bluuebunny/crossref_metadata_2025 huggingface dataset:
The genetic architecture of human cerebellar morphology supports a key role for the cerebellum in human evolution and psychopathology
Authors: Moberget Torgeir , van der Meer Dennis , Bahrami Shahram , Roelfs Daniel , Frei Oleksandr , Kaufmann Tobias , Fernandez-Cabello Sara , Kim Milin , Wolfers Thomas , Diedrichsen Joern , Smeland Olav B. , Shadrin Alexey , Dale Anders , Andreassen Ole A. , Westlye Lars T.
Published: February 2023

The functional domain of the cerebellum has expanded beyond motor control to also include cognitive and affective functions. In line with this notion, cerebellar volume has increased over recent primate evolution, and cerebellar alterations have been linked to heritable mental disorders. To map the genetic architecture of human cerebellar morphology, we here studied a large imaging genetics sample from the UK Biobank (n discovery = 27,302; n replication: 11,264) with state-of-the art neuroimaging and biostatistics tools. Multivariate GWAS on regional cerebellar MRI features yielded 351 significant genetic loci (228 novel, 94% replicated). Lead SNPs showed positive enrichment for relatively recent genetic mutations over the last 20-40k years (i.e., overlapping the Upper Paleolithic, a period characterized by rapid cultural evolution), while gene level analyses revealed enrichment for human-specific evolution over the last ∼6-8 million years. Finally, we observed genetic overlap with major mental disorders, supporting cerebellar involvement in psychopathology.

Teaser

Genome-wide analysis of cerebellar morphology reveals links to recent human evolution and psychopathology
Low Antibody Titers Demonstrate Significantly Increased Rate of SARS-CoV-2 Infection in a Highly Vaccinated Population from the National Basketball Association
Authors: Tai Caroline G. , Haviland Miriam J. , Kissler Steven M. , Lucia Rachel M. , Merson Michael , Maragakis Lisa L. , Ho David D. , Anderson Deverick J. , DiFiori John , Grubaugh Nathan D. , Grad Yonatan H. , Mack Christina DeFilippo
Published: February 2023

SARS-CoV-2 antibody titers may serve as a correlate for immunity and could inform optimal booster timing. The relationship between antibody titer and protection from infection was evaluated in 2,323 vaccinated individuals from the National Basketball Association who had antibody levels measured from 9/12/2021—12/31/2021. Cox-proportional hazards models were used to estimate risk of infection within 90-days of serologic testing by titer level (<250, 250-800, and >800 AU/mL) and individuals were censored on date of booster receipt. The cohort was 78.2% male, 68.1% aged ≤ 40 years, and 56.4% vaccinated (primary series) with the Pfizer-BioNTech mRNA vaccine. Among the 2,248 individuals not yet boosted at testing, those with titers <250 AU/mL (adj HR: 2.4; 95% CI: 1.5, 3.7) and 250-800 800 AU/mL (adj HR: 1.5; 95% CI: 0.98, 2.4) had greater infection risk compared to those with titers >800 AU/mL. Serologic titers could inform individual COVID-19 risk and booster scheduling.
Glutathione supports lipid abundancein vivo
Authors: Asantewaa Gloria , Tuttle Emily T. , Ward Nathan P. , Kang Yun Pyo , Kim Yumi , Kavanagh Madeline E. , Girnius Nomeda , Chen Ying , Duncan Renae , Rodriguez Katherine , Hecht Fabio , Zocchi Marco , Smorodintsev-Schiller Leonid , Scales TashJaé Q. , Taylor Kira , Alimohammadi Fatemeh , Sechrist Zachary R , Agostini-Vulaj Diana , Schafer Xenia L. , Chang Hayley , Smith Zachary , O’Connor Thomas N. , Whelan Sarah , Selfors Laura M. , Crowdis Jett , Gray G. Kenneth , Bronson Roderick T. , Brenner Dirk , Rufini Alessandro , Dirksen Robert T. , Hezel Aram F. , Huber Aaron R. , Munger Josh , Cravatt Benjamin F. , Vasiliou Vasilis , Cole Calvin L , DeNicola Gina M. , Harris Isaac S.
Published: February 2023

Cells rely on antioxidants to survive. The most abundant antioxidant is glutathione (GSH). The synthesis of GSH is non-redundantly controlled by the glutamate-cysteine ligase catalytic subunit (GCLC). GSH imbalance is implicated in many diseases, but the requirement for GSH in adult tissues is unclear. To interrogate this, we developed a series ofin vivomodels to induceGclcdeletion in adult animals. We find that GSH is essential to lipid abundancein vivo. GSH levels are reported to be highest in liver tissue, which is also a hub for lipid production. While the loss of GSH did not cause liver failure, it decreased lipogenic enzyme expression, circulating triglyceride levels, and fat stores. Mechanistically, we found that GSH promotes lipid abundance by repressing NRF2, a transcription factor induced by oxidative stress. These studies identify GSH as a fulcrum in the liver’s balance of redox buffering and triglyceride production.
Phylogenetic distance and structural diversity directing a reclassification of glycopeptide antibiotics
Authors: Gavriilidou Athina , Adamek Martina , Rodler Jens-Peter , Kubach Noel , Kramer Susanna , Huson Daniel H. , Cryle Max J. , Stegmann Evi , Ziemert Nadine
Published: February 2023

Antibiotics have been an essential part of modern medicine since their initial discovery. The continuous search for new antibiotic candidates remains a necessity given the increasing emergence of resistance to antimicrobial compounds among pathogens. The glycopeptide antibiotics (GPAs) represent an important group of last resort antibiotics which inhibit bacterial growth through non-covalent binding to the cell wall precursor lipid II. The so far reported GPAs exhibit an enormous diversity in the biosynthetic gene clusters that encode their production, which is in turn reflected in the variety of their structures. GPAs are typically composed of seven amino acids, which are highly crosslinked and decorated with a variable collection of sugar moieties as well as other modifications. Based on their structural characteristics, they have been classified into four main types. More recently, atypical GPAs have been identified that differ from type I-IV GPAs in both their structure and function and have consequently been classified as type V GPAs. Given these differences, we studied the phylogeny of all gene sequences related to the biosynthesis of the GPAs and observed a clear evolutionary diversification between the lipid II binding GPA classes and the so-called type V GPAs. Here we suggest the adoption of a phylogeny-driven reclassification and a separation of classical lipid II binding GPAs from type V GPAs, which we propose to identify instead as glycopeptide- related peptides (GRPs).
Habitat restoration and the recovery of metacommunities
Authors: Gawecka Klementyna A. , Bascompte Jordi
Published: February 2023

Ecosystem restoration is becoming a widely recognised solution to the biodiversity crisis. However, there is a gap between restoration science and practice. Specifically, we lack a theoretical framework which would improve our understanding of ecosystems’ recovery and allow us to optimise restoration design. Here, we narrow this gap by developing spatially explicit metacommunity models and studying the recovery dynamics of communities during restoration. We show that community response depends on how damaged the landscape is prior to restoration, with highly fragmented landscapes imposing greater challenges to community recovery. In such cases, we found that the recovery depends on the type of interaction and the structure of the interaction network. Finally, we demonstrate that community recovery can be maximised with careful spatial planning. When recovering communities composed of antagonistic interactions, restoration should target areas adjacent to the most species-rich sites. In the case of mutualistic communities, the same strategy should be adopted in the short-term, whereas in the long-term, restoration should be extended to sites that improve the overall connectivity of the landscape. Our results highlight the importance of considering interactions between species and spatial planning in restoration projects.
Mechanical control of neural plate folding by apical domain alteration
Authors: Matsuda Miho , Rozman Jan , Ostvar Sassan , Kasza Karen E. , Sokol Sergei Y.
Published: February 2023

Vertebrate neural tube closure is associated with complex changes in cell shape and behavior, however, the relative contribution of these processes to tissue folding is not well understood. In this study, we evaluated morphology of the superficial cell layer in theXenopusneural plate. At the stages corresponding to the onset of tissue folding, we observed the alternation of cells with apically constricting and apically expanding apical domains. The cells had a biased orientation along the anteroposterior (AP) axis. This apical domain heterogeneity required planar cell polarity (PCP) signaling and was especially pronounced at neural plate hinges. Vertex model simulations suggested that spatially dispersed isotropically constricting cells cause the elongation of their non-constricting counterparts along the AP axis. Consistent with this hypothesis, cell-autonomous induction of apical constriction inXenopusectoderm cells was accompanied by the expansion of adjacent non-constricting cells. Our observations indicate that a subset of isotropically constricting cells can initiate neural plate bending, whereas a ‘tug-of-war’ contest between the force-generating and responding cells reduces its shrinking along the AP axis. This mechanism is an alternative to anisotropic shrinking of cell junctions that are perpendicular to the body axis. We propose that neural folding relies on PCP-dependent transduction of mechanical signals between neuroepithelial cells.
Conserved Chamber-Specific Polyploidy Maintains Heart Function inDrosophila
Authors: Chakraborty Archan , Peterson Nora G. , King Juliet S. , Gross Ryan T. , Pla Michelle Mendiola , Thennavan Aatish , Zhou Kevin C. , DeLuca Sophia , Bursac Nenad , Bowles Dawn E. , Wolf Matthew J. , Fox Donald T.
Published: February 2023

Developmentally programmed polyploidy (whole-genome-duplication) of cardiomyocytes is common across evolution. Functions of such polyploidy are essentially unknown. Here, we reveal roles for precise polyploidy levels in cardiac tissue. We highlight a conserved asymmetry in polyploidy level between cardiac chambers inDrosophilalarvae and humans. InDrosophila, differential Insulin Receptor (InR) sensitivity leads the heart chamber to reach a higher ploidy/cell size relative to the aorta chamber. Cardiac ploidy-reduced animals exhibit reduced heart chamber size, stroke volume, cardiac output, and acceleration of circulating hemocytes. TheseDrosophilaphenotypes mimic systemic human heart failure. Using human donor hearts, we reveal asymmetry in nuclear volume (ploidy) and insulin signaling between the left ventricle and atrium. Our results identify productive and likely conserved roles for polyploidy in cardiac chambers and suggest precise ploidy levels sculpt many developing tissues. These findings of productive cardiomyocyte polyploidy impact efforts to block developmental polyploidy to improve heart injury recovery.
Aldehyde accumulation inMycobacterium tuberculosiswith defective proteasomal degradation results in copper sensitivity
Authors: Limón Gina , Samhadaneh Nora M. , Pironti Alejandro , Darwin K. Heran
Published: February 2023

Mycobacterium tuberculosisis a major human pathogen and the causative agent of tuberculosis disease.M. tuberculosisis able to persist in the face of host-derived antimicrobial molecules nitric oxide and copper. However,M. tuberculosiswith defective proteasome activity is highly sensitive to nitric oxide and copper, making the proteasome an attractive target for drug development. Previous work linked nitric oxide susceptibility with the accumulation ofpara-hydroxybenzaldehyde inM. tuberculosismutants with defective proteasomal degradation. In this study, we found thatpara-hydroxybenzaldehyde accumulation was also responsible for copper sensitivity in these strains. We showed that exogenous addition ofpara-hydroxybenzaldehyde to wild-typeM. tuberculosiscultures sensitized bacteria to copper to a degree similar to that of a proteasomal degradation mutant. We determined thatpara-hydroxybenzaldehyde reduced the production and function of critical copper resistance proteins of the regulated in copper repressor (RicR) regulon. Further, we extended these Cu-sensitizing effects to an aldehyde thatM. tuberculosismay face within the macrophage. Collectively, this study is the first to mechanistically propose how aldehydes can renderM. tuberculosissusceptible to an existing host defense and could support a broader role for aldehydes in controllingM. tuberculosisinfections.

IMPORTANCE

M. tuberculosisis a leading cause of death by a single infectious agent, causing 1.5 million deaths annually. An effective vaccine forM. tuberculosisinfections is currently lacking, and prior infection does not typically provide robust immunity to subsequent infections. Nonetheless, immunocompetent humans can controlM. tuberculosisinfections for decades. For these reasons, a clear understanding of how mammalian immunity inhibits mycobacterial growth is warranted. In this study, we show aldehydes can increaseM. tuberculosissusceptibility to copper, an established antibacterial metal used by immune cells to controlM. tuberculosisand other microbes. Given that activated macrophages produce increased amounts of aldehydes during infection, we propose host-derived aldehydes may help control bacterial infections, making aldehydes a previously unappreciated antimicrobial defense.
Insight into the central and nodal cells transcriptome of the streptophyte green algaChara brauniiS276
Authors: Heß Daniel , Holzhausen Anja , Hess Wolfgang R.
Published: February 2023

Chara brauniiis an emerging model system for streptophyte terrestrialization and early land plant evolution. In this study, tissue containing nodal cells was prepared under the stereomicroscope and an RNA-seq dataset generated and compared to transcriptome data from whole plantlets. In both samples, transcript coverage was high for genes encoding ribosomal proteins and a homolog of the putative PAX3- and PAX7-binding protein 1. Gene ontology-based functional assignments revealed for the nodal cell sample main upregulated molecular functions related to protein binding, nucleic acid binding and DNA binding. Looking at specific genes, several signalling-related genes and genes encoding sugar-metabolizing enzymes were found to be expressed at a higher level in the nodal cell sample, while photosynthesis-and chloroplast-related genes were expressed at a comparatively lower level. We detected the transcription of 21 different genes encoding DUF4360-containing cysteine-rich proteins. The data contribute to the growing understanding of charophyte developmental genetics by providing a first insight into the transcriptome composition ofCharacentral and nodal cells.
Quantum entropy reveals chromosomal disorder of ancestry tracts in genetic admixture
Authors: Xiong Tianzhu , Bu Kaifeng
Published: February 2023

Ancestry tracts are contiguous haplotype blocks inherited from distinct groups of common ancestors. The genomic distribution of ancestry tracts (or local ancestry) provides rich information about evolutionary mechanisms shaping the genetic composition of hybrids. The correlation structure of ancestry tracts has been particularly useful in both empirical and theoretical studies, but there is a lack ofdescriptivemeasures operating on arbitrarily large genomic blocks to summarize this correlation structure without imposing too many assumptions about admixture. We here develop an approach inspired by quantum information theory to quantify this correlation structure. The key innovation is to represent local ancestry as quantum states, where less correlation in local ancestry leads to elevated quantum entropy. By leveraging a variety of entropy measures on local ancestry signals, we show that entropy is deeply connected to co-ancestry probabilities between and within haplotypes, so that ancestral recombination graphs become pivotal to the study of entropy dynamics in admixture. We use this approach to characterize a standard neutral admixture model with an arbitrary number of sources, and recover entropic laws governing the dynamics of ancestry tracts under recombination and genetic drift, which resembles the second law of thermodynamics. In application, entropy is well-defined on arbitrarily large genomic blocks with either phased or unphased local ancestry, and is insensitive to a small amount of noise. These properties are superior to simple statistics on ancestry tracts such as tract length and junction density. Finally, we construct an entropic index reflecting the degree of intermixing among ancestry tracts over a chromosomal block. This index confirms that the Z chromosome in a previously studied butterfly hybrid zone has the least potential of ancestry mixing, thus conforming to the “large-X/Z” effect in speciation. Together, we show that quantum entropy provides a useful framework for studying ancestry tract dynamics in both theories and real systems.
Vutiglabridin Alleviates Cellular Senescence Process of Dysfunctional Replication, Metabolic Regulation, and Circadian Clock in Primary Human Dermal Fibroblasts
Authors: Heo Jin-Woong , Lee Hye Eun , Lee Jimin , Choi Leo Sungwong , Shin Jaejin , Mun Ji Young , Park Hyung Soon , Park Sang Chul , Nam Chang-Hoon
Published: February 2023

The process of cellular senescence, which is characterized by stable cell cycle arrest, is strongly associated with dysfunctional cellular metabolism and circadian rhythmicity, both of which are reported to result from and also be causal to cellular senescence. As a result, modifying any of them - senescence, metabolism, or the circadian clock - may affect all three simultaneously. Obesity accelerates aging by disrupting the homeostasis of reactive oxygen species (ROS) via an increased mitochondrial burden of fatty acid oxidation. As a result, if senescence, metabolism, and circadian rhythm are all linked, anti-obesity treatments may improve metabolic regulation while also alleviating senescence and circadian rhythm. Vutiglabridin is a small molecule in clinical trials that improves obesity by enhancing mitochondrial function. We found that chronic treatment of senescent primary human dermal fibroblasts (HDFs) with vutiglabridin alleviates all investigated markers of cellular senescence (SA-β-gal,CDKN1A, CDKN2A) and dysfunctional cellular circadian rhythm (BMAL1), while remarkably preventing the alterations of mitochondrial function and structure that occur during the process of cellular senescence. Our results demonstrate the significant senescence-alleviating effects of vutiglabridin, specifically with the restoration of cellular circadian rhythmicity and metabolic regulation. These data support the potential development of vutiglabridin against aging-associated diseases and corroborate the intricate link between cellular senescence, metabolism, and the circadian clock.
Comparative analysis between two GT4 glycosyltransferases related to polysaccharide biosynthesis inRhodococcus jostiiRHA1
Authors: Cereijo Antonela E. , Ferretti María V. , Iglesias Alberto A. , Álvarez Héctor M. , Asencion Diez Matías D.
Published: February 2023

The bacterial genusRhodococcuscomprises organisms that perform an oleaginous behavior under certain growth conditions and the ratio of carbon and nitrogen availability. Thus,Rhodococcusspp have outstanding biotechnological features as microbial producers of biofuel precursors, which would be used instead of lipids from crops. It was postulated that lipid and glycogen metabolism inRhodococciare closely related. Thus, a better understanding of rhodococcal carbon partitioning requires identifying the catalytic steps redirecting sugar moieties to temporal storage molecules, such as glycogen and trehalose. In this work, we analyzed two glycosyl-transferases GT4 fromR. jostii,RjoGlgAb andRjoGlgAc, which were annotated as α-glucan-α-1,4-glucosyl transferases, putatively involved in glycogen synthesis. Both enzymes were recombinantly produced inE. coliBL21 (DE3) cells, purified to near homogeneity, and kinetically characterized.RjoGlgAb andRjoGlgAc presented the “canonical” glycogen synthase (EC 2.4.1.21) activity. Besides, both enzymes were actives as maltose-1P synthases (GlgM, EC 2.4.1.342), although to a different extent. In this scenario,RjoGlgAc is a homologous enzyme to the mycobacterial GlgM, with similar behavior regarding kinetic parameters and glucosyl-donor (ADP-glucose) preference.RjoGlgAc was two orders of magnitude more efficient to glucosylate glucose-1P than glycogen. Also, this rhodococcal enzyme used glucosamine-1P as a catalytically efficient aglycon. On the other hand, both activities exhibited byRjoGlgAb depicted similar kinetic efficiency and a preference for short-branched α-1,4-glucans. Curiously,RjoGlgAb presented a super-oligomeric conformation (higher than 15 subunits), representing a novel enzyme with a unique structure to function relationships. Results presented herein constitute a milestone regarding polysaccharide biosynthesis in Actinobacteria, leading to (re)discovery of methyl-glucose lipo-polysaccharide metabolism inRhodococci.
Exposure to Zika and chikungunya viruses impacts aspects of the vectorial capacity ofAedes aegyptiandCulex quinquefasciatus
Authors: Crespo Mônica , Guedes Duschinka , Paiva Marcelo , Sobral Mariana , Helvecio Elisama , Alves Rafael , Tadeu George , Oliveira Claudia , Melo-Santos Maria Alice Varjal , Barbosa Rosângela , Ayres Constância
Published: February 2023

Zika (ZIKV) and chikungunya (CHIKV) are arboviruses that cause infections in humans and can causeclinical complications, representing a worldwide public health problem.Aedes aegyptiis the primary vector of these pathogens andCulex quinquefasciatusmay be a potential ZIKV vector. This study aimed to evaluate fecundity, fertility, survival, longevity, and blood feeding activity inAe. aegyptiafter exposure to ZIKV and CHIKV and, inCx. quinquefasciatusexposed to ZIKV.Three colonies were evaluated: AeCamp(Ae. aegypti -field),RecL (Ae. aegypti -laboratory)and CqSLab (Cx. quinquefasciatus -laboratory). Seven to 10 days-old females from these colonies were exposed to artificial blood feeding with CHIKV or ZIKV. CHIKV caused reduction in fecundity and fertilityinthe natural population, AeCamp and reduction in survival and fertility in RecL.ZIKV impacted survival in RecL, fertility in AeCamp. and fecundity and fertility in CqSLab. Both viruses had no effect on blood feeding activity. These results show that CHIKV produces a higher biological cost inAe. aegypti, compared to ZIKV, and ZIKV differently alters the biological performance in colonies ofAe. aegyptiandCx. quinquefasciatus. These results provide a better understanding over the processes of virus-vector interaction and can shed light on the complexity of arbovirus transmission.
Neurovascular coupling conversely modulates emotion
Authors: Ruan Jiayu , Quan Xinghua , Zhang Yiyi , Xie Huiqi , Zhang Dongdong , Wang Wentao , Zhao Bingrui , Lu Danping , Jia Jie-Min
Published: February 2023

Emotion induces changes in regional cerebral blood flow (rCBF), a manifestation of neurovascular coupling (NVC). However, whether rCBF changes during NVC might, in turn, influence emotion is unclear. Here, by establishing arteriolar-optogenetic control of rCBF in free-moving mice, we demonstrate rCBF changes themselves induce emotional changes, and NVC actively modulates emotion. NVC deficiency impairs emotional flexibility, leading to contextually inappropriate emotional rigidity. Conversely, enhancing NVC counteracts this rigidity. To categorize inappropriate responses, we developed a predictive platform based on neural-activity patterns of the basolateral amygdala (BLA) in the mice exposed to a range of contexts. This platform revealed that NVC deficiency leads to BLA activations in a bipolar form, whereby predicting context-dependent hyper-reactivity and hypo-reactivity. Notably, this prediction was verified by actual physiological and behavioral responses. Mechanistically, neuronal mechanosensory receptor Piezo2 is essential for NVC-modulated emotion flexibility. Our findings establish NVC as an allostatic program for shaping emotion flexibility.
A multi-omics integrative approach unravels novel genes and pathways associated with senescence escape after targeted therapy in NRAS mutant melanoma
Authors: Gureghian Vincent , Herbst Hailee , Kozar Ines , Mihajlovic Katarina , Malod-Dognin Noël , Ceddia Gaia , Angeli Cristian , Margue Christiane , Randic Tijana , Philippidou Demetra , Tetsi Nomigni Milène , Hemedan Ahmed , Tranchevent Leon-Charles , Longworth Joseph , Bauer Mark , Badkas Apurva , Gaigneaux Anthoula , Muller Arnaud , Ostaszewski Marek , Tolle Fabrice , Pržulj Nataša , Kreis Stephanie
Published: February 2023

Therapy Induced Senescence (TIS) leads to sustained growth arrest of cancer cells. The associated cytostasis has been shown to be reversible and cells escaping senescence further enhance the aggressiveness of cancers. Together with targeted therapeutics, senolytics, specifically targeting senescent cancer cells, constitute a promising avenue for improved cancer treatments. Understanding how cancer cells evade senescence is needed to optimise the clinical benefits of this therapeutic approach. Here we characterised the response of three different NRAS mutant melanoma cell lines to a combination of CDK4/6 and MEK inhibitors over 33 days. Transcriptomic data show that all cell lines trigger a senescence programme coupled with strong induction of interferons. Kinome profiling revealed the activation of Receptor Tyrosine Kinases (RTKs) and enriched downstream signaling of neurotrophin, ErbB and insulin pathways. Characterisation of the miRNA interactome associates miR-211-5p with resistant phenotypes. Finally, iCELL-based integration of bulk and single-cell RNA-seq data identified biological processes perturbed during senescence, and predicts new genes involved in its escape. Overall, our data associate insulin signaling with persistence of a senescent phenotype and suggest a new role for interferon gamma in senescence escape through the induction of EMT and the activation of ERK5 signaling.
Systematic Nature Positive Markets
Authors: Bush Alex , Simpson Katherine , Hanley Nick
Published: February 2023

Despite decades of global commitments, and increasingly urgent warning of environmental instability, the demand for land to support economic production is still increasing. Isolated and disorganized actions will not be enough to avert ecosystem failures. As many developers are already required to compensate for their ecological impacts through restoration, many see markets trading biodiversity credits as a financial mechanism to counteract degradation and drive investment in conservation. The challenge stems from a desire to recognize the multidimensional nature of biodiversity that contributes to ecosystem integrity without making suitable offsets intractable to supply. Instead, most regulators have opted to streamline ecological assessment, and undermine ecological rigour, in favour of promoting offset supply and economic efficiency. As a result, all evidence suggests offset trading programs have so far failed to mitigate losses, let alone support “nature positive” outcomes. To overcome this disconnect, and support more effective and equitable biodiversity markets, we propose credits be defined by theirreplaceabilityof a site, a metric long-established in the domain of systematic conservation planning. Irreplaceability avoids the limitations of like-for-like trading, reduces costs of offsetting to developers and society, ensures farmers willing to sell are fairly rewarded for loss of earnings, and that sites critical to achieving conservation goals are safeguarded. We developed an ecological-economic model of a biodiversity offset market to demonstrate irreplaceability guarantees no net loss of biodiversity and is the most efficient metric for guiding investment toward the recovery of Nature.
Cell-type deconvolution of bulk RNA-Seq from kidney using opensource bioinformatic tools
Authors: Riojas Angelica M. , Spradling-Reeves Kimberly D. , Christensen Clinton L. , Hall-Ursone Shannan , Cox Laura A.
Published: February 2023

Traditional bulk RNA-Seq pipelines do not assess cell-type composition within heterogeneous tissues. Therefore, it is difficult to determine whether conflicting findings among samples or datasets are the result of biological differences or technical differences due to variation in sample collections. This report provides a user-friendly, open source method to assess cell-type composition in bulk RNA-Seq datasets for heterogeneous tissues using published single cell (sc)RNA-Seq data as a reference. As an example, we apply the method to analysis of kidney cortex bulk RNA-Seq data from female (N=8) and male (N=9) baboons to assess whether observed transcriptome sex differences are biological or technical, i.e., variation due to ultrasound guided biopsy collections. We found cell-type composition was not statistically different in female versus male transcriptomes based on expression of 274 kidney cell-type specific transcripts, indicating differences in gene expression are not due to sampling differences. This method of cell-type composition analysis is recommended for providing rigor in analysis of bulk RNA-Seq datasets from complex tissues. It is clear that with reduced costs, more analyses will be done using scRNA-Seq; however, the approach described here is relevant for data mining and meta analyses of the thousands of bulk RNA-Seq data archived in the NCBI GEO public database.

Author Summary

This method, which provides a simple method for assessing sampling biases in bulk RNA-Seq datasets with evaluation of cell-type composition, will aid researchers in assessing whether bulk RNA-Seq from different studies of the same heterogeneous tissue are comparable. The additional layer of information can help determine if differential gene expression observed is biological or technical, i.e., cell composition variation among study samples. The described method uses publicly available bioinformatics resources and does not require coding expertise or high-capacity computational processing. Development of tools accessible to scientists without computing expertise will contribute to greater rigor and reproducibility for bioinformatic analyses of transcriptome data.
Rab7 dependent regulation of goblet cell protein CLCA1 modulates gastrointestinal homeostasis
Authors: Gaur Preksha , Rajendran Yesheswini , Srivastava Bhagyashree , Markandey Manasvini , Fishbain-Yoskovitz Vered , Mohapatra Gayatree , Suhail Aamir , Chaudhary Shikha , Tyagi Shaifali , Yadav Subhash C , Pandey Amit K , Merbl Yifat , Bajaj Avinash , Ahuja Vineet , Srikanth Chittur V
Published: February 2023

Inflammation in ulcerative colitis is typically restricted to the mucosal layer of distal gut. Disrupted mucus barrier coupled with microbial dysbiosis has been reported to occur prior to the onset of inflammation. Here, we show the involvement of vesicular trafficking protein Rab7 in regulating the colonic mucus system. We identified a lowered Rab7 expression in goblet cells of colon during human and murine colitis.In vivoRab7 knocked down mice (Rab7KD) displayed a compromised mucus layer, increased microbial permeability and depleted gut microbiota with enhanced susceptibility to dextran sodium-sulfate induced colitis. These abnormalities emerged owing to altered mucus composition, as revealed by mucus proteomics, with increased expression of mucin protease Chloride channel accessory 1 (CLCA1). Mechanistically, Rab7 maintained optimal CLCA1 levels by controlling its lysosomal degradation, a process that was dysregulated during colitis. Overall, our work establishes a role for Rab7 dependent control of CLCA1 secretion required for maintaining mucosal homeostasis.
High-gamma activity is coupled to low-gamma oscillations in precentral cortices and modulates with movement and speech
Authors: Nie Jeffrey Z. , Flint Robert D. , Prakash Prashanth , Hsieh Jason K. , Mugler Emily M. , Tate Matthew C. , Rosenow Joshua M. , Slutzky Marc W.
Published: February 2023

Planning and executing motor behaviors requires coordinated neural activity among multiple cortical and subcortical regions of the brain. Phase-amplitude coupling between the high-gamma band amplitude and the phase of low frequency oscillations (theta, alpha, beta) has been proposed to reflect neural communication, as has synchronization of low-gamma oscillations. However, coupling between low-gamma and high-gamma bands has not been investigated. Here, we measured phase-amplitude coupling between low- and high-gamma in monkeys performing a reaching task and in humans either performing finger movements or speaking words aloud. We found significant coupling between low-gamma phase and high-gamma amplitude in multiple sensorimotor and premotor cortices of both species during all tasks. This coupling modulated with the onset of movement. These findings suggest that interactions between the low and high gamma bands are markers of network dynamics related to movement and speech generation.
A non-canonical Hippo pathway represses the expression of ΔNp63
Authors: Low-Calle Ana Maria , Ghoneima Hana , Ortega Nicholas , Cuibus Adriana M. , Katz Chen , Tong David , Prives Carol , Prywes Ron
Published: February 2023

The p63 transcription factor, a member of the p53 family, plays an oncogenic role in squamous cancers, while in breast cancers its expression is often repressed. In the canonical conserved Hippo pathway, known to play a complex role in regulating growth of cancer cells, the protein kinases MST1/2 and LATS1/2 act sequentially to phosphorylate and inhibit the YAP/TAZ transcription factors. We found that in the MCF10A mammary epithelial cell line as well as in squamous and breast cancer cell lines, expression of ΔNp63 RNA and protein is strongly repressed by inhibition of the Hippo pathway protein kinases in a manner that is independent of p53. While MST1/2 and LATS1 are required for p63 expression, the next step of the pathway, namely phosphorylation and degradation of the YAP/TAZ transcriptional activators is not required for repression of p63. This suggests that regulation of p63 expression occurs by a non-canonical version of the Hippo pathway. We additionally identified additional genes that were similarly regulated suggesting the broader importance of this pathway. Interestingly, we observed that experimentally lowering p63 expression leads to increased YAP protein levels, thereby constituting a feedback loop. These results, which reveal the intersection of the Hippo and p63 pathways, may prove useful for the control of their activities in cancer cells.

One Sentence Summary

Regulation of p63 expression occurs by a non-canonical version of the Hippo pathway in mammary epithelial, breast carcinoma and head and neck squamous carcinoma cells
Comparative membrane proteomics reveals diverse cell regulators concentrated at the nuclear envelope
Authors: Cheng Li-Chun , Zhang Xi , Baboo Sabyasachi , Nguyen Julie A , Martinez-Bartolomé Salvador , Loose Esther , Diedrich Jolene , Yates John R , Gerace Larry
Published: February 2023

The nuclear envelope (NE) is a subdomain of the ER with prominent roles in nuclear organization, largely mediated by its distinctive protein composition. We developed methods to reveal novel, low abundance transmembrane (TM) proteins concentrated at the NE relative to the peripheral ER. Using label-free proteomics that compared isolated NEs to cytoplasmic membranes, we first identified proteins with apparent NE enrichment. In subsequent authentication, ectopically expressed candidates were analyzed by immunofluorescence microscopy to quantify their targeting to the NE in cultured cells. Ten proteins from a validation set were found to associate preferentially with the NE, including oxidoreductases, enzymes for lipid biosynthesis and regulators of cell growth and survival. We determined that one of the validated candidates, the palmitoyltransferase Zdhhc6, modifies the NE oxidoreductase Tmx4 and thereby modulates its NE levels. This provides a functional rationale for the NE concentration of Zdhhc6. Overall, our methodology has revealed a group of previously unrecognized proteins concentrated at the NE and additional candidates. Future analysis of these can potentially unveil new mechanistic pathways associated with the NE.
Laurasian legacies in the Gondwanan tree fern order Cyatheales
Authors: Ramírez-Barahona Santiago
Published: February 2023

Abstract

Present-day geographic and phylogentic patterns often reflect the Gondwana–Laurasia separation and subsequent history of continental drift. However, some lineages show non-overlapping fossil distributions relative to extant species and in some cases extant ‘Gondwanan’ lineages have ‘Laurasian’ extinct relatives. Here, I combined distribution data for 101 fossils and 442 extant species of tree ferns (Cyatheales) to reconstruct their biogeographic history over the last 220 million years. The time calibrated tree showed most tree ferns families originating during the Jurassic and the onset of crown group diversification beginning during the Cretaceous; a major shift in diversification rates occurred in the largest tree fern family (Cyatheaceae) that comprises ~90% of extant diversity in the group. Biogeographical reconstructions based on extant distributions alone supported a Gondwanan origin for the group; the most probable ancestral range encompassed Australasia and South America. Alternatively, incorporating fossil distribution data into reconstructions showed a Laurasian origin and a most probable ancestral range in Eurasia. These results evince the Laurasian legacies of the Cyatheales spanning the Triassic–Cretaceous, which otherwise remain hidden from biogeographic inferences. These results show that extant-only biogeographic analyses are limited when fossils distribution are more wide spread than in the present-day, highlighting the need to directly incorporate fossils into biogeographical analyses and improve the reliability of ancestral geographic range estimation.
Gene regulatory dynamics during craniofacial development in a carnivorous marsupial
Authors: Cook Laura E. , Feigin Charles Y. , Hills John , Vespasiani Davide M. , Pask Andrew J. , Gallego Romero Irene
Published: February 2023

Marsupials and placental mammals exhibit significant differences in reproductive and life history strategies. Marsupials are born highly underdeveloped after an extremely short period of gestation, leading to prioritization of the development of structures critical for post-birth survival in the pouch. Critically, they must undergo accelerated development of the oro-facial region compared to placentals. Previously we described the accelerated development of the oro-facial region in the carnivorous Australian marsupial, the fat-tailed dunnartSminthopsis crassicaudatathat has one of the shortest gestations of any mammal. By combining genome comparisons of the mouse and dunnart with functional data for the enhancer-associated chromatin modifications, H3K4me3 and H3K27ac, we investigated divergence of craniofacial regulatory landscapes between these species. This is the first description of genome-wide face regulatory elements in a marsupial, with 60,626 putative enhancers and 12,295 putative promoters described. We also generated craniofacial RNA-seq data for the dunnart to investigate expression dynamics of genes near predicted active regulatory elements. While genes involved in regulating facial development were largely conserved in mouse and dunnart, the regulatory landscape varied significantly. Additionally, a subset of dunnart-specific enhancers were associated with genes highly expressed only in dunnart relating to cranial neural crest proliferation, embryonic myogenesis and epidermis development. Comparative RNA-seq analyses of facial tissue revealed dunnart-specific expression of genes involved in the development of the mechanosensory system. Accelerated development of the dunnart sensory system likely relates to the sensory cues received by the nasal-oral region during the postnatal journey to the pouch. Together these data suggest that accelerated face development in the dunnart may be driven by dunnart-specific enhancer activity. Our study highlights the power of marsupial-placental comparative genomics for understanding the role of enhancers in driving temporal shifts in development.
BOLD response is more than just magnitude: improving detection sensitivity through capturing hemodynamic profiles
Authors: Chen Gang , Taylor Paul A. , Reynolds Richard C. , Leibenluft Ellen , Pine Daniel S. , Brotman Melissa A. , Pagliaccio David , Haller Simone P.
Published: February 2023

Typical FMRI analyses assume a canonical hemodynamic response function (HRF) with a focus on the overshoot peak height, while other morphological aspects are largely ignored. Thus, in most reported analyses, the overall effect is reduced from a curve to a single scalar. Here, we adopt a data-driven approach to HRF estimation at the whole-brain voxel level, without assuming a response profile at the individual level. Then, we estimate the response in its entirety with a roughness penalty at the population level to improve predictive accuracy, inferential efficiency, and cross-study reproducibility. Using a fast event-related FMRI dataset, we demonstrate the extent of under-fitting and information loss that occurs when adopting the canonical approach. We also address the following questions:

How much does the HRF shape vary across regions, conditions, and groups?

Does an agnostic approach improve sensitivity to detect an effect compared to an assumed HRF?

Can examining HRF shape help validate the presence of an effect complementing statistical evidence?

Could the HRF shape provide evidence for whole-brain BOLD response during a simple task?
Histone variant H2B.Z acetylation is necessary for maintenance ofToxoplasma gondiibiological fitness
Authors: Vanagas Laura , Muñoz Daniela , Cristaldi Constanza , Ganuza Agustina , Nájera Rosario , Bonardi Mabel C. , Turowski Valeria R. , Guzman Fanny , Deng Bin , Kim Kami , Sullivan William J. , Angel Sergio O.
Published: February 2023

Through regulation of DNA packaging, histone proteins are fundamental to a wide array of biological processes. A variety of post-translational modifications (PTMs), including acetylation, constitute a proposed histone code that is interpreted by “reader” proteins to modulate chromatin structure. Canonical histones can be replaced with variant versions that add an additional layer of regulatory complexity. The protozoan parasiteToxoplasma gondiiis unique among eukaryotes in possessing a novel variant of H2B designated H2B.Z. The combination of PTMs and the use of histone variants is important for gene regulation inT. gondii,offering new targets for drug development. In this work,T. gondiiparasites were generated in which the 5 N-terminal acetylatable lysines in H2B.Z were mutated to either alanine (c-Myc-A) or arginine (c-Myc-R). c-Myc-A mutant only displayed a mild effect in its ability to kill mice. c-Myc-R mutant presented an impaired ability to grow and an increase in differentiation to latent bradyzoites. This mutant line was also more sensitive to DNA damage, displayed no virulence in mice, and provided protective immunity against future infection. While nucleosome composition was unaltered, key genes were abnormally expressed duringin vitrobradyzoite differentiation. Our results show that the N-terminal positive charge patch of H2B.Z is important for these procceses. Pull down assays with acetylated N-terminal H2B.Z peptide and unacetylated one retrieved common and differential interactors. Acetylated peptide pulled down proteins associated with chromosome maintenance/segregation and cell cycle, opening the question of a possible link between H2B.Z acetylation status and mitosis.
Bone mineral properties and 3D orientation of human lamellar bone around cement lines and the Haversian system
Authors: Grünewald Tilman A. , Johannes Andreas , Wittig Nina K. , Palle Jonas , Rack Alexander , Burghammer Manfred , Birkedal Henrik
Published: February 2023

Bone is a complex, biological tissue made up primarily of collagen fibrils and biomineral nanoparticles. The importance of hierarchical organization in bone was realized early on, but the actual interplay between structural features and the properties on the nanostructural and crystallographic level is still a matter of intense discussion. Bone is the only mineralized tissue that can be remodeled and, at the start of the formation of new bone during this process, a structure called a cement line is formed on which regular bone grows. Here, the orientational relationship of nanostructural and crystallographic constituents as well as the structural properties of both nanostructural and crystallographic constituents around cement lines and the Haversian system in human lamellar bone are investigated. A combination of small- and wide-angle X-ray scattering tensor tomography is employed together with diffraction tomography and synchrotron computed tomography to generate a multi-modal image of the sample. This work shows that the mineral properties vary as a function of the distance to the Haversian canal and, importantly, shows that the cement line has differing mineral properties from the surrounding lamellar bone, in particular with respect to crystallite size and degree of orientation. Cement lines make up a significant portion of the bone matrix despite their small size, hence the reported findings on an altered mineral structure, together with the spatial modulation around the Haversian canal, have implications for the formation and mechanics of bone.
Determinants of efficiency of non-bank financial institutions: an empirical evidence from Bangladesh
Authors: Rahman Mohammad Mizenur , Khaled Rahman Syed Mohammad , Ahmed Sakib
Published: February 2023

Purpose

The purpose of this study is to evaluate the effect of some internal features that influence the efficiency of non-bank financial institutions (NBFIs) in Bangladesh.

Design/methodology/approach

The study selected the top 15 Dhaka Stock Exchange (DSE)-listed NBFIs according to purposive sampling. The study period was from 2016 to 2020. Secondary data were collected from annual reports. The cost-to-income ratio was a dependent variable that was used as a proxy of operational efficiency. The ordinary least square regression technique was applied to measure the impact of firm-specific factors on efficiency.

Findings

Results showed that number of employees, branch number, firm size and deposit ratio have a significant effect on efficiency at 5% level. The number of branches and employees showed a negative impact, whereas firm size and deposit ratio showed a positive effect on the firms' efficiency. The deposit ratio is negatively related because deposit interest expenses were more than offset by interest income generation through the conversion of deposits into loans.

Practical implications

The study has practical and policy implications on NBFIs' managers, employees, shareholders, depositors, clients, regulatory authorities and government as efficiency enhancement would bring financial soundness.

Originality/value

This study shed light on some firm-specific factors that can be changed to increase operational efficiency or reduce the cost-to-income ratio. The novelty of the study is that it identified some significant associations between firm-specific factors and the operational efficiency of NBFIs.