bluuebunny/crossref_metadata_2025 huggingface dataset:
Kaptive 2.0: updated capsule and lipopolysaccharide locus typing for the Klebsiella pneumoniae species complex
Authors: Lam Margaret M. C. , Wick Ryan R. , Judd Louise M. , Holt Kathryn E. , Wyres Kelly L.
Published: March 2022

The outer polysaccharide capsule and lipopolysaccharide (LPS) antigens are key targets for novel control strategies targeting

Klebsiella pneumoniae

and related taxa from the

K. pneumoniae

species complex (KpSC), including vaccines, phage and monoclonal antibody therapies. Given the importance and growing interest in these highly diverse surface antigens, we had previously developed Kaptive, a tool for rapidly identifying and typing capsule (K) and outer LPS (O) loci from whole genome sequence data. Here, we report two significant updates, now freely available in Kaptive 2.0 (https://github.com/katholt/kaptive): (i) the addition of 16 novel K locus sequences to the K locus reference database following an extensive search of >17 000 KpSC genomes; and (ii) enhanced O locus typing to enable prediction of the clinically relevant O2 antigen (sub)types, for which the genetic determinants have been recently described. We applied Kaptive 2.0 to a curated dataset of >12 000 public KpSC genomes to explore for the first time, to the best of our knowledge, the distribution of predicted O (sub)types across species, sampling niches and clones, which highlighted key differences in the distributions that warrant further investigation. As the uptake of genomic surveillance approaches continues to expand globally, the application of Kaptive 2.0 will generate novel insights essential for the design of effective KpSC control strategies.
Direct estimates of absolute ventilation in primary health care clinics in South Africa
Authors: Beckwith Peter G , Karat Aaron S , Govender Indira , Deol Arminder , McCreesh Nicky , Kielmann Karina , Baisley Kathy , Grant Alison D , Yates Tom A
Published: March 2022

Background

Healthcare facilities are important sites for the transmission of pathogens spread via bioaerosols, such as Mycobacterium tuberculosis (Mtb). Natural ventilation can play an important role in reducing this transmission. In primary health care (PHC) clinics in low and middle-income settings, susceptible people, including healthcare workers, are exposed to individuals with infectious pulmonary tuberculosis. We measured rates of natural ventilation in PHC clinics in KwaZulu-Natal and Western Cape provinces, South Africa.

Methods and Findings

We measured ventilation in clinic spaces using a tracer-gas release method. In spaces where this was not possible, we estimated ventilation using data on indoor and outdoor carbon dioxide levels, under reasonable assumptions about occupants’ metabolic rates. Ventilation was measured i) under usual conditions and ii) with all windows and doors fully open. We used these ventilation rates to estimate the risk of Mtb transmission using the Wells-Riley Equation. We obtained ventilation measurements in 33 clinical spaces in 10 clinics: 13 consultation rooms, 16 waiting areas and 4 other clinical spaces. Under usual conditions, the absolute ventilation rate was much higher in waiting rooms (median 1769 m3/hr, range 338–4815 m3/hr) than in consultation rooms (median 197 m3/hr, range 0–1451 m3/hr). Ventilation was better in permanent than in temporary structures. When compared with usual conditions, fully opening existing doors and windows resulted in a median two-fold increase in ventilation. Our Wells-Riley estimates show that, following sustained exposure, or contact with highly infectious index cases, some risk of Mtb infection may persist in the best ventilated clinical spaces unless other components of transmission risk are also addressed.

Conclusions

Among the clinical spaces studied, we observed substantial variation in natural ventilation. Ventilation interventions may have considerable impact on Mtb transmission in this setting. We recommend these form part of a package of infection prevention and control interventions.
Oral health professionals and child abuse and neglect: a scoping review protocol
Authors: Han Heuiwon , Morse Zac , Koziol-McLain Jane , Lees Amanda B
Published: March 2022

Introduction

Child abuse and neglect can seriously impair social development, learning, physical, and psychological health. Oral health practitioners can recognize the orofacial manifestations of maltreatment in a dental setting, provide necessary support, and refer concern to child protection agencies to prevent further harm. There is a need to understand the responsiveness of oral health practitioners to a child protection concern. This protocol outlines the systematic processes to map evidence in the field of child protection in oral health.

Methods and analysis

This review will be guided by the PRISMA-ScR and the JBI guidelines. Primary and secondary studies, reviews, guidelines, and editorial articles written in English will be included in the review. A three-step search will be implemented. An initial search is conducted to finalised the search terms and eligbility criteria followed by a second search involving sensitive searches of databases (Scopus, MEDLINE, CINAHL, Dentistry & Oral Science Source, and Cochrane Library). A third search will involve grey literature searching for unpublished materials. Government and international health organization websites will be searched during the third search. Eligible studies will be screened based on the participants (oral health practitioners), the concept (child protection) and the context (dental setting) and data extracted by two reviewers. Outcomes from the data extraction chart will be synthesized through exploratory narratives.

Ethics and dissemination

This study involves neither human participants nor unpublished secondary data. As such, ethics approval is not required. Findings will be disseminated through publication in a peer-reviewed journals, professional networks, and conferences.

Strengths and limitations of this study

This study will systemically identify literature from a broad range of databases and map evidence in the field of child protection in oral health.

The review will take a rigorous approach adhering to the PRISMA-ScR and and the JBI guidelines.

Multiple reviewers will conduct screening and data extraction independently to facilitate reliability.

A limitation is that only sources in English will be reviewed.
Use of therapeutic play in nursing care for school-age children: a scoping review
Authors: da Silva Luanna Gomes , de Oliveira Célida Juliana , de Oliveira Joseph Dimas , Bandeira Paulo Felipe Ribeiro , de Matos José Hiago Feitosa , Gomes Emiliana Bezerra , de Beltrão Izabel Cristina Santiago Lemos , Martins Álissan Karine Lima
Published: March 2022

Background

Therapeutic play is an important strategy in nursing care to relieve emotional discomfort of school-age children. The aim of this scoping review was to map the use of therapeutic play in nursing care for school-age children.

Methods

Searches in the databases: MEDLINE, CINAHL, Scopus, BDENF, LILACS and CAPES theses and dissertations portal. A total of 1,486 records were identified and 32 included in the review. Eligibility criteria: The literature on children aged 6 to 12 participating in therapeutic play sessions in nursing care in any place, in the form of original articles, theses and dissertations, in English, Spanish or Portuguese. There was no time limit.

Results

The focus theme has been described since 1987 in the national and international scientific literature. There is consensus on the benefits of therapeutic play in nursing care for school-age children in various situations, especially in the hospital context, with proven efficacy in research that encourages the application of this strategy in nursing practice, but there are barriers for its implementation.

Conclusion

The review identified the settings, situations, benefits, barriers and gaps regarding the use of therapeutic play in nursing care for school-age children.

Implications

The positive results reported in the studies can be used to enrich discussions about the use of therapeutic play in nursing practice for school-age children and encourage awareness of the importance of this strategy. The gaps identified contribute to future research.
Modifications to student quarantine policies in K–12 schools implementing multiple COVID-19 prevention strategies restores in-person education without increasing SARS-CoV-2 transmission risk, January-March 2021
Authors: Dawson Patrick , Worrell Mary Claire , Malone Sara , Fritz Stephanie A. , McLaughlin Heather P. , Montgomery Brock K. , Boyle Mary , Gomel Ashley , Hayes Samantha , Maricque Brett , Lai Albert M. , Neidich Julie A. , Tinker Sarah C. , Lee Justin S. , Tong Suxiang ,   COVID-19 Response Fieldwork and Laboratory Teams, Orscheln Rachel C. , Charney Rachel , Rebmann Terri ,   Missouri School District Data and Coordination Group, Mooney Jon , Rains Catherine , Yoon Nancy , Petit Machelle , Towns Katie , Goddard Clay , Schmidt Spring , Barrios Lisa C. , Neatherlin John C. , Salzer Johanna S. , Newland Jason G.
Published: March 2022

Objective

To determine whether modified K–12 student quarantine policies that allow some students to continue in-person education during their quarantine period increase schoolwide SARS-CoV-2 transmission risk following the increase in cases in winter 2020-2021.

Methods

We conducted a prospective cohort study of COVID-19 cases and exposures among students and staff (n=65,621) in 103 Missouri public schools. Participants were offered free, saliva-based RT-PCR testing. An adjusted Cox regression model compared hazard rates of school-based SARS-CoV-2 infections between schools with a modified versus standard quarantine policy.

Results

From January–March 2021, a projected 23 (1%) school-based transmission events occurred among 1,636 school close contacts. There was no difference in the adjusted hazard rates of school-based SARS-CoV-2 infections between schools with a modified versus standard quarantine policy (hazard ratio=1.00; 95% confidence interval: 0.97–1.03).

Discussion

School-based SARS-CoV-2 transmission was rare in 103 K–12 schools implementing multiple COVID-19 prevention strategies. Modified student quarantine policies were not associated with increased school incidence of COVID-19. Modifications to student quarantine policies may be a useful strategy for K–12 schools to safely reduce disruptions to in-person education during times of increased COVID-19 community incidence.
Structural connectivity gradient associated with a dichotomy reveals the topographic organization of the macaque insular cortex
Authors: Cao Long , Du Zongchang , Cui Yue , Zhang Yuanchao , Lu Yuheng , Zhang Baogui , Liu Yanyan , Hou Xiaoxiao , Liu Xinyi , Cheng Luqi , Li Kaixin , Yang Zhengyi , Fan Lingzhong , Jiang Tianzi
Published: March 2022

Histology studies revealed that the macaque insular cortex was characterized by the gradual organizations containing agranular, dysgranular and granular insula. However, no consensus has been reached on the elaborate subdivisions of macaque insula. Until now, no neuroimaging study to our knowledge combining connectivity-based gradients and parcellation has been performed to investigate the topographic organization of the macaque insular cortex. In this study, we used high-resolution ex vivo diffusion-weighted imaging data to explore the macaque insular cortex’s global gradient organization and subdivisions. We found a rostrocaudal organization of the dominant gradient in the macaque insula using a diffusion map embedding. Meanwhile, extracting the 25% top and bottom components from the dominant and second gradient, which explained variance over 60% in total within ten gradients, the connectivity-based parcellation method was performed to subdivide each component into two subregions confirmed by the cross-validation analysis. Furthermore, permutations tests identified that two subregions from each component showed significant differences between their connectivity fingerprints. Finally, we found that the dominant and second gradients were significantly correlated with the T1w/T2w and cortical thickness maps in the macaque insula. Taken together, the global gradients combining the subdivisions examined the topographic organization of the macaque insular cortex based on the structural connectivity, which may contribute to a better understanding of the intricate insular cortex anatomy.
Shared and distinct brain regions targeted for immediate early gene expression by ketamine and psilocybin
Authors: Davoudian Pasha A. , Shao Ling-Xiao , Kwan Alex C.
Published: March 2022

Psilocybin is a psychedelic with therapeutic potential. While there is growing evidence that psilocybin exerts its beneficial effects through enhancing neural plasticity, the exact brain regions involved are not completely understood. Determining the impact of psilocybin on plasticity-related gene expression throughout the brain can broaden our understanding of the neural circuits involved in psychedelic-evoked neural plasticity. In this study, whole-brain serial two-photon microscopy and light sheet microscopy were employed to map the expression of the immediate early gene, c-Fos, in male and female mice. The drug-induced c-Fos expression following psilocybin administration was compared to that of subanesthetic ketamine and saline control. Psilocybin and ketamine produced acutely comparable elevations in c-Fos expression in numerous brain regions, including anterior cingulate cortex, locus coeruleus, primary visual cortex, central and basolateral amygdala, medial and lateral habenula, and claustrum. Select regions exhibited drug-preferential differences, such as dorsal raphe and insular cortex for psilocybin and the CA1 subfield of hippocampus for ketamine. To gain insights into the contributions of receptors and cell types, the c-Fos expression maps were related to brain-widein situhybridization data. The transcript analyses showed that the endogenous levels ofGrin2aandGrin2bare predictive of whether a cortical region is sensitive to drug-evoked neural plasticity for both ketamine and psilocybin. Collectively, the systematic mapping approach produced an unbiased list of brain regions impacted by psilocybin and ketamine. The data are a resource that highlights previously underappreciated regions for future investigations. Furthermore, the robust relationships between drug-evoked c-Fos expression and endogenous transcript distributions suggest glutamatergic receptors as a potential convergent target for how psilocybin and ketamine produce their rapid-acting and long-lasting therapeutic effects.
Enteroendocrine cell lineages that differentially control feeding and gut motility
Authors: Hayashi Marito , Kaye Judith A. , Douglas Ella R. , Joshi Narendra R. , Gribble Fiona , Reimann Frank , Liberles Stephen D.
Published: March 2022

Enteroendocrine cells are specialized sensory cells of the gut-brain axis that are sparsely distributed along the intestinal epithelium. The functions of enteroendocrine cells have classically been inferred by the gut hormones they release. However, individual enteroendocrine cells typically produce multiple, sometimes apparently opposing, gut hormones in combination, and some gut hormones are also produced elsewhere in the body. Here, we developed approaches involving intersectional genetics to enable selective access to enteroendocrine cells in vivo. We constructed Villin1-p2a-FlpO knock-in mice to restrict reporter expression to intestinal epithelium and through combined use of Cre and Flp alleles, effectively targeted major transcriptome-defined enteroendocrine cell lineages that produce serotonin, glucagon-like peptide 1, cholecystokinin, somatostatin, or glucose insulinotropic peptide. Chemogenetic activation of different enteroendocrine cell types variably impacted feeding behavior, nausea-associated behaviors (conditioned flavor avoidance), and gut motility. Defining the physiological roles of different enteroendocrine cell types provides an essential framework for understanding sensory biology of the intestine.
The miR-15a/16-1 and miR-15b/16-2 clusters regulate early B cell development by limiting IL-7 receptor expression
Authors: Hutter Katharina , Rülicke Thomas , Szabo Tamas G. , Andersen Lill , Villunger Andreas , Herzog Sebastian
Published: March 2022

Pleiotropic functions of miRNAs as transcriptional repressors have been reported for multiple biological processes. One prominent miRNA family is the miR-15 family, which is a well-established tumor-suppressor in B-cell chronic lymphocytic leukemia (CLL). The miR-15 family consists of three bicistronic clusters, miR-15a/16-1, miR-15b/16-2 and miR-497/195, all sharing the same seed sequence suggesting that loss one cluster can be functionally compensated by the remaining miR-15 family members. Thus, a combined deletion may be necessary to reveal its physiological functionin vivo.

A combined knockout of the most prominent miR-15 clusters, miR-15a/16-1 and miR-15b/16-2 in the hematopoietic system reveals a novel role of the miR-15 family in early B cell development highlighted by an increase of the pro-B cell compartment. Mechanistically, this effect is mediated by enhanced IL-7 receptor expression, which we identified as direct miR-15 target gene. Notably, elevated IL-7 receptor levels were sufficient to trigger increased activation of the STAT5 and PI3K/AKT pathways. Moreover, derepression of directly targeted cell cycle regulators such asCcne1, Chek1andWee1further facilitates G-to-S transition.

Thus, by deregulating a target gene network of cell cycle and signaling mediators, loss of the miR-15 family establishes a pro-proliferative milieu manifesting in an enlarged pro-B cell pool.
CNETML: Maximum likelihood inference of phylogeny from copy number profiles of spatio-temporal samples
Authors: Lu Bingxin , Curtius Kit , Graham Trevor A. , Yang Ziheng , Barnes Chris P.
Published: March 2022

Phylogenetic trees based on copy number alterations (CNAs) for multi-region samples of a single cancer patient are helpful to understand the spatio-temporal evolution of cancers, especially in tumours driven by chromosomal instability. Due to the high cost of deep sequencing data, low-coverage data are more accessible in practice, which only allow the calling of (relative) total copy numbers due to the lower resolution. However, methods to reconstruct sample phylogenies from CNAs often use allele-specific copy numbers and those using total copy number are mostly distance matrix or maximum parsimony methods which do not handle temporal data or estimate mutation rates. In this work, we developed a new maximum likelihood method based on a novel evolutionary model of CNAs, CNETML, to infer phylogenies from spatio-temporal samples taken within a single patient. CNETML is the first program to jointly infer the tree topology, node ages, and mutation rates from total copy numbers when samples were taken at different time points. Our extensive simulations suggest CNETML performed well even on relative copy numbers with subclonal whole genome doubling events and under slight violation of model assumptions. The application of CNETML to real data from Barrett’s esophagus patients also generated consistent results with previous discoveries and novel early CNAs for further investigations.
Evaluation of the Panbio™ COVID-19 Antigen Rapid Diagnostic Test in subjects infected with Omicron using different specimens
Authors: Galliez Rafael Mello , Bomfim Larissa , Mariani Diana , de Carvalho Leitão Isabela , Pinto Castiñeiras Anna Carla , Alves Gonçalves Cassia Cristina , da Silva Bianca Ortiz , Cardoso Pedro Henrique , Arruda Monica Barcelos , Alvarez Patricia , Ota Victor Akira , Marins Rodrigues Débora Gomes , da Costa Luciana Jesus , Costa Ferreira Orlando da , Pinto Castiñeiras Terezinha Marta Pereira , Faffe Debora Souza , Tanuri Amilcar
Published: March 2022

Community testing is a crucial tool for the early identification of SARS-CoV-2 infection and transmission control. The emergence of the highly mutated Omicron variant (B.1.1.259) raised concerns about its primary site of replication, impacting sample collection, and its detectability by rapid antigens tests. We tested the Antigen Rapid Diagnostic Test (Ag-RDT) performance using nasal, oral, and saliva specimens for COVID-19 diagnosis in 192 symptomatic individuals, using RT-qPCR from nasopharyngeal samples as control. Variant of Concern (VOC) investigation was determined by the 4Plex SARS-CoV-2 screening kit. SARS-CoV-2 positivity rate was 66.2%, with 99% of the positive samples showing an amplification profile consistent with that of the Omicron variant. Nasal Ag-RDT showed higher sensitivity (89%) than oral (12.6%) and saliva (22.1%) Ag-RDTs. Our data showed the good performance of the Ag-RDT in a pandemic scenario dominated by the Omicron VOC. Furthermore, our data also demonstrated that nasal specimens perform better than oral and saliva ones for Omicron Ag-RDT detection.
Impact of diabetes mellitus on the stabilization and osseointegration of dental implants: a retrospective study in Greece
Authors: Katsiroumpa Aglaia , Galanis Petros , Diamantis Ioannis , Georgikopoulou Sofia , Katsoulas Theodoros , Konstantakopoulou Olympia , Katsimperi Elissavet , Konstantinou Evangelos
Published: March 2022

Introduction

Adequate dental restoration including the use of implants is critical in healthy eating habits of diabetic patients and appropriate metabolic control.

Aim

To investigate the relationship between diabetes mellitus and dental implants stabilization and osseointegration.

Methods

A retrospective study was conducted in a private dental clinic in Athens. Data collection referred to the period between January 2016 and August 2021. During this time period, all cases related to implant placement in diabetic patients at the clinic were recorded. In particular, 93 implants were recorded in 36 diabetic patients. During the same time period, 93 implant cases involving non-diabetics at the clinic were randomly taken from the clinic records to provide the comparison group. The implant stability quotient was measured immediately after implant placement and after four months.

Results

The mean value of the implant stability quotient immediately after implant placement was 75.97 in non-diabetics and 76.85 in diabetics (p=0.42). The mean value of the implant stability quotient after four months was 78.92 in non-diabetics and 78.44 in diabetics (p=0.58). The mean value of the implant stability quotient in non-diabetics increased statistically significantly in the first four months from 75.97 to 78.92 (p<0.001). The mean value of the implant stability quotient in diabetics increased statistically significantly in the first four months from 76.85 to 78.44 (p=0.011). No implant loss was recorded in both diabetics and non-diabetics (p=1). According to multivariate analysis, patients who did not have bio-materials placed during implantation, patients who had not undergone previous surgical procedures and patients who had implants placed in the mandible had better implant stability.

Conclusions

The stability of the implants increased statistically significant in the first four months of implant placement. No relationship was found between diabetes mellitus and dental implants stabilization and osseointegration. However, studies with a larger sample size and longer follow-up of patients are needed to better clarify the risks and benefits of dental implants in diabetic patients.
Reversible edema following electric drilling of macaque craniotomy
Authors: Boshra Rober , Eradath Manoj , Dougherty Kacie , Wu Bichan , Morea Britney M. , Pinsk Mark , Kastner Sabine
Published: March 2022

In-vivo electrophysiology requires direct access to brain tissue, necessitating the development and refinement of surgical procedures and techniques that promote the health and well-being of the animal subjects. Here, we report a series of findings noted on structural magnetic resonance imaging (MRI) scans in monkeys with MRI-compatible implants following small craniotomies that provide access for intracranial electrophysiology. We found distinct brain regions exhibiting hyperintensities in T2-weighted scans that were prominent underneath the sites at which craniotomies had been performed. We interpreted these hyperintensities as edema of the neural tissue and found that they were predominantly present following electric drilling, but not when manual, hand-operated drills were used. Further, the anomalies subsided within 2-3 weeks following surgery. Our report highlights the utility of MRI-compatible implants that promote clinical examination of the animal’s brain, sometimes revealing findings that may go unnoticed when incompatible implants are used. We show replicable differences in outcome when using electric vs. mechanical devices, both ubiquitous in the field. If electric drills are used, our report cautions electrophysiological recordings from tissue directly underneath the craniotomy for the first 2-3 weeks following the procedure due to putative edema.
The effect of auditory stimulation on the nonlinear dynamics of heart rate: the impact of emotional valence and arousal
Authors: Dimitriev Dmitri , Indeykina Olga , Dimitriev Aleksey
Published: March 2022

Background

Although it is known that sound exposure evokes changes in autonomic activity, the effects of noise and music on the nonlinear behavior of heart rate fluctuations remain poorly understood and controversial. This study aims to assess the influence of sound subjective emotional valence and arousal on the nonlinear characteristics of the autonomic nervous system during passive listening.

Methods

In this study, forty-two subjects listened to four sounds: (1) white noise, (2) road traffic noise, (3) excitatory music, and (4) a lullaby. The experiment consisted of two consecutive sessions: five minutes of rest, followed by five minutes of listening. RR intervals were recorded during both sessions. The following linear and nonlinear heart rate variability indices were computed: SDNN, RMSSD, F, HF, approximate (ApEn) and sample entropy (SampEn), correlation dimension (D2), Poincare plot indices (SD1, SD2), fractal scaling exponents (alpha1, alpha2), and recurrence plot indices (Lmean, Lmax, DET, LAM, Vmax, TT, ShanEn).

Results

Excitatory music was associated with significant decrease in SDNN and RMSSD, diminished HF, and a substantial reduction in LF. Excitatory music exposure induced significant increases in DET, SD1 and SD2, but changes in DFA, SampEn, and D2 were nonsignificant. Traffic noise, white noise, and the lullaby did not cause significant changes in the measures of heart rate variability.

Conclusion

Presentation of music evoking strong negative emotions elicits a prominent decrease in respiratory sinus arrhythmia. Poincare plot and recurrence plot measures possess high sensitivity to high arousal and unpleasant music. Contrary to previous studies, we did not find the effects of relaxing music on heart rate variability.
TATTOO-seq delineates spatial and cell type-specific regulatory programs during limb patterning
Authors: Bastide Sébastien , Chomsky Elad , Saudemont Baptiste , Loe-Mie Yann , Schmutz Sandrine , Novault Sophie , Marlow Heather , Tanay Amos , Spitz François
Published: March 2022

The coordinated differentiation of progenitor cells into specialized cell types and their spatial organization into distinct domains is central to embryogenesis. Here, we applied a new unbiased spatially resolved single-cell transcriptomics method to identify the genetic programs that underlie the emergence of specialized cell types during limb development and their integration in space. We uncovered combinations of transcription factors whose expression patterns are predominantly associated with cell type specification or spatial position, enabling the deconvolution of cell fate and position identity. We demonstrate that the embryonic limb undergoes a complex multi-scale re-organization upon perturbation of one of its spatial organizing centers, including the loss of specific cell populations, specific alterations in the molecular identities of other pre-existing cell states and changes in their relative spatial distribution. Altogether, our study shows how multi-dimensional single-cell and spatially resolved molecular atlases could reveal the interconnected genetic networks that regulate the intricacies of organogenesis and its reorganization upon genetic alterations.
Revisiting Long-Distance Axon Growth Ability in the Developing Spinal Cord using a Novel Lesion Paradigm
Authors: Ruven Carolin , Kaiser Julia , Patel Payal , Serraino Francesca , Kawaguchi Riki , Sahni Vibhu
Published: March 2022

Established experimental lesions in the developing central nervous system (CNS) disrupt microenvironments critical for long-distance axon growth and guidance. Therefore, the precise developmental time at which the CNS ceases its capacity to support long-distance axon growth remains unknown. Accordingly, we established a new microsurgical approach to axotomize developing corticospinal tract (CST) axons in the neonatal spinal cord while leaving their local microenvironments relatively intact. This enables unambiguous investigation of long-distance CST growth ability in the CNS. Surprisingly, we find that CST axons lose their capacity for long-distance growth even during the developmental period of CST extension. While this ability remains intact in spinal locations where normal CST extension is occurring, it is completely abolished at sites distant from these locations. Further, the developmental time window for which this ability is maintained is much shorter than for other forms of axon growth such as sprouting. Long-distance CST growth ability does not correlate with astrocytic or microglial activation, nor with myelination levels. These results indicate that long-distance CST growth is controlled by mechanisms that operate early in development in a time- and region-specific manner.
The dynamics of speciation in the gall-forming aphidGeoicaspp. within and amongPistaciahost tree species
Authors: Ben-Shlomo Rachel , Talal Stav , Inbar Moshe
Published: March 2022

Trees of the genusPistaciaserve as obligate hosts for gall-forming aphids (Hemiptera, Aphididae, Fordini). Each aphid species induces a characteristic gall on a singlePistaciahost species. The genusGeoica(Fordini) induce similar spherical closed galls on the lower side of the leaflet’s midvein, on differentPistaciaspecies. Two species ofPistaciatrees that harborGeoicagalls grow naturally in Israel:P.palaestinaandP. atlantica.We analyzed the phylogeny and the genetic structure of theGeoicaspecies complex in Israel, and assessed the genetic differentiation and the level of host plant specificity of the aphids betweenP.atlanticaandP. palaestina. We found that the splitting of the genus betweenP. atlanticaandP. palaestinais estimated to have occurred 24–25 Ma (the Oligocene/Miocene boundary). Five different haplotypes suggesting five different species have been further speciating amongGeoicaspp., galling onP. atlantica, and an additional three species, onP. palaestina.

Accession Numbers (COI sequences):

MW452548 - Pp-Q-7d-Gamla - Haplotype-VI

MW452549 - Pp-Q-10b-Gamla - Haplotype-VII

MW452550 - Pp-A-1a-Mezar - Haplotype-VII

MW452551 - Pp-S-6c-Sasa - Haplotype-VI

MW452552 - Pp-New Hermon-2-5 - Haplotype-VIII

MW452553 - Pa-Q-10a-II Gamla - Haplotype-IV

MW452554 - Pa-Q-5d Gamla - Haplotype-II

MW452555 - Pa-A-2f Mezar - Haplotype-IV

MW452556 - Pa-E-13 Anafa - Haplotype-III

MW452557 - Pa-K-10a Adolam - Haplotype-IV

MW452558 - Pa-K-3a Adolam - Haplotype-II

MW452559 - Pa-N-2a Nizana - Haplotype-I

MW452560 - Pa-Z-1-3 Hazeva - Haplotype-I

MW452561 - Pa-SL-3-3 Jordan-Sela - Haplotype-V
Stroke disconnectome decodes reading networks
Authors: Forkel Stephanie J. , Labache Loïc , Nachev Parashkev , de Schotten Michel Thiebaut , Hesling Isabelle
Published: March 2022

Cognitive functional neuroimaging has been around for over 30 years and has shed light on the brain areas relevant for reading. However, new methodological developments enable mapping the interaction between functional imaging and the underlying white matter networks. In this study, we used such a novel method, called the disconnectome, to decode the reading circuitry in the brain. We used the resulting disconnection patterns to predict the typical lesion that would lead to reading deficits after brain damage. Our results suggest that white matter connections critical for reading include fronto-parietal U-shaped fibres and the vertical occipital fasciculus (VOF). The lesion most predictive of a reading deficit would impinge on the left temporal, occipital, and inferior parietal gyri. This novel framework can systematically be applied to bridge the gap between the neuropathology of language and cognitive neuroscience.
The effects of explicit and implicit information on modulation of corticospinal excitability during hand-object interactions
Authors: Rens Guy , Davare Marco , van Polanen Vonne
Published: March 2022

Fingertip force scaling during hand-object interactions typically relies on visual information about the object and sensorimotor memories from previous object interactions. Here, we investigated whether contextual information, that is not explicitly linked to the intrinsic object properties (e.g., size or weight) but is informative for motor control requirements, can mediate force scaling. For this, we relied on two separate behavioral tasks during which we applied transcranial magnetic stimulation (TMS) to probe corticospinal excitability (CSE), as a window onto the primary motor cortex role in controlling fingertip forces. In experiment 1, participants performed a force tracking task, where we manipulated available implicit and explicit visual information. That is, either the force target was fully visible, or only the force error was displayed as a deviation from a horizontal line. We found that participants’ performance was better when the former condition, in which they had explicit access to predictive information. However, we did not find differences in CSE modulation based on the type of visual information. On the other hand, CSE was modulated by the change in muscle contraction, i.e., contraction vs. relaxation and fast vs. slow changes. In sum, these findings indicate that CSE only reflects the ongoing motor command. In experiment 2, other participants performed a sequential object lifting task of visually identical objects that were differently weighted, in a seemingly random order. Within this task, we hid short series of incrementally increasing object weights. This allowed us to investigate whether participants would scale their forces for specific object weights based on the previously lifted object (i.e., sensorimotor effect) or based on the implicit information about the hidden series of incrementally increasing weights (i.e., extrapolation beyond sensorimotor effects). Results showed that participants did not extrapolate fingertip forces based on the hidden series but scaled their forces solely on the previously lifted object. Unsurprisingly, CSE was not modulated differently when lifting series of random weights versus series of increasing weights. Altogether, these results in two different grasping tasks suggest that CSE encodes ongoing motor components but not sensorimotor cues that are hidden within contextual information.

Highlights

Explicit visual cues and sensorimotor experience are key for object grasping

Investigating influence of implicit, contextual information on object grasping

Explicit but not implicit cues improve motor performance during object grasping

Explicit but not implicit cues modulate corticospinal excitability
slendr: a framework for spatio-temporal population genomic simulations on geographic landscapes
Authors: Petr Martin , Haller Benjamin C. , Ralph Peter L. , Racimo Fernando
Published: March 2022

One of the goals of population genetics is to understand how evolutionary forces shape patterns of genetic variation over time. However, because populations evolve across both time and space, most evolutionary processes also have an important spatial component, acting through phenomena such as isolation by distance, local mate choice, or uneven distribution of resources. This spatial dimension is often neglected, partly due to the lack of tools specifically designed for building and evaluating complex spatio-temporal population genetic models. To address this methodological gap, we present a new framework for simulating spatially-explicit genomic data, implemented in a new R package calledslendr(www.slendr.net), which leverages a SLiM simulation back-end script bundled with the package. With this framework, the users can programmatically and visually encode spatial population ranges and their temporal dynamics (i.e., population displacements, expansions, and contractions) either on real Earth landscapes or on abstract custom maps, and schedule splits and gene-flow events between populations using a straightforward declarative language. Additionally,slendrcan simulate data from traditional, non-spatial models, either with SLiM or using an alternative built-in coalescentmsprimeback end. Together with its R-idiomatic interface to thetskitlibrary for tree-sequence processing and analysis,slendropens up the possibility of performing efficient, reproducible simulations of spatio-temporal genomic data entirely within the R environment, leveraging its wealth of libraries for geospatial data analysis, statistics, and visualization. Here, we present the design of theslendrR package and demonstrate its features on several practical example workflows.
A novel method for reliably measuring miniature and spontaneous postsynaptic potentials/currents in whole-cell patch clamp recordings in the central nervous system
Authors: Dervinis Martynas , Major Guy
Published: March 2022

Measurements of miniature postsynaptic currents (mPSCs) or potentials (mPSPs) in the soma of neurons of the central nervous system (CNS) provide a way of quantifying the synaptic function at the network level and, therefore, are routine in the neurophysiology literature. These miniature responses (or minis) are thought to be elicited by the spontaneous release of a single neurotransmitter vesicle, also called quantum. As such their measurement at the soma can potentially offer a technically straightforward way of estimating ‘quantal sizes’ of central synapses. However, popular methods for detecting minis in whole-cell recordings fall short of being able to reliably distinguish them from background physiological noise. This issue has received very limited attention in the literature and its scope as well as the relative performance of existing algorithms have not been quantified. As a result, solutions for reliably measuring the quantal size in somatic recordings also do not exist. As the first step in proposing and testing a potential solution, we developed and described a novel mPSP/mPSC detection algorithm as part of our quantal analysis software called ‘minis’. We tested its performance in detecting real and simulated minis in whole-cell recordings from pyramidal neurons in rat neocortical slices and compared it to two of the most-used mini detection algorithms. This benchmarking revealed superior detection by our algorithm. The release version of the algorithm also offers great flexibility via graphical and programming interfaces.
Vaginal microbiome-host interactions modeled in a human vagina-on-a-chip
Authors: Mahajan Gautam , Doherty Erin , To Tania , Sutherland Arlene , Grant Jennifer , Junaid Abidemi , Gulati Aakanksha , LoGrande Nina Teresa , Izadifar Zohreh , Timilsina Sanjay Sharma , Horváth Viktor , Plebani Roberto , France Michael , Hood-Pishchany Indriati , Rakoff-Nahoum Seth , Kwon Douglas S. , Goyal Girija , Prantil-Baun Rachelle , Ravel Jacques , Ingber Donald E.
Published: March 2022

Background

A dominance of non-iners Lactobacillus species in the vaginal microbiome is optimal and strongly associated with gynecological and obstetric health, while the presence of diverse obligate or facultative anaerobic bacteria and a paucity in Lactobacillus species, similar to communities found in bacterial vaginosis (BV), is considered non-optimal and associated with adverse health outcomes. Various therapeutic strategies are being explored to modulate the composition of the vaginal microbiome; however, there is no human model that faithfully reproduces the vaginal epithelial microenvironment for preclinical validation of potential therapeutics or testing hypotheses about vaginal epithelium-microbiome interactions.

Results

Here, we describe an organ-on-a-chip (Organ Chip) microfluidic culture model of the human vaginal mucosa (Vagina Chip) that is lined by hormone-sensitive, primary vaginal epithelium interfaced with underlying stromal fibroblasts, which sustains a low physiological oxygen concentration in the epithelial lumen. We show that the Vagina Chip can be used to assess colonization by optimal L. crispatus consortia as well as non-optimal Gardnerella vaginalis-containing consortia, and to measure associated host innate immune responses. Co-culture of the L. crispatus consortia was accompanied by maintenance of epithelial cell viability, accumulation of D- and L-lactic acid, maintenance of a physiologically relevant low pH, and down regulation of proinflammatory cytokines. In contrast, co-culture of G. vaginalis-containing consortia in the Vagina Chip resulted in epithelial cell injury, a rise in pH, and upregulation of proinflammatory cytokines.

Conclusion

This study demonstrates the potential of applying human Organ Chip technology to create a preclinical model of the human vaginal mucosa that can be used to better understand interactions between the vaginal microbiome and host tissues, as well as to evaluate the safety and efficacy of live biotherapeutics products.
Target-agnostic discovery of Rett Syndrome therapeutics by coupling computational network analysis and CRISPR-enabled in vivo disease modeling
Authors: Novak R. , Lin T. , Kaushal S. , Sperry M. , Vigneault F. , Gardner E. , Loomba S. , Shcherbina K. , Keshari V. , Dinis A. , Vasan A. , Chandrasekhar V. , Takeda T. , Turner J.R. , Levin M. , Ingber D.E.
Published: March 2022

Many neurodevelopmental genetic disorders, such as Rett syndrome, are caused by a single gene mutation but trigger changes in expression and regulation of numerous other genes. This severely impair functions of multiple organs and organ systems beyond the central nervous system (CNS), adding to the challenge of developing broadly effective treatments based on a single drug target. This challenge is further complicated by the lack of sufficiently broad and biologically relevant drug screens, and the inherent complexity in identifying clinically relevant targets responsible for diverse phenotypes. Here, we combined human gene regulatory network-based computational drug prediction with in vivo screening in a population-level diversity, CRISPR-edited, Xenopus laevis tadpole model of Rett syndrome to carry out target-agnostic drug discovery, which rapidly led to the identification of the FDA-approved drug vorinostat as a potential repurposing candidate. Vorinostat broadly improved both CNS and non-CNS (e.g., gastrointestinal, respiratory, inflammatory) abnormalities in a pre-clinical mouse model of Rett syndrome. This is the first Rett syndrome treatment to demonstrate pre-clinical efficacy across multiple organ systems when dosed after the onset of symptoms, and network analysis revealed a putative therapeutic mechanism for its cross-organ normalizing effects based on its impact on acetylation metabolism and post-translational modifications of microtubules. Although traditionally considered an inhibitor of histone deacetylases (HDAC), vorinostat unexpectedly restored protein acetylation across both hypo- and hyperacetylated tissues, suggesting non-HDAC-mediated therapeutic mechanisms supported by proteomic analysis.
Computational exploration of bio-remediation solution for mixed plastic waste
Authors: Sunny  , Maurya Ankita , Vats Mohit Kumar , Khare Sunil Kumar , Srivastava Kinshuk Raj
Published: March 2022

The plastic materials are recalcitrant in the open environment, surviving longer without complete remediation. The current disposal methods of used plastic material are not efficient; consequently, plastic wastes are infiltrating the natural resources of the biosphere. A sustaining solution for plastic waste is either recycling or making it part of the earth’s biogeochemical cycle. We have collected, manually mined, and analyzed the previous reports on plastic biodegradation. Our results demonstrate that the biodegradation pattern of plastics follows the chemical classification of plastic types. Based on clustering analysis, the distant plastic types are grouped into two broad categories of plastic types, C-C (non-hydrolyzable) and C-X (hydrolyzable). The genus enrichment analysis suggests that Pseudomonas and Bacillus from bacteria and Aspergillus and Penicillium from fungal are potential genera for bioremediation of mixed plastic waste. Overall results have pointed towards a possible solution of mixed plastic waste either in a circular economy or open remediation. The meta-analysis of the reports revealed a historical inclination of biodegradation studies towards C-X type of plastic; however, the C-C class is dominated in overall plastic production. An interactive web portal of reports is hosted at plasticbiodegradation.com for easy access by other researchers for future studies
The non-catalytic role of DNA polymerase epsilon in replication initiation in human cells
Authors: Vipat Sameera , Gupta Dipika , Jonchhe Sagun , Anderspuk Hele , Rothenberg Eli , Moiseeva Tatiana N.
Published: March 2022

DNA polymerase epsilon in an essential enzyme, responsible for the synthesis of the leading strand during DNA replication. Deficiencies and mutations in DNA polymerase epsilon catalytic subunit (POLE1) cause severe developmental abnormalities and cancers. Paradoxically, the non-catalytic C-terminal domain of yeast polymerase epsilon catalytic subunit (Pol2) is sufficient for cell survival. The non-catalytic essential function of Pol2 in yeast has been associated with its role in the assembly of the replicative helicase CMG. However, the understanding of POLE1 functions in DNA replication initiation in human cells is falling behind. In this study we use an auxin-inducible degron system to study the effect of POLE1 depletion on replication initiation in human cells. Surprisingly, in the absence of POLE1, human cells were able to assemble CMG helicase and initiate DNA synthesis that failed shortly after. Expression of POLE1 C-terminal non-catalytic domain was enough to rescue replication initiation and support slow, but processive DNA synthesis, which was dependent on the POLE1-POLE2 interaction. We propose a model where in human cells POLE1/POLE2 are not essential for CMG assembly, but are required during later steps of replication initiation. Our study provides some insights into the role of DNA polymerase epsilon in replication initiation in human cells.
A reinforcement learning algorithm shapes maternal care in mice
Authors: Xie Yunyao , Huang Longwen , Corona Alberto , Pagliaro Alexa H. , Shea Stephen D.
Published: March 2022

The neural substrates for processing classical rewards such as food or drugs of abuse are well-understood. In contrast, the mechanisms by which organisms perceive social contact as rewarding and subsequently modify their interactions are unclear. Here we tracked the gradual emergence of a repetitive and highly-stereotyped parental behavior and show that trial-by-trial performance correlates with the history of midbrain dopamine (DA) neuron activity. We used a novel behavior paradigm to manipulate the subject’s expectation of imminent pup contact and show that DA signals conform to reward prediction error, a fundamental component of reinforcement learning (RL). Finally, closed-loop optogenetic inactivation of DA neurons at the onset of pup contact dramatically slowed emergence of parental care. We conclude that this prosocial behavior is shaped by an RL mechanism in which social contact itself is the primary reward.

One-Sentence Summary

Maternal interactions with offspring are shaped by a dopaminergic reinforcement learning mechanism.