprogramming mediated by peroxisomes and UDP-glucose ceramide glycosyltransferase (UGCG). Compromising peroxisome biogenesis, by repressing PEX3 expression, potentiates the pro-apoptotic effects of MAPKi via an induction of ceramides, an effect limited by UGCG-mediated ceramide metabolism. Co-targeting PEX3 and UGCG selectively eliminates a subset of metabolically active, drug-tolerant CD36+melanoma persister cells, thereby sensitizing melanoma to MAPKi and delaying resistance. Increased levels of peroxisomal genes andUGCGare found in patient-derived MAPKi-relapsed melanomas, and simultaneously inhibiting PEX3 and UGCG restores MAPKi sensitivity in multiple models of therapy resistance. Finally, triple therapy comprised of a newly identified inhibitor of the PEX3-PEX19 interaction, a UGCG inhibitor and a MAPKi demonstrates potent anti-tumor activity in pre-clinical melanoma models, thus representing a promising approach for melanoma treatment.

Highlights

Inhibiting peroxisome biogenesis uncovers a metabolic vulnerability in melanoma

CD36+persister melanoma cells tolerate MAPK-targeted therapy through peroxisome/UGCG mediated metabolic rewiring

Dual blockade of PEX3 and UGCG potentiates melanoma response to MAPK-targeted therapies and restores therapeutic sensitivity in MAPKi-resistant tumors

NNC 55-0396 is a PEX3-PEX19 binding inhibitor with potent anti-tumor activity in melanoma
Pleiotropic effects of BAFF on the senescence-associated secretome and growth arrest
Authors: Rossi Martina , Anerillas Carlos , Idda Maria Laura , Munk Rachel , Shin Chang Hoon , Donegà Stefano , Tsitsipatis Dimitrios , Herman Allison B. , Martindale Jennifer L. , Yang Xiaoling , Piao Yulan , Mazan-Mamczarz Krystyna , Fan Jinshui , Ferrucci Luigi , De Supriyo , Abdelmohsen Kotb , Gorospe Myriam
Published: October 2022

Senescent cells release a variety of cytokines, proteases, and growth factors collectively known as the senescence-associated secretory phenotype (SASP). Sustained SASP contributes to a pattern of chronic inflammation associated with aging and implicated in many age-related diseases. Here, we investigated the expression and function of the immunomodulatory cytokine BAFF (B-cell activating factor), a SASP protein, in multiple senescence models. We first characterized BAFF production across different senescence models, including senescent human diploid fibroblasts (WI-38, IMR-90) and monocytic leukemia cells (THP-1), and tissues of mice induced to undergo senescence. We then identified IRF1 (interferon response factor 1) as a transcription factor required for promotingBAFFmRNA transcription in senescence. We discovered that suppressing BAFF production decreased the senescent phenotype of both fibroblasts and monocyte-derived THP-1 cells, overall reducing IL6 secretion, SA-β-Gal staining, and γ-H2AX accumulation. Importantly, however, the influence of BAFF on the senescence program was cell type-specific: in monocytes, BAFF promoted the early activation of NF-κB and general SASP secretion, while in fibroblasts, BAFF contributed to the production and function of TP53 (p53). We propose that BAFF is elevated across senescence models and is a potential target for senotherapy.
Optogenetic manipulation of second messengers in neurons and cardiomyocytes with microbial rhodopsins and adenylyl cyclase
Authors: Hagio Hanako , Hosaka Shiori , Koyama Wataru , Song Aysenur Deniz , Narantsatsral Janchiv , Matsuda Koji , Shimizu Takashi , Hososhima Shoko , Tsunoda Satoshi P , Kandori Hideaki , Hibi Masahiko
Published: October 2022

Even though microbial photosensitive proteins have been used for optogenetics, their use should be optimized to precisely control second messengersin vivo. We exploitedGtCCR4andKnChR, cation channelrhodopsins from algae,BeGC1, a guanylyl cyclase rhodopsin from a fungus, and photoactivated adenylyl cyclases (PACs) from cyanobacteria (OαPAC) or bacteria (bPAC), to control cell functions in zebrafish. Optical activation ofGtCCR4 andKnChR in the hindbrain reticulospinal V2a neurons, which are involved in locomotion, immediately induced swimming behavior, whereas activation ofBeGC1 or PACs was achieved at a short latency.KnChR had the highest locomotioninducing activity of all the channelrhodopsins examined. Activation ofGtCCR4 andKnChR in cardiomyocytes induced cardiac arrest, whereas activation ofbPAC gradually induced bradycardia.KnChR activation led to an increase in intracellular Ca2+in the heart, suggesting that depolarization caused cardiac arrest. These data suggest that these optogenetic tools can be used to reveal the roles of second messengers in various cell types in vertebrates.

Impact statement

We identified efficient and useful microbial channelrhodopsin, guanylyl cyclase rhodopsin, and photoactivated adenylyl cyclase that regulate neural activity and cardiac function in zebrafish.

Major subject areas

Neuroscience, Cell biology

Research organism

Zebrafish (Danio rerio)
Optogenetic manipulation of Gq- and Gi/o-coupled receptor signaling in neurons and heart muscle cells
Authors: Hagio Hanako , Koyama Wataru , Hosaka Shiori , Song Aysenur Deniz , Narantsatsral Janchiv , Matsuda Koji , Sugihara Tomohiro , Shimizu Takashi , Koyanagi Mitsumasa , Terakita Akihisa , Hibi Masahiko
Published: October 2022

G protein-coupled receptors (GPCRs) transmit extracellular signals into the cell depending on the type of G protein. To analyze the functions of GPCR signaling, we developed optogenetic tools using animal G protein-coupled bistable rhodopsins that can be controlled into active and inactive states by light irradiation. We expressed Gq- and Gi/o-coupled bistable rhodopsins in hindbrain reticulospinal V2a neurons, which are involved in locomotion, or in cardiomyocytes of zebrafish. Light stimulation of the reticulospinal V2a neurons expressing Gq-coupled spider Rh1 resulted in an increase in the level of cytoplasmic Ca2+and evoked swimming behavior. Light stimulation of cardiomyocytes expressing the Gi/o-coupled mosquito Opn3, pufferfish TMT opsin, or lamprey parapinopsin induced cardiac arrest, and the effect was suppressed by treatment with pertussis toxin or barium, suggesting that Gi/o-dependent regulation of inward-rectifier K+channels controls cardiac function. These data indicate that these rhodopsins are useful for optogenetic control of GPCR-mediated signaling in neurons and cardiomyocytesin vivo.

Impact statement

Animal G protein-coupled bistable rhodopsins can regulate Gq and Gi-mediated signaling in a light-dependent manner in neurons and cardiomyocytes, making them useful for analyzing roles of GPCR signalingin vivo.
GoldRush: Ade novolong read genome assembler with linear time complexity
Authors: Wong Johnathan , Coombe Lauren , Nikolić Vladimir , Zhang Emily , Nip Ka Ming , Sidhu Puneet , Warren René L , Birol Inanç
Published: October 2022

Motivation

Current state-of-the-art long readde novogenome assemblers follow the Overlap Layout Consensus (OLC) paradigm, an O(n2) algorithm in its naïve implementation. While the most time- and memory-intensive step of OLC —the all-vs-all sequencing read alignment process— was improved and reimplemented in modern long read assemblers, these tools still often require excessive computational memory when assembling a typical 50X human genome dataset.

Results

Here we present GoldRush, ade novogenome assembly algorithm with linear time complexity in the number of input long sequencing reads. We tested GoldRush on Oxford Nanopore Technologies datasets with different base error profiles describing the genomes of three human cell lines (NA24385, HG01243 and HG02055),Oryza sativa(rice), andSolanum lycopersicum(tomato). GoldRush achieved NGA50 lengths of 18.3-22.2 Mbp for the three human datasets, with two of the three assemblies having the fewest extensive misassemblies, and NGA50 lengths of 0.3 and 2.6 Mbp for the 373 Mbp and 824 Mbp genomes of rice and tomato, respectively. Further, GoldRush assembled all genomes within a day, using at most 54.5 GB of RAM. These results demonstrate that our algorithm and new assembly paradigm can be used to assemble large genomesde novoefficiently in compute memory space, with resulting assembly contiguity comparable to that of state-of-the-art OLC genome assemblers.

Availability

https://github.com/bcgsc/goldrush
The rostral intralaminar nuclear complex of the thalamus supports striatally-mediated action reinforcement
Authors: Cover Kara K. , Lieberman Abby G. , Heckman Morgan M. , Mathur Brian N.
Published: October 2022

The dorsal striatum (DS) mediates the selection of actions for reward acquisition necessary for survival. Striatal pathology contributes to several neuropsychiatric conditions, including aberrant selection of actions for specific rewards in addiction. A major source of glutamate driving striatal activity is the rostral intralaminar nuclei of the thalamus (rILN). Yet, the information that is relayed to the striatum to support action selection is unknown. Here we discovered that rILN neurons projecting to the DS integrated information from several subcortical and cortical sources and that these rILN→DS neurons stably signaled at two time points in mice performing an action sequence task reinforced by sucrose reward: action initiation and reward acquisition.In vivoactivation of this pathway increased the number of successful trials whereas inhibition decreased the number of successful trials. These findings illuminate a role for the rostral intralaminar nuclear complex in reinforcing actions.
Predictive modeling of antibiotic eradication therapy success for new-onsetPseudomonas aeruginosapulmonary infections in children with cystic fibrosis
Authors: Graña-Miraglia Lucía , Morales-Lizcano Nadia , Wang Pauline W. , Hwang David M. , Yau Yvonne C. W. , Waters Valerie J. , Guttman David S.
Published: October 2022

ChronicPseudomonas aeruginosa(Pa) lung infections are the leading cause of mortality among cystic fibrosis (CF) patients; therefore, the eradication of new-onset Pa lung infections is an important therapeutic goal that can have long-term health benefits. The use of early antibiotic eradication therapy (AET) has been shown to eradicate the majority of new-onset Pa infections, and it is hoped that identifying the underlying basis for AET failure will further improve treatment outcomes. Here we generated random forest machine learning models to predict AET outcomes based on pathogen genomic data. We used a nested cross validation design, population structure control, and recursive feature selection to improve model performance and showed that incorporating population structure control was crucial for improving model interpretation and generalizability. Our best model, controlling for population structure and using only 30 recursively selected features, had an area under the curve of 0.87 for a holdout test dataset. The top-ranked features were generally associated with motility, adhesion, and biofilm formation.

AUTHOR SUMMARY

Cystic fibrosis (CF) patients are susceptible to lung infections by the opportunistic bacterial pathogenPseudomonas aeruginosa(Pa) leading to increased morbidity and earlier mortality. Consequently, doctors use antibiotic eradication therapy (AET) to clear these new-onset Pa infections, which is successful in 60%-90% of cases. The hope is that by identifying the factors that lead to AET failure, we will improve treatment outcomes and improve the lives of CF patients. In this study, we attempted to predict AET success or failure based on the genomic sequences of the infecting Pa strains. We used machine learning models to determine the role of Pa genetics and to identify genes associated with AET failure. We found that our best model could predict treatment outcome with an accuracy of 0.87, and that genes associated with chronic infection (e.g., bacterial motility, biofilm formation, antimicrobial resistance) were also associated with AET failure.
A Clade-D Auxin Response Factor is a Major Regulator of Auxin Signaling inPhyscomitrium patens
Authors: Bascom Carlisle , Prigge Michael , Szutu Whitnie , Bantle Alexis , Irmak Sophie , Tu Daniella , Estelle Mark
Published: October 2022

Auxin Response Factors (ARFs) are a family of transcription factors that are responsible for regulating gene expression in response to changes in auxin level. The analysis of ARF sequence and activity indicates that there are two major groups-activators and repressors. One clade of ARFs, clade-D, is sister to clade-A activating ARFs, but are unique in that they lack a DNA binding domain. Clade-D ARFs are present in lycophytes and bryophytes but absent in pteridophytes and spermatophytes. The transcriptional activity of clade-D ARFs, as well as how they regulate gene expression, is not well understood. Here, we report that clade-D ARFs are transcriptional activators in the model bryophyteP. patensand have a major role in the development of this species. Δarfd1,d2protonemata exhibit a delay in filament branching, as well as a delay in a key cell differentiation event. Additionally, leafy gametophore development in Δarfd1,d2lines lag behind wild-type. We present evidence that ARFd1 interacts with activating, but not repressing, ARFs. An ARFd1 hypomorph,arfd1T653L, cannot multimerize. Therefore, we propose a model by which clade-D ARFs enhance gene expression by oligomerizing to DNA-bound archetypal ARFs.
The N-terminal GTPase of Miro1 regulates oligomer formation
Authors: Eberhardt Emily L. , Mohamed Abdallah A. , Vos Seychelle , Cianfrocco Michael A.
Published: October 2022

The outer-mitochondrial membrane protein Miro1 is critical for the regulation of mitochondrial trafficking. Miro1 contains two GTPase domains, where changes in the N-terminal GTPase nucleotide state strongly affects mitochondrial trafficking. Previous work showed that the GTP-locked mutation Miro1P13Vdecreases trafficking and affects mitochondrial dynamics. Despite showing a clear role in Miro1 function, the molecular basis for this activity remains unknown. Usingin vitroreconstitution, we demonstrate that Miro1 self-associates to form dimers and higher-ordered species. Structural characterization of Miro1P13Vsuggests that the oligomers adopt a range of conformationsin vitro. Additionally, Miro1P13Vhas diminished interaction with its downstream cargo adapter TRAK1. These results indicate that the NGTPase of Miro1 facilitates the formation of higher-ordered species and suggests that changes in the oligomeric state may regulate mitochondrial trafficking through reduced association with TRAK1.
Diet changes thermal acclimation capacity, but not acclimation rate in a marine ectotherm (Girella nigricans) during warming
Authors: Hardison Emily A. , Schwieterman Gail D. , Eliason Erika J.
Published: October 2022

Global climate change is increasing thermal variability in coastal marine environments and the frequency, intensity, and duration of marine heatwaves. At the same time, nutritional resources are being altered by anthropogenic environmental changes. Marine ectotherms often cope with changes in temperature through physiological acclimation, which can take several weeks to occur and is a nutritionally demanding process. Here, we tested the hypothesis that different ecologically relevant diets (omnivorous, herbivorous, carnivorous) can impact thermal acclimation rate and capacity, using a temperate omnivorous fish as a model (opaleye;Girella nigricans). We measured acute thermal performance curves for maximum heart rate because cardiac function has been observed to set upper thermal limits in ectotherms. Opaleye acclimated rapidly after warming, but their thermal limits and acclimation rate were not affected by diet. However, the fish’s acclimation capacity for maximum heart rate was sensitive to diet, with fish in the herbivorous treatment displaying the smallest change in heart rate throughout acclimation. Mechanistically, ventricle fatty acid composition differed with diet treatment and was significantly related to cardiac performance in ways consistent with homoviscous adaptation. Our results suggest that diet is an important, but often overlooked, determinant of thermal performance in ectotherms on environmentally relevant timescales.
Role of horizontal gene transfers and microbial ecology in the evolution of fluxes through the tricarboxylic acid cycle
Authors: Sokolskyi Tymofii , DasSarma Shiladitya
Published: October 2022

The origin of carbon fixation is a fundamental question in astrobiology. While the Calvin cycle is the most active on the modern Earth, the reductive TCA cycle (rTCA) pathway for carbon fixation has been proposed to have played an important role in early evolution. In this study, we examined the evolution of key enzymes in the rTCA, which are rare in extant organisms, occurring in a few groups of Bacteria and Archaea. We investigated one of the least common reactions of this pathway, cleavage of citrate into oxaloacetate and acetyl-CoA, which can be performed by either a two-enzyme system (CCS/CCL) or a single enzyme (ACL) that is assumed to be the result of fusion of the two active sites into a single polypeptide. For broader context, we also studied functionally diverged homologs of these enzymes, succinyl-CoA synthetase (SCS) and citrate synthase (CS). Our phylogenetic analysis of these enzymes in Bacteria and Archaea shows that SCS, a homolog of CCS from distant bacterial taxa capable of citrate cleavage, are monophyletic, suggesting linked horizontal gene transfers of SCS and citrate cleavage enzymes. We also found evidence of the horizontal transfer of SCS from a clade of anaerobic Archaea (Archaeoglobi, Methanomicrobia or Crenarchaeota) to an ancestor of Cyanobacteria/Melainabacteria clade – both of whom share a succinate semialdehyde shunt in their oxidative TCA cycles. We also identified new bacterial and archaeal taxa for which complete rTCA cycles are theoretically possible, includingSyntrophobacter, Desulfofundulus, Beggiatoa, Caldithrix, Ca. Acidulodesulfobacterales andCa. Micrarachaeota. Finally, we suggest a possibility for syntrophically-regulated fluxes through oxidative and reductive TCA reactions in microbial communities particularly Haloarchaea-Nanohaloarchaea symbiosis and its implications for the Purple Earth hypothesis. We discuss how the inclusion of an ecological perspective in the studies of evolution of ancient metabolic pathways may be beneficial to understand origins of life.
Structure-based stabilization of SOSIP Env enhances recombinant ectodomain durability and yield
Authors: Wrapp Daniel , Mu Zekun , Thakur Bhishem , Janowska Katarzyna , Ajayi Oluwatobi , Barr Maggie , Parks Robert , Hahn Beatrice H. , Acharya Priyamvada , Saunders Kevin O. , Haynes Barton F.
Published: October 2022

The envelope glycoprotein (Env) is the main focus of HIV-1 vaccine development due to its critical role in viral entry. Despite advances in protein engineering, many Env proteins remain recalcitrant to recombinant expression due to their inherent metastability, making biochemical and immunological experiments impractical or impossible. Here we report a novel proline-stabilization strategy to facilitate the production of prefusion Env trimers. This approach, termed “2P”, works synergistically with previously described SOSIP mutations and dramatically increases the yield of recombinantly expressed Env ectodomains without altering the antigenic or conformational properties of native Env. We determined that the 2P mutations function by enhancing the durability of the prefusion conformation and that this stabilization strategy is broadly applicable to evolutionarily and antigenically diverse Envs. These findings provide a new Env stabilization platform to facilitate biochemical research and expand the number of Env variants that can be developed as future HIV-1 vaccine candidates.
Multifocal two-photon excitation fluorescence microscopy reveals hop diffusion of H-Ras membrane anchors in epidermal cells of zebrafish embryos
Authors: Gora Radoslaw J. , Vlieg Redmar C. , Jonkers Sven , van Noort John , Schaaf Marcel J.M.
Published: October 2022

Developments in fluorescence microscopy techniques have enabled imaging of individual fluorescently labelled proteins in biological systems, and in the current study, a single-molecule microscopy (SMM) technique has been appliedin vivo, using the zebrafish embryo model. We have used multifocal two-photon excitation fluorescence microscopy (2PEFM) to study the dynamics of a GFP-fused H-Ras membrane-anchoring domain, GFP-C10H-Ras, in the epidermal cells of living embryos. In previous studies, a fast and a slow diffusing population of GFP-C10H-Ras molecules had been found. The application of the multifocal 2PEFM technique enabled us to focus on the slow diffusing population, which appears to occur in clusters that diffuse within microdomains of the epidermal cell membranes. Based on their mobility on a short timescale (≤ 1s) we could distinguish between a subpopulation that was diffusing and one that was virtually immobile. Owing to the multifocal 2PEFM imaging mode, we were able to dramatically reduce photobleaching which enabled us to follow the GFP-C10H-Ras particles over a prolonged time (> 3 s) and reconstruct their molecular trajectories of the diffusing subpopulation. These trajectories exhibited that the C10H-Ras particles continuously switch between a diffusing state and brief bursts of increased diffusion. As a result, they display an anomalous mobility pattern that can be referred to as hop diffusion. Taken together, this study demonstrates that multifocal 2PEFM offers a powerful approach to studying individual particles for prolonged periods of time, and that using this approach we were able to uncover the hopping behavior of GFP-C10H-Ras.

SUMMARY STATEMENT

By application of the two-photon excitation single-molecule microscopy to living zebrafish embryos, anomalous diffusion modes of individual H-Ras membrane anchors in epidermal cells were found.
The Penultimate Step of Proteasomal ATPase Assembly is Mediated by a Nas2-Dependent Switch
Authors: Sekaran Suganya , Park Soyeon
Published: October 2022

The proteasome holoenzyme is a complex molecular machine that degrades most proteins. In the proteasome holoenzyme, six distinct ATPase subunits (Rpt1 through Rpt6) enable protein degradation by injecting protein substrates into it. Individual Rpt subunits assemble into a heterohexameric “Rpt ring” in a stepwise manner, by binding to their cognate chaperones. Completion of the heterohexameric Rpt ring correlates with release of a specific chaperone, Nas2, however it is unclear whether and how this event may ensure proper Rpt ring assembly. Here, we examined the action of Nas2 by capturing the poorly characterized, penultimate step of heterohexameric Rpt ring assembly. We show that Nas2 uses steric hindrance to block premature progression of the penultimate step into the final step of Rpt ring assembly. Importantly, Nas2 can activate an assembly checkpoint via its steric activity, when the last ATPase subunit, Rpt1, cannot be added in a timely manner. This checkpoint can be relieved via Nas2 release, when it recognizes proper addition of Rpt1 to one side of its cognate Rpt5, and ATP hydrolysis by Rpt4 on the other side of Rpt5, allowing completion of Rpt ring assembly. Our findings reveal dual criteria for Nas2 release, as a mechanism to ensure both the composition and functional competence of a newly assembled proteasomal ATPase, to generate the proteasome holoenzyme.
Decision and response monitoring during working memory are sequentially represented in the human insula
Authors: Llorens A. , Bellier L. , Blenkmann A.O. , Ivanovic J. , Larsson P.G. , Lin J.J. , Endestad T. , Solbakk A.-K. , Knight R.T.
Published: October 2022

Emerging research supports a role of the insula in human cognition. Here, we used intracranial EEG to investigate the spatiotemporal dynamics in the insula during a verbal working memory (vWM) task. We found robust effects for theta, beta, and high frequency activity (HFA) during probe presentation requiring a decision. Theta and beta band activity showed differential involvement across left and right insulae while sequential HFA modulations were observed along the anteroposterior axis. HFA in anterior insula tracked decision making and subsequent HFA was observed in posterior insula after the behavioral response. Our results provide electrophysiological evidence of engagement of different insula subregions in both decision-making and response monitoring during vWM and expand our knowledge of the role of the insula in complex human behavior.
Genetic control of a sex-specific piRNA program
Authors: Chen Peiwei , Aravin Alexei A.
Published: October 2022

Sexually dimorphic traits in morphologies are widely studied, but those in essential molecular pathways remain largely unexplored. Previous work showed substantial sex differences inDrosophilagonadal piRNAs, which guide PIWI proteins to silence selfish genetic elements thereby safeguarding fertility. However, the genetic control mechanisms of piRNA sexual dimorphism remain unknown. Here, we showed that most sex differences in the piRNA program originate from the germline rather than gonadal somatic cells. Building on this, we dissected the contribution of sex chromosome and cellular sexual identity towards the sex-specific germline piRNA program. We found that the presence of the Y chromosome is sufficient to recapitulate some aspects of the male piRNA program in a female cellular environment. Meanwhile, sexual identity controls the sexually divergent piRNA production from X-linked and autosomal loci, revealing a crucial input from sex determination into piRNA biogenesis. Sexual identity regulates piRNA biogenesis through Sxl and this effect is mediated in part through chromatin proteins Phf7 and Kipferl. Together, our work delineated the genetic control of a sex-specific piRNA program, where sex chromosome and sexual identity collectively sculpt an essential molecular trait.
One-carbon metabolic enzymes are regulated during cell division and make distinct contributions to the metabolome and cell cycle progression inSaccharomyces cerevisiae
Authors: Hammer Staci E. , Polymenis Michael
Published: October 2022

Enzymes of one-carbon metabolism play pivotal roles in proliferating cells. They are involved in the metabolism of amino acids, nucleotides, and lipids and the supply of all cellular methylations. However, there is limited information about how these enzymes are regulated during cell division and how cell cycle kinetics are affected in several loss-of-function mutants of one-carbon metabolism. Here, we report that the levels of theS. cerevisiaeenzymes Ade17p and Cho2p, involved in thede novosynthesis of purines and phosphatidylcholine, respectively, are cell cycle-regulated. Cells lacking Ade17p, Cho2p, or Shm2p (an enzyme that supplies one-carbon units from serine) have distinct alterations in size homeostasis and cell cycle kinetics. Loss of Ade17p leads to a specific delay at START, when cells commit to a new round of cell division, while loss of Shm2p has broader effects, reducing growth rate. Furthermore, the inability to synthesize phosphatidylcholinede novoincho2Δcells delays START and reduces the coherence of nuclear elongation late in the cell cycle. Loss of Cho2p also leads to profound metabolite changes. Besides the expected changes in the lipidome,cho2Δcells have reduced levels of amino acids, resembling cells shifted to poorer media. These results reveal the different ways that one-carbon metabolism allocates resources to affect cell proliferation at multiple cell cycle transitions.
Ecological effects of genome size in yellow starthistle (Centaurea solstitialis) vary between invaded and native ranges
Authors: Cang F. Alice , Dlugosch Katrina M.
Published: October 2022

Invasive species have become a pervasive threat on every continent and across a broad array of environments. Several traits predicted to promote invasion success, such as small seed size, rapid vegetative growth and short time to reproduction, are correlated with smaller genome sizes in a number of systems. To understand the influence of genome size on plant invasion dynamics, we compared genome sizes and traits inCentaurea solstitialis(YST) genotypes from the Californian invasion to those from their native source region in Spain. We conducted a common garden experiment and genome size survey to ask: (1) Is the invasion associated with genome size reduction? (2) To what extent can differences in genome size explain previously observed increases in plant size and reproduction in YST invasions? (3) Finally, we tested for expected evolutionary patterns in genome size across populations, including evidence of selection favouring reduced genome sizes at higher elevations, and evidence of stochastic processes leading to increases in genome sizes where effective population sizes are smaller. We found a reduction in corrected genome size in the invaded range, as well as significant interaction effects of range x elevation on genome size, and range x genome size on flowering time variation. Specifically, larger genomes tended to flower later and genome size decreased with increasing elevation in the invasion only. These emergent relationships in invading YST suggest potential selection for smaller genomes following introduction of YST to its invaded range. We also found a significant effect of measurement date on genome size estimation by flow cytometry, and this effect was more pronounced among native range genotypes.
Maximization of Energy Recovery from Starch Processing Wastewater by Thermophilic Dark Fermentation Coupled with Microbial fuel Cell Technology
Authors: Kumar Mohit , Pandit Soumya , Patel Vinay , Das Debabrata
Published: October 2022

Utilization of organic wastewater for hydrogen production has dual advantages of clean energy generation and bioremediation which is sustainable for a longer period. To maximize the energy recovery from starch rich wastewater, a two stage system comprising of thermophilic dark fermentation coupled with microbial fuel cell was employed. A single parameter optimization strategy was implemented for the operation of the batch system. The maximum cumulative hydrogen production obtained was 2.56 L L−1with a 48 % reduction in COD under the optimal conditions of 35 g L−1initial substrate concentration (COD), temperature 60oC, and pH 6.5. The H2yield and H2production rate were 6.8 mol H2/kg CODreducedand 731.3 mL L−1h−1respectively. The effect of the organic loading rate (OLR) on H2production rate was studied in a continuous stirred tank reactor (CSTR). A maximum hydrogen production rate of 913 mL L−1h−1was observed at an OLR of 5.6 g L− 1h−1. Effluent recycle played an important role in the improvement of H2production. A maximum H2production rate of 1224 mL L−1h−1was observed at a recycle ratio of 0.6. Power density of 4.2 W m−3was observed with MFC using the dark fermentative spent media neutralized with carbonate buffer at an optimal pH of 7. A total COD reduction of 86% was observed.
Subcortical Auditory Model including Efferent Dynamic Gain Control with Inputs from Cochlear Nucleus and Inferior Colliculus
Authors: Farhadi Afagh , Jennings Skyler G. , Strickland Elizabeth A. , Carney Laurel H.
Published: October 2022

We developed an auditory model with a time-varying, gain-control signal based on the physiology of the efferent system and the sub-cortical neural pathways. The medial olivocochlear (MOC) efferent stage of the model receives excitatory projections from both fluctuation-sensitive model neurons of the inferior colliculus (IC) and wide-dynamic-range model neurons of the cochlear nucleus. The response of the model MOC stage dynamically controls cochlear gain via simulated outer hair cells. In response to amplitude-modulated (AM) noise, firing rates of most IC neurons with band-enhanced modulation transfer functions in awake rabbits increase over a time course consistent with the dynamics of the MOC efferent feedback. These changes in the rates of IC neurons in awake rabbits were employed to adjust the parameters of the efferent stage of the proposed model. Responses of the proposed model to AM noise were able to simulate the increasing IC rate over time, while the model without the efferent system did not show this trend. The proposed model with efferent gain control provides a powerful tool for testing hypotheses, shedding insight on mechanisms in hearing, specifically those involving the efferent system.
Phosphate Starvation Signaling Increases Mitochondrial Membrane Potential through Respiration-independent Mechanisms
Authors: Ouyang Yeyun , Cunningham Corey N. , Berg Jordan A. , Toshniwal Ashish G. , Hughes Casey E. , Van Vranken Jonathan G. , Jeong Mi-Young , Cluntun Ahmad A. , Lam Geanette , Winter Jacob M. , Akdoǧan Emel , Dove Katja K. , Gygi Steven P. , Dunn Cory D , Winge Dennis R , Rutter Jared
Published: October 2022

Mitochondrial membrane potential directly powers many critical functions of mitochondria, including ATP production, mitochondrial protein import, and metabolite transport. Its loss is a cardinal feature of aging and mitochondrial diseases, and cells closely monitor membrane potential as an indicator of mitochondrial health. Given its central importance, it is logical that cells would modulate mitochondrial membrane potential in response to demand and environmental cues, but there has been little exploration of this question. We report that loss of the Sit4 protein phosphatase in yeast increases mitochondrial membrane potential, both through inducing the electron transport chain and the phosphate starvation response. Indeed, a similarly elevated mitochondrial membrane potential is also elicited simply by phosphate starvation or by abrogation of the Pho85-dependent phosphate sensing pathway. This enhanced membrane potential is primarily driven by an unexpected activity of the ADP/ATP carrier. We also demonstrate that this connection between phosphate limitation and enhancement of the mitochondrial membrane potential is also observed in primary and immortalized mammalian cells as well as inDrosophila. These data suggest that mitochondrial membrane potential is subject to environmental stimuli and intracellular signaling regulation and raise the possibility for therapeutic enhancement of mitochondrial functions even with defective mitochondria.
Experiences in the use of multiple doses of convalescent plasma in critically ill patients with COVID-19
Authors: Aguilar Ricardo , López-Verges Sandra , Quintana Anarellys , Morris Johanna , Lopez Lineth , Cooke Ana , Quiel Dimas , Buitron Natalie , Pérez Yaseikiry , Lobo Lesbia , Ballesteros Maura , Pitti Yaneth , Diaz Yamilka , Saenz Lisseth , Franco Danilo , Castillo Daniel , Valdespino Elimelec , Blanco Isabel , Romero Emilio , Cubilla-Batista Idalina , Villarreal Alcibiades
Published: October 2022

At the beginning of the SARS-CoV-2 pandemic, transfusion of COVID-19 convalescent plasma (CCP) was considered as one of the possibilities to help severe patients to overcome COVID-19 disease. The use of CCP has been controversial as its effectiveness depends on many variables from the plasma donor and the COVID-19 patient, for example, time of convalescence or symptoms onset. This was a feasibility study assessing the safety of multiple doses of CCP in mechanically ventilated intubated patients with respiratory failure due to COVID-19. Thirty (30) patients with severe respiratory failure, in ICU, with invasive mechanical ventilation received up to 5 doses of 300 to 600 ml of CP on alternate days (0,2,4,6 and 8) until extubation, futility, or death. Nineteen patients received five doses, seven received four, and four had 2 or 3 doses. On day 28 of follow-up, 57% of patients recovered and were at home and the long-term mortality observed was 27%. The ten severe adverse events reported in the study were unrelated to CCP transfusion. This study suggests that transfusion of multiple doses of convalescent plasma (CP) is safe. This strategy may represent an option to use in new studies, given the potential benefit of CCP transfusions in the early stage of infection in unvaccinated populations and in settings where monoclonal antibodies or antivirals are contraindicated or not available.

Summary box

Transfusion of multiple doses (up to 5 doses) of 300-600 ml of convalescent plasma from COVID-19 recovered patients is safe as it does not induce more severe effects than a single dose.

Independent of the number of transfused doses, most patients had detectable levels of total and neutralizing antibodies in plasma.

Future studies are needed to determine if multiple transfusion doses are more efficient in preventing severity than a single dose.
The genomic epidemiology of SARS-CoV-2 variants of concern in Kenya
Authors: Githinji George , Lambisia Arnold W. , Omah Ifeanyi , O’Toole Aine , Mohamed Khadija Said , de Laurent Zaydah R. , Makori Timothy O. , Mwanga Mike , Mburu Maureen W. , Morobe John M. , Ong’era Edidah M. , Ndwiga Leonard , Gathii Kimita , Thiongo Kelvin , Omuoyo Don Williams O. , Chepkorir Edith , Musyoki Jennifer , Kingwara Leonard , Matoke Damaris , Oyola Samuel O. , Onyango Clayton , Waitumbi John , Bulimo Wallace , Khamadi Samoel , Kiiru John N. O. , Kinyanjui Samson , Cotten Matthew , Tsofa Benjamin , Ochola-Oyier Isabella , Rambaut Andrew , Nokes D. James , Bejon Philip , Agoti Charles
Published: October 2022

The emergence and establishment of SARS-CoV-2 variants of concern presented a major global public health crisis across the world. There were six waves of SARS-CoV-2 cases in Kenya that corresponded with the introduction and eventual dominance of the major SARS-COV-2 variants of concern, excepting the first 2 waves that were both wild-type virus. We estimate that more than 1000 SARS-CoV-2 introductions occurred in the two-year epidemic period (March 2020 – September 2022) and a total of 930 introductions were associated with variants of concern namely Beta (n=78), Alpha(n=108), Delta(n=239) and Omicron (n=505). A total of 29 introductions were associated with A.23.1 variant that circulated in high frequencies in Uganda and Rwanda. The actual number of introductions is likely to be higher than these conservative estimates due to limited genomic sequencing. Our data suggested that cryptic transmission was usually underway prior to the first real-time identification of a new variant, and that multiple introductions were responsible. Following emergence of each VOC and subsequent introduction, transmission patterns were associated with hotspots of transmission in Coast, Nairobi and Western Kenya and follows established land and air transport corridors. Understanding the introduction and dispersal of major circulating variants and identifying the sources of new introductions is important to inform public health control strategies within Kenya and the larger East-African region. Border control and case finding reactive to new variants is unlikely to be a successful control strategy.
Programmatic Effectiveness of a Pediatric Typhoid Conjugate Vaccine Campaign in Navi Mumbai, India
Authors: Hoffman Seth A. , LeBoa Christopher , Date Kashmira , Haldar Pradeep , Harvey Pauline , Shimpi Rahul , An Qian , Zhang Chenhua , Jayaprasad Niniya , Horng Lily , Fagerli Kirsten , Borhade Priyanka , Chakraborty Debjit , Bahl Sunil , Katkar Arun , Kunwar Abhishek , Yewale Vijay , Andrews Jason R. , Bhatnagar Pankaj , Dutta Shanta , Luby Stephen P.
Published: October 2022

Background

The WHO recommends vaccines for prevention and control of typhoid fever, especially where antimicrobial-resistant typhoid circulates. In 2018 the Navi Mumbai Municipal Corporation (NMMC), implemented a TCV campaign. The campaign targeted all children aged 9-months through 14-years within NMMC boundaries (∼320,000 children) over 2 vaccination phases. The phase 1 campaign occurred from July 14-August 25, 2018 (71% coverage, ∼113,420 children). We evaluated the campaign’s programmatic effectiveness in reducing typhoid cases at the community level.

Methods

We established prospective, blood culture-based surveillance at 6 hospitals in Navi Mumbai, offering blood cultures to children presenting with fever for at least 3 days. We employed a cluster-randomized test-negative design to estimate the effectiveness of the vaccination campaign on pediatric typhoid cases. We matched culture-confirmed typhoid cases with up to 3 culture-negative controls by age and date of blood culture and assessed community vaccine campaign phase as an exposure using conditional logistic regression.

Results

Between September 1, 2018–March 31, 2021, we identified 81 typhoid cases and matched these with 238 controls. Cases were 0.44 times as likely to live in vaccine campaign communities (campaign effectiveness, 56%, 95%CI: 25%-74%, p=0.002). Cases ≥ 5-years-old were 0.37 times as likely (95% CI: 0.19-0.70; p-value = 0.002) and cases during the first year of surveillance were 0.30 times as likely (95% CI: 0.14-0.64; p-value = 0.002) to live in vaccine campaign communities.

Conclusions

Our findings support the use of TCV mass vaccination campaigns as effective population-based tools to combat typhoid fever.

In 2018, the Navi Mumbai Municipal Corporation conducted a typhoid conjugate vaccine campaign in half of its communities. Utilizing a test-negative design, we estimate that this campaign reduced typhoid risk by 56% (25-74%) in vaccinated communities compared to non-campaign communities.
Parkinson’s disease impairs cortical sensori-motor decision-making cascades
Authors: Tomassini A. , Cope T. E. , Zhang J. , Rowe J. B.
Published: October 2022

The transformation from perception to action requires a set of decisions about the nature of the percept, identification and selection of response options, and execution of the appropriate motor response. The unfolding of such decisions is mediated by distributed representations of the decision variables - evidence and intentions – that are represented through oscillatory activity across the cortex. Here we combine magneto-electroencephalography and linear ballistic accumulator models of decision-making to reveal the impact of Parkinson’s disease during the selection and execution of action. We used a visuomotor task in which we independently manipulated uncertainty in sensory and action domains. A generative accumulator model was optimized to single-trial neurophysiological correlates of human behaviour, mapping the cortical oscillatory signatures of decision-making, and relating these to separate processes accumulating sensory evidence and selecting a motor action. We confirmed the role of widespread beta oscillatory activity in shaping the feed-forward cascade of evidence accumulation from resolution of sensory inputs to selection of appropriate responses. By contrasting the spatiotemporal dynamics of evidence accumulation in age-matched healthy controls and people with Parkinson’s disease, we identified disruption of the beta-mediated cascade of evidence accumulation as the hallmark of atypical decision-making in Parkinson’s disease. In frontal cortical regions, there was inefficient processing and transfer of perceptual information. Our findings emphasize the intimate connection between abnormal visuomotor function and pathological oscillatory activity in neurodegenerative disease. We propose that disruption of the oscillatory mechanisms governing fast and precise information exchanges between the sensory and motor systems contributes to behavioural changes in people with Parkinson’s disease.
Impact of COVID-19 related maternal stress on fetal brain development: A Multimodal MRI study
Authors: Rajagopalan Vidya , Reynolds William T. , Zepeda Jeremy , Lopez Jeraldine , Ponrartana Skorn , Wood John , Ceschin Rafael , Panigrahy Ashok
Published: October 2022

Background

Disruptions in perinatal care and support due to the COVID-19 pandemic was an unprecedented but significant stressor among pregnant women. Various neurostructural differences have been re-ported among fetuses and infants born during the pandemic compared to pre-pandemic counterparts. The relationship between maternal stress due to pandemic related disruptions and fetal brain is yet unexamined.

Methods

Pregnant participants with healthy pregnancies were prospectively recruited in 2020-2022 in the greater Los Angeles Area. Participants completed multiple self-report assessments for experiences of pandemic related disruptions, perceived stress, and coping behaviors and underwent fetal MRI. Maternal perceived stress exposures were correlated with quantitative multimodal MRI measures of fetal brain development using ltivariate models.

Results

Fetal brain stem volume increased with increased maternal perception of pandemic related stress positively correlated with normalized fetal brainstem volume (suggesting accelerated brainstem maturation). In contrast, increased maternal perception of pandemic related stress correlated with reduced global fetal brain temporal functional variance (suggesting reduced functional connectivity).

Conclusions

We report alterations in fetal brainstem structure and global functional fetal brain activity associated with increased maternal stress due to pandemic related disruptions, suggesting altered fetal programming. Long term follow-up studies are required to better understand the sequalae of these early multi-modal brain disruptions among infants born during the COVID-19 pandemic.