bluuebunny/crossref_metadata_2025 huggingface dataset:
Clinical Challenges in Pediatric Ventilation Liberation: A Meta-Narrative Review
Authors: van Dijk Jefta , Blokpoel Robert G. T. , Abu-Sultaneh Samer , Newth Christopher J. L. , Khemani Robinder G. , Kneyber Martin C. J.
Published: July 2022

OBJECTIVES:

To map the evidence for ventilation liberation practices in pediatric respiratory failure using the Realist And MEta-narrative Evidence Syntheses: Evolving Standards publication standards.

DATA SOURCES:

CINAHL, MEDLINE, COCHRANE, and EMBASE. Trial registers included the following: ClinicalTrials.gov, European Union clinical trials register, International Standardized Randomized Controlled Trial Number register.

STUDY SELECTION:

Abstracts were screened followed by review of full text. Articles published in English language incorporating a heterogeneous population of both infants and older children were assessed.

DATA EXTRACTION:

None.

DATA SYNTHESIS:

Weaning can be considered as the process by which positive pressure is decreased and the patient becomes increasingly responsible for generating the energy necessary for effective gas exchange. With the growing use of noninvasive respiratory support, extubation can lie in the middle of the weaning process if some additional positive pressure is used after extubation, while for some extubation may constitute the end of weaning. Testing for extubation readiness is a key component of the weaning process as it allows the critical care practitioner to assess the capability and endurance of the patient’s respiratory system to resume unassisted ventilation. Spontaneous breathing trials (SBTs) are often seen as extubation readiness testing (ERT), but the SBT is used to determine if the patient can maintain adequate spontaneous ventilation with minimal ventilatory support, whereas ERT implies the patient is ready for extubation.

CONCLUSIONS:

Current literature suggests using a structured approach that includes a daily assessment of patient’s readiness to extubate may reduce total ventilation time. Increasing evidence indicates that such daily assessments needs to include SBTs without added pressure support. Measures of elevated load as well as measures of impaired respiratory muscle capacity are independently associated with extubation failure in children, indicating that these should also be assessed as part of ERT.
Radiomic Analysis of Pulmonary Nodules for Distinguishing Malignancy From Benignancy: The Value of Using Iodine Maps From Dual-Energy Computed Tomography
Authors: Zhong Yan , Xu Hai , Zhang Wei , Li Hai , Yu Tong-Fu , Yuan Mei
Published: July 2022

Objective

The aim of the study is to investigate the diagnostic accuracy of radiomics on iodine maps from dual-energy computed tomography (DECT) in distinguishing lung cancer from benign pulmonary nodules.

Methods

This retrospective study was approved by the institutional review board, and written informed consent was waived. A total of 109 patients with 55 malignant nodules and 62 benign nodules underwent contrast-enhanced DECT. Eight iodine uptake parameters on iodine maps generated by DECT were calculated and established a predictive model. Eighty-seven radiomics features of entire tumor were extracted from iodine maps and established a radiomics model. The iodine uptake model and radiomics model were independently built based on the highly reproducible features using the least absolute shrinkage and selection operator method. The diagnostic accuracy of 2 models were assessed using receiver operating curve analysis. For external validation, 47 patients (25 benign and 22 malignant) from another hospital were assigned to testing data set.

Results

All iodine uptake features showed significant association with malignancy (P < 0.01) and 2 selected features (mean value of virtual noncontrast images and mean value of vital part on contrast-enhanced image) constituted the iodine model. The radiomics model comprised 2 features (original shape sphericity and original glszm small area high gray level emphasis), which showed good discrimination both in the training cohort (area under the curve, 0.957) and validation cohort (area under the curve, 0.800). Radiomics model showed superior performance than iodine uptake model (accuracy, 89.7% vs 80.6%).

Conclusions

Radiomics model extracted from iodine maps provided a robust diagnostic tool for discriminating pulmonary malignant nodules and had high potential in clinical application.
Role of intergenic interactions among folate cycle genes in the development of fetal growth retardation
Authors: Efremova Olesya , Ponomarenko Irina , Churnosov Mikhail
Published: July 2022

Objective:

Metabolic disturbances in the folate cycle in mothers can lead to fetal growth retardation (FGR). This study was to analyze the role of intergenic interactions among maternal folate cycle genes in the development of FGR.

Methods:

This case-control study recruited 365 women in the third trimester of pregnancy, including 122 FGR patients and 243 controls. The women were genotyped for 5 polymorphisms of the 4 folate cycle genes: MTR (rs1805087), MTRR (rs1801394), serine hydroxymethyl transferase (SHMT1; rs1979277), and TYMS (rs699517 and rs2790). The SNP × SNP interactions in the two-, three-, and four-locus models were analyzed using the multifactor dimensionality reduction method and a modification of it (the model-based multifactor dimensionality reduction method).

Results:

Four loci of maternal folate cycle genes (rs1805087 MTR, rs2790 TYMS, rs1801394 MTRR, and rs1979277 SHMT1) were associated with FGR in 3 significant models of single nucleotide polymorphism (SNP) × SNP interactions (two-, three-, and four-locus models) (P <0.05). The highest contribution to FGR was made by polymorphic loci rs1979277 SHMT1 (1.70% of entropy), rs1805087 MTR (0.96%), and interactions between rs1979277 SHMT1 × rs1805087 MTR (-1.11%) and rs1801394 MTRR × rs1979277 SHMT1 (−0.64%). The four-locus maternal genotype combination AG rs1801394 MTRR × AA rs1805087 MTR × CT rs1979277 SHMT1 × AG rs2790 TYMS was associated with an increased risk of FGR (β = 2.69, P = 0.012). FGR-associated SNPs were correlated with the expression of 16 genes (MTR, MTRR, SHMT1, ALKBH5, CTD-2303H24.2, ENOSF1, FAM106A, FOXO3B, LGALS9C, LLGL1, MIEF2, NOS2P2, RP11-806L2.6, SMCR8, TOP3A, and USP32P2) in various tissues and organs related to FGR pathophysiology.

Conclusion:

SNP × SNP interactions of maternal folate cycle genes (MTR, MTRR, SHMT1, and TYMS) are associated with the development of FGR.
A Homozygous Protein-Truncating Mutation in ACTL7A Causes Male Infertility Characterized by Fertilization Failure
Authors: Chen Yao , Chen Biao-Bang , Sang Qing , Wang Lei , Zhao Jun-Li , Sun Xiao-Xi
Published: July 2022

Objective:

This study aimed to screen for novel mutations in ACTL7A and expand the spectrum of known mutations responsible for recurrent fertilization failure.

Methods:

Whole-exome sequencing was performed on samples from couples who experienced recurrent assisted reproductive technology failure and visited the General Hospital of Ningxia Medical University. Western blotting and quantitative RT-PCR were used to investigate the effects of the mutation on HEK293T cells.

Results:

Samples from 12 couples with total fertilization failure or poor fertilization (fertilization rate < 20%) were subjected to whole-exome sequencing, and a novel homozygous protein-truncating mutation (c. 1101dupC, p. S368Qfs*5) in ACTL7A was identified in a patient with recurrent poor fertilization. The mutant resulted in a truncated protein as well as decreased protein expression level in HEK293T cells.

Conclusion:

Our findings expand the mutational and phenotypic spectrum of ACTL7A, thus providing a potential diagnostic marker for fertilization failure due to male factors.
The Repeatable Battery for the Assessment of Neuropsychological Status, While Useful for Measuring Cognitive Changes in Manifest Huntington Disease, May Show Limited Utility in Premanifest Disease
Authors: Mustafa Andrea I. , Corey-Bloom Jody , Beltran-Najera Ilex , Snell Chase , Castleton Jordan , Smith Haileigh , Gilbert Paul E.
Published: July 2022

Background:

The Repeatable Battery for the Assessment of Neuropsychological Status (RBANS) is a brief, standardized neuropsychological test that assesses several areas of cognitive function. Recent studies, although sparse, have examined the use of the RBANS to detect cognitive deficits in individuals with manifest Huntington disease (HD); however, no studies have investigated its utility to detect cognitive deficits in individuals with premanifest HD (PreHD), where cognitive symptoms are thought to be more subtle.

Objective:

To assess cognitive deficits in individuals with HD, particularly in individuals with PreHD, using an easily administered, brief but comprehensive, neuropsychological test.

Method:

We administered the RBANS to 31 individuals with HD, 29 individuals with PreHD, and 22 healthy controls (HC) at an academic HD clinical research center and collected RBANS Total, Index, and subtest scores for group comparisons.

Results:

The HD group had significantly lower RBANS Total, Index, and subtest scores than the HC. The PreHD group had significantly lower RBANS Total scores and Coding subtest scores than the HC, but no other significant group differences were identified.

Conclusion:

Our results substantiate previous findings of significant impairment on the RBANS in individuals with HD. In addition, we are the first to demonstrate that, although the RBANS can identify deficits in psychomotor speed and information processing in individuals with PreHD, it does not appear to have the ability to detect impairment in any additional cognitive domains in individuals with PreHD.
Distinguishing Between Genuine and Feigned Dementia Using Event-related Potentials
Authors: Price August M. , Palumbo Rocco , Marin Anna , Uppal Prayerna , Suh Cheongmin , Budson Andrew E. , Turk Katherine W.
Published: July 2022

Background:

Individuals with probable Alzheimer disease (AD) may perform below cutoffs on traditional, memory-based performance validity tests. Previous studies have found success using event-related potentials (ERPs) to detect feigned neurocognitive impairment in younger populations.

Objective:

To evaluate the utility of an auditory oddball task in conjunction with the P3b peak amplitude to distinguish probable AD from simulated dementia.

Method:

Twenty individuals with probable AD and 20 older healthy controls (HC) underwent an ERP auditory oddball protocol and the Test of Memory Malingering (TOMM). The HC were asked to perform honestly for one condition and to simulate dementia for the other. The individuals with probable AD were asked to perform honestly. The P3b peak amplitude and button press accuracy were collected from each participant and were analyzed to determine their effectiveness in detecting performance validity.

Results:

The P3b peak amplitude remained stable regardless of behavioral condition in the HC group. When combined with the TOMM Trial 2 score, the P3b peak amplitude further improved the ability to correctly differentiate individuals with probable AD from HC simulating dementia with 100% sensitivity and 90% specificity.

Conclusion:

The P3b peak amplitude was found to be an effective physiologic measure of cognitive impairment in individuals with probable AD compared with HC simulating dementia. When combined with the TOMM Trial 2 score, the P3b peak amplitude served as a promising performance validity measure for differentiating individuals with probable AD from HC simulating dementia.
Pathways to primate hip function
Authors: Aguilar Lucrecia K. , Collins Clint E. , Ward Carol V. , Hammond Ashley S.
Published: July 2022

Understanding how diverse locomotor repertoires evolved in anthropoid primates is key to reconstructing the clade's evolution. Locomotor behaviour is often inferred from proximal femur morphology, yet the relationship of femoral variation to locomotor diversity is poorly understood. Extant acrobatic primates have greater ranges of hip joint mobility—particularly abduction—than those using more stereotyped locomotion, but how bony morphologies of the femur and pelvis interact to produce different locomotor abilities is unknown. We conducted hypothesis-driven path analyses via regularized structural equation modelling (SEM) to determine which morphological traits are the strongest predictors of hip abduction in anthropoid primates. Seven femoral morphological traits and two hip abduction measures were obtained from 25 primate species, split into broad locomotor and taxonomic groups. Through variable selection and fit testing techniques, insignificant predictors were removed to create the most parsimonious final models. Some morphological predictors, such as femur shaft length and neck-shaft angle, were important across models. Different trait combinations best predicted hip abduction by locomotor or taxonomic group, demonstrating group-specific linkages among morphology, mobility and behaviour. Our study illustrates the strength of SEM for identifying biologically important relationships between morphology and performance, which will have future applications for palaeobiological and biomechanical studies.
Topological bio-scaling analysis as a universal measure of protein folding
Authors: Shityakov Sergey , Skorb Ekaterina V. , Nosonovsky Michael
Published: July 2022

Scaling relationships for polymeric molecules establish power law dependencies between the number of molecular segments and linear dimensions, such as the radius of gyration. They also establish spatial topological properties of the chains, such as their dimensionality. In the spatial domain, power exponentsα= 1 (linear stretched molecule),α= 0.5 (the ideal chain) andα= 0.333 (compact globule) are significant. During folding, the molecule undergoes the transition from the one-dimensional linear to the three-dimensional globular state within a very short time. However, intermediate states with fractional dimensions can be stabilized by modifying the solubility (e.g. by changing the solution temperature). Topological properties, such as dimension, correlate with the interaction energy, and thus by tuning the solubility one can control molecular interaction. We investigate these correlations using the example of a well-studied short model of Trp-cage protein. The radius of gyration is used to estimate the fractal dimension of the chain at different stages of folding. It is expected that the same principle is applicable to much larger molecules and that topological (dimensional) characteristics can provide insights into molecular folding and interactions.
Endogenous modulation of pain relief: evidence for dopaminergic but not opioidergic involvement
Authors: Desch Simon , Schweinhardt Petra , Seymour Ben , Flor Herta , Becker Susanne
Published: July 2022

Relief of ongoing pain is a potent motivator of behavior, directing actions to escape from or reduce potentially harmful stimuli. Whereas endogenous modulation of pain events is well characterized, relatively little is known about the modulation of pain relief and its corresponding neurochemical basis. Here we studied pain modulation during a probabilistic relief-seeking task (a ‘wheel of fortune’ gambling task), in which people actively or passively received reduction of a tonic thermal pain stimulus. We found that relief perception was enhanced by active decisions and unpredictability, and greater in high novelty-seeking trait individuals, consistent with a model in which relief is tuned by its informational content. We then probed the roles of dopaminergic and opioidergic signaling, both of which are implicated in relief processing, by embedding the task in a double-blinded cross-over design with administration of the dopamine precursor levodopa and the opioid receptor antagonist naltrexone. We found that levodopa, but not naltrexone, enhanced each of these information-specific aspects of relief modulation. These results show that dopaminergic signaling has a key role in modulating the perception of pain relief to optimize motivation and behavior.
Spatiotemporal evolution of the ccRCC microenvironment links intra-tumoral heterogeneity to immune escape
Authors: Golkaram Mahdi , Kuo Fengshen , Gupta Sounak , Carlo Maria I. , Salmans Michael L. , Vijayaraghavan Raakhee , Tang Cerise , Makarov Vlad , Rappold Phillip , Blum Kyle A. , Zhao Chen , Mehio Rami , Zhang Shile , Godsey Jim , Pawlowski Traci , DiNatale Renzo G. , Morris Luc GT , Durack Jeremy , Russo Paul , Kotecha Ritesh R. , Coleman Jonathan , Chen Ying-Bei , Reuter Victor E , Motzer Robert J , Voss Martin H. , Liu Li , Reznik Ed , Chan Timothy A. , Ari Hakimi A.
Published: July 2022

Background

Intratumoral heterogeneity (ITH) is a hallmark of clear cell renal cell carcinoma (ccRCC) that reflects the trajectory of evolution and influences clinical prognosis. Here we seek to elucidate how ITH and tumor evolution during immune checkpoint inhibitor (ICI) treatment can lead to therapy resistance.

Methods

Here, we spatiotemporally profiled the genomic and immunophenotypic characteristics of 29 ccRCC patients, including pre- and post-therapy samples from 17 ICI treated patients. Deep multi-regional whole exome and transcriptome sequencing were performed on 29 patients at different time points before and after ICI therapy. T cell repertoire was also monitored from tissue and peripheral blood collected from a subset of patients to study T cell clonal expansion during ICI therapy.

Results

Angiogenesis, lymphocytic infiltration, and myeloid infiltration varied significantly across regions of the same patient, potentially confounding their utility as biomarkers of ICI response. Elevated ITH associated with a constellation of both genomic features (HLA LOH, CDKN2A/B loss) and microenvironmental features, including elevated myeloid expression, reduced peripheral T cell receptor (TCR) diversity, and putative neoantigen depletion. Hypothesizing that ITH may itself play a role in shaping ICI response, we derived a transcriptomic signature associated with neoantigen depletion that strongly associated with response to ICI and targeted therapy treatment in several independent clinical trial cohorts.

Conclusions

These results argue that genetic and immune heterogeneity jointly co-evolve and influence response to ICI in ccRCC.

Trial registration

We completed a single-arm pilot study at Memorial Sloan Kettering Cancer Center (MSKCC; ClinicalTrials.gov identifier NCT02595918) to examine the safety and feasibility of neoadjuvant nivolumab in patients with localized RCC.
Human Microbiome Mixture Analysis using Weighted Quantile Sum Regression
Authors: Eggers Shoshannah , Bixby Moira , Renzetti Stefano , Curtin Paul , Gennings Chris
Published: July 2022

Studies of the health effects of the microbiome often measure overall associations by using diversity metrics, and individual taxa associations in separate analyses, but do not consider the correlated relationships between taxa in the microbiome. In this study, we applied random subset weighted quantile sum regression with repeated holdouts (WQSRSRH), a mixture method successfully applied to ‘omic data to account for relationships between many predictors, to processed amplicon sequencing data from the Human Microbiome Project. We simulated a binary variable associated with 20 operational taxonomic units (OTUs). WQSRSRH was used to test for the association between the microbiome and the simulated variable, adjusted for sex, and sensitivity and specificity were calculated. The WQSRSRH method was also compared to other standard methods for microbiome analysis. The method was further illustrated using real data from the Growth and Obesity Cohort in Chile to assess the association between the gut microbiome and body mass index. In the analysis with simulated data, WQSRSRH predicted the correct directionality of association between the microbiome and the simulated variable, with an average sensitivity and specificity of 75% and 70%, respectively, in identifying the 20 associated OTUs. WQSRSRH performed better than all other comparison methods. In the illustration analysis of the gut microbiome and obesity, the WQSRSRH analysis identified an inverse association between body mass index and the gut microbe mixture, identifying Bacteroides, Clostridium, and Ruminococcus, among others, as important genera in the negative association. The application of WQSRSRH to the microbiome allows for analysis of the mixture effect of all the taxa in the microbiome, while simultaneously identifying the most important to the mixture, and allowing for covariate adjustment. It outperformed other methods when using simulated data, and in analysis with real data found results consistent with other study findings.
A comprehensive analysis of gut and skin microbiota in canine atopic dermatitis in Shiba Inu dogs
Authors: Thomsen Mirja , Künstner Axel , Wohlers Inken , Olbrich Michael , Lenfers Tim , Osumi Takafumi , Shimazaki Yotaro , Nishifuji Koji , Ibrahim Saleh M , Watson Adrian , Busch Hauke , Hirose Misa
Published: July 2022

Background

Like its human counterpart, canine atopic dermatitis (cAD) is a chronic relapsing condition; thus, most cAD-affected dogs will require lifelong treatment to maintain an acceptable quality of life. A potential intervention is modulation of the composition of gut microbiota, and in fact, probiotic treatment has been proposed and tried in human atopic dermatitis (AD) patients. Since dogs are currently receiving intensive medical care, this will be the same option for dogs, while evidence of gut dysbiosis in cAD is still missing, although skin microbial profiling in cAD has been conducted in several studies. Therefore, we conducted a comprehensive analysis of both gut and skin microbiota in cAD in one specific cAD-predisposed breed, Shiba Inu. Additionally, we evaluated the impact of commonly used medical management on cAD (Janus kinase; JAK inhibitor, oclacitinib) on the gut and skin microbiota. Furthermore, we genotyped the Shiba Inu dogs according to the mitochondrial DNA haplogroup and assessed its association with the composition of the gut microbiota.

Results

Staphylococcus was the most predominant bacterial genus observed in the skin; Escherichia/Shigella and Clostridium sensu stricto were highly abundant in the gut of cAD-affected dogs. In the gut microbiota, Fusobacteria and Megamonas were highly abundant in healthy dogs but significantly reduced in cAD-affected dogs. The abundance of these bacterial taxa was positively correlated with the effect of the treatment and state of the disease. Oclacitinib treatment on cAD-affected dogs shifted the composition of microbiota towards that in healthy dogs, and the latter brought it much closer to healthy microbiota, particularly in the gut. Additionally, even within the same dog breed, the mtDNA haplogroup varied, and there was an association between the mtDNA haplogroup and gut microbial composition.

Conclusions

Dysbiosis of both the skin and the gut was observed in cAD in Shiba Inu dogs. Our findings provide a basis for the potential treatment of cAD by manipulating the gut microbiota as well as the skin microbiota.
FEZ1 participates in human embryonic brain development by modulating neuronal progenitor subpopulation specification and migration
Authors: Qu Yinghua , An Omer , Yang Henry , Toh Yi-Chin , En John Chua Jia
Published: July 2022

Abnormal neuronal networks arising from perturbations during early brain development contribute to neurodevelopmental disorders. Mutations and deletions of human Fasciculation and Elongation Protein Zeta 1 (FEZ1) are found in schizophrenia and Jacobsen syndrome patients. However, its roles in human brain development and manifestation of clinical pathological symptoms remain unknown. Here, using human cerebral organoids (hCOs), we observed that FEZ1 expression is turned on early during brain development and is detectable in both neuroprogenitor subtypes and immature neurons. Deletion of FEZ1 disrupts expression of genes involved in neuronal and synaptic development. Using single-cell RNA sequencing, we further uncovered an abnormal expansion of homeodomain-only protein homeobox (HOPX)− outer radial glia (oRG) in FEZ1-null hCOs, occurring at the expense of HOPX+ oRG. HOPX− oRGs show higher cell mobility as compared to HOPX+ oRGs, which is accompanied by the ectopic localization of the neuroprogenitors to the outer layer of FEZ1-null hCOs. Moreover, abnormal encroachment of TBR2+ intermediate progenitors into CTIP2+ deep layer neurons indicated that cortical layer formation is disrupted in FEZ1-null hCOs. Collectively, our findings highlight the involvement of FEZ1 in early cortical brain development and how it contributes to neurodevelopmental disorders.
Holographic stimulation of opposing amygdala ensembles bidirectionally modulates valence-specific behavior
Authors: Piantadosi Sean C , Zhou Zhe Charles , Pizzano Carina , Pedersen Christian E , Nguyen Tammy K , Thai Sarah , Stuber Garret D , Bruchas Michael R
Published: July 2022

The basolateral amygdala (BLA) is an evolutionarily conserved brain region, well known for valence processing. Despite this central role, the relationship between activity of BLA neuronal ensembles in response to appetitive and aversive stimuli and the subsequent expression of valence-specific behavior has remained elusive. Here we leverage 2-photon calcium imaging combined with single cell holographic photostimulation through an endoscopic lens implanted in the deep brain to demonstrate a direct causal role for discrete ensembles of BLA neurons in the control of oppositely valenced behavior. We report that targeted photostimulation of individual groups of appetitive or aversive BLA neurons shifts behavioral responses toward those behaviors which recruited a specific consumption or avoidance ensemble. Here we identify that neuronal encoding of valence in the BLA is graded and relies on the relative proportion of individual BLA neurons recruited in a stable appetitive or aversive ensemble.
NOTCH3 active immunotherapy reduces NOTCH3 deposition in brain capillaries in a CADASIL mouse model
Authors: Oliveira Daniel V. , Coupland Kirsten G. , Jin Shaobo , Del Gaudio Francesca , Wang Sailan , Fox Rhys , Rutten Julie W. , Sandin Johan , Lundkvist Johan , Lesnik Oberstein Saskia A. J. , Lendahl Urban , Karlström Helena
Published: July 2022

Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) is the most common monogenic form of familial small vessel disease and no preventive or curative therapy is available. CADASIL is caused by mutations in the NOTCH3 gene, resulting in a mutated NOTCH3 receptor, with aggregation of the NOTCH3 extracellular domain (ECD) around vascular smooth muscle cells. In this study we have developed a novel active immunization therapy specifically targeting CADASIL-like aggregated NOTCH3 ECD. Immunizing CADASIL TgN3R182C150 mice with aggregates composed of CADASIL-R133C mutated and wild type EGF1-5 repeats for a total of four months resulted in a marked reduction (38-48%) in NOTCH3 deposition around brain capillaries, increased microglia activation and lowered serum levels of NOTCH3 ECD. Active immunization did not impact body weight, general behavior or the number and integrity of vascular smooth muscle cells in the retina, suggesting that the therapy is tolerable. This is the first therapeutic study reporting a successful reduction of CADASIL-like NOTCH3 accumulation in mice supporting further development towards clinical application for the benefit of CADASIL patients.
The olivary input to the cerebellum dissociates sensory events from movement plans
Authors: Pi Jay S. , Fakharian Mohammad Amin , Hage Paul , Sedaghat-Nejad Ehsan , Muller Salomon Z. , Shadmehr Reza
Published: July 2022

The inferior olive is thought to act as an instructor that mentors the Purkinje cells (P-cells) of the cerebellum. As a result, if during a behavior two groups of P-cells received different kinds of information from their olivary inputs, then each group might contribute to different aspects of that behavior. Here, we designed a saccade task in marmosets that dissociated sensory and motor events and then recorded the complex and simple spikes of hundreds of P-cells. We found that the olivary input to one group of P-cells robustly reported the direction of the random visual target, whereas the input to another group principally reported the spatial properties of the forthcoming movement. When a saccade encountered a sensory prediction error, but the subject chose not to make a corrective movement, the error was reported to the first group of P-cells, not the second group. In the first group the simple spikes were suppressed during fixation, then produced a burst before saccade onset that acted primarily as an agonist which accelerated the movement. In the second group the simple spikes were not suppressed during fixation and did not provide an agonist assistance. Rather, the simple spikes acted as an antagonist that decelerated the movement. Therefore, the olive differentiated the P-cells based on whether they would receive primarily sensory or motor information, and this dissociated their contributions to both control of movements and holding still.

Significance statement

The inferior olive provides more than just error information to the P-cells: it also informs them regarding the spatial properties of forthcoming movements. However, these two kinds of information are sent to two different groups of cells. The P-cells whose olivary input directionally report a visual event have a simple spike response that accelerates the saccade toward that same direction. The P-cells whose olivary input directionally predicts a forthcoming movement have a simple spike response that decelerates the saccade in that same direction.
Thermodynamic analysis of the GASrighttransmembrane motif supports energetic model of dimerization
Authors: Vázquez Gladys Díaz , Cui Qiang , Senes Alessandro
Published: July 2022

The GASrightmotif, best known as the fold of the glycophorin A transmembrane dimer, is one of the most common dimerization motifs in membrane proteins, characterized by its hallmark GxxxG-like sequence motifs (GxxxG, AxxxG, GxxxS, and similar). Structurally, GASrightdisplays a right-handed crossing angle and short inter-helical distance. Contact between the helical backbones favors the formation of networks of weak hydrogen bonds between Cα–H carbon donors and carbonyl acceptors on opposing helices (Cα–H∙∙∙O=C). To understand the factors that modulate the stability of GASright, we previously presented a computational and experimental structure-based analysis of 26 predicted dimers. We found that the contributions of van der Waals packing and Cα–H hydrogen bonding to stability, as inferred from the structural models, correlated well with relative dimerization propensities estimated experimentally with thein vivoassay TOXCAT. Here we test this model with a quantitative thermodynamic analysis. We used FRET to determine the free energy of dimerization of a representative subset of 7 of the 26 original TOXCAT dimers using FRET. To overcome the technical issue arising from limited sampling of the dimerization isotherm, we introduced a globally fitting strategy across a set of constructs comprising a wide range of stabilities. This strategy yielded precise thermodynamic data that show strikingly good agreement between the original propensities and ΔG° of association in detergent, suggesting that TOXCAT is a thermodynamically driven process. From the correlation between TOXCAT and thermodynamic stability, the predicted free energy for all the 26 GASrightdimers was calculated. These energies correlate with thein silicoΔE scores of dimerization that were computed on basis of their predicted structure. These findings corroborate our original model with quantitative thermodynamic evidence, strengthening the hypothesis that van der Waals and Cα–H hydrogen bond interactions are the key modulators of GASrightstability.

Secondary Abstract

We present a thermodynamic analysis of the dimerization of the GASrightmotif, a common dimerization motif in membrane proteins. Previously, we found that the stability of GASrightis modulated by van der Waals packing and weak hydrogen bonds between Cα–H carbon donors and carbonyl acceptors on opposing helices. The experimental dimerization propensities were obtained with anin vivoassay. Here we assess this model quantitatively by measuring the free energy of dimerization of a subset of the original dimers. The thermodynamic data show strikingly good agreement between the original propensities and their ΔG° of association, confirming the model and strengthening the hypothesis that van der Waals and Cα–H hydrogen bond interactions are the key modulators of GASrightstability.
Talaromyces marneffei suppresses human macrophages inflammatory by producing the truncated protein NCOR2-013 via TUT1-regulated alternative splicing
Authors: Wei Wudi , Wang Gang , Zhang Hong , Bao Xiuli , An Sanqi , Luo Qiang , He Jinhao , Chen Lixiang , Liu Yuxuan , Ning Chuanyi , Lai Jingzhen , Yuan Zongxiang , Chen Rongfeng , Jiang Junjun , Ye Li , Liang Hao
Published: July 2022

Talaromyces marneffei (T. marneffei) immune-escaping is an important factor for high mortality of talaromycosis. It is currently known that T. marneffei performs these functions through a variety of strategies, however, the role of alternative splicing (AS) in this process is poorly understood. Here we depicted the AS landscape in the macrophage upon T. marneffei infection via high-throughput RNA sequencing. Moreover, we identified a truncated protein of NCOR2/SMRT, namedly NCOR2-013, was significantly upregulated upon T. marneffei infection. Mechanistic analysis indicates that NCOR2-013 forms a co-repression complex with TBL1XR1/TBLR1 and HDAC3, thereby inhibiting JunB-mediated transcriptional activation of pro-inflammatory cytokines via the inhibition of histone acetylation. Also, we identified TUT1 as the AS regulator that involved in facilitating T. marneffei immune evasion via regulation of NCOR2-013 production. Collectively, the findings indicate that T. marneffei escapes macrophages killing through the TUT1-mediated the alternative splicing of NCOR2-013, which providing a new insight into the molecular mechanisms of T. marneffei immune evasion, and a potential targets for talaromycosis therapy.
Conditional forest models built using metagenomic data could accurately predictSalmonellacontamination in Northeastern streams
Authors: Chung Taejung , Yan Runan , Weller Daniel L. , Kovac Jasna
Published: July 2022

The use of water contaminated withSalmonellafor produce production contributes to foodborne disease burden. To reduce human health risks, there is a need for novel, targeted approaches for assessing the pathogen status of agricultural water. We investigated the utility of water microbiome data for predictingSalmonellacontamination of streams used to source water for produce production. Grab samples were collected from 60 New York streams in 2018 and tested forSalmonella. Separately, DNA was extracted from the samples and used for Illumina shotgun metagenomic sequencing. Reads were trimmed and used to assign taxonomy with Kraken2. Conditional forest (CF), regularized random forest (RRF), and support vector machine (SVM) models were implemented to predictSalmonellacontamination. Model performance was determined using 10-fold cross-validation repeated 10 times to quantify area under the curve (AUC) and Kappa score. Taxa identified as the most informative for accurately predictingSalmonellacontamination based on conditional variable importance were compared to taxa identified by ALDEx2 as being differentially abundant betweenSalmonella-positive and - negative samples. CF models outperformed the other two algorithms based on AUC (0.82 - CF, 0.76 - RRF, 0.67 - SVM) and Kappa score (0.41- CF, 0.38 - RRF, 0.19 - SVM). CF and differential abundance tests both identifiedAeromonas(VI = 0.32) andTabrizicola(VI = 0.12) as the two most informative taxa for predictingSalmonellacontamination. The taxa identified in this study warrant further investigation as indicators ofSalmonellacontamination in Northeastern freshwater streams.

IMPORTANCE

Understanding the associations between surface water microbiome composition and the presence of foodborne pathogens, such asSalmonella, can facilitate the identification of novel indicators ofSalmonellacontamination. This study assessed the utility of microbiome data and three machine learning algorithms for predictingSalmonellacontamination of Northeastern streams. The research reported here both expanded the knowledge on the microbiome composition of surface waters and identified putative novel indicators (i.e.,AeromonasandTabrizicola) forSalmonellain Northeastern streams. These putative indicators warrant further research to assess whether they are consistent indicators ofSalmonellafor regions, waterways, and years not represented in the dataset used in this study.
Natural Variation in Diauxic Shift between Patagonian Saccharomyces eubayanus Strains
Authors: Molinet Jennifer , Eizaguirre Juan I. , Quintrel Pablo , Bellora Nicolás , Villarroel Carlos A. , Villarreal Pablo , Benavides-Parra José , Nespolo Roberto F. , Libkind Diego , Cubillos Francisco A.
Published: July 2022

The study of natural variation can untap novel alleles with immense value for biotechnological applications. Saccharomyces eubayanus Patagonian isolates exhibit differences in the diauxic shift between glucose and maltose, representing a suitable model to study their natural genetic variation for novel strains for brewing. However, little is known about the genetic variants and chromatin regulators responsible for these differences. Here, we show how genome-wide chromatin accessibility and gene expression differences underlie distinct diauxic shift profiles in S. eubayanus. We identified two strains with a rapid diauxic shift between glucose and maltose (CL467.1 and CBS12357) and one strain with a remarkably low fermentation efficiency and longer lag phase during diauxic shift (QC18). This is associated in the QC18 strain to lower transcriptional activity and chromatin accessibility of specific genes of maltose metabolism, and higher expression levels of glucose transporters. These differences are governed by the HAP complex, which differentially regulates gene expression depending on the genetic background. We found in the QC18 strain a contrasting phenotype to those described in S. cerevisiae, where hap411, hap511 and cin511 knockouts significantly improved the QC18 growth rate in the glucose-maltose shift. The most profound effects were found between CIN5 allelic variants, suggesting that Cin5p could strongly activate a repressor of the diauxic shift in the QC18 strain, but not necessarily in the other strains. The differences between strains could originate from the tree host from which the strains were obtained, which might determine the sugar source preference and the brewing potential of the strain.

Importance

The diauxic shift has been studied in the budding yeast under laboratory conditions, however, few studies have addressed the diauxic shift between carbon sources under fermentative conditions. Here, we study the transcriptional and chromatin structure differences that explain the natural variation in fermentative capacity and efficiency during diauxic shift of natural isolates of S. eubayanus. Our results show how natural genetic variants in transcription factors impact sugar consumption preferences between strains. These variants have different effects depending on the genetic background, with a contrasting phenotype to those previously described in S. cerevisiae. Our study shows how relatively simple genetic/molecular modifications/editing in the lab can facilitate the study of natural variation of microorganisms for the brewing industry.
Spatio-temporal estimates of HIV risk group proportions for adolescent girls and young women across 13 priority countries in sub-Saharan Africa
Authors: Howes Adam , Risher Kathryn A. , Kính Nguyen Van , Stevens Oliver , Jia Katherine M. , Wolock Timothy M. , Esra Rachel T. , Zembe Lycias , Wanyeki Ian , Mahy Mary , Benedikt Clemens , Flaxman Seth R. , Eaton Jeffrey W.
Published: July 2022

The Global AIDS Strategy 2021-2026 identifies adolescent girls and young women (AGYW) as a priority population for HIV prevention, and recommends differentiating intervention portfolios geographically based on local HIV incidence and individual risk behaviours. We estimated prevalence of HIV risk behaviours and associated HIV incidence at health district level among AGYW living in 13 countries in sub-Saharan Africa. We analysed 46 geospatially-referenced national household surveys conducted between 1999-2018 across 13 high HIV burden countries in sub-Saharan Africa. Female survey respondents aged 15-29 years were classified into four risk groups (not sexually active, cohabiting, non-regular or multiple partner[s] and female sex workers [FSW]) based on reported sexual behaviour. We used a Bayesian spatio-temporal multinomial regression model to estimate the proportion of AGYW in each risk group stratified by district, year, and five-year age group. Using subnational estimates of HIV prevalence and incidence produced by countries with support from UNAIDS, we estimated new HIV infections in each risk group by district and age group. We then assessed the efficiency of prioritising interventions according to risk group. Data consisted of 274,970 female survey respondents aged 15-29. Among women aged 20-29, cohabiting (63.1%) was more common in eastern Africa than non-regular or multiple partner(s) (21.3%), while in southern countries non-regular or multiple partner(s) (58.9%) were more common than cohabiting (23.4%). Risk group proportions varied substantially across age groups (65.9% of total variation explained), countries (20.9%), and between districts within each country (11.3%), but changed little over time (0.9%). Prioritisation based on behavioural risk, in combination with location- and age-based prioritisation, reduced the proportion of population required to be reached in order to find half of all expected new infections from 19.4% to 10.6%. FSW were 1.3% of the population but 10.6% of all expected new infections. Our risk group estimates provide data for HIV programmes to set targets and implement differentiated prevention strategies outlined in the Global AIDS Strategy. Successfully implementing this approach would result in more efficiently reaching substantially more of those at risk for infections.
Efficient Tracing of the SARS-CoV-2 Omicron Variants in Santa Barbara County Using a Rapid Quantitative Reverse Transcription PCR Assay
Authors: Aralis Zach , Comer Stewart , Ansorg Henning , Palmer Carl , Smith Jennifer , Feinstein Stu , Fitzgibbons Lynn N. , Arias Carolina
Published: July 2022

The recent emergence of the SARS-CoV-2 Omicron variant is associated with a dramatic surge of cases around the globe in late 2021 and early 2022. The numerous mutations in this variant, particularly in the Spike protein, enhance its transmission, increase immune evasion, and limit treatment with monoclonal antibodies. Identifying a community’s introduction to a novel SARS-CoV-2 variant with new clinical features related to treatment options and infection control needs is imperative to inform decisions by clinicians and public health officials, and traditional sequencing techniques often take weeks to result. Here, we describe a quantitative reverse transcription PCR assay (RT-qPCR) to accurately and precisely detect the presence of the Omicron sublineages BA.1/BA1.1 and BA.2 viral RNA from patient samples in less than four hours. The assay uses primers targeting the BA.1/BA1.1 unique mutations N211del, L212I, and L214 insertion EPE in the Spike protein gene, and the BA.2 specific mutations T19I and L24/P25/P26 deletion in the Spike protein gene. Using this assay, we detected 169 cases of Omicron, 164 BA.1/BA1.1 and 5 BA.2, from 270 residual SARS-CoV-2 positive samples collected for diagnostic purposes from Santa Barbara County (SBC) between December 2021 to February 2022. The RT-qPCR results show concordance with whole viral genome sequencing. Our observations indicate that Omicron was the dominant variant in SB County and is likely responsible for the surge of cases in the area during the sampling period. Using this inexpensive and accurate test, the rapid detection of Omicron in patient samples allowed clinicians to modify treatment strategies and public health officers to enhance contact tracing strategies. This RT-qPCR assay offers an alternative to current variant-specific detection approaches, provides a template for the fast design of similar assays, and allows the rapid, accurate, and inexpensive detection of Omicron variants in patient samples. It can also be readily adapted to new variants as they emerge in the future.
APOEε4 carriership associates with microglial activation independently of Aβ plaques and tau tangles
Authors: Ferrari-Souza João Pedro , Lussier Firoza Z. , Leffa Douglas T. , Therriault Joseph , Tissot Cécile , Bellaver Bruna , Lukasewicz Ferreira Pâmela C. , Malpetti Maura , Wang Yi-Ting , Povala Guilherme , Benedet Andréa L. , Ashton Nicholas J. , Chamoun Mira , Servaes Stijn , Bezgin Gleb , Kang Min Su , Stevenson Jenna , Rahmouni Nesrine , Pallen Vanessa , Poltronetti Nina Margherita , O’Brien John T. , Rowe James B. , Cohen Ann D. , Lopez Oscar L. , Tudorascu Dana L. , Karikari Thomas K. , Klunk William E. , Villemagne Victor L. , Soucy Jean-Paul , Gauthier Serge , Souza Diogo O. , Zetterberg Henrik , Blennow Kaj , Zimmer Eduardo R. , Rosa-Neto Pedro , Pascoal Tharick A.
Published: July 2022

Microglial activation is an early phenomenon in Alzheimer’s disease (AD) that may occur prior to and independently of amyloid-β (Aβ) aggregation. Recent studies in transgenic animal models suggest that the apolipoprotein E ε4 (APOEε4) allele may be a culprit of early microglial activation in AD. However, it is unclear whether the APOEε4 genotype is associated with microglial reactivity in the living human brain. Here, we tested whether APOEε4 carriership is associated with microglial activation in individuals across the aging and AD spectrum. We studied 118 individuals who had positron emission tomography (PET) for Aβ ([18F]AZD4694), tau ([18F]MK6240), and microglial activation ([11C]PBR28), as well as clinical, genetic, and magnetic resonance imaging data. We found that APOEε4 carriership was associated with increased microglial activation mainly in early Braak-staging regions within the medial temporal cortex, and this effect of APOEε4 was independent of Aβ and tau deposition. Furthermore, microglial activation mediated the Aβ-independent effects of APOEε4 on downstream tau accumulation, neurodegeneration, and clinical impairment. Interestingly, the physiological distribution of APOE mRNA expression, obtained from the Allen Human Atlas, predicted the patterns of APOEε4-related microglial activation in our population, suggesting that the deleterious effects of APOEε4 occur at the level of gene expression. These results support a model in which the APOEε4 has Aβ-independent effects on AD pathogenesis by activating microglia in brain regions associated with early tau deposition. Our findings provide a rationale for the development of novel AD therapies targeting the interplay between ApoE and neuroinflammation.