bluuebunny/crossref_metadata_2025 huggingface dataset:
Classification of Skull Shape Deformities Related to Craniosynostosis on 3D Photogrammetry
Authors: Kronig Sophia A.J. , Kronig Otto D.M. , Vrooman Henri A. , Van Adrichem Léon N.A.
Published: August 2022

Implementation of the Utrecht Cranial Shape Quantificator (UCSQ) classification method on 3D photogrammetry in patients with different types of craniosynostosis is the aim of the present study. Five children (age <1 year) of every group of the common craniosynostoses (scaphocephaly, brachycephaly, trigonocephaly, right-sided and left-sided anterior plagiocephaly) were randomly included. The program 3-Matic (v13.0) was used to import and analyze the included 3dMD photos. Three external landmarks were placed. Using the landmarks, a base plane was created, as well as a plane 4 cm superior to the base plane. Using UCSQ, we created sinusoid curves of the patients, the resulting curves were analyzed and values were extracted for calculations. Results per patient were run through a diagnostic flowchart in order to determine correctness of the flowchart when using 3D photogrammetry. Each of the patients (n=25) of the different craniosynostosis subgroups is diagnosed correctly based on the different steps in the flowchart. This study proposes and implements a diagnostic approach of craniosynostosis based on 3D photogrammetry. By using a diagnostic flowchart based on specific characteristics for every type of craniosynostosis related to specific skull deformities, diagnosis can be established. All variables are expressed in number and are therefore objective.
Restoration of Lower Facial and Neck Esthetics by Application of Pre-Expanded Bipedicle Scalp and Free Scapular Flaps
Authors: Pei Jiaomiao , Zhang Juan , Li Yang , Liu Chaohua , Song Baoqiang
Published: August 2022

Objective:

To introduce the surgical procedures and experiences in restoration of lower facial esthetics for a male and a female patients who suffered from burn injuries. The difference of surgical methods which varied from sexes were discussed.

Materials and Methods:

The clinical data of the patients was collected and retrospectively analyzed. The cervical contracture was repaired by pre-expanded free scapular flaps with sufficient pliable tissue for large defects. Moreover, for the male patient, prefabricated double pedicle scalp flap was applied to rebuild the beard region. The patients were followed up for 2 years. Surgical procedures and outcomes were detailed in the article.

Results:

All the flaps were survived well. The facial hair-bearing area of the man was recovered with natural appearance. The reconstructed mental cervical angels and mandibular margins were clear. The neck extension mobility was improved. The 2 patients were satisfied with the outcomes of the treatments.

Conclusion:

The treatments of facial and neck scar varied from sexes and different requirements. For male patient, the combination of scalp and scapular flaps was a feasible method to achieve natural beard and cervical appearance. For female patient, bilateral expanded scapular flaps could meet the demands of large tissue supply and a relative hidden donor site.
COVID-19 associated myopathy
Authors: Aschman Tom , Stenzel Werner
Published: August 2022

Purpose of review

The global spread of severe acute respiratory syndrome coronavirus 2 resulted in many cases of acute and postacute muscular symptoms. In this review, we try to decipher the potential underlying pathomechanisms and summarize the potential links between viral infection and muscle affection.

Recent findings

Disregarding single case studies that do not allow safe conclusions due to the high number of infections, histopathological evidence of myositis has only been reported in deceased individuals with severe COVID-19. Postacute myalgia and weakness seem to occur in a subset of patients up to one year after initial infection, reminiscent of postinfectious syndromes (PIS) described in prior epidemics and pandemics of the past.

COVID-19 associated myopathy likely comprises different entities with heterogeneous pathomechanisms. Individual factors such as disease severity and duration, age, sex, constitutional susceptibilities, and preexisting conditions are important to consider when formulating a diagnosis. Persisting symptoms show overlapping features with PIS or postintensive care syndrome. In lack of strong evidence for a direct infection of myocytes, inflammatory myopathies associated with COVID-19 are presumably immune-mediated. Differential diagnosis of rheumatological and nonmuscular neurological origin coinciding with the infection need to be considered, due to the extremely high numbers of newly occurring infections the last 2 years.
Early Detection of Emerging SARS-CoV-2 Variants of Interest for Experimental Evaluation
Authors: Wallace Zachary S. , Davis James , Niewiadomska Anna Maria , Olson Robert D. , Shukla Maulik , Stevens Rick , Zhang Yun , Zmasek Christian M. , Scheuermann Richard H.
Published: August 2022

Since the beginning of the COVID-19 pandemic, SARS-CoV-2 has demonstrated its ability to rapidly and continuously evolve, leading to the emergence of thousands of different sequence variants, many with distinctive phenotypic properties. Fortunately, the broad availability of next generation sequencing (NGS) technologies across the globe has produced a wealth of SARS- CoV-2 genome sequences, offering a comprehensive picture of how this virus is evolving so that accurate diagnostics and reliable therapeutics for COVID-19 can be maintained. The millions of SARS-CoV-2 sequences deposited into genomic sequencing databases, including GenBank, BV-BRC, and GISAID are annotated with the dates and geographical regions of sample collection, and can be aligned to the Wuhan-Hu-1 reference genome to extract the constellation of nucleotide and amino acid substitutions. By aggregating these data into concise datasets, the spread of variants through space and time can be assessed. Variant tracking efforts have focused on the spike protein due to its critical role in viral tropism and antibody neutralization. To identify emerging variants of concern as early as possible, we developed a computational pipeline to process the genomic data from public databases and assign risk scores based on both epidemiological and functional parameters. Epidemiological dynamics are used to identify variants exhibiting substantial growth over time and across geographical regions. In addition, experimental data that quantify Spike protein regions critical for adaptive immunity are used to predict variants with consequential immunogenic or pathogenic impacts. These growth assessment and functional impact scores are combined to produce a Composite Score for any set of Spike substitutions detected. With this systematic approach to routinely score and rank emerging variants, we have established a method to identify threatening variants early and prioritize them for experimental evaluation.
Common genetic variant of GC associated with vitamin D deficiency in a Chinese population in the Netherlands
Authors: Man Ping Wai , Böhringer Stefan , Houwink Elisa J.F. , Lin Wenzhi , Numans Mattijs E. , Lips Paul , Middelkoop Barend J. C.
Published: August 2022

Background

Genome-wide association studies among European populations have identified four single nucleotide polymorphisms (SNPs) in genes involved in vitamin D transport and metabolism affecting 25-hydroxyvitamin D [25(OH)D] concentration: rs2282679 in GC, rs6013897 near CYP24A1, rs10741657 near CYP2R1, and rs12785878 near DHCR7. It is, however, unknown whether the association with 25(OH)D can also be observed in a Chinese population living in the Netherlands.

Methods

Observational study. Analyses were performed under an additive (univariate and multivariate) and genotypic model using logistic regression.

Results

The C allele (minor allele frequency 0.28) of rs2282679 in GC was associated with vitamin D deficiency as defined by the Health Council of the Netherlands: 25(OH)D <30 nmol/l (or <50 nmol/l for persons aged ≥70 years). Univariate and multivariate odds ratios, 1.52 (95% CI 1.03, 2.24) and 1.57 (95% CI 1.04, 2.39), respectively, were not significant after Bonferroni correction. However, after extending the data by a meta-analysis, a significant association between C allele of rs2282679 and vitamin D deficiency (< 50 nmol/l) was observed (odds ratio 1.33; 95% CI 1.16, 1.52).

Conclusion

Our findings suggest that, apart from sun exposure, lifestyle, and environmental factors, a common variant of GC may be associated with vitamin D deficiency.
Outcome of COVID-19 in hospitalised immunocompromised patients: an analysis of the WHO ISARIC CCP-UK prospective cohort study
Authors: Turtle Lance , Thorpe Mathew , Drake Thomas M , Swets Maaike , Palmieri Carlo , Russell Clark D , Ho Antonia , Aston Stephen , Wootton Daniel G , Richter Alex , de Silva Thushan I , Hardwick Hayley E , Leeming Gary , Law Andy , Openshaw Peter JM , Harrison Ewen M ,   ISARIC4C investigators, Baillie J Kenneth , Semple Malcolm G , Docherty Annemarie B
Published: August 2022

Background

Immunocompromised patients may be at higher risk of mortality if hospitalised with COVID-19 compared with immunocompetent patients. However, previous studies have been contradictory. We aimed to determine whether immunocompromised patients were at greater risk of in-hospital death, and how this risk changed over the pandemic.

Methods

We included patients >=19yrs with symptomatic community-acquired COVID-19 recruited to the ISARIC WHO Clinical Characterisation Protocol UK. We defined immunocompromise as: immunosuppressant medication preadmission, cancer treatment, organ transplant, HIV, or congenital immunodeficiency. We used logistic regression to compare the risk of death in both groups, adjusting for age, sex, deprivation, ethnicity, vaccination and co-morbidities. We used Bayesian logistic regression to explore mortality over time.

Findings

Between 17/01/2020 and 28/02/2022 we recruited 156,552 eligible patients, of whom 21,954 (14%) were immunocompromised. 29% (n=6,499) of immunocompromised and 21% (n=28,608) of immunocompetent patients died in hospital. The odds of in-hospital mortality were elevated for immunocompromised patients (adjOR 1.44, 95% CI 1.39-1.50, p<0.001). As the pandemic progressed, in-hospital mortality reduced more slowly for immunocompromised patients than for immunocompetent patients. This was particularly evident with increasing age: the probability of the reduction in hospital mortality being less for immunocompromised patients aged 50-69yrs was 88% for men and 83% for women, and for those >80yrs was 99% for men, and 98% for women.

Conclusions

Immunocompromised patients remain at elevated risk of death from COVID-19. Targeted measures such as additional vaccine doses and monoclonal antibodies should be considered for this group.

Funding

National Institute for Health Research; Medical Research Council; Chief Scientist Office, Scotland.
Microglia associations with brain pericytes and the vasculature are reduced in Alzheimer’s disease
Authors: Morris Gary P. , Foster Catherine G. , Courtney Jo-Maree , Collins Jessica M. , Cashion Jake M. , Brown Lachlan S. , Howells David W. , DeLuca Gabriele C. , Canty Alison J. , King Anna E. , Ziebell Jenna M. , Sutherland Brad A.
Published: August 2022

Cerebral blood flow is important for the maintenance of brain function and its dysregulation has been implicated in Alzheimer’s disease (AD). Subpopulations of microglia have well-characterised associations with the vasculature in the central nervous system but the precise relationship between microglia and cells which exist on the vasculature is not yet clear. In this study we explored the relationship between microglia and pericytes, a vessel-resident cell type that has a major role in the regulation of cerebral blood flow and maintenance of the blood brain barrier. Using fixed tissue sections and in vivo live imaging, we discovered a subset of microglia that closely associated with pericytes, termed PEricyte-associated Microglia (PEM). PEM are present throughout all regions of the brain and spinal cord in NG2DsRed x CX3CR1+/GFP mice, and in the human frontal cortex. They reside adjacent to pericytes at all levels of the capillary tree and can maintain their position for at least 28 days. PEM associate with pericytes lacking astroglial endfeet coverage but are segregated from pericytes by capillary basement membranes and capillary vessel width is similarly increased beneath pericytes with or without an associated PEM. Deletion of the microglia fractalkine receptor (CX3CR1) did not disrupt the association between pericytes and PEM, suggesting the association is not reliant on fractalkine signalling. Finally, we found that the proportion of microglia that are capillary-associated and PEM declines in the superior frontal gyrus (SFG) in AD, which is exacerbated by the APOE ε3/ε4 genotype. In summary, we identify and characterise a subpopulation of microglia that specifically associate with pericytes and find this population is reduced in the SFG in AD. This reduction may be a novel mechanism contributing to vascular dysfunction in diseases such as AD.
Adaptive radioresistance of Enterohemorrhagic Escherichia coli O157:H7 results in genomic loss of shiga toxin-encoding prophages
Authors: Gaougaou Ghizlane , Vincent Antony T. , Krylova Kateryna , Habouria Hajer , Bessaiah Hicham , Baraketi Amina , Veyrier Frédéric J. , Dozois Charles M. , Déziel Eric , Lacroix Monique
Published: August 2022

Enterohemorragic Escherichia coli (EHEC) O157:H7 is a foodborne pathogen producing shiga toxins (Stx1 and Stx2), can cause hemorrhagic diarrhea, and life-threatening infections. O157:H7 strain EDL933 carries prophages CP-933V and BP-933W that encode shiga toxin genes (stx1 and stx2 respectively). The aim of this work was to investigate the mechanisms of adaptive resistance of EHEC strain EDL933 to a typically “lethal” dose of γ-irradiation (1.5 kGy). Adaptive selection through six passages of exposure to 1.5 kGy resulted in the loss of CP-933V and BP-933W prophages from the genome and mutations within three genes: wrbA, rpoA, and Wt_02639 (molY). Three selected EHEC clones that became irradiation-adapted to the 1.5 kGy dose (C1, C2 and C3) demonstrated increased resistance to oxidative stress, sensitivity to acid pH, and decreased cytotoxicity to Vero cells. To confirm that loss of prophages plays a role in increased radioresistance, C1 and C2 clones were exposed to bacteriophage containing lysates. Although, phage BP-933W could lysogenize C1, C2, and E.coli K-12 strain MG1655, it was not found to have integrated into the bacterial chromosome in C1-Φ and C2-Φ lysogens. Interestingly, for the E. coli K-12 lysogen (K12-Φ), BP-933W DNA had integrated at the wrbA gene (K12-Φ). Both C1-Φ and C2-Φ lysogens regained sensitivity to oxidative stress, were more effectively killed by a 1.5 kGy γ-irradiation dose and had regained cytotoxicity and acid resistance phenotypes. Further, the K12-Φ lysogen became cytotoxic, more sensitive to γ-irradiation and oxidative stress and slightly more acid resistant.

Importance

Gamma (γ)-irradiation of food products can provide an effective means of eliminating bacterial pathogens such as enterohemorrhagic Escherichia coli (EHEC) O157:H7, a significant foodborne pathogen that can cause severe disease due to the production of Shiga toxins. To decipher the mechanisms of adaptive resistance of the O157:H7 strain EDL933, we evolved clones of this bacterium resistant to a lethal dose of γ-irradiation by repeatedly exposing bacterial cells to irradiation following a growth restoration over six successive passages. Our findings provide evidence that adaptive selection involved modifications in the bacterial genome including deletion of the CP-933V and BP-933W prophages. These mutations in EHAC O157:H7 resulted in loss of stx1, stx2, loss of cytotoxicity to epithelial cells and decreased resistance to acidity, critical virulence determinants of EHEC, concomitant with increased resistance to lethal irradiation and oxidative stress. These findings demonstrate that the potential adaptation of EHEC to high doses of radiation would involve elimination of the Stx encoding phages and likely lead to a substantial attenuation of virulence.
Variant-risk-exon interplay impacts circadian rhythm and dopamine signaling pathway in severe psychiatric disorders
Authors: Worf Karolina , Matosin Natalie , Gerstner Nathalie , Fröhlich Anna S. , Koller Anna C. , Degenhardt Franziska , Thiele Holger , Rietschel Marcella , Udawela Madhara , Scarr Elizabeth , Dean Brian , Theis Fabian J. , Knauer-Arloth Janine , Mueller Nikola S.
Published: August 2022

In psychiatric disorders, common and rare genetic variants cause widespread dysfunction of cells and their interactions, especially in the prefrontal cortex, giving rise to psychiatric symptoms. To better understand these processes, we traced the effects of common and rare genetics, and cumulative disease risk scores, to their molecular footprints in human cortical single-cell types. We demonstrated that examining gene expression at single-exon resolution is crucial for understanding the cortical dysregulation associated with diagnosis and genetic risk derived from common variants. We then used disease risk scores to identify a core set of genes that serve as a footprint of common and rare variants in the cortex. Pathways enriched in these genes included dopamine regulation, circadian entrainment, and hormone regulation. Single-nuclei-RNA-sequencing pinpointed these enriched genes to excitatory cortical neurons. This study highlights the importance of studying sub-gene-level genetic architecture to classify psychiatric disorders based on biology rather than symptomatology, to identify novel targets for treatment development.
Gain and loss of function variants in EZH1 disrupt neurogenesis timing and cause overlapping neurodevelopmental disorders
Authors: Gracia-Diaz Carolina , Zhou Yijing , Yang Qian , Lee Chul-Hwan , Espana-Bonilla Paula , Zhang Shuo , Padilla Natàlia , Fueyo Raquel , Otrimski Garrett , Li Dong , Sheppard Sarah , Mark Paul , Harr Margaret H. , Hakonarson Hakon , Rodan Lance , Jackson Adam , Vasudevan Pradeep , Powel Corrina , Mohammed Shehla , Maddirevula Sateesh , Alzaidan Hamad , Faqeih Eissa A. , Efthymiou Stephanie , Turchetti Valentina , Rahman Fatima , Maqbool Shazia , Salpietro Vincenzo , Ibrahim Shahnaz H , di Rosa Gabriella , Houlden Henry , Estaras Conchi , Hurst Anna C.E. , Thompson Michelle L. , Chassevent Anna , Smith-Hicks Constance L. , de la Cruz Xavier , Holtz Alexander , Torti Erin , Hajianpour MJ , Rieubland Claudine , Braun Dominique , Banka Siddharth ,   Genomic England Research Consortium, Heller Elizabeth A. , Saade Murielle , Song Hongjun , Ming Guo-Li , Alkuraya Fowzan S. , Maroofian Reza , Agrawal Pankaj B. , Reinberg Danny , Bhoj Elizabeth J. , Martinez-Balbas Marian A. , Akizu Naiara
Published: August 2022

Genetic disruption of chromatin regulators is frequently found in neurodevelopmental disorders (NDDs). While chromatin regulators are attractive therapeutic targets, studies to determine their implication in the etiology of NDDs are limited, preventing advances in diagnosis and treatment strategies. Here, we uncover pathogenic variants in the chromatin modifier Enhancer of Zeste Homologue 1 (EZH1) as the cause of overlapping recessive and dominant NDDs in 17 individuals. EZH1 encodes one of the two alternative histone H3 lysine 27 (K27) methyltransferases of the Polycomb Repressive Complex 2 (PRC2). Unlike the other PRC2 subunits, which are associated with the pathogenesis of human cancers and developmental disorders, the implication of EZH1 in human development and disease is largely unknown. Using cellular models and biochemical studies, we demonstrate that recessive variants cause EZH1 loss of function (LOF), while dominant variants are all missense mutations that modify the catalytic activity of EZH1, thus generating a gain of function (GOF) effect. Consistent with a pathogenic effect, depletion or overexpression of EZH1 perturbs neuronal differentiation in the developing chick embryo neural tube. Furthermore, using human pluripotent stem cell (hPSC) derived neural cultures and forebrain organoids, we show that EZH1 LOF and GOF variants respectively delay and accelerate the schedule of cortical projection neuron generation. Our work identifies EZH1 LOF and GOF variants as the genetic basis of previously undefined NDDs and uncovers an essential role of EZH1 in regulating the timing of neurogenesis.
Safety and Immunogenicity of Intradermal Administration of Fractional Dose CoronaVac®, ChAdOx1 nCoV-19 and BNT162b2 as Primary Series Vaccination
Authors: Chatsiricharoenkul Somruedee , Niyomnaitham Suvimol , Posen H. Joshua , Toh Zheng Quan , Licciardi Paul V , Wongprompitak Patimaporn , Duangchinda Thaneeya , Pakchotanon Pattarakul , Chantima Warangkana , Chokephaibulkit Kulkanya
Published: August 2022

There is a limited supply of COVID-19 vaccines, with less than 20% of eligible populations in low-income countries having received one dose. Intradermal delivery of fractional dose vaccines is one way to improve global vaccine access, but no studies have reported data on intradermal delivery of COVID-19 primary series vaccination. We conducted a pilot study to examine the safety and immunogenicity of three intradermal primary series regimens – heterologous regimen of CoronaVac and ChAdOx1 (CoronaVac-ChAdOx1), homologous regimen of ChAdOx1 (ChAdOx1-ChAdOx1), and homologous regimen of BNT162b2 (BNT162b2-BNT162b2). Each dose was 1/5th or 1/6th of the standard dose. Two additional exploratory arms of intradermal vaccination for the second dose following an intramuscular first dose of ChAdOx1 and BNT162b2 were included. Intradermal vaccination was found to be immunogenic and safe. The antibody responses generated by the intradermal primary series were highest in the BNT162b2 arms. The anti-receptor binding domain (anti-RBD) IgG concentration following fractional dose intradermal vaccination was similar to that of standard dose intramuscular vaccination of the same regimen, except for BNT162b2. The BNT162b2 intradermal series generated a lower antibody concentration than the reference intramuscular series, despite generating the highest antibody concentration of all three intradermal primary series regimens. Neutralizing antibody responses against the SARS-CoV-2 ancestral strain were consistent with what was observed for anti-RBD IgG, with lower titers for SARS-CoV-2 variants. The FRNT50 titers were lowest against the omicron variant, being undetectable (GMT≤10) in about a quarter of study participants. T-cell responses against spike- and nucleocapsid-membrane-open reading frame proteins were also detected following intradermal vaccination. Adverse effects following intradermal vaccination were generally comparable with post-intramuscular vaccination effects. Taken together, our data suggest that intradermal vaccination using 1/5th or 1/6th of standard COVID-19 intramuscular vaccination dosing generates similar immune responses with tendency of lower systemic adverse reactions than intramuscular vaccination. Our findings have implications in settings where COVID-19 vaccines are in shortage.
Portable nucleic acid tests for rapid detection of monkeypox virus
Authors: Bhadra Sanchita , Ellington Andrew D.
Published: August 2022

We report two isothermal nucleic acid amplification assays for detection of monkeypox virus (MPXV) clades 2 and 3 that include the strains responsible for the current global outbreak of monkeypox. The assays use loop-mediated isothermal amplification (LAMP) to amplify two distinct sequences in the MPXV genome. Readout specificity is ensured by oligonucleotide strand displacement (OSD) probes integrated in one-pot LAMP-OSD reactions. OSD probes undergo toehold-mediated strand displacement hybridization to LAMP amplicon loop sequences derived from MPXV clades 2 and 3 resulting in fluorescence readable both in realtime and visually at endpoint. We also perform both assays on two different portable devices, the GeneTiger and the miniPCR, to exemplify compatibility with minimum infrastructure point-of-care (POC) testing in clinical and at-home settings. Both assays could readily detect single digit copies of MPXV synthetic double stranded DNA templates within 30 min.
Limbic progesterone receptors regulate spatial memory
Authors: Joshi Suchitra , Williams Cedric L , Kapur Jaideep
Published: August 2022

Progesterone and its receptors (PRs) participate in mating and reproduction, but their role in spatial declarative memory, is not understood. Male and female mice express PRs in regions that support spatial memory: the hippocampus and entorhinal cortex. PRs were predominantly expressed in excitatory neurons in Pgr-Cre mice injected with AAV-delivered flexed tdTomato. Furthermore, segesterone, a specific PR agonist, activated neurons in the entorhinal cortex (EC) and the hippocampus. We assessed the PR function in these spatial memory circuit neurons by examining the performance of mice lacking this receptor (PRKO) in novel object recognition, object placement, and Y-maze alternation tasks. In the recognition test, wild-type littermates spent significantly more time exploring the new object than male PRKO mice. The EC-specific deletion of PRs was sufficient to induce a deficit in detecting familiar versus never experienced or new objects. We confirmed deficits in spatial memory of PRKO mice by testing them on the Y-maze forced alternation task. In contrast to spatial tasks, PR removal did not alter the response to fear conditioning. PRs also support spatial memory in female mice. These studies provide novel insights into the role of PR in facilitating spatial, declarative memory in males and females, which may help with finding reproductive partners.

SIGNIFICANCE STATEMENT

Brain progesterone receptors play an essential role in facilitating mating and reproductive behaviors, but their role in spatial memory and, therefore, mate-finding is not described. Principal, excitatory neurons of the entorhinal cortex and hippocampus express progesterone receptors. These receptors facilitate spatial memory in male and female mice, which may enhance mate-finding reproductive function and food foraging.
Follicle-innervating Aδ-low threshold mechanoreceptors organize through a population-dependent mechanism
Authors: Pomaville Matthew B. , Wright Kevin M.
Published: August 2022

The mammalian somatosensory system is comprised of multiple neuronal populations that form specialized, highly organized sensory endings in the skin. The organization of somatosensory endings is essential to their functions, yet the mechanisms which regulate this organization remain unclear. Using a combination of genetic and molecular labeling approaches, we examined the development of mouse hair follicle-innervating low-threshold mechanoreceptors (LTMRs) and explored competition for innervation targets as a mechanism involved in the patterning of their receptive fields. We show that follicle innervating neurons are present in the skin at birth and that LTMR receptive fields gradually add follicle-innervating endings during the first two postnatal weeks. Using a constitutive Bax knockout to increase the number of neurons in adult animals, we show that two LTMR subtypes have differential responses to an increase in neuronal population size: Aδ-LTMR neurons shrink their receptive fields to accommodate the increased number of neurons innervating the skin, while C-LTMR neurons do not. Our findings suggest that competition for hair follicles to innervate plays a role in the patterning and organization of follicle-innervating LTMR neurons.

Summary Statement

Aδ follicle-innervating low-threshold mechanoreceptor neurons form tiled receptive fields through competition for hair follicles during the early postnatal period.
Circadian ribosome profiling reveals a role for thePeriod2upstream open reading frame in sleep
Authors: Millius Arthur , Yamada Rikuhiro , Fujishima Hiroshi , Maeda Kazuhiko , Standley Daron M. , Sumiyama Kenta , Perrin Dimitri , Ueda Hiroki R.
Published: August 2022

Many mammalian proteins have circadian cycles of production and degradation, and many of these rhythms are altered post-transcriptionally. We used ribosome profiling to examine post-transcriptional control of circadian rhythms by quantifying RNA translation in the liver over a 24-h period from circadian-entrained mice transferred to constant darkness conditions and by comparing ribosome binding levels to protein levels for 16 circadian proteins. We observed large differences in ribosome binding levels compared to protein levels, and we observed delays between peak ribosome binding and peak protein abundance. We found extensive binding of ribosomes to upstream open reading frames (uORFs) in circadian mRNAs, including the core clock genePeriod2 (Per2). An increase in the number of uORFs in the 5’UTR was associated with a decrease in ribosome binding in the main coding sequence and a reduction in expression of synthetic reporter constructs. Mutation of thePer2uORF increased luciferase and fluorescence reporter expression in 3T3 cells and increased luciferase expression in PER2:LUC MEF cells. Mutation of thePer2uORF in mice increasedPer2mRNA expression, enhanced ribosome binding onPer2, and reduced total sleep time compared to that in wild-type mice. These results suggest that uORFs affect mRNA post-transcriptionally, which can impact physiological rhythms and sleep.

Significance Statement

Period (Per)is an iconic gene in the field of circadian rhythms since its discovery in 1971 by Seymour Benzer and Ronald Konopka in fruit flies. The inhibitory feedback loop of PER protein drives circadian rhythms. We show thatPer2is regulated by an upstream open reading frame (uORF) in the 5’ untranslated region ofPeriod2mRNA. Mutation of thePer2uORF altered the amplitude of luciferase reporter expression in well-characterized cell culture models.Per2uORF mutant mice had significantly elevatedPer2mRNA levels and exhibited sleep loss, particularly during light-to-dark and dark-to-light transitions, which suggests a role for uORFs in modulating molecular and physiological circadian rhythms.
Sex-, strain and lateral differences in brain cytoarchitecture across a large mouse population
Authors: Elkind David , Hochgerner Hannah , Aloni Etay , Shental Noam , Zeisel Amit
Published: August 2022

The mouse brain is by far the most intensively studied among mammalian brains, yet basic measures of its cytoarchitecture remain obscure. For example, quantifying cell numbers, and the interplay of sex-, strain-, and individual variability in cell density and volume is out of reach for many regions. The Allen Mouse Brain Connectivity project produces high-resolution full brain images of hundreds of brains. Although these were created for a different purpose, they reveal details of neuroanatomy and cytoarchitecture. Here, we used this population to systematically characterize cell density and volume for each anatomical unit in the mouse brain. We developed a deep neural network-based segmentation pipeline that uses the auto-fluorescence intensities of images to segment cell nuclei even within the densest regions, such as the dentate gyrus. We applied our pipeline to 537 brains of males and females from C57BL/6J and FVB.CD1 strains. Globally, we found that increased overall brain volume does not result in uniform expansion across all regions. Moreover, region-specific density changes are often negatively correlated with the volume of the region, therefore cell count does not scale linearly with volume. Many regions, including layer 2/3 across several cortical areas, showed distinct lateral bias. We identified the greatest strain-specific or sex-specific differences in the medial amygdala (MEA), bed nuclei (BST), lateral septum and olfactory system (e.g., MOB, AOB, TR) and prefrontal areas (e.g., ORB) – yet, inter-individual variability was always greater than the effect size of a single qualifier. We provide the results of this analysis as an accessible resource for the community.
Effectiveness of anterior cruciate ligament injury prevention programmes in sport: a scoping review
Authors: Margelli Michele , De Mucci Francesco , Nadaletto Francesco , Manfroni Tommaso Marzi , Beccari Andrea
Published: August 2022

Background

Anterior cruciate ligament injury is the most common ligament injury of the knee and one of the most serious and common injuries in sport. This injury causes a number of both short-term and longterm negative consequences that negatively impact both sports performance and quality of life in general. The literature has recognised the need to improve primary prevention with the aim of decreasing the ACL injury rate. For this reason, numerous ACL-specific prevention programmes have been proposed in recent years that include various types of exercises and different methods of administration. The main objective of this scoping will be to report what the literature tells us about these programmes and prevention for ACL injuries.

Inclusion criteria

Every study about prevention programmes for LCA injury on athletes of all ages participating in professional or amateur sports will be included. This scoping review will consider studies conducted in any context.

Methods

The proposed scoping review will be conducted in accordance with the Joanna Briggs Institute methodology (JBI) for scoping reviews.

The search will be carried out on 6 databases:MEDLINE, Cochrane Central, Scopus, CINHAL, Embase, and PEDro.

Selection and data extraction will be conducted by two blind independent researchers and inconsistencies will be resolved by a third reviewer.

The results will be presented in a schematic, tabular and descriptive format that will line up with the objectives and scope of the review.

Conclusions

This review provides a comprehensive overview of prevention for ACL injuries in sport, in particular the effectiveness of existing prevention programmes. The information provided will be useful for physiotherapists and athletic trainers during the sports season and as a therapeutic education tool. The results of this research will be published in scientific research databases.
Parental Deprivation- and Threat-Based Factors Associated with Youth Emotion-Based Neurocircuitry and Externalizing Behavior: A Systematic Review
Authors: Feeney Kathleen E. , Lobo Rosario Pintos , Hare Megan M. , Morris Stephanie S.J. , Laird Angela R. , Musser Erica D.
Published: August 2022

Parental factors, including negative parenting practices (e.g., family conflict, low monitoring), parental depression, and parental substance use, are associated with externalizing behaviors in youth; however, the mediating role of youth’s neurocircuitry in explaining these associations has been less studied. Both the dimensional and stress acceleration models provide frameworks for understanding how frontolimbic and frontoparietal networks implicated in emotional attention and regulation processes may be associated with parental factors. The current review builds upon this work by examining how deprivation- and threat-based parental factors are associated with youth externalizing behaviors through youth neurocircuitry involved in emotional functioning. A systematic review using PRISMA guidelines was completed and included five studies assessing parenting behaviors, six studies assessing parental depressive symptoms and/or diagnosis, and 12 studies assessing parental history of substance use. Overall, reviewed studies provided support for the dimensional and stress acceleration models within the context of deprivation and threat. There was limited support for the proposed mediation model, as only six studies tested for mediation. Specific recommendations for future work include more deliberate planning related to sample composition, improved clarity related to parental constructs, and consistency in methodology in order to better understand associations between contextual parental influences and youth neural and behavioral functioning.
Motivationally salient cue processing measured using the Monetary Incentive Delay (MID) task with electroencephalography (EEG): A potential marker of apathy in Huntingtons Disease
Authors: Davis Marie-Claire , Hill Aron T , Fitzgerald Paul B , Stout Julie C , Hoy Kate E
Published: August 2022

We explored the utility of the Monetary Incentive Delay (MID) task with concurrent encephalography (EEG) as a marker of apathy in people with Huntingtons disease (HD) as well as neurotypical controls. Specifically, we assessed between and within-group differences in the amplitude of the P300 and Contingent Negative Variation (CNV) event-related potentials as a function of motivational salience. In contrast to neurotypical controls, HD participants' ERP amplitudes were not differentially modulated by motivationally salient cues (i.e., signalling potential gain or loss) compared to neutral cues. Difference waves isolating amplitude specific to the motivationally salient cues were calculated for the P300 and CNV. Only the difference waves for ERPs elicited by gain cues differentiated the groups. The CNV difference wave was also significantly correlated with clinical measures of apathy and processing speed in the HD group. These findings provide initial support for the use of the MID with EEG as a marker of apathy in HD, and its potential as a sensitive outcome measure for novel treatment development.
Single-cell Transcriptomics Reveal Different Maturation Stages and Sublineages Commitment of Human Thymic Invariant Natural Killer T cells
Authors: Maas-Bauer Kristina , Acharya Swati , Baker Jeanette , Lewis David B. , Negrin Robert S. , Simonetta Federico
Published: August 2022

Invariant natural killer T (iNKT) cells are a subset of heterogenous T-cells with potent cytotoxic and immunomodulatory properties. During thymic development, murine iNKT cells go through different maturation stages and differentiate into distinct sublineages, namely iNKT1, iNKT2, and iNKT17 cells. To define maturation stages and to assess sublineage commitment of human iNKT cells during thymic development, we performed single-cell RNA sequencing analysis on human thymic iNKT cells. We show that these iNKT cells displayed heterogeneity and unsupervised analysis identified two clusters: one with an immature profile with high expression of genes that are important for iNKT cell development and enriched in cells expressing an iNKT2 signature, whereas a second cluster displayed a mature, terminally differentiated profile resembling murine iNKT1 cells. Trajectory analysis suggested an ontological relationship between the two clusters. Our work provides the first single cell transcriptomic analysis of thymic human iNKT cells offering new insights into their developmental process in humans.
Macrophage migrates on alternate non-adhesive surfaces
Authors: Xing Fulin , Dong Hao , Yang Jianyu , Fan Chunhui , Hou Mengdi , Zhang Ping , Hu Fen , Zhou Jun , Chen Liangyi , Pan Leiting , Xu Jingjun
Published: August 2022

Macrophages migrate across tissues upon immune demand, but their motility on heterogeneous substrates remains unclear. Protein-repelling reagents, e.g., poly(ethylene) glycol (PEG), are routinely employed to resist cell adhering and migrating. Contrary to this perception, we discovered a unique locomotion of macrophages in vitro that they overcome non-adhesive PEG gaps to reach adhesive regions in a mesenchymal mode. Adhesion to adhesive regions was a prerequisite for macrophages to perform further locomotion on the PEG regions, or else they kept a suspended round shape. Podosomes were found highly enriched on the PEG region, which supported macrophage migration. Myosin IIA played a negative role in macrophage motility. Moreover, a developed cellular Potts model reproduced the experimental observations. These findings uncovered a new migratory behavior on non-adhesive surfaces in macrophages.

One-Sentence Summary

Macrophages can migrate across non-adhesive surfaces that are absolute boundaries for other cell types.
Neuregulin1 nuclear signaling influences adult neurogenesis and regulates a schizophrenia susceptibility gene network within the mouse dentate gyrus
Authors: Rajebhosale Prithviraj , Jone Alice , Johnson Kory R. , Hofland Rohan , Palarpalar Camille , Khan Samara , Role Lorna W. , Talmage David A.
Published: August 2022

Neuregulin1 (Nrg1) signaling is critical for aspects of neuronal development and function from fate specification to synaptic plasticity. Type III Nrg1 is a synaptic protein which engages in bi-directional signaling with its receptor ErbB4. Forward signaling engages ErbB4 phosphorylation, whereas back signaling engages two known mechanisms: 1. local axonal PI3K-AKT signaling, and 2. cleavage by gamma secretase resulting in cytosolic release of the intracellular domain (ICD), which can traffic to the nucleus (Bao, Wolpowitz et al. 2003, Hancock, Canetta et al. 2008). To dissect the contribution of these alternate signaling strategies to neuronal development we generated a transgenic mouse with a missense mutation (V321L) in the Nrg1 transmembrane domain that disrupts nuclear back signaling with minimal effects on forward signaling or local back-signaling and was previously found to be associated with psychosis (Walss-Bass, Liu et al. 2006). We combined RNA sequencing, retroviral fate mapping of neural stem cells, behavioral analyses, and various network analyses of transcriptomic data to investigate the effect of disrupting Nrg1 nuclear back-signaling in the dentate gyrus (DG) of male and female mice.

The V321L mutation impairs nuclear translocation of the Nrg1 ICD and alters gene expression in the DG. V321L mice show reduced stem cell proliferation, altered cell cycle dynamics, fate specification defects, and dendritic dysmorphogenesis. Orthologs of known schizophrenia (SCZ)-susceptibility genes were dysregulated in the V321L DG. These genes coordinated a larger network with other dysregulated genes. WGCNA and protein-interaction network analyses revealed striking similarity between DG transcriptomes of V321L mouse and humans with schizophrenia.

SIGNIFICANCE STATEMENT

Synaptic contact is predicted to be a regulator of the generation of nuclear signaling by Nrg1. Here we show that a schizophrenia-associated mutation in Nrg1 disrupts its ability to communicate extracellular signals to the neuronal genome which results in altered expression of a gene network enriched for orthologs of schizophrenia-susceptibility genes. The striking overlap in functional and molecular alterations between a single rare homozygous missense mutation (V321L) and schizophrenia patient data (complex polygenic and environmental burden) underscores potential convergence of rare and common variants on the same cellular and molecular phenotypes. Furthermore, our data indicate that the evolutionarily conserved gene networks that form the basis for this risk are necessary for coordinating neurodevelopmental events in the DG.
Piezo1 as a force-through-membrane sensor in red blood cells
Authors: Vaisey George , Banerjee Priyam , North Alison J. , Haselwandter Christoph A. , Mackinnon Roderick
Published: August 2022

Piezo1 is the stretch activated Ca2+ channel in red blood cells that mediates homeostatic volume control. Here we study the organization of Piezo1 in red blood cells using a combination of super resolution microscopy techniques and electron microscopy. Piezo1 adopts a non- uniform distribution on the red blood cell surface, with a bias towards the biconcave “dimple”. Trajectories of diffusing Piezo1 molecules, which exhibit confined Brownian diffusion on short timescales and hopping on long timescales, also reflect a bias towards the dimple. This bias can be explained by “curvature coupling” between the intrinsic curvature of the Piezo dome and the curvature of the red blood cell membrane. Piezo1 does not form clusters with itself, nor does it co-localize with F-actin, Spectrin or the Gardos channel. Thus, Piezo1 exhibits the properties of a force-through-membrane sensor of curvature and lateral tension in the red blood cell.
Development of highly potent non-covalent inhibitors of SARS-CoV-2 3CLpro
Authors: Hou Ningke , Shuai Lei , Zhang Lijing , Xie Xuping , Tang Kaiming , Zhu Yunkai , Yu Yin , Zhang Wenyi , Tan Qiaozhu , Zhong Gongxun , Wen Zhiyuan , Wang Chong , He Xijun , Huo Hong , Gao Haishan , Xu You , Xue Jing , Peng Chen , Zou Jing , Schindewolf Craig , Menachery Vineet , Su Wenji , Yuan Youlang , Shen Zuyuan , Zhang Rong , Yuan Shuofeng , Yu Hongtao , Shi Pei-Yong , Bu Zhigao , Huang Jing , Hu Qi
Published: August 2022

The SARS-CoV-2 virus is the causal agent of the ongoing pandemic of coronavirus disease 2019 (COVID-19). There is an urgent need for potent, specific antiviral compounds against SARS-CoV-2. The 3C-like protease (3CLpro) is an essential enzyme for the replication of SARS-CoV-2 and other coronaviruses, and thus is a target for coronavirus drug discovery. Nearly all inhibitors of coronavirus 3CLpro reported so far are covalent inhibitors. Here, we report the development of specific, non-covalent inhibitors of 3CLpro. The most potent one, WU-04, effectively blocks SARS-CoV-2 replications in human cells with EC50 values in the 10-nM range. WU-04 also inhibits the 3CLpro of SARS-CoV and MERS-CoV with high potency, indicating that it is a pan-inhibitor of coronavirus 3CLpro. WU-04 showed anti-SARS-CoV-2 activity similar to that of PF-07321332 (Nirmatrelvir) in K18-hACE2 mice when the same dose was administered orally. Thus, WU-04 is a promising drug candidate for coronavirus treatment.

One-Sentence Summary

A oral non-covalent inhibitor of 3C-like protease effectively inhibits SARS-CoV-2 replication.
E-cadherin/HMR-1 and PAR-3 break symmetry at stable cell contacts in a developing epithelium
Authors: Naturale Victor F. , Pickett Melissa A. , Feldman Jessica L.
Published: August 2022

Tissue-wide patterning is essential to multicellular development, requiring cells to individually generate polarity axes and coordinate them in space and time with neighbors. Using the C. elegans intestinal epithelium, we identified a patterning mechanism informed by stabilized cell/cell contact and executed via the scaffolding protein PAR-3 and the transmembrane protein E-cadherin/HMR-1. Intestinal cells break symmetry as PAR-3 and HMR-1 recruit apical determinants into micron-scale ‘local polarity complexes’ (LPCs) at homotypic contacts. LPCs undergo a HMR-1-based migration to a common tissue midline, thereby establishing tissue-wide polarity. Thus, symmetry breaking results from PAR-3-dependent intracellular polarization coupled to HMR-1-based tissue-level communication that occurs through a non-adhesive signaling role for HMR-1. Intestinal cells gain initial asymmetry from differential contact duration as homotypic contacts last longer than heterotypic contacts, thus providing stable platforms for LPC assembly and offering a logical and likely conserved framework for how internal epithelia with no obvious pre-existing asymmetries can polarize.