bluuebunny/crossref_metadata_2025 huggingface dataset:
Repetition-dependent adaptation and Prediction error signalling in Schizophrenia patients with auditory hallucinations: A Roving Mismatch Negativity Study
Authors: Bose Anushree , Nayok Swarna Buddha , Pathak Harsh , Bagali Kiran Basawaraj , Chhabra Harleen , Suhas Satish , Shivakumar Venkataram , Sreeraj Vanteemar S. , Narayanaswamy Janardhanan C. , Venkatasubramanian Ganesan
Published: May 2023

Background

Prediction error is the surprise that is elicited when the sensory expectations are first established and then violated. Positive symptoms of schizophrenia, like auditory hallucinations (AH), are thought to arise from dysregulated prediction error-signalling. Roving mismatch negativity (rMMN) is a unique event-related potential (ERP) based assessment that allows examination of repetition-dependent adaptation and deviance detection—complimentary processes that are integral to prediction-error signalling. In the rMMN paradigm, the deviant tone becomes the new standard with several repetitions. Also, the number of repetitions of the standard stimuli keeps changing throughout the experiment; longer repetitions yield a more positive ERP response; this phenomenon is Repetition Positivity (RP). Longer repetitions of standard stimuli elicit stronger deviance detection when interrupted, and this is called deviant negativity (DN). A difference waveform between RP and DN reflects the strength of prediction error signalling, the mismatch negativity (MMN).

Methods

Twenty-three schizophrenia patients with auditory hallucinations (SZ-AH) and twenty-three healthy controls (HC) underwent rMMN assessment. Standard stimuli were repeated in sets of 3, 8 and 33. The first tone of the succeeding set became the deviant for the preceding set, yielding three components for RP (RP3, RP8, RP33), DN (DN3, DN8, DN33), and MMN (MMN3, MMN8, MMN33). Amplitudes and latencies of these components were compared between SZ-AH and HC. We also looked for potential associations between rMMN indices (amplitudes and latencies) and clinical scores in SZ-AVH. We examined the correlation between the RP-DN pair for all three repetition sets (3, 8, 33).

Results

SZ-AH had suppressed DN (DN3, DN8, DN33) and MMN33 amplitudes in comparison to HC. However, none of the RP amplitudes were diminished. Only MMN33 latency was significantly longer in SZ-AH than in HC. Amplitudes and latencies associated with repetition set of 8 showed a significant correlation with the frequency and loudness of AH. HC showed a strong positive correlation between RP-DN pairs; SZ-AH did not, except for the RP33-DN33 pair.

Discussion

The link between repetition-dependent sensory adaptation and deviance detection is compromised in SZ-AH patients. Though RP profile (RP3, RP8, RP33) is unimpaired in SZ-AVH, it is potentially due to AH interfering with auditory information processing and not because of intact short-term plasticity of the echoic memory trace.
Molecular Spectrum and Chromatographic- Haematological Characterisation of Alpha Thalassemia Minor (-α/-α), and Alpha Silent Carriers (-α/-αα)
Authors: Uçucu Süheyl
Published: May 2023

Background and aims

Alpha-thalassaemia is a group of disorders characterised by wide phenotypic variation caused by mutations in the α-globin genes (α1 and α2) of chromosome 16.

The aim of this study was to investigate the molecular profile of α-thalassemia variants and to compare and characterise the chromatographic behaviour and haematological properties of α-thalassemia minor (-α/-α, --/ααα) and α-silent carriers (-α/ααα) on HPLC.

Materials & Methods

A dataset of 200 individuals consisting of 42 alpha thalassemia minor (-α/-α, -- /ααα), 103 alpha silent carriers (-α/αα) and 55 normal participants from the Human Genetics Unit (HGU) of the Faculty of Medicine, Colombo, Srilanka was included. Blood samples from each patient were analysed by PCR for genotyping, haemogram and high performance liquid chromatography (HPLC) for characterisation. These data were then comparatively analysed using standard descriptive statistics.

Results

It was analysed in three sections as haematological, biochemical and molecular. Haematologically, alpha thalassaemia silent carrier was completely normal; alpha thalassaemia minor: decreased haemoglobin level; decreased MCV and MCH, normal RBC count. Alpha Thalassaemia Minor patients show a statistically significant difference from alpha silent carriers and normal population in terms of MCV, MCH, HGB, PCV, RDW.

Biochemically, alpha thalassaemia silent carriers were found to have normal alpha-globin chain production, alpha thalassaemia minor: low HBA2 as determined by HPLC. In terms of HPLC tests, similar results were observed between alpha thalassaemia minor patients and alpha silent carriers and between alpha thalassaemia minor patients and the normal group, with no statistical significance for all parameters except HBA2. Molecularly, the most common mutations in both variants are _α3.7 and _α4.2 mutations.

Conclusion

In summary, despite the haematological and biochemical differences between α-thalassaemia minor and normal individuals, both variants of alpha thalassaemia present a diagnostic conundrum, as CBC and HPLC results for individuals are comparable to normal humans. Although MCV, MCH, HGB, PCV and HBA2 levels differ between alpha thalassaemia minor carriers, alpha silent carriers and the normal group, conventional haemoglobin electrophoresis and haemogram alone have been found insufficient for the diagnosis of alpha thalassaemia. Therefore, although HPLC does not seem to be sufficient to distinguish between normal individuals and the two variants, the decrease in HBA2 levels is an important finding. Identifying a mutated alpha globin gene requires newer molecular diagnostic tests such as next generation sequencing (NGS) and quantitative PCR (qPCR). It should be noted that a given genotype can greatly alter the clinical manifestation by the presence of additional mutations, making the relationship between genotype and phenotype highly variable.
Reduced Spinal Cord Gray Matter in Patients with Fibromyalgia Using Opioids Long-term
Authors: Baker Anne K. , Park Su Hyoun , Weber Kenneth A. , Martucci Katherine T.
Published: May 2023

Objective

Chronic pain involves alterations in brain gray matter volume (GMV). Moreover, opioid medications are known to reduce GMV in numerous brain regions involved in pain processing. However, no research has evaluated (1) chronic pain-related GMV alterations in the spinal cord or (2) the effect of opioids on spinal cord GMV. Accordingly, this study evaluated spinal cord GMV in health controls and patients with fibromyalgia who were using and not using opioids long-term.

Methods

We analyzed average C5 - C7 GMV of the spinal cord dorsal and ventral horns in separate female cohorts of healthy controls (HC, n = 30), fibromyalgia patients not using opioids (FMN, n = 31), and fibromyalgia patients using opioids long-term (FMO, n = 27). To assess the effect of group on average dorsal and ventral horn GMV, we conducted a one-way multivariate analysis of covariance.

Results

After controlling for age, we observed a significant effect of group on ventral horn GMV (p= 0.03, η2= 0.09), and on dorsal horn GMV (p= 0.05, η2= 0.08). Tukey’s posthoc comparisons showed that, compared to HC participants, FMOs had significantly lower ventral (p= 0.01) and dorsal (p= 0.02) GMVs. Among FMOs only, ventral horn GMV was significantly positively associated with pain severity and interference, and both dorsal and ventral GMVs were significantly positively associated with cold pain tolerance.

Conclusion

Long-term opioid use may impact sensory processing in fibromyalgia via gray matter changes within the cervical spinal cord.
Pushed to extremes: distinct effects of high temperature vs. pressure on the structure of an atypical phosphatase
Authors: Guerrero Liliana , Ebrahim Ali , Riley Blake T. , Kim Minyoung , Huang Qingqiu , Finke Aaron D. , Keedy Daniel A.
Published: May 2023

Protein function hinges on small shifts of three-dimensional structure. Elevating temperature or pressure may provide experimentally accessible insights into such shifts, but the effects of these distinct perturbations on protein structures have not been compared in atomic detail. To quantitatively explore these two axes, we report the first pair of structures at physiological temperature vs. high pressure for the same protein, STEP (PTPN5). We show that these perturbations have distinct and surprising effects on protein volume, patterns of ordered solvent, and local backbone and side-chain conformations. This includes novel interactions between key catalytic loops only at physiological temperature, and a distinct conformational ensemble for another active-site loop only at high pressure. Strikingly, in torsional space, physiological temperature shifts STEP toward previously reported active-like states, while high pressure shifts it toward a previously uncharted region. Together, our work argues that temperature and pressure are complementary, powerful, fundamental macromolecular perturbations.
Enhanced Feature Selection for Microbiome Data using FLORAL: Scalable Log-ratio Lasso Regression
Authors: Fei Teng , Funnell Tyler , Waters Nicholas R. , Raj Sandeep S. , Sadeghi Keimya , Dai Anqi , Miltiadous Oriana , Shouval Roni , Lv Meng , Peled Jonathan U. , Ponce Doris M. , Perales Miguel-Angel , Gönen Mithat , van den Brink Marcel R. M.
Published: May 2023

Identifying predictive biomarkers of patient outcomes from high-throughput microbiome data is of high interest, while existing computational methods do not satisfactorily account for complex survival endpoints, longitudinal samples, and taxa-specific sequencing biases. We presentFLORAL(https://vdblab.github.io/FLORAL/), an open-source computational tool to perform scalable log-ratio lasso regression and microbial feature selection for continuous, binary, time-to-event, and competing risk outcomes, with compatibility of longitudinal microbiome data as time-dependent covariates. The proposed method adapts the augmented Lagrangian algorithm for a zero-sum constraint optimization problem while enabling a two-stage screening process for extended false-positive control. In extensive simulation and real-data analyses,FLORALachieved consistently better false-positive control compared to other lasso-based approaches, and better sensitivity over popular differential abundance testing methods for datasets with smaller sample size. In a survival analysis in allogeneic hematopoietic-cell transplant, we further demonstrated considerable improvement byFLORALin microbial feature selection by utilizing longitudinal microbiome data over only using baseline microbiome data.
SAP: Synteny-aware gene function prediction for bacteria using protein embeddings
Authors: Urhan Aysun , Cosma Bianca-Maria , Earl Ashlee M. , Manson Abigail L. , Abeel Thomas
Published: May 2023

Motivation

Today, we know the function of only a small fraction of the protein sequences predicted from genomic data. This problem is even more salient for bacteria, which represent some of the most phylogenetically and metabolically diverse taxa on Earth. This low rate of bacterial gene annotation is compounded by the fact that most function prediction algorithms have focused on eukaryotes, and conventional annotation approaches rely on the presence of similar sequences in existing databases. However, often there are no such sequences for novel bacterial proteins. Thus, we need improved gene function prediction methods tailored for prokaryotes. Recently, transformer-based language models - adopted from the natural language processing field - have been used to obtain new representations of proteins, to replace amino acid sequences. These representations, referred to as protein embeddings, have shown promise for improving annotation of eukaryotes, but there have been only limited applications on bacterial genomes.

Results

To predict gene functions in bacteria, we developed SAP, a novel synteny-aware gene function prediction tool based on protein embeddings from state-of-the-art protein language models. SAP also leverages the unique operon structure of bacteria through conserved synteny. SAP outperformed both conventional sequence-based annotation methods and state-of-the-art methods on multiple bacterial species, including for distant homolog detection, where the sequence similarity to the proteins in the training set was as low as 40%. Using SAP to identify gene functions across diverse enterococci, of which some species are major clinical threats, we identified 11 previously unrecognized putative novel toxins, with potential significance to human and animal health.

Availability

https://github.com/AbeelLab/sap

Contact

t.abeel@tudelft.nl

Supplementary information

Supplementary data are available atBioinformaticsonline.
A stable microtubule bundle formed through an orchestrated multistep process controls quiescence exit
Authors: Laporte Damien , Massoni-Laporte Aurélie , Lefranc Charles , Dompierre Jim , Mauboules David , Nsamba Emmanuel. T. , Royou Anne , Gal Lihi , Schuldiner Maya , Gupta Mohan L. , Sagot Isabelle
Published: May 2023

Cells fine-tune microtubule assembly in both space and time, to give rise to distinct edifices with specific cellular functions. In proliferating cells, microtubules are highly dynamics, and proliferation cessation often leads to their stabilization. One of the most stable microtubule structures identified to date is the nuclear bundle assembled in quiescent yeast. In this report, we characterize the original multistep process driving the assembly of this structure. This Aurora B-dependent mechanism follows a precise temporality that relies on the sequential actions of kinesin-14, kinesins-5 and involves both microtubule-kinetochore and kinetochore-kinetochore interactions. Upon quiescence exit, the microtubule bundle is disassembled via a cooperative process involving kinesin-8 and its full disassembly is required prior to cells re-entry into proliferation. Overall, our study provides the first description, at the molecular scale, of the entire life cycle of a stable microtubule structurein vivo, and sheds light on its physiological function.
LEADER (Leaf Element Accumulation from Deep Roots): a nondestructive phenotyping platform to estimate rooting depth in the field
Authors: Hanlon Meredith T. , Brown Kathleen M. , Lynch Jonathan P.
Published: May 2023

Deeper rooted crops are an avenue to increase plant water and nitrogen uptake under limiting conditions and increase long-term soil carbon storage. Measuring rooting depth, however, is challenging due to the destructive, laborious, or imprecise methods that are currently available. Here, we present LEADER (Leaf Element Accumulation from DEep Roots) as a method to estimate in-field root depth of maize plants. We use both X-Ray fluorescence spectroscopy (XRF) and ICP-OES (Inductively Coupled Plasma Optical Emission spectroscopy) to measure leaf elemental content and relate this to metrics of root depth. Principal components of leaf elemental content correlate with measures of root length in four genotypes (R2= 0.8 for total root length), and we use linear discriminant analysis to classify plants as having different metrics related to root depth across four field sites in the United States. We can correctly classify the plots with the longest root length at depth with high accuracy (accuracy greater than 0.6) at two of our field sites (Hancock, WI and Rock Spring, PA). We also use strontium (Sr) as a tracer element in both greenhouse and field studies, showing that elemental accumulation of Sr in leaf tissue can be measured with XRF and can estimate root depth. We propose the adoption of LEADER as a tool for measuring root depth in different plant species and soils. LEADER is faster and easier than any other methods that currently exist and could allow for extensive study and understanding of deep rooting.
Cognitive outcome and its neural correlates after cardiorespiratory arrest in childhood
Authors: Geva Sharon , Hoskote Aparna , Saini Maneet , Clark Christopher A. , Banks Tina , Chong Kling W. K. , Baldeweg Torsten , de Haan Michelle , Vargha-Khadem Faraneh
Published: May 2023

Hypoxia-ischaemia (HI) can result in structural brain abnormalities, which in turn can lead to behavioural deficits in various cognitive and motor domains, in both adult and paediatric populations. Cardiorespiratory arrest (CA) is a major cause of hypoxia-ischaemia in adults, but it is relatively rare in infants and children. While the effects of adult CA on brain and cognition have been widely studied, to date, there are no studies examining the neurodevelopmental outcome of children who suffered CA early in life.

Here, we studied the long-term outcome of 28 children who suffered CA during infancy or childhood (i.e., before age 16). They were compared to a group of control participants (n = 28) matched for age, gender and socio-economic status. The patient group had impairments in the domains of memory, language and academic attainment (measured using standardised tests; impairment defined as a score > 1.5 standard deviations below the control group mean). Individual scores within the impaired range were most commonly found within the memory domain (79%), followed by attainment (50%), and language (36%). The patient group also had reduced whole brain grey matter volume, and reduced volume and fractional anisotropy of the white matter.

In addition, lower performance on memory tests was correlated with bilaterally reduced volume of the hippocampi, thalami, and striatum, while lower attainment scores were correlated with bilateral reduction of fractional anisotropy in the superior cerebellar peduncle, the main output tract of the cerebellum.

We conclude that patients who suffered early CA are at risk of developing specific cognitive deficits associated with structural brain abnormalities.
Adaptive planning depth in human problem solving
Authors: Eluchans Mattia , Lancia Gian Luca , Maselli Antonella , D’Alessando Marco , Gordon Jeremy , Pezzulo Giovanni
Published: May 2023

We humans are capable of solving challenging planning problems, but the range of adaptive strategies that we use to address them are not yet fully characterized. Here, we designed a series of problem-solving tasks that require planning at different depths. After systematically comparing the performance of participants and planning models, we found that when facing problems that require planning to a certain number of subgoals (from 1 to 8), participants make an adaptive use of their cognitive resources – namely, they tend to select an initial plan having the minimum required depth, rather than selecting the same depth for all problems. These results support the view of problem solving as a bounded rational process, which adapts costly cognitive resources to task demands.
Impaired microglia-mediated synaptic pruning in the nucleus accumbens during adolescence results in persistent dysregulation of familiar, but not novel social interactions in sex-specific ways
Authors: Kirkland Julia M. , Edgar Erin L. , Patel Ishan , Kopec Ashley M.
Published: May 2023

Evolutionarily conserved, peer-directed social behaviors are essential to participate in many aspects of human society. These behaviors directly impact psychological, physiological, and behavioral maturation. Adolescence is an evolutionarily conserved period during which reward-related behaviors, including social behaviors, develop via developmental plasticity in the mesolimbic dopaminergic ‘reward’ circuitry of the brain. The nucleus accumbens (NAc) is an intermediate reward relay center that develops during adolescence and mediates both social behaviors and dopaminergic signaling. In several developing brain regions, synaptic pruning mediated by microglia, the resident immune cells of the brain, is important for normal behavioral development. In rats, we previously demonstrated that microglial synaptic pruning also mediates NAc and social development during sex-specific adolescent periods and via sex-specific synaptic pruning targets. In this report, we demonstrate that interrupting microglial pruning in NAc during adolescence persistently dysregulates social behavior towards a familiar, but not novel social partner in both sexes, via sex-specific behavioral expression. This leads us to infer thatnaturally occurringNAc pruning serves to reduce social behaviors primarily directed toward a familiar conspecific in both sexes, but in sex-specific ways.
A short isoform of the UNC-6/Netrin receptor UNC-5 is required for growth cone polarity and robust growth cone protrusion inCaenorhabditis elegans
Authors: Mahadik Snehal S. , Lundquist Erik A.
Published: May 2023

UNC-6/Netrin is a conserved bi-functional guidance cue which regulates dorsal-ventral axon guidance inC. elegans. In the Polarity/Protrusion model of UNC-6/Netrin mediated dorsal growth away from UNC-6/Netrin, The UNC-5 receptor first polarizes the VD growth cone such that filopodial protrusions are biased dorsally. Based on this polarity, the UNC-40/DCC receptor stimulates growth cone lamellipodial and filopodial protrusion dorsally. The UNC-5 receptor maintains dorsal polarity of protrusion, and inhibits growth cone protrusion ventrally, resulting in net dorsal growth cone advance. Work presented here demonstrates a novel role of a previously undescribed, conserved short isoform of UNC-5 (UNC-5B). UNC-5B lacks the cytoplasmic domains of UNC-5 long, including the DEATH domain, the UPA/DB domain, and most of the ZU5 domain. Mutations that specifically affect only theunc-5long isoforms were hypomorphic, suggesting a role ofunc-5Bshort. A mutation specifically affectingunc-5Bcause loss of dorsal polarity of protrusion and reduced growth cone filopodial protrusion, the opposite ofunc-5long mutations. Transgenic expression ofunc-5Bpartially rescuedunc-5axon guidance defects, and resulted in large growth cones. Tyrosine 482 (Y482) in the cytoplasmic juxtamembrane region has been shown to be important for UNC-5 function, and is present in both UNC-5 long and UNC-5B short. Results reported here show that Y482 is required for the function of UNC-5 long and for some functions of UNC-5B short. Finally, genetic interactions withunc-40andunc-6suggest that UNC-5B short acts in parallel to UNC-6/Netrin to ensure robust growth cone lamellipodial protrusion. In sum, these results demonstrate a previously-undescribed role for the UNC-5B short isoform, which is required for dorsal polarity of growth cone filopodial protrusion and to stimulate growth cone protrusion, in contrast to the previously-described role of UNC-5 long in inhibiting growth cone protrusion.
descSPIM: Affordable and Easy-to-Build Light-Sheet Microscopy for Tissue Clearing Technique Users
Authors: Otomo Kohei , Omura Takaki , Nozawa Yuki , Saito Yuri , Susaki Etsuo A.
Published: May 2023

Despite the easier use of multiple tissue clearing techniques in recent years, poor access to adequate light-sheet fluorescence microscopy remains a major obstacle for biomedical end users. Here, we propose a solution by developing descSPIM (desktop-equipped SPIM forcleared specimens) as a low-cost ($20,000–50,000), low-expertise (one-day installation by a non-expert), yet practically substantial do-it-yourself light-sheet microscopy. Academically open-sourced (https://github.com/dbsb-juntendo/descSPIM), descSPIM allows routine three-dimensional imaging of cleared samples in minutes.
Neural interactions in the human frontal cortex dissociate reward and punishment learning
Authors: Combrisson Etienne , Basanisi Ruggero , Gueguen Maelle , Rheims Sylvain , Kahane Philippe , Bastin Julien , Brovelli Andrea
Published: May 2023

How human prefrontal and insular regions interact while maximizing rewards and minimizing punishments is unknown. Capitalizing on human intracranial recordings, we demonstrate that the functional specificity toward reward or punishment learning is better disentangled by interactions compared to local representations. Prefrontal and insular cortices display non-selective neural populations to rewards and punishments. Non-selective responses, however, give rise to context-specific interareal interactions. We identify a reward subsystem with redundant interactions between the orbitofrontal and ventromedial prefrontal cortices, with a driving role of the latter. In addition, we find a punishment subsystem with redundant interactions between the insular and dorsolateral cortices, with a driving role of the insula. Finally, switching between reward and punishment learning is mediated by synergistic interactions between the two subsystems. These results provide a unifying explanation of distributed cortical representations and interactions supporting reward and punishment learning.
Chronic alcohol consumption dysregulates innate immune response to SARS-CoV-2 in the lung
Authors: Lewis Sloan A. , Cinco Isaac R. , Doratt Brianna M. , Blanton Madison B. , Hoagland Cherise , Davies Michael , Grant Kathleen A. , Messaoudi Ilhem
Published: May 2023

Alcohol consumption is widespread with over half of the individuals over 18 years of age in the U.S. reporting alcohol use in the last 30 days. Moreover, 9 million Americans engaged in binge or chronic heavy drinking (CHD) in 2019. CHD negatively impacts pathogen clearance and tissue repair, including in the respiratory tract, thereby increasing susceptibility to infection. Although, it has been hypothesized that chronic alcohol consumption negatively impacts COVID-19 outcomes; the interplay between chronic alcohol use and SARS-CoV-2 infection outcomes has yet to be elucidated. Therefore, in this study we investigated the impact of chronic alcohol consumption on SARS-CoV-2 anti-viral responses in bronchoalveolar lavage cell samples from humans with alcohol use disorder and rhesus macaques that engaged in chronic drinking. Our data show that in both humans and macaques, the induction of key antiviral cytokines and growth factors was decreased with chronic ethanol consumption. Moreover, in macaques fewer differentially expressed genes mapped to Gene Ontology terms associated with antiviral immunity following 6 month of ethanol consumption while TLR signaling pathways were upregulated. These data are indicative of aberrant inflammation and reduced antiviral responses in the lung with chronic alcohol drinking.
Syntheses of Pyrimidine-Modified Seleno-DNAs as Stable Antisense Molecules
Authors: Fang Ziyuan , Dantsu Yuliya , Chen Cen , Zhang Wen , Huang Zhen
Published: May 2023

Chemically modified antisense oligonucleotides (ASO) currently in pre-clinical and clinical experiments mainly focus on the 2′-position derivatizations to enhance stability and targeting affinity. Considering the possible incompatibility of 2′-modifications with RNase H stimulation and activity, we have hypothesized that the atom specific modifications on nucleobases can retain the complex structure and RNase H activity, while enhancing ASO’s binding affinity, specificity, and stability against nucleases. Herein we report a novel strategy to explore our hypothesis by synthesizing the deoxynucleoside phosphoramidite building block with the seleno-modification at 5-position of thymidine, as well as its Se-oligonucleotides. Via X-ray crystal structural study, we found that the Se-modification was located in the major groove of nucleic acid duplex and didn’t cause the thermal and structural perturbations. Surprisingly, our nucleobase-modified Se-DNAs were exceptionally resistant to nuclease digestion, while compatible with RNase H activity. This affords a novel avenue for potential antisense modification in the form of Se-antisense oli-gonucleotides (Se-ASO).
How environmental drivers of spatial synchrony interact
Authors: Reuman Daniel C. , Castorani Max C.N. , Cavanaugh Kyle C. , Sheppard Lawrence W. , Walter Jonathan A. , Bell Tom W.
Published: May 2023

Spatial synchrony, the tendency for populations across space to show correlated fluctuations, is a fundamental feature of population dynamics, linked to central topics of ecology such as population cycling, extinction risk, and ecosystem stability. A common mechanism of spatial synchrony is the Moran effect, whereby spatially synchronized environmental signals drive population dynamics and hence induce population synchrony. After reviewing recent progress in understanding Moran effects, we here elaborate a general theory of how Moran effects of different environmental drivers acting on the same populations can interact, either synergistically or destructively, to produce either substantially more or markedly less population synchrony than would otherwise occur. We provide intuition for how this newly recognized mechanism works through theoretical case studies and application of our theory to California populations of giant kelp. We argue that Moran interactions should be common. Our theory and analysis explain an important new aspect of a fundamental feature of spatiotemporal population dynamics.
Parallel Evolution of Linezolid ResistantStaphylococcus aureusin Patients with Cystic Fibrosis
Authors: Pitcher Nicholas J. , Feder Andries , Bolden Nicholas , Zirbes Christian F. , Pamatmat Anthony J. , Boyken Linda , Hill Jared J. , Thurman Andrew L. , Reeb Valérie C. , Porterfield Harry S. , Moustafa Ahmed M. , Planet Paul J. , Fischer Anthony J.
Published: May 2023

Background

Linezolid is an antibiotic used to treat seriousStaphylococcus aureusinfections. Resistance to linezolid is considered rare but could emerge with repeated dosing. We recently reported widespread prescription of linezolid for a cohort of patients with cystic fibrosis (CF).

Objectives

The goals of this study were to determine the incidence of linezolid resistance in CF and identify molecular mechanisms for linezolid resistance.

Methods

We identified patients withS. aureusresistant to linezolid (MIC > 4) at the University of Iowa CF Center between 2008 and 2018. We obtained isolates from these patients and retested susceptibility to linezolid using broth microdilution. We used whole genome sequencing to perform phylogenetic analysis of linezolid resistant isolates and examine sequences for mutations or accessory genes that confer linezolid resistance.

Main Results

Between 2008 and 2018, 111 patients received linezolid and 4 of these patients cultured linezolid resistantS. aureus. We sequenced 11 resistant and 21 susceptible isolates from these 4 subjects. Phylogenetic analysis indicated that linezolid resistance developed in ST5 or ST105 backgrounds. Three individuals had linezolid resistantS. aureuswith a G2576T mutation in 23S rRNA. One of these subjects additionally had amutS-mutL-hypermutatingS. aureusthat produced 5 resistant isolates with multiple ribosomal subunit mutations. In one subject, the genetic basis for linezolid resistance was unclear.

Conclusions

Linezolid resistance evolved in 4 of 111 patients in this study. Linezolid resistance occurred by multiple genetic mechanisms. All resistant strains developed in ST5 or ST105 MRSA backgrounds.

Key Point

Linezolid resistance arises through multiple genetic mechanisms and could be facilitated by mutator phenotypes. Linezolid resistance was transient, possibly due to growth disadvantage.
Genetic manipulation of candidate phyla radiation bacteria provides functional insights into microbial dark matter
Authors: Wang Yaxi , Gallagher Larry A. , Andrade Pia A. , Liu Andi , Humphreys Ian R. , Turkarslan Serdar , Cutler Kevin J. , Arrieta-Ortiz Mario L. , Li Yaqiao , Radey Matthew C. , McLean Jeffrey S. , Cong Qian , Baker David , Baliga Nitin S. , Peterson S. Brook , Mougous Joseph D.
Published: May 2023

The study of bacteria has yielded fundamental insights into cellular biology and physiology, biotechnological advances and many therapeutics. Yet due to a lack of suitable tools, the significant portion of bacterial diversity held within the candidate phyla radiation (CPR) remains inaccessible to such pursuits. Here we show that CPR bacteria belonging to the phylum Saccharibacteria exhibit natural competence. We exploit this property to develop methods for their genetic manipulation, including the insertion of heterologous sequences and the construction of targeted gene deletions. Imaging of fluorescent protein-labeled Saccharibacteria provides high spatiotemporal resolution of phenomena accompanying epibiotic growth and a transposon insertion sequencing genome-wide screen reveals the contribution of enigmatic Saccharibacterial genes to growth on their Actinobacteria hosts. Finally, we leverage metagenomic data to provide cutting-edge protein structure-based bioinformatic resources that support the strainSouthlakia epibionticumand its corresponding host,Actinomyces israelii, as a model system for unlocking the molecular underpinnings of the epibiotic lifestyle.
Synergistic Binding of the Halide and Cationic Prime Substrate of the l-Lysine 4-Chlorinase, BesD, in Both Ferrous and Ferryl States
Authors: Slater Jeffrey W. , Neugebauer Monica E. , McBride Molly J. , Sil Debangsu , Lin Chi-Yun , Katch Bryce J. , Boal Amie K. , Chang Michelle C.Y. , Silakov Alexey , Krebs Carsten , Bollinger J. Martin
Published: May 2023

An aliphatic halogenase requires four substrates: 2-oxoglutarate (2OG), halide (Cl−or Br−), the halogenation target (“prime substrate”), and dioxygen. In well-studied cases, the three non-gaseous substrates must bind to activate the enzyme’s Fe(II) cofactor for efficient capture of O2. Halide, 2OG, and (lastly) O2all coordinate directly to the cofactor to initiate its conversion to acis-halo-oxo-iron(IV) (haloferryl) complex, which abstracts hydrogen (H•) from the non-coordinating prime substrate to enable radicaloid carbon-halogen coupling. We dissected the kinetic pathway and thermodynamic linkage in binding of the first three substrates of thel-lysine 4-chlorinase, BesD. After 2OG adds, subsequent coordination of the halide to the cofactor and binding of cationicl-Lys near the cofactor are associated with strong heterotropic cooperativity. Progression to the haloferryl intermediate upon addition of O2does not trap the substrates in the active site and, in fact, markedly diminishes cooperativity between halide andl-Lys. The surprising lability of the BesD•[Fe(IV)=O]•Cl•succinate•l-Lys complex engenders pathways for decay of the haloferryl intermediate that do not result inl-Lys chlorination, especially at low chloride concentrations; one identified pathway involves oxidation of glycerol. The mechanistic data imply that (i) BesD may have evolved from a hydroxylase ancestor either relatively recently or under weak selective pressure for efficient chlorination and (ii) that acquisition of its activity may have involved the emergence of linkage betweenl-Lys binding and chloride coordination following loss of the anionic protein-carboxylate iron ligand present in extant hydroxylases.
Characterizing spatiotemporal population receptive fields in human visual cortex with fMRI
Authors: Kim Insub , Kupers Eline R. , Lerma-Usabiaga Garikoitz , Grill-Spector Kalanit
Published: May 2023

The use of fMRI and computational modeling has advanced understanding of spatial characteristics of population receptive fields (pRFs) in human visual cortex. However, we know relatively little about the spatiotemporal characteristics of pRFs because neurons’ temporal properties are one to two orders of magnitude faster than fMRI BOLD responses. Here, we developed an image-computable framework to estimate spatiotemporal pRFs from fMRI data. First, we developed a simulation software that predicts fMRI responses to a time varying visual input given a spatiotemporal pRF model and solves the model parameters. The simulator revealed that ground-truth spatiotemporal parameters can be accurately recovered at the millisecond resolution from synthesized fMRI responses. Then, using fMRI and a novel stimulus paradigm, we mapped spatiotemporal pRFs in individual voxels across human visual cortex in 10 participants. We find that a compressive spatiotemporal (CST) pRF model better explains fMRI responses than a conventional spatial pRF model across visual areas spanning the dorsal, lateral, and ventral streams. Further, we find three organizational principles of spatiotemporal pRFs: (i) from early to later areas within a visual stream, spatial and temporal integration windows of pRFs progressively increase in size and show greater compressive nonlinearities, (ii) later visual areas show diverging spatial and temporal integration windows across streams, and (iii) within early visual areas (V1-V3), both spatial and temporal integration windows systematically increase with eccentricity. Together, this computational framework and empirical results open exciting new possibilities for modeling and measuring fine-grained spatiotemporal dynamics of neural responses in the human brain using fMRI.

Significance Statement

We developed a computational framework for estimating spatiotemporal receptive fields of neural populations using fMRI. This framework pushes the boundary of fMRI measurements, enabling quantitative evaluation of neural spatial and temporal processing windows at the resolution of visual degrees and milliseconds, which was thought to be unattainable with fMRI. We not only replicate well-established visual field and pRF size maps, but also estimates of temporal summation windows from electrophysiology. Notably, we find that spatial and temporal windows as well as compressive nonlinearities progressively increase from early to later visual areas in multiple visual processing streams. Together, this framework opens exciting new possibilities for modeling and measuring fine-grained spatiotemporal dynamics of neural responses in the human brain using fMRI.
Colon resident CD8+ T cells from people with HIV on antiretroviral therapy exhibit mitochondrial dysfunction and impaired responses
Authors: Adhikari Upasana Das , Shah Palak V. , Froehle Leah M. , Linder Alice H. , Flagg Meaghan , Rawlings Crystal , Junca Muntsa R. , Folarin Lilian , Karim Farina , Li Jonathan , Kloverpris Henrik , Kwon Douglas S.
Published: May 2023

CD8+ tissue-resident memory T cells (CD8+ TRM) play an important role in mediating immune responses against HIV in the gastrointestinal (GI) mucosa. Antiretroviral therapy (ART) successfully supresses HIV replication in the blood, but fails to restore GI homeostasis, particularly within gut associated lymphoid tissue (GALT). The importance of cellular metabolism in shaping CD8+ TRM antiviral function has emerged as a crucial aspect of general immunoregulation. To gain better insight into the immunoregulation of CD8+ TRM during HIV, we characterized the function of blood and colon CD8+ T cells in people with HIV (PWH) on ART and HIV-uninfected individuals. We show that a higher proportion of activated CD8+ TRM persisted in the colon of PWH on ART, and these cells exhibited weaker immune response and compromised mitochondrial function compared to their peripheral counterparts. We also observed decreased mitochondrial function in CD8+ T cell in the colon compared to peripheral blood in PWH on ART. The study indicates that mitochondrial bioenergetic properties may be an indicator of colonic CD8+ TRM dysfunction in PWH on ART and highlights the importance of understanding cellular metabolism in shaping CD8+ TRM function to develop targeted immunotherapies for PWH.
A Systematic Review of Peruvian Contributions to Scientific Publications on Experimental Research Against COVID-19
Authors: Coronel-Monje Katiusca , Candia-Puma Mayron Antonio , Vilca-Alosilla Juan Jeferson , Goyzueta-Mamani Luis Daniel , Aguilar Bravo Herbert Mishaelf , Sánchez Zegarra Jorge Augusto , Barazorda-Ccahuana Haruna Luz , Ferraz Coelho Eduardo Antonio , Chávez-Fumagalli Miguel Angel
Published: May 2023

Abstract

One of the countries most adversely affected by the COVID-19 outbreak was Peru. Worldwide scientific knowledge creation has significantly grown because of this pandemic. This systematic study aims to examine several facets of Peru’s experimental scientific production concerning COVID-19. Between December 2019 and June 2022, searches were made in the PubMed database for experimental scientific articles created in Peruvian institutions. The systematic review resulted in nine studies that meet the requirements. Data were extracted and analyzed on the type of biomedical research, the study’s applicability, the thematic area and specific thematic, journal impact factor and quartile, funding, grants, and institution of affiliation for the first and correspondence authors. The results revealed that Peru needs to promote policies to boost research funding and the number of researchers to produce information that will be useful for managing diseases in the future. Yet, despite the funding provided by national organizations like National Council for Science, Technology, and Technological Innovation (CONCYTEC), there were few publications and little international collaboration. The studies that have been published focus mostly on applied research in the areas of diagnostics, sanitary products, and treatment and transmission, and they have great visibility because they are indexed in Q1 journals. This thorough study revealed Peru’s inadequate reaction to COVID-19 regarding experimental scientific research. Peruvian authorities should think about supporting the required policies to boost the number of researchers and financial aid to produce information that may be utilized to manage potential new diseases in the future.
A brainstem to hypothalamic arcuate nucleus GABAergic circuit drives feeding
Authors: Martinez de Morentin Pablo B , Gonzalez J Antonio , Dowsett Georgina K.C. , Martynova Yuliia , Yeo Giles S.H. , Sylantyev Sergiy , Heisler Lora K
Published: May 2023

The obesity epidemic is principally driven by the consumption of more calories than the body requires. It is therefore essential that the mechanisms underpinning feeding behavior are defined. The brainstem nucleus of the solitary tract (NTS) receives direct information from the digestive system and projects to second order regions in the brain. Though γ-Aminobutyric acid is widely expressed in the NTS (GABANTS), its function has not been defined. Characterization of GABA cells using single nucleus RNA sequencing (Nuc-Seq) identified at least 19 clusters. Here we provide insight into the function of GABANTScells, revealing that selective activation of GABANTSneurons significantly controls food intake and body weight. Optogenetic interrogation of GABANTScircuitry identified GABANTS→arcuate nucleus of the hypothalamus (ARC) projections as appetite suppressive without creating aversion. Electrophysiological analysis revealed GABANTS→ARC stimulation inhibits hunger promoting agouti-related protein/neuropeptide Y (AgRP/NPY) neurons via GABA release. Adopting an intersectional genetics strategy, we clarify that the GABANTS→ARC circuit induces satiety. These data identify GABANTSas a new modulator of feeding behavior, body weight and controller of orexigenic AgRP/NPY activity, thereby providing insight into the neural underpinnings of obesity.

Highlights

Nucleus of the solitary tract (NTS) GABA neurons are responsive to nutritional status.

Chemogenetic GABANTSneuron activation reduces food intake and body weight.

GABANTSprojections to the hypothalamic arcuate nucleus (ARC) promote satiety.

Optogenetic GABANTS→ARC stimulation inhibits orexigenic AgRP/NPY neurons.

In Brief

Martinez de Morentin et al. identify GABAergic neurons in the nucleus of the solitary tract as a new player in the circuit governing feeding behavior and body weight.
Discovering knowledge map and evolutionary path of HRM and ER: using the STM combined with Word2vec
Authors: Yu Dejian , Xiang Bo
Published: May 2023

Purpose

The purpose of this study is to comprehensively review the human resource management (HRM) and employment relations (ERs) field and explore the knowledge map, knowledge evolution trends and paths and paradigm shifts within this field.

Design/methodology/approach

The Structural Topic Model in combination with Word2vec is proposed and applied in this work. First, this paper detects and interprets the research topics by reviewing 23,786 papers from 29 important journals in this field from 1990 to 2021. Then, this research explores popularity trends by aggregating topic proportions from a temporal perspective. Finally, this work explores the research topic evolution from the semantic perspective.

Findings

This paper obtains the following findings: (1) Sixteen research topics are identified, which provide the basic research overview of the whole field. (2) The changes in topic popularity over time map the tendency for employee benefits to be valued. (3) The evolutionary trajectories of temporal local topics are provided, which reflect the mechanisms of the paradigm and ideological migration and fusion.

Originality/value

This work adopts state-of-the-art textual as well as semantic mining techniques to establish a comprehensive knowledge map for HRM and ER research. Furthermore, these results uniquely demonstrate the pluralistic ideological orientation at the social level is gradually integrated into more micro levels, such as enterprises and individuals. These are the contents that were mentioned from previous studies by scholars, but not meticulously verified and interpreted.
Measuring implicit motivations: a qualitative approach
Authors: Nazarpour Mohammad Mahdi , Askari Azadeh
Published: May 2023

Purpose

The present study aims to investigate the psychometric properties of the picture story exercise (PSE), a tool for measuring implicit motivations in Iran.

Design/methodology/approach

The research method is descriptive correlation and was conducted in two studies. In the first study 24 psychology master’s students were selected by convenience sampling method and tested them to check retest and inter-coder reliability. The second study investigated the correlation between self-reports and the PSE test on a sample of managers. Its statistical population comprised all the managers of a refinery company, 50 people were selected by convenience sampling method. To check the concurrent validity of the PSE test, the participants of the second study, completing the PSE, also completed the needs questionnaire of Steers and Porter (1979).

Findings

The findings showed that the PSE test in the Iranian sample had high retest reliability (0.62 on mean) and inter-coder reliability (0.87 on mean), and, following previous research, it does not show a significant relationship with self-reported motives.

Practical implications

PSE can be used in future research as a tool that has demonstrated its reliability and validity in the Iranian sample.

Originality/value

Measurement of implicit motives is a practical factor for predicting people’s behavior, the necessity of using tools that can accurately evaluate implicit motives is strongly felt. Taking into account the fact that so far, in Iranian samples, implicit motivations have not been measured, therefore, the current research is trying to answer this question, whether one of the most important and prominent tools that were made for this purpose and used in various studies can also be used in Iranian samples.