bluuebunny/crossref_metadata_2025 huggingface dataset:
The Manual Therapy and Strengthening for the Hip (MASH) Trial: Protocol for a Multisite Randomized Trial of a Subgroup of Older Adults With Chronic Back and Hip Pain
Authors: Pugliese Jenifer M , Coyle Peter C , Knox Patrick J , Sions J Megan , Patterson Charity G , Pohlig Ryan T , Simon Corey B , Weiner Debra K , George Steven Z , Piva Sara , Hicks Gregory E
Published: October 2021

Objective

Chronic low back pain (CLBP) is a disabling and costly condition for older adults that is difficult to properly classify and treat. In a cohort study, a subgroup of older adults with CLBP who had elevated hip pain and hip muscle weakness was identified; this subgroup differentiated itself by being at higher risk for future mobility decline. The primary purpose of this clinical trial is to evaluate whether a hip-focused low back pain (LBP) treatment provides better disability and physical performance outcomes for this at-risk group compared with a spine-focused LBP treatment.

Methods

This study is a multisite, single-blinded, randomized controlled, parallel arm, Phase II trial conducted across 3 clinical research sites. A total of 180 people aged between 60 and 85 years with CLBP and hip pain are being recruited. Participants undergo a comprehensive baseline assessment and are randomized into 1 of 2 intervention arms: hip-focused or spine-focused. They are treated twice weekly by a licensed physical therapist for 8 weeks and undergo follow-up assessments at 8 weeks and 6 months after randomization. Primary outcome measures include the Quebec Low Back Disability Scale and the 10-Meter Walk Test, which are measures of self-report and performance-based physical function, respectively.

Impact

This multicenter, randomized clinical trial will determine whether a hip-focused or spine-focused physical therapist intervention results in improved disability and physical performance for a subgroup of older adults with CLBP and hip pain who are at increased risk of mobility decline. This trial will help further the development of effective interventions for this subgroup of older adults with CLBP.
The importance of tree internal water storage under drought conditions
Authors: Preisler Yakir , Hölttä Teemu , Grünzweig José M , Oz Itay , Tatarinov Fedor , Ruehr Nadine K , Rotenberg Eyal , Yakir Dan
Published: October 2021

Global warming and drying trends, as well as the increase in frequency and intensity of droughts, may have unprecedented impacts on various forest ecosystems. We assessed the role of internal water storage (WS) in drought resistance of mature pine trees in the semi-arid Yatir Forest. Transpiration (T), soil moisture and sap flow (SF) were measured continuously, accompanied by periodical measurements of leaf and branch water potential (Ψleaf) and water content (WC). The data were used to parameterize a tree hydraulics model to examine the impact of WS capacitance on the tree water relations. The results of the continuous measurements showed a 5-h time lag between T and SF in the dry season, which peaked in the early morning and early afternoon, respectively. A good fit between model results and observations was only obtained when the empirically estimated WS capacitance was included in the model. Without WS during the dry season, Ψleaf would drop below a threshold known to cause hydraulic failure and cessation of gas exchange in the studied tree species. Our results indicate that tree WS capacitance is a key drought resistance trait that could enhance tree survival in a drying climate, contributing up to 45% of the total daily transpiration during the dry season.
Clonal hematopoiesis detection in cancer patients using cell free DNA sequencing
Authors: Fairchild Lauren , Whalen Jeanne , D’Aco Katie , Wu Jincheng , Gustafson Carroll B. , Solovieff Nadia , Su Fei , Leary Rebecca , Campbell Catarina D. , Balbin O. Alejandro
Published: October 2021

In the context of cancer, clonal hematopoiesis of indeterminate potential (CHIP) is associated with the development of therapy-related myeloid neoplasms and shorter overall survival. Cell-free DNA (cfDNA) sequencing is becoming widely adopted for genomic screening of cancer patients but has not been used extensively to determine CHIP status due to a requirement for matched blood and tumor sequencing. Here we present an accurate machine learning approach to determine clonal hematopoiesis (CH) status from cfDNA sequencing alone and apply our model to 4,096 oncology clinical cfDNA samples. Using this method, we determine that 26% of patients in this cohort have evidence of CH and CH is most common in lung cancer patients. Matched RNAseq data shows signals of increased inflammation, especially neutrophil activation, within the tumor microenvironment of CH-positive patients. Additionally, CH patients showed evidence of neutrophil activation systemically, pointing to a potential mechanism of action for the worse outcomes associated with CH status. Neutrophil activation may be one of many mechanisms however, as estrogen positive breast cancer patients harboring TET2 frameshift mutations had worse outcomes but similar neutrophil levels to CH-negative patients.

One Sentence Summary

We train an accurate machine learning model to detect clonal hematopoiesis in cancer and characterize associated changes in the tumor microenvironment.
Dynamic Subcortical Modulators of Human Default Mode Network Function
Authors: Harrison Ben J. , Davey Christopher G. , Savage Hannah S. , Jamieson Alec J. , Leonards Christine A. , Moffat Bradford A. , Glarin Rebecca K. , Steward Trevor
Published: October 2021

The brain’s ‘default mode network’ (DMN) enables flexible switching between internally and externally focused cognition. Precisely how this modulation occurs is not well understood, although may involve key subcortical mechanisms, including hypothesized influences from the basal forebrain (BF) and mediodorsal thalamus (MD). Here, we used ultra-high field (7T) functional magnetic resonance imaging to examine the involvement of the BF and MD across states of task-induced DMN activity modulation. Specifically, we mapped DMN activity suppression (‘deactivation’) when participants transitioned between rest and externally focused task performance, as well as DMN activity engagement (‘activation’) when task performance was internally (i.e., self) focused. Consistent with recent rodent studies, the BF showed overall activity suppression with DMN cortical regions when comparing the rest to external task conditions. Further analyses, including dynamic causal modelling, confirmed that the BF drove changes in DMN cortical activity during these rest-to-task transitions. The MD, by comparison, was specifically engaged during internally focused cognition and demonstrated a broad excitatory influence on DMN cortical activation. These results provide the first direct evidence in humans of distinct basal forebrain and thalamic circuit influences on the control of DMN function and suggest novel mechanistic avenues for ongoing translational research.
Efficacy of anti-microbial gel vapours against aerosolised coronavirus, bacteria, and fungi
Authors: Kalaiselvan Parthasarathi , Yasir Muhammad , Willcox Mark , Vijay Ajay Kumar
Published: October 2021

Background

The urban population spends up to 90% of their time indoors. The indoor environment harbours a diverse microbial population including viruses, bacteria, and fungi. Pathogens present in the indoor environment can be transmitted to humans through aerosols.

Aim

This study evaluated the efficacy of an antimicrobial gel containing a mix of essential oils against aerosols of bacteria, fungi, and coronavirus.

Methods

The antimicrobial gel was allowed to vapourize inside a glass chamber for 10 or 20 minutes. Microbial aerosols of Escerichia coli, Aspergillus flavus spores or murine hepatitis virus MHV 1, a surrogate of SARS CoV-2 was passed through the gel vapours and then collected on a 6-stage Andersen sampler. The number of viable microbes present in the aerosols collected in the different stages were enumerated and compared to number of viable microbes in control microbial aerosols that were not exposed to the gel vapours.

Results

Vaporizing the antimicrobial gel for 10 and 20 minutes resulted in a 48% (p = 0.002 Vs. control) and 53% (p = 0.001 Vs. control) reduction in the number of MHV-1 in the aerosols, respectively. The antimicrobial gel vaporised for 10 minutes, reduced the number of viable E. coli by 51% (p = 0.032 Vs. control) and Aspergillus flavus spores by 72% (p=0.008 Vs. control) in the aerosols.

Conclusions

The antimicrobial gel may be able to reduce aerosol transmission of microbes.
COVID-19 Vaccine Failure in Chronic Lymphocytic Leukemia and Monoclonal B-Lymphocytosis; Humoral and Cellular Immunity
Authors: Shen Yandong , Freeman Jane A. , Holland Juliette , Solterbeck Ann , Naidu Kartik , Soosapilla Asha , Downe Paul , Tang Catherine , Kerridge Ian , Wallman Lucinda , Van Bilsen Nenna , Milogiannakis Vanessa , Akerman Anouschka , Martins Costa Gomes Gabriela , Sandgren Kerrie , Cunningham Anthony L , Turville Stuart , Mulligan Stephen P.
Published: October 2021

Chronic lymphocytic leukemia (CLL) is associated with immunocompromise and high risk of severe COVID-19 disease and mortality. Monoclonal B-Lymphocytosis (MBL) patients also have immune impairment. We evaluated humoral and cellular immune responses in 181 patients with CLL (160) and MBL (21) to correlate failed seroconversion (<50AU/mL SARS-CoV-2 II IgG assay, antibody to spike protein, Abbott Diagnostics) following each of 2 vaccine doses with clinical and laboratory parameters. Following first and second doses, 79.2% then 45% of CLL, and 50% then 9.5% of MBL respectively remained seronegative, indicating 2 vaccine doses are crucial. There was significant association between post-dose 2 antibody level with pre-vaccination reduced IgM (p<0.0001), IgG2 (p<0.035), IgG3 (p<0.046), and CLL therapy within 12 months (p<0.001) in univariate analysis. By multivariate analysis, reduced IgM (p<0.0002) and active therapy (p<0.0002) retained significance. There was no significant correlation with age, gender, CLL duration, IgG, IgA or lymphocyte subsets. Anti-spike protein levels varied widely and were lower in CLL, than MBL, and both lower than normal donors. Neutralization activity showed anti-spike levels <1000AU/mL were usually negative for both an early viral clade and the contemporary Delta variant. There were 72.9% of CLL and 53.3% of MBL who failed to reach anti-spike levels >1000AU/mL. In a representative subset of 32 CLL patients, 80% had normal T-cell responses by IFNγ and IL-2 FluoroSpot assay. Failed seroconversion occurred in 36.6%% of treatment-naive patients, 52.9% treatment-naive with reduced IgM, 78.1% on therapy, and 85.7% on ibrutinib. Vaccination failure is very common in CLL, including early-stage disease.

6 Key Novel Findings

Comparison CLL vs MBL vs normal

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45% of CLL and 9.5% of MBL fail to seroconvert with 2 doses of COVID-19 vaccine

Neutralization assay

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SARS CoV-2 IgG levels <1000 AU/mL rarely associated with neutralization activity.

COVID-19-specific T-cell function by FluoroSpot IFN-g and IL-2 production

IgG, A, M class and IgG subclass:correlations by univariate and multivariate analysis

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IgM (OR 7.29 p<0.0001), IgG2 and IgG3 subclass univariate significance

Correlation withtherapy– ICT, targeted therapies, and those on Ig replacement

High risk of vaccination failure for all CLL, including early-stage disease, and MBL

Key Points

CLL and MBL show significantly impaired anti-spike antibody, viral neutralization, with cellular immune response to COVID-19 vaccination

Failure to seroconvert is associated with low IgM, IgG2, IgG3, and recent therapy; many CLL and MBL patients remain COVID-19 vulnerable
Chemogenetic Stimulation of Tonic Locus Coeruleus Activity Strengthens the Default Mode Network
Authors: Oyarzabal Esteban A. , Hsu Li-Ming , Das Manasmita , Harry Chao Tzu-Hao , Zhou Jingheng , Song Sheng , Zhang Weiting , Smith Kathleen G. , Sciolino Natale R. , Evsyukova Irina Y. , Yuan Hong , Lee Sung-Ho , Cui Guohong , Jensen Patricia , Ian Shih Yen-Yu
Published: October 2021

The default mode network (DMN) of the brain is involved in cognition, emotion regulation, impulsivity, and balancing between internally and externally focused states. DMN dysregulation has been implicated in several neurological and neuropsychiatric disorders. In this study, we used functional magnetic resonance imaging (fMRI), positron emission tomography (PET), and spectral fiber-photometry to investigate the selective neuromodulatory effect of norepinephrine (NE)-releasing noradrenergic neurons in the locus coeruleus (LC) on the DMN in mice. Chemogenetic-induced tonic LC-NE activity decreased cerebral blood volume (CBV) and glucose uptake, and increased synchronous low frequency fMRI activity within the frontal cortices of the DMN. Fiber-photometry results corroborated these findings, showing that LC-NE activation induced NE release, enhanced calcium-weighted neuronal spiking, and reduced CBV in the anterior cingulate cortex. These data suggest that LC-NE alters conventional stimulus-evoked coupling between neuronal activity and CBV in the frontal DMN. We also demonstrated that chemogenetic activation of LC-NE neurons strengthened functional connectivity within the frontal DMN, and this effect was causally mediated by reduced modulatory inputs from retrosplenial and hippocampal regions to the association cortices of the DMN.
Direct precise measurement of the stall torque of the flagellar motor in E. coli
Authors: Wang Bin , Yue Guanhua , Zhang Rongjing , Yuan Junhua
Published: October 2021

The flagellar motor drives the rotation of flagellar filaments, propeling the swimming of flagellated bacteria. The maximum torque the motor generates, the stall torque, is a key characteristics of the motor function. Direct measurements of the stall torque carried out three decades ago suffered from large experimental uncertainties, and subsequently there were only indirect measurements. Here, we applied magnetic tweezer to directly measure the stall torque in E. coli. We precisely calibrated the torsional stiffness of the magnetic tweezer, and performed motor resurrection experiments at stall, accomplishing a precise determination of the stall torque per torque-generating unit (stator unit). From our measurements, each stator passes 2 protons per step, indicating a tight coupling between motor rotation and proton flux.
Mapping neurotransmitter systems to the structural and functional organization of the human neocortex
Authors: Hansen Justine Y. , Shafiei Golia , Markello Ross D. , Smart Kelly , Cox Sylvia M. L. , Nørgaard Martin , Beliveau Vincent , Wu Yanjun , Gallezot Jean-Dominique , Aumont Étienne , Servaes Stijn , Scala Stephanie G. , DuBois Jonathan M. , Wainstein Gabriel , Bezgin Gleb , Funck Thomas , Schmitz Taylor W. , Spreng R. Nathan , Galovic Marian , Koepp Matthias J. , Duncan John S. , Coles Jonathan P. , Fryer Tim D. , Aigbirhio Franklin I. , McGinnity Colm J. , Hammers Alexander , Soucy Jean-Paul , Baillet Sylvain , Guimond Synthia , Hietala Jarmo , Bédard Marc-André , Leyton Marco , Kobayashi Eliane , Rosa-Neto Pedro , Ganz Melanie , Knudsen Gitte M. , Palomero-Gallagher Nicola , Shine James M. , Carson Richard E. , Tuominen Lauri , Dagher Alain , Misic Bratislav
Published: October 2021

Neurotransmitter receptors support the propagation of signals in the human brain. How receptor systems are situated within macroscale neuroanatomy and how they shape emergent function remains poorly understood, and there exists no comprehensive atlas of receptors. Here we collate positron emission tomography data from >1 200 healthy individuals to construct a whole-brain 3-D normative atlas of 19 receptors and transporters across 9 different neurotransmitter systems. We find that receptor profiles align with structural connectivity and mediate function, including neurophysiological oscillatory dynamics and resting state hemodynamic functional connectivity. Using the Neurosynth cognitive atlas, we uncover a topographic gradient of overlapping receptor distributions that separates extrinsic and intrinsic psychological processes. Finally, we find both expected and novel associations between receptor distributions and cortical thinning patterns across 13 disorders. We replicate all findings in an independently collected autoradiography dataset. This work demonstrates how chemoarchitecture shapes brain structure and function, providing a new direction for studying multi-scale brain organization.
inPOSE: a flexible toolbox for chromosomal cloning and amplification of bacterial transgenes
Authors: Shukla Ranti Dev , Zvara Ágnes , Avramucz Ákos , Biketova Alona Yu. , Nyerges Akos , Puskás László G. , Fehér Tamás
Published: October 2021

Cloning genes and operons encoding heterologous functions in bacterial hosts is almost exclusively carried out today using plasmid vectors. This has multiple drawbacks, including the need for constant selection and the variation in copy numbers. Chromosomal integration of transgenes has always offered a viable alternative, however, to date it has been of limited use due to its tedious nature and to being limited often to a single copy. We introduce here a strategy that uses bacterial insertion sequences, the simplest autonomous transposable elements to insert and amplify genetic cargo into a bacterial chromosome. Transgene insertion can take place either as transposition or homologous recombination, and copy-number amplification is achieved using controlled copy-paste transposition. We display successful use of IS1 and IS3 for this purpose in Escherichia coli cells, using various selection markers. We demonstrate the insertion of selectable genes, an unselectable gene, and a five-gene operon in up to two copies in a single step. We continue with the amplification of the inserted cassette to double-digit copy numbers within two rounds of transposase induction and selection. Finally, we analyze the stability of the cloned genetic constructs in the lack of selection and find it to be superior to all investigated plasmid-based systems. Due to the ubiquitous nature of transposable elements, we believe that with proper design, this strategy can be adapted to numerous further bacterial species.
Impact of antibiotic perturbation on intestinal viral communities in mice
Authors: Anderson Jacqueline Moltzau , Lachnit Tim , Lipinski Simone , Falk-Paulsen Maren , Rosenstiel Philip
Published: October 2021

Viruses and bacteriophages have a strong impact on intestinal barrier function and the composition and functional properties of commensal bacterial communities. To improve our understanding of the role of the enteric intestinal virome, we longitudinally characterized the virome in fecal samples from wild-type (WT) C57BL/6J and knock-out (KO) NOD2 mice in response to an antibiotic perturbation. Sequencing of viral-like-particles (VLPs) demonstrated both a high diversity and high inter-individual variation of the murine gut virome composed of eukaryotic viruses and bacteriophages. Antibiotics also had a significant impact on the gut murine virome causing a delayed resilience independent of genotype. However, compositional shifts in the virome and bacteriome were highly correlated, suggesting that the loss of specific phages may contribute to a dysregulation of the bacterial community composition. Bacteriophage species may be playing an important role in either upregulating or downregulating the bacterial community, and restoring a healthy virome may therefore be a central goal of microbiota-targeted therapies.
Response of total (DNA) and metabolically active (RNA) microbial communities in Miscanthus × giganteus cultivated soil to different nitrogen fertilization rates
Authors: Yang Jihoon , Lee Jaejin , Choi Jinlyung , Ma Lanying , Heaton Emily , Howe Adina
Published: October 2021

Miscanthus x giganteus is a promising high-yielding perennial plant to meet growing bioenergy demands but the degree to which the soil microbiome affects its nitrogen cycling and subsequently, biomass yield remains unclear. In this study, we hypothesize that contributions of metabolically active soil microbial membership may be underestimated with DNA-based approaches. We assessed the response of the soil microbiome to nitrogen availability in terms of both DNA and RNA soil microbial communities from the Long-term Assessment of Miscanthus Productivity and Sustainability (LAMPS) field trial. DNA and RNA were extracted from 271 samples, and 16S SSU rRNA amplicon sequencing was performed to characterize microbial community structure. Significant differences were observed in the resulting soil microbiomes and were best explained by the sequencing library of origin, either DNA and RNA. Similar numbers of taxa were detected in DNA and RNA microbial communities, with more than 90% of taxa shared. However, the profile of dominant taxa within DNA and RNA differed, with varying proportions of Actinobacteria and Proteobacteria and Firmicutes and Proteobacteria. Only RNA microbial communities showed seasonal responses to nitrogen fertilization, and these differences were associated with nitrogen-cycling bacteria. The relative abundance of bacteria associated with nitrogen cycling was 7-folds higher in RNA than in DNA, and genes associated with denitrifying bacteria were significantly enriched in RNA, suggesting that these bacteria may be underestimated with DNA-only approaches. Our findings indicate that RNA-based SSU characterization can be a significant and complementing resource for understanding the role of soil microbiomes in bioenergy crop production.

Importance

Miscanthus x giganteus is becoming a cornerstone of bioeconomy cropping systems, but it remains unclear how the soil microbiome supplies nitrogen to this low-input crop. DNA-based techniques are used to provide community characterization but may miss important metabolically active taxa. By analyzing both DNA- and actively transcribed RNA-based microbial communities, we found that nitrogen cycling taxa in the soil microbiome may be underestimated using only DNA-based approaches. Accurately understanding the role of microbes and how they cycle nutrients is important for the development of sustainable bioenergy crops, and RNA-based approaches are recommended as a complement to DNA approaches to better understand the microbial, plant, and management interactions.
A User Preference Analysis Of Commercial Breath Ketone Sensors To Inform The Development Of Portable Breath Ketone Sensors For Diabetes Management In Young People
Authors: Brew-Sam Nicola , Desborough Jane , Parkinson Anne , Murugappan Krishnan , Daskalaki Eleni , Brown Ellen , Ebbeck Harry , Pedley Lachlan , Hannon Kristal , Brown Karen , Pedley Elizabeth , Ebbeck Genevieve , Tricoli Antonio , Suominen Hanna , Nolan Christopher J. , Phillips Christine
Published: October 2021

Background. Portable breath ketone sensors may help people with Type 1 Diabetes Mellitus (T1DM) avoid episodes of diabetic ketoacidosis; however the design features preferred by users have not been studied. We aimed to elucidate breath analysis and design preferences associated with commercial breath ketone devices among young people with T1DM aged 12-16 years and their parents in order to inform the development of a breath ketone sensor prototype for diabetes management.
Research Designs and Methods. Two commercially available breath ketone sensors, designed for ketogenic diet monitoring, were explored over one week by ten young people with T1DM to get an insight into breath measurements. Participants interacted with the devices at least twice daily for five days, taking breath ketone, blood ketone and blood glucose measurements. Semi-structured interviews were conducted post-testing with the young participants and their caregivers to elicit preferences related to breath analysis and to inform the co-design of a diabetes breath ketone sensor prototype. To validate the results from a professional healthcare perspective, we interviewed two diabetes educators working in pediatric care about their perspective of young people using breath ketone sensors.
Results. Participants acknowledged the non-invasiveness of breath sensors as compared to blood testing. Affordability, reliability and accuracy were identified as prerequisites for breath ketone sensors used for diabetes management. Design features valued by young people included portability, ease of use, sustainability, readability and suitability for use in public. The time required to use breath sensors was similar to that for blood testing. The requirement to maintain a 10-second breath exhalation posed a challenge for users. Diabetes educators highlighted the ease of use of breath devices especially for young people with insufficient blood ketone testing.
Conclusions. Breath ketone sensors for diabetes management bear potential to facilitate ketone testing in young people. Our study affirms features for young people that drive usability of breath sensors among this population, and provides a model of user preference assessment.
Circular RNA detection identifiescircPSEN1alterations in brain specific to Autosomal Dominant Alzheimer Disease
Authors: Chen Hsiang-Han , Eteleeb Abdallah , Wang Ciyang , Fernandez Maria Victoria , Budde John P. , Bergmann Kristy , Norton Joanne , Wang Fengxian , Ebl Curtis , Morris John C. , Perrin Richard J. , Bateman Randall J. , McDade Eric , Xiong Chengjie , Goate Alison , Farlow Martin , Chhatwal Jasmeer , Schofield Peter R , Chui Helena , Harari Oscar , Cruchaga Carlos , Ibanez Laura ,   Dominantly Inherited Alzheimer Network
Published: October 2021

Background

Autosomal-dominant Alzheimer’s disease (ADAD) is caused by pathogenic mutations inAPP, PSEN1, andPSEN2, which usually lead to an early age at onset (<65). Circular RNAs are a family of non-coding RNAs highly expressed in the nervous system and especially in synapses. We aimed to investigate differences in brain gene expression of linear and circular transcripts from the three ADAD genes in controls, sporadic AD, and ADAD.

Methods

We obtained and sequenced RNA from brain cortex using standard protocols. Linear counts were obtained using the TOPMed pipeline; circular counts, using python package DCC. After stringent quality control (QC), we obtained the counts forPSEN1, PSEN2and APP genes. Only circPSEN1passed QC. We used DESeq2 to compare the counts across groups, correcting for biological and technical variables. Finally, we performedin-silicofunctional analyses using the Circular RNA interactome website and DIANA mirPath software.

Results

Our results show significant differences in gene counts of circPSEN1in ADAD individuals, when compared to sporadic AD and controls (ADAD=22, AD=274, Controls=25 – ADADvsCO: log2FC=0.786, p=9.08×10-05, ADADvsAD: log2FC=0.576, p=2.00×10-03). The high gene counts are contributed by two circPSEN1species (hsa_circ_0008521 and hsa_circ_0003848). No significant differences were observed in linearPSEN1gene expression between cases and controls, indicating that this finding is specific to the circular forms. In addition, the high circPSEN1levels do not seem to be specific toPSEN1mutation carriers; the counts are also elevated in APP andPSEN2mutation carriers.In-silicofunctional analyses suggest that circPSEN1is involved in several pathways such as axon guidance (p=3.39×10−07), hippo signaling pathway (p=7.38×10−07), lysine degradation (p=2.48×10−05) or Wnt signaling pathway (p=5.58×10−04) among other KEGG pathways. Additionally, circPSEN1counts were able to discriminate ADAD from sporadic AD and controls with an AUC above 0.70.

Conclusions

Our findings show the differential expression of circPSEN1is increased in ADAD. Given the biological function previously ascribed to circular RNAs and the results of ourin-silicoanalyses, we hypothesize that this finding might be related to neuroinflammatory events that lead or that are caused by the accumulation of amyloid-beta.
Contributions of occupation characteristics and educational attainment to racial/ethnic inequities in COVID-19 mortality
Authors: Matthay Ellicott C. , Duchowny Kate A. , Riley Alicia R. , Thomas Marilyn , Chen Yea-Hung , Bibbins-Domingo Kirsten , Glymour M. Maria
Published: October 2021

Background

Racial/ethnic inequities in COVID-19 mortality are hypothesized to be driven by education and occupation, but limited empirical evidence has assessed these mechanisms.

Objective

To quantify the extent to which educational attainment and occupation explain racial/ethnic inequities in COVID-19 mortality.

Design

Observational cohort.

Setting

California.

Participants

Californians aged 18-65 years.

Measurements

We linked all COVID-19-confirmed deaths in California through February 12, 2021 (N=14,783), to population estimates within strata defined by race/ethnicity, sex, age, USA nativity, region of residence, education, and occupation. We characterized occupations using measures related to COVID-19 exposure including essential sector, telework-ability, and wages. Using sex-stratified regressions, we predicted COVID-19 mortality by race/ethnicity if all races/ethnicities had the same education and occupation distribution as White people and if all people held the safest educational/occupational positions.

Results

COVID-19 mortality per 100,000 ranged from 15 for White and Asian females to 139 for Latinx males. Accounting for differences in age, nativity, and region, if all races/ethnicities had the education and occupation distribution of Whites, COVID-19 mortality would be reduced for Latinx males (−22%) and females (−23%), and Black males (−1%) and females (−8%), but increased for Asian males (+22%) and females (+23%). Additionally, if all individuals had the COVID-19 mortality associated with the safest educational and occupational position (Bachelor’s degree, non-essential, telework, highest wage quintile), there would have been 57% fewer COVID-19 deaths.

Conclusion

Educational and occupational disadvantage are important risk factors for COVID-19 mortality across all racial/ethnic groups, especially Latinx individuals. Eliminating avoidable excess risk associated with low-education, essential, on-site, and low-wage jobs may reduce COVID-19 mortality and inequities, but is unlikely to be sufficient to achieve equity.
Characterizing Sleep Disorders in an Autism-Specific Collection of Electronic Health Records
Authors: Singer EV , Niarchou M , Maxwell-Horn A , Hucks D , Johnston R , Sutcliffe J , Davis LK , Malow BA
Published: October 2021

Background

Sleep problems are common in individuals with autism spectrum disorder (ASD). This study reviews one detailed approach to querying the electronic health record (EHR).

Methods

We developed methods for identifying individuals with ASD and defined their sleep problems using International Classification of Diseases (ICD) codes or key words. We examined treatment responses to melatonin.

Results

Sleep problems were documented in 86% of patients and using specific keywords yielded more sleep diagnoses than ICD codes alone. About two-thirds of patients benefitted from melatonin.

Conclusions

Our study provides a framework for using deidentified medical records to characterize sleep, a common co-occurring condition, in ASD. Using specific keywords could be helpful in future work that queries the EHR.
Ruxolitinib As a Salvage Therapy for Acute and Chronic Graft-versus-Host Disease in Children and Young Adults: a single institution experience
Authors: Mavers Melissa , Klinger Edna , Shyr David C , Shah Ami J , Bertaina Alice , Soni Sandeep
Published: October 2021

Background

Ruxolitinib, a Janus kinase (JAK)-1/JAK-2 inhibitor that reduces T-cell activation and proliferation leading to a potent anti-inflammatory effect, was recently approved to treat steroid-refractory acute graft-versus-host disease (aGvHD) and is under study for chronic GvHD (cGvHD). However, there are few reports on its use in pediatric and young adult patients with GvHD.

Methods

We retrospectively report our single center experience with ruxolitinib in 15 patients aged 11-29 years: 5 patients with steroid refractory/steroid dependent aGvHD and 10 patients with cGvHD who had failed at least one systemic therapy.

Results

In the aGvHD group, ruxolitinib led to an overall response rate (ORR) of 40% at day 28 and 80% with longer follow-up (complete response, CR 60%), with a median of 21 days (5-74) to achieve a response. In the cGvHD group (9 evaluable patients), we observed an ORR of 67% and a CR of 22%, with a median of 78 days (35-180) to achieve a response. Adverse events included cytopenias, gastrointestinal symptoms, infections, and an allergic reaction attributable to ruxolitinib.

Conclusions

Overall, our results show that ruxolitinib is an effective salvage therapy for severe GvHD in pediatric and young adult patients. The toxicities noted warrant adequate antimicrobial prophylaxis and close monitoring of blood counts.
Pneumococcal Vaccination Coverage and Uptake Among Adults in Switzerland: A Nationwide Cross-Sectional Study of Vaccination Records
Authors: Zens Kyra D. , Baroutsou Vasiliki , Fehr Jan S. , Lang Phung
Published: October 2021

Streptococcus pneumoniae, or pneumococcus, is a common, opportunistic pathogen which can cause severe disease, particularly in adults 65+. In Switzerland, vaccination is recommended for children under 5 and for adults with health predispositions; vaccination of healthy adults 65+ is not recommended. In 2020 we conducted a nationwide, cross-sectional survey of vaccination records to evaluate pneumococcal vaccination coverage and factors affecting uptake among adults 18-85. We found that nationwide coverage was 4.5% without significant regional differences. Coverage was comparable between men and women and between those aged 18-39 (3.0%) and 40-64 (3.2%). Coverage was significantly higher among those 65-85 (9.6%). While 2.7% of individuals reporting no health predisposition were vaccinated, 14.8% with asthma or chronic pulmonary disease, 27.1% with immunosuppression, 12.9% with diabetes, 11.6% with heart, liver, or kidney disease, and 25.9% with >1 health risk were vaccinated. Adjusted odds of vaccination for all health predispositions except heart, liver, or kidney disease were significantly increased. Among unvaccinated individuals “not enough information about the topic” and “not suggested by a doctor/healthcare provider” were the major reasons for abstaining from vaccination. Respondents reporting a health predisposition were significantly less likely to report “not at increased risk due to chronic health conditions or age” as a reason for not being vaccinated (3.7% versus 29.1%) and were more likely to report willingness to be vaccinated in the future compared to those not-at-risk (54.2% versus 39.9%). Our results indicate that pneumococcal vaccination coverage in Switzerland is low among both individuals 65-85 and among those with predisposing health risks. It appears that at-risk individuals are aware of their increased risk, but feel they do not have enough information on the topic to seek vaccination, or have not been recommended a vaccination by their physician.
R-loop mapping and characterization during Drosophila embryogenesis reveals developmental plasticity in R-loop signatures
Authors: Munden Alexander , Benton Mary Lauren , Capra John A. , Nordman Jared
Published: October 2021

R-loops are involved in transcriptional regulation, DNA and histone post-translational modifications, genome replication and genome stability. To what extent R-loop abundance and genome-wide localization is actively regulated during metazoan embryogenesis is unknown. Drosophila embryogenesis provides a powerful system to address these questions due to its well-characterized developmental program, the sudden onset of zygotic transcription and available genome-wide ChIP and transcription data sets. Here, we measure the overall abundance and genome localization of R-loops in early and late-stage embryos relative to Drosophila cultured cells. We demonstrate that absolute R-loop levels change during embryogenesis and that resolution of R-loops is critical for embryonic development. R-loop mapping by strand-specific DRIP-seq reveals that R-loop localization is plastic across development, both in the genes which form R-loops and where they localize relative to gene bodies. Importantly, these changes are not driven by changes in the transcriptional program. Negative GC skew and absolute changes in AT skew are associated with R-loop formation in Drosophila. Furthermore, we demonstrate that while some chromatin binding proteins and histone modification such as H3K27me3 are associated with R-loops throughout development, other chromatin factors associated with R-loops in a developmental specific manner. Our findings highlight the importance and developmental plasticity of R-loops during Drosophila embryogenesis.
Impact of a 7-day homogeneous diet on interpersonal variation in human gut microbiomes and metabolomes
Authors: Guthrie Leah , Spencer Sean Paul , Perelman Dalia , Van Treuren Will , Han Shuo , Yu Feiqiao Brian , Sonnenburg Erica D. , Fischbach Michael A. , Meyer Timothy W. , Sonnenburg Justin L.
Published: October 2021

Metabolism of dietary compounds by the gut microbiota generates a vast array of microbiome-dependent metabolites (MDMs), which are highly variable between individuals. The uremic MDMs (uMDMs) phenylacetylglutamine (PAG), p-cresol sulfate (PCS) and indoxyl sulfate (IS) accumulate during renal failure and are associated with poor outcomes. Targeted dietary interventions may reduce toxic MDMs generation; however, it is unclear if interindividual differences in diet or gut microbiome dominantly contribute to MDM variance. Here we use a 7-day homogeneous average American diet to standardize dietary precursor availability in 21 healthy individuals. Notably, the coefficient of variation in three uMDMs of interest, PAG, PCS, and IS (primary outcome), did not significantly decrease. The majority of circulating MDMs maintained variation despite identical diets. These results highlight the highly personalized profile of MDMs and limited contribution of short-term dietary heterogeneity, suggesting that dietary modification may need to be paired with microbial therapies to control MDM profiles.
A hold-and-feed mechanism drives directional DNA loop extrusion by condensin
Authors: Shaltiel Indra A. , Datta Sumanjit , Lecomte Léa , Hassler Markus , Kschonsak Marc , Bravo Sol , Stober Catherine , Eustermann Sebastian , Haering Christian H.
Published: October 2021

SMC protein complexes structure genomes by extruding DNA loops, but the molecular mechanism that underlies their activity has remained unknown. We show that the active condensin complex entraps the bases of a DNA loop in two separate chambers. Single-molecule and cryo-electron microscopy provide evidence for a power-stroke movement at the first chamber that feeds DNA into the SMC-kleisin ring upon ATP binding, while the second chamber holds on upstream of the same DNA double helix. Unlocking the strict separation of ‘motor’ and ‘anchor’ chambers turns condensin from a one-sided into a bidirectional DNA loop extruder. We conclude that the orientation of two topologically bound DNA segments during the course of the SMC reaction cycle determines the directionality of DNA loop extrusion.
Comprehensive Structure and Functional Adaptations of the Yeast Nuclear Pore Complex
Authors: Akey Christopher W. , Singh Digvijay , Ouch Christna , Echeverria Ignacia , Nudelman Ilona , Varberg Joseph M , Yu Zulin , Fang Fei , Shi Yi , Wang Junjie , Salzberg Daniel , Song Kangkang , Xu Chen , Gumbart James C. , Suslov Sergey , Unruh Jay , Jaspersen Sue L , Chait Brian T. , Sali Andrej , Fernandez-Martinez Javier , Ludtke Steven J. , Villa Elizabeth , Rout Michael P.
Published: October 2021

Nuclear Pore Complexes (NPCs) mediate the nucleocytoplasmic transport of macromolecules. Here we provide a structure of the yeast NPC in which the inner ring is resolved by cryo-EM at - helical resolution to show how flexible connectors tie together different structural and functional layers in the spoke. These connectors are targets for phosphorylation and regulated disassembly in cells with an open mitosis. Moreover, some nucleoporin pairs and karyopherins have similar interaction motifs, which suggests an evolutionary and mechanistic link between assembly and transport. We also provide evidence for three major NPC variants that foreshadow functional specializations at the nuclear periphery. Cryo-electron tomography extended these studies to provide a comprehensive model of the in situ NPC with a radially-expanded inner ring. Our model reveals novel features of the central transporter and nuclear basket, suggests a role for the lumenal ring in restricting dilation and highlights the structural plasticity required for transport by the NPC.
Modeling the efficacy of CRISPR gene drive for schistosomiasis control
Authors: Grewelle Richard E. , Perez-Saez Javier , Tycko Josh , Namigai Erica K.O. , Rickards Chloe G. , De Leo Giulio A.
Published: October 2021

CRISPR gene drives could revolutionize the control of infectious diseases by accelerating the spread of engineered traits that limit parasite transmission in wild populations. While much effort has been spent developing gene drives in mosquitoes, gene drive technology in molluscs has received little attention despite the role of freshwater snails as obligate, intermediate hosts of parasitic flukes causing schistosomiasis – a disease of poverty affecting more than 200 million people worldwide. A successful drive in snails must overcome self-fertilization, which prevents a drive’s spread. Simultaneous hermaphroditism is a feature of snails – distinct from gene drive model organisms – and is not yet incorporated in gene drive models of disease control. Here we developed a novel population genetic model accounting for snails’ sexual and asexual reproduction, susceptibility to parasite infection regulated by multiple alleles, fitness differences between genotypes, and a range of drive characteristics. We then integrated this model with an epidemiological model of schistosomiasis transmission and snail population dynamics. Simulations showed that gene drive establishment can be hindered by a variety of biological and ecological factors, including selfing. However, our model suggests that, under a range of conditions, gene drive mediated immunity in snails could maintain rapid disease reduction achieved by annual chemotherapy treatment of the human population, leading to long-term elimination. These results indicate that gene drives, in coordination with existing public health measures, may become a useful tool to reduce schistosomiasis burden in selected transmission settings with effective CRISPR construct design and close evaluation of the genetic and ecological landscape.
Polarization and cell-fate decision facilitated by the adaptor Ste50 in Saccharomyces cerevisiae
Authors: Sharmeen Nusrat , Law Chris , Wu Cunle
Published: October 2021

In response to pheromone, many proteins localize on the plasma membrane of yeast cell to reform it into a polarized shmoo structure. The adaptor protein Ste50, long known as a pheromone signal enhancer critical for shmoo polarization, has never been explored systematically for its localization and function in the polarization process. Time-lapse single-cell imaging and quantitation shown here characterizes Ste50p involvement in the establishment of cell polarity. We found early localization of Ste50p patches on the cell cortex that mark the point of shmoo initiation, these polarity sites move, and patches remain associated with the growing shmoo tip in a pheromone concentration timedependent manner until shmoo maturation. By quantitative analysis we show that polarization corelates with the rising levels of Ste50p, enabling rapid individual cell responses to pheromone that corresponds to a critical level of Ste50p at the initial G1 phase. We exploited the quantitative differences in the pattern of Ste50p expression to corelate with the cell-cell phenotypic heterogeneity showing Ste50p involvement in the cellular differentiation choice. Taken together, these findings present spatiotemporal localization of Ste50p during yeast polarization, suggesting that Ste50p is a component of the polarisome, and plays a critical role in regulating the polarized growth of shmoo during pheromone response.
Lineage, Identity, and Fate of Distinct Progenitor Populations in the Embryonic Olfactory Epithelium
Authors: Paronett Elizabeth M. , Bryan Corey A. , Maynard Thomas M. , LaMantia Anthony-S.
Published: October 2021

We defined a temporal dimension of precursor diversity and lineage in the developing mouse olfactory epithelium (OE) at mid-gestation that results in genesis of distinct cell classes. Slow, symmetrically dividing Meis1+/ Pax7+ progenitors in the early differentiating lateral OE give rise to small numbers of Ascl1+ precursors in the dorsolateral and ventromedial OE. Few of the initial progeny of the Ascl1+ precursors immediately generate olfactory receptor neurons (ORNs). Instead, most early progeny of this temporally defined precursor cohort, labeled via temporally discreet tamoxifen-dependent Ascl1Cre-driven recombination, populate a dorsomedial OE domain comprised of proliferative Ascl1+ as well as Ascl1-cells from which newly generated ORNs are mostly excluded. The most prominent early progeny of these Ascl1+ OE precursors are migratory mass cells associated with the nascent olfactory nerve (ON) in the frontonasal mesenchyme. These temporal, regional and lineage distinctions are matched by differences in proliferative capacity and modes of division in isolated, molecularly distinct lateral versus medial OE precursors. By late gestation, the progeny of the temporally and spatially defined Ascl1+ precursor cohort include few proliferating precursors. Instead, these cells generate a substantial subset of OE sustentacular cells, spatially restricted ORNs, and ensheathing cells associated with actively growing as well as mature ON axons. Accordingly, from the earliest stages of OE differentiation, distinct temporal and spatial precursor identities provide a template for acquisition of subsequent OE and ON cellular diversity.
The early embryonic transcriptome of a HawaiianDrosophilapicture-wing fly shows evidence of altered gene expression and novel gene evolution
Authors: Chenevert Madeline , Miller Bronwyn , Karkoutli Ahmad , Rusnak Anna , Lott Susan , Atallah Joel
Published: October 2021

A massive adaptive radiation on the Hawaiian archipelago has produced approximately one quarter of the fly species in the family Drosophilidae. The HawaiianDrosophilaclade has long been recognized as a model system for the study of both the ecology of island endemics and the evolution of developmental mechanisms, but relatively few genomic and transcriptomic datasets are available for this group. We present here a differential expression analysis of the transcriptional profiles of two highly conserved embryonic stages in the Hawaiian picture-wing flyDrosophila grimshawi. When we compared our results to previously published datasets across the family Drosophilidae, we identified cases of both gains and losses of gene representation inD. grimshawi, including an apparent delay in Hox gene activation. We also found high expression of unannotated genes. Most transcripts of unannotated genes with open reading frames do not have homologs in non-HawaiianDrosophilaspecies, although the vast majority have sequence matches in other genomes of the Hawaiian picture-wing flies. Some of these genes may have arisen from non-coding sequence in the ancestor of Hawaiian flies or during the evolution of the clade. Our results suggests that both the modified use of ancestral genes and the evolution of new ones may occur in rapid radiations.

RESEARCH HIGHLIGHTS

The early embryonic transcriptome of the Hawaiian flyDrosophila grimshawishows a loss of expression of conserved Stage 5 genes, including the Hox genes

The de novo evolution of embryonically expressed genes may be occurring in the HawaiianDrosophilalineage

AUTHORS’ STATEMENT

This paper is not being considered for publication elsewhere. This study formed part of Madeline Chenevert’s M.S. thesis.