bluuebunny/crossref_metadata_2025_split huggingface dataset:
The pain conductor: brainstem modulation in acute and chronic pain
Authors: Crawford Lewis S. , Boorman Damien C. , Keay Kevin A. , Henderson Luke A. 
Published: May 2022

Purpose of review
It is well established in experimental settings that brainstem circuits powerfully modulate the multidimensional experience of pain. This review summarizes current understanding of the roles of brainstem nuclei in modulating the intensity of pain, and how these circuits might be recruited therapeutically for pain relief in chronic and palliative settings.

Recent findings
The development of ultra-high field magnetic resonance imaging and more robust statistical analyses has led to a more integrated understanding of brainstem function during pain. It is clear that a number of brainstem nuclei and their overlapping pathways are recruited to either enhance or inhibit incoming nociceptive signals. This review reflects on early preclinical research, which identified in detail brainstem analgesic function, putting into context contemporary investigations in humans that have identified the role of specific brainstem circuits in modulating pain, their contribution to pain chronicity, and even the alleviation of palliative comorbidities.

Summary
The brainstem is an integral component of the circuitry underpinning pain perception. Enhanced understanding of its circuitry in experimental studies in humans has, in recent years, increased the possibility for better optimized pain-relief strategies and the identification of vulnerabilities to postsurgical pain problems. When integrated into the clinical landscape, these experimental findings of brainstem modulation of pain signalling have the potential to contribute to the optimization of pain management and patient care from acute, to chronic, to palliative states.
Sphingomonas psychrotolerans sp. nov., isolated from root surface of Leontopodium leontopodioides in the Tianshan Mountains, Xinjiang, China
Authors: Luo Yang , Zhou Meng , Wang Fang , Sheng Hongmei 
Published: May 2022

A novel rod-shaped, Gram-stain-negative, aerobic bacterial strain, designated Cra20T, was isolated from the root surface of Leontopodium leontopodioides collected in the Tianshan Mountains, Xinjiang, PR China. Phylogenetic analysis based on 16S rRNA gene sequences, indicated that strain Cra20T was affiliated with the genus

Sphingomonas

, and was most closely related to

Sphingomonas gei

ZFGT-11T (99.0 %),

Sphingomonas naasensis

KIS18-15T (97.8%) and

Sphingomonas kyeonggiensis

THG-DT81T (97.2 %). The average nucleotide identity values between strain Cra20T,

S. gei

ZFGT-11T,

S. naasensis

KIS18-15T and

S. kyeonggiensis

THG-DT81T were 86.2, 84.2 and 78.2 %, respectively. The genomic DNA G+C content of strain Cra20T was 65.6 mol% (whole genome sequence), and Q-10 was the predominant ubiquinone. The major cellular fatty acids of strain Cra20T were summed feature 8 (comprising C18 : 1
ω6c and/or C18 : 1
ω7c, 67.3 %) and C14 : 0 2-OH (6.4 %). On the basis of genotypic, phenotypic and biochemical data, strain Cra20T is considered to represent a novel species of the genus

Sphingomonas

, for which the name Sphingomonas psychrotolerans sp. nov. is proposed. The type strain is Cra20T (=CGMCC 1.15510T=NBRC 112697T).
KIF1A is kinetically tuned to be a super-engaging motor under hindering loads
Authors: Pyrpassopoulos Serapion , Gicking Allison M. , Zaniewski Taylor M. , Hancock William O. , Ostap E. Michael 
Published: May 2022

AbstractKIF1A is a highly processive vesicle transport motor in the kinesin-3 family. Mutations in KIF1A lead to neurodegenerative diseases including hereditary spastic paraplegia. We applied optical tweezers to study the ability of KIF1A to generate and sustain force against hindering loads. We used both the three-bead assay, where force is oriented parallel to the microtubule, and the traditional single-bead assay, where force is directed along the radius of the bead, resulting in a vertical force component. The average force and attachment duration of KIF1A in the three-bead assay were substantially greater than those observed in the single-bead assay. Thus, vertical forces accelerate termination of force ramps of KIF1A. Average KIF1A termination forces were slightly lower than the kinesin-1 KIF5B, and the median attachment duration of KIF1A was >10-fold shorter than KIF5B under hindering loads. KIF1A rapidly reengages with microtubules after detachment, as observed previously. Strikingly, quantification enabled by the three-bead assay shows that reengagement largely occurs within 2 ms of detachment, indicating that KIF1A has a nearly tenfold faster reengagement rate than KIF5B. We found that rapid microtubule reengagement is not due to KIF1A’s positively charged loop-12; however, removal of charge from this loop diminished the unloaded run length at near physiological ionic strength. Both loop-12 and the microtubule nucleotide state have modulatory effects on reengagement under load, suggesting a role for the microtubule lattice in KIF1A reengagement. Our results reveal adaptations of KIF1A that lead to a novel model of super-engaging transport under load.
The U.S. faculty job market survives the SARS-CoV-2 global pandemic
Authors: Kozik Ariangela J , Hagan Ada , Jadavji Nafisa M , Smith Christopher T , Haage Amanda 
Published: May 2022

AbstractPurposeThis paper aims to identify the extent to which the COVID-19 pandemic disrupted the academic job market and the ways in which faculty job applicants altered their applications in response to a changing academia.Design/methodology/approachThe data presented here is the portion relevant to COVID-19 collected in a survey of faculty job applicants at the end of the 2019-2020 job cycle in North America (spring 2020). An additional “mid-pandemic” survey was used in fall 2020 for applicants participating in the following job search cycle to inquire about how they were adapting their application materials. A portion of data from the 2020-2022 job cycle surveys was used to represent the “late-pandemic”. Job posting data from the Higher Education Recruitment Consortium (HERC) is also used to study job availability.FindingsExamination of faculty job postings from 2018 through 2022 found that while they decreased in 2020, the market recovered in 2021 and beyond. While the market recovered, approximately 10% of the faculty job offers reported by 2019–20 survey respondents were rescinded. Respondents also reported altering their application documents in response to the pandemic as well as delaying or even abandoning their faculty job search.OriginalityThis paper provides a longitudinal perspective with quantitative data on how the academic job market changed through the major events of the COVID-19 pandemic in North America, a subject of intense discussion and stress, particularly amongst early career researchers.
Development of the Intestinal Microbiome in Cystic Fibrosis in Early Life
Authors: Price Courtney E. , Hampton Thomas H. , Valls Rebecca A. , Barrack Kaitlyn E. , O’Toole George A. , Madan Juliette C. , Coker Modupe O. 
Published: May 2022

ABSTRACTCystic Fibrosis is a heritable disease that causes altered physiology at mucosal sites; these changes result in chronic infection in the lung, significant gastrointestinal complications as well as dysbiosis of the gut microbiome, although the latter has been less well explored. Here, we describe the longitudinal development of the gut microbiome in a cohort of children with cystic fibrosis (cwCF) from birth through early childhood (0-4 years of age) using 16S rRNA gene amplicon sequencing of stool samples as a surrogate for the gut microbiota. Similar to healthy populations, alpha diversity of the gut microbiome increases significantly with age, but diversity plateaus ∼2 years of age for this CF cohort. Several taxa that have been associated with dysbiosis in CF change with age towards a more healthy-like composition; notable exceptions include Akkermansia, which decreases with age, and Blautia, which increases with age. We also examined the relative abundance and prevalence of nine taxa associated with CF lung disease, several of which persist across early life, highlighting the possibility of the lung being seeded directly from the gut early in life. Finally, we applied the Crohn’s dysbiosis index to each sample, and found that high Crohn’s-associated dysbiosis early in life (<2 years) was associated with significantly lower Bacteroides in samples collected from 2-4 years of age. Together, these data indicate a persisting dysbiosis in the gut microbiota as well as markers associated with inflammatory bowel disease early in life for cwCF.IMPORTANCECystic Fibrosis is a heritable disease that disrupts ion transport at mucosal surfaces, causing a buildup of mucus and dysregulation of microbial communities in both the lungs and the intestines. Persons with CF are known to have dysbiotic gut microbial communities, but the development of these communities over time beginning at birth have not been thoroughly studied. Here, we describe the development of the gut microbiome of cwCF throughout the first four years of life, during the critical window of both gut microbiome and immune development. Our findings indicate a persisting dysbiosis, the possibility of the gut microbiota as a reservoir of airway pathogens and a surprisingly early indication of a microbiota associated with inflammatory bowel disease.
Is point wise analysis of the Humphrey visual field feasible as a primary outcome in idiopathic intracranial hypertension?
Authors: Mollan Susan P , Bodoza Samuel , Ní Mhéalóid Áine , Mitchell James L , Miller Neil R. , Montesano Giovanni , Crabb David P , Wall Michael , Brock Kristian , Sinclair Alexandra J 
Published: May 2022

AbstractPurposeUsing the Idiopathic Intracranial Hypertension Weight Trial (IIH:WT) data, this study aimed to determine if point analysis of the Humphrey visual field (HVF) could be more informative than the perimetric mean deviation (PMD) as an IIH trial outcome measure.MethodsIIH:WT was a randomized controlled trial that recruited 66 people with active IIH (mean ± standard deviation age 32 ± 7.8 years). Event-based analysis using a pointwise analysis of the numerical sensitivity data was performed. The number of participants that would be eligible for analysis was calculated when the data were enriched to reflect a medically treated cohort defined as a PMD between -2dB to -7dB.ResultsThe HVF 24-2 mean ± standard deviation PMD in the worse eye was ™3.5 ± 1.1dB, (range,™2.0 to ™6.4dB), and point sensitivity showed a preference for peripheral and blind spot locations. Those points between 0 and -10dB demonstrated negligible ability to improve compared with those between -10dB and -25dB. In evaluating feasibility for a medical intervention trial, 346 points were available for analysis between -10dB and -25dB bilaterally compared with 4123 in baseline sensitivities of 0 to -10dB.ConclusionsMildly affected baseline sensitivities were unlikely to show considerable change over 24 months. There were fewer points available for analysis and greater variability if moderately affected baseline points were chosen. If point analysis was used as an outcome measure in a medical intervention trial, the majority of points would not demonstrate clinically meaningful change, thus offering little advantage over PMD.
Perception of self- and externally-generated visual stimuli: Evidence from EEG and behaviour
Authors: Ody Edward , Straube Benjamin , He Yifei , Kircher Tilo 
Published: May 2022

AbstractEfference copy-based forward model mechanisms may help us to distinguish between self- and externally-generated sensory consequences. Previous studies have shown that neural activity and perception associated with self-initiated sensory consequences are reduced (sensory suppression). For example, event-related potentials (ERPs) elicited by tones that follow a button press are reduced in amplitude relative to ERPs elicited by passively attended tones. However, previous EEG studies investigating visual stimuli in this context are rare, provide inconclusive results, and lack adequate control conditions with passive movements. Furthermore, although self-initiation is known to modulate behavioural responses, it is not known whether differences in the amplitude of ERPs also reflect differences in perception of sensory outcomes. In this study, we presented to participants visual stimuli consisting of grey discs following either active button presses, or passive button presses, in which an electromagnet moved the participant’s finger. Two discs presented visually 500-1250 ms apart followed each button press, and participants judged which of the two was more intense. Early components of the primary visual response (N1 and P2) over the occipital electrodes were suppressed in the active condition. Interestingly, suppression in the intensity judgement task was only correlated with suppression of the visual P2 component. These data support the notion of efference copy-based forward model predictions in the visual sensory modality, but especially later processes (P2) seem to be perceptually relevant. Taken together, the results challenge the assumption that N1 differences reflect perceptual suppression and emphasise the relevance of the P2 ERP component.
Internally-controlled and dynamic optical measures of functional tumor biology
Authors: Chung Taemoon , Garcia Libia , Swamynathan Manojit M. , Froeling Fieke E.M. , Trotman Lloyd C. , Tuveson David A. , Lyons Scott K. 
Published: May 2022

AbstractImaging defined aspects of functional tumor biology with bioluminescent reporter transgenes is a popular approach amongst the research community in drug development, as it is sensitive, relatively high-throughput and low cost. However, the lack of internal controls subject functional bioluminescence to a number of unpredictable variables that reduce this powerful tool to semi-quantitative interpretation of large-scale effects. Here we report the generation of sensitive and quantitative live reporters for two key measures of functional cancer biology and pharmacologic stress: the cell cycle and oxidative stress. We developed a two-colored readout, where two independent enzymes convert a common imaging substrate into spectrally distinguishable light. The signal intensity of one color is dependent upon biological state, whereas the other color is constitutively expressed. The ratio of emitted colored light corrects the functional signal for independent procedural variables, substantially improving the robustness and interpretation of relatively low-fold changes in functional signal intensity after drug treatment.The application of these readouts in vitro is highly advantageous, as peak cell response to therapy can now be readily visualized for single or combination treatments and not simply assessed at an arbitrary and destructive timepoint. Spectral imaging in vivo can be challenging, but we also present evidence to show that the reporters can work in this context as well. Collectively, the development and validation of these internally controlled reporters allow researchers to robustly and dynamically visualize tumor cell biology in response to treatment. Given the prevalence of bioluminescence imaging, this presents significant and much needed opportunities for preclinical therapeutic development.
Modified methods for bovine sperm RNA isolation for consistent quality and RNA yield
Authors: Dewry Raju Kumar , Mohanty Tushar Kumar , Nath Sapna , Bhakat Mukesh , Yadav Hanuman Prasad , Baithalu Rubina Kumari 
Published: May 2022

AbstractSperm mRNA transcriptional profiling can be used to evaluate the fertility of breeding bulls. This study aimed to compare the modified RNA isolation methods for higher RNA yield and quality from freshly ejaculated sperm of cattle and buffalo bull for further transcriptome analysis. Ten fresh ejaculates from each Sahiwal (n = 10 bulls x 10 ejaculates) and Murrah bulls (n = 10 bulls x 10 ejaculates) were used for RNA isolation. Swim-up technique was used for live sperm separation and recovery. From the recovered live sperm, total sperm RNA was isolated by conventional methods (TRIzol, Double TRIzol), membrane-based methods combined with TRIzol (RNeasy + TRIzol) with the addition of β-mercaptoethanol (BME) and Kit (RNeasy mini) methods in fresh semen. Among different isolation methods; the membrane-based modified methods combined with TRIzol (RNeasy + TRIzol) with the addition of β-mercaptoethanol (BME) resulted significantly (P < 0.05) higher total RNA quantity (300-340 ng/μL) and better purity in different concentrations of spermatozoa viz., 30-40 million, 70-80 million and 300-400 million sperm. The study concluded that the inclusion of BME to the combined membrane-based methods with somatic cell lysis buffer solution was best for constant increased yield and purity of RNA isolation from Sahiwal cattle and Murrah buffalo bull sperm. This method will help with the interpretation of data from animal models and the consistency of clinical assessments of male factor fertility employing RNA molecular biomarkers.
Ubx5-Cdc48 assists the protease Wss1 at DNA-protein crosslink sites in yeast
Authors: Noireterre Audrey , Bagdiul Ivona , Serbyn Nataliia , Stutz Françoise 
Published: May 2022

ABSTRACTDNA-protein crosslinks (DPCs) pose a serious threat to genome stability. The yeast proteases Wss1, 26S proteasome and Ddi1 are safeguards of genome integrity by acting on a plethora of DNA-bound proteins in different cellular contexts. The AAA ATPase Cdc48/p97 is known to assist Wss1/SPRTN in clearing DNA-bound complexes, however its contribution to DPC proteolysis remains unclear. Here, we show that the Cdc48 adaptor Ubx5 is detrimental in yeast mutants defective in DPC processing. Using an inducible site-specific crosslink, we show that Ubx5 accumulates at persistent DPC lesions in the absence of Wss1, which prevents their efficient removal from the DNA. Abolishing Cdc48 binding or complete loss of Ubx5 suppresses the sensitivity of wss1Δ cells to DPC inducing agents by favoring alternate repair pathways. We provide evidence for cooperation of Ubx5-Cdc48 and Wss1 in the genotoxin-induced degradation of RNAPII, a described candidate substrate of Wss1. We propose that Ubx5-Cdc48 assists Wss1 for proteolysis of a subset of DNA-bound proteins. Together, our findings reveal a central role for Ubx5 in DPC clearance and repair.
Generating Interacting Protein Sequences using Domain-to-Domain Translation
Authors: Meynard-Piganeau Barthelemy , Fabbri Caterina , Weigt Martin , Pagnani Andrea , Feinauer Christoph 
Published: May 2022

AbstractMotivationBeing able to artificially design novel proteins of desired function is pivotal in many biological and biomedical applications. Generative statistical modeling has recently emerged as a new paradigm for designing amino acid sequences, including in particular models and embedding methods borrowed from Natural Language Processing (NLP). However, most approaches target single proteins or protein domains, and do not take into account any functional specificity or interaction with the context. To extend beyond current computational strategies, we develop a method for generating protein domain sequences intended to interact with another protein domain. Using data from natural multi-domain proteins, we cast the problem as a translation problem from a given interactor domain to the new domain to be generated, i.e. we generate artificial partner sequences conditional on an input sequence.ResultsEvaluating our model’s quality using diverse metrics, in part related to distinct biological questions, we show that our method outperforms state-of-the-art shallow auto-regressive strategies. We also explore the possibility of fine-tuning pre-trained large language models for the same task and of using Alphafold 2 for assessing the quality of sampled sequences.
TRACKING HEMATOPOIETIC STEM CELL EVOLUTION IN A WISKOTT-ALDRICH CLINICAL TRIAL
Authors: Pellin Danilo , Biasco Luca , Scala Serena , Serio Clelia Di , Wit Ernst C. 
Published: May 2022

Hematopoietic Stem Cells (HSC) are the cells that give rise to all other blood cells and, as such, they are crucial in the healthy development of individuals. Wiskott-Aldrich Syndrome (WAS) is a severe disorder affecting the regulation of hematopoietic cells and is caused by mutations in the WASP gene. We consider data from a revolutionary gene therapy clinical trial, where HSC harvested from 3 WAS patients’ bone marrow have been edited and corrected using viral vectors. Upon re-infusion into the patient, the HSC multiply and differentiate into other cell types. The aim is to unravel the cell multiplication and cell differentiation process, which has until now remained elusive.This paper models the replenishment of blood lineages resulting from corrected HSC via a multivariate, density-dependent Markov process and develops an inferential procedure to estimate the dynamic parameters given a set of temporally sparsely observed trajectories. Starting from the master equation, we derive a system of non-linear differential equations for the evolution of the first- and second-order moments over time. We use these moment equations in a generalized method-of-moments framework to perform inference. The performance of our proposal has been evaluated by considering different sampling scenarios and measurement errors of various strengths using a simulation study. We also compared it to another state-of-the-art approach and found that our method is statistically more efficient.By applying our method to the Wiskott-Aldrich Syndrome gene therapy data we found strong evidence for a myeloid-based developmental pathway of hematopoietic cells where fates of lymphoid and myeloid cells remain coupled even after the loss of erythroid potential.All code used in this manuscript can be found in the online Supplement, and the latest version of the code is available at github. com/dp3ll1n/SLCDP_v1.0.
A high-throughput approach to predict A-to-I effects on RNA structure indicates a change of double-stranded content in non-coding RNAs
Authors: Ponti Riccardo Delli , Broglia Laura , Vandelli Andrea , Armaos Alexandros , Burgas Marc Torrent , Sanchez de Groot Natalia , Tartaglia Gian Gaetano 
Published: May 2022

ABSTRACTRNA molecules undergo a number of chemical modifications whose effects can alter their structure and molecular interactions. Previous studies have shown that RNA editing can impact the formation of ribonucleoprotein complexes and influence the assembly of membrane-less organelles such as stress-granules. For instance, N6-methyladenosine (m6A) enhances SG formation and N1-methyladenosine (m1A) prevents their transition to solid-like aggregates. Yet, very little is known about adenosine to inosine (A-to-I) modification that is very abundant in human cells and not only impacts mRNAs but also non-coding RNAs. Here, we built the CROSSalive predictor of A-to-I effects on RNA structure based on high-throughput in-cell experiments. Our method shows an accuracy of 90% in predicting the single and double-stranded content of transcripts and identifies a general enrichment of double-stranded regions caused by A-to-I in long intergenic non-coding RNAs (lincRNAs). For the individual cases of NEAT1, NORAD and XIST, we investigated the relationship between A-to-I editing and interactions with RNA-binding proteins using available CLIP data. We found that A-to-I editing is linked to alteration of interaction sites with proteins involved in phase-separation, which suggests that RNP assembly can be influenced by A-to-I. CROSSalive is available athttp://service.tartaglialab.com/new_submission/crossalive.