bluuebunny/crossref_metadata_2025 huggingface dataset:
Transitioning the Healthy Chicago Survey From a Telephone Mode to Self-administered by Mail Mode
Authors: Unangst Jennifer , Lewis Taylor , Laflamme Emily , Prachand Nik , Weaver Kingsley
Published: March 2022

Context:

As response rates to health surveys conducted by telephone continue to decline and costs continue to increase, practitioners are increasingly considering a transition to self-administered mail contact modes.

Objective:

To compare empirical differences observed across adjacent administrations of the Healthy Chicago Survey (HCS) conducted by telephone versus self-administered via mail contact.

Design:

Data from the 2016, 2018, and 2020 administrations of the HCS are contrasted, and demographic distributions are benchmarked against the American Community Survey to investigate differences that may be linked to the HCS' transition from a telephone to self-administered mail mode between 2018 and 2020.

Setting:

All survey data were collected from adult residents of Chicago, Illinois, between 2016 and 2020.

Main Outcome Measures:

Costs, response rates, key health statistics, demographic distributions, and measures of precision generated from the HCS.

Results:

The mail mode led to a response rate increase of 6.8% to 38.2% at half the cost per complete. Mail respondents are more likely to be nonminority, female, and hold a college degree. Key health statistic differences are mixed, but design effects are larger in the mail mode, which we attribute to more detailed geographic stratification and weighting employed in 2020.

Conclusions:

The mail mode is a less costly data collection strategy for the HCS, but it comes with trade-offs. The quasi-random selection of an individual in the household exacerbates sociodemographic distribution disparities.
Lessons for Oncology From the COVID-19 Pandemic
Authors: Roberts Thomas J. , Lennes Inga T.
Published: March 2022

After several decades of slow expansion, the use of virtual care in oncology rapidly expanded during the COVID-19 pandemic. Data from cancer centers across the country show that most patients and providers were satisfied with components of virtual care, and virtual care may be able to improve access to care. However, the rapid implementation of programs during the pandemic worsened disparities in access to virtual care. Health systems must develop strategies to monitor quality, support patients and providers, promote health equity, and overcome regulatory challenges to successfully deliver care in hybrid systems that combine in-person and virtual care.
Maintaining and Advancing Quality Cancer Care During a Global Pandemic
Authors: Oyer Randall Alan , Pierce Lori , Lathan Christopher , Sagar Bhuvana
Published: March 2022

The care of patients with cancer occurs in a fast-moving, high-pressure, and high-stakes ecosystem. Early in 2020, that complex ecosystem was further complicated by the advent of the COVID-19 pandemic. We address actions taken by care providers and systems during the initial phases of the pandemic, and how those actions preserved lifesaving and life-sustaining cancer care despite severely constrained resources. We outline cancer care principles and guidelines that were developed, shared, and adopted by cancer care organizations across the country. Care delivery concerns that arose during the pandemic, including equipment and personnel shortages, moral distress for care providers, and exacerbation of health care inequities are addressed. Process and operations changes taken by payers to serve their clients are described. Lessons learned are highlighted, along with a call to action that we learn from the experience, broaden our cancer care delivery mission, and commit to structural changes that will permanently improve the capacity of cancer care teams.
Examining the Impact of Tislelizumab Added to Chemotherapy on Health-Related Quality-of-Life Outcomes in Previously Untreated Patients With Nonsquamous Non–Small Cell Lung Cancer
Authors: Lu Shun , Yu Yan , Barnes Gisoo , Qiu Xiusong , Bao Yuanyuan , Tang Boxiong
Published: March 2022

Purpose

This study assessed the effects of tislelizumab, a programmed cell death protein 1 inhibitor, in combination with chemotherapy versus chemotherapy alone as first-line treatment on health-related quality of life (HRQoL) in patients with advanced nonsquamous non–small cell lung cancer (nSQ-NSCLC).

Methods

Patients in this randomized, open-label, multicenter phase III study RATIONALE 304 (NCT03663205) with histologically confirmed stage IIIB/IV nSQ-NSCLC were randomized 2:1 to tislelizumab plus platinum-pemetrexed (arm T + PP) or platinum-pemetrexed alone (arm PP). Health-related QoL was measured using the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire Core 30 items and the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire–Lung Cancer. Key patient-reported outcome endpoints include mean score change from baseline at weeks 12 (during chemotherapy) and 18 (following chemotherapy) in the 30-item Quality of Life Questionnaire Core's global health status/quality of life (GHS/QoL) and time to deterioration in GHS/QoL.

Results

Three hundred thirty-two patients received at least 1 dose of study drug and completed at least 1 HRQoL assessment. Global health status/QoL score improved in arm T + PP at week 18 (between-group least square mean difference, 5.7; 95% confidence interval [CI], 1.0–10.5; P = 0.018). Patients in arm T + PP experienced greater reduction in coughing (−5.9; 95% CI, −11.6 to −0.1; P = 0.044), dyspnea (−3.8; 95% CI, −7.8 to 0.1; P = 0.059), chest pain (−6.2; 95% CI, −10.8 to −1.6; P = 0.008), and peripheral neuropathy (−2.6; 95% CI, −5.5 to 0.2; P = 0.066). Median time to deterioration in GHS/QoL was not achieved for either arm.

Discussion

The addition of tislelizumab to platinum-based chemotherapy was associated with improvements in nSQ-NSCLC patients' HRQoL as well as the important disease-specific symptoms of coughing, chest pain, and dyspnea.

ClinicalTrials.gov Identifier: NCT03663205
Insights for Oncology Trials Garnered From the Rapid Development of an mRNA COVID-19 Vaccine
Authors: Hyer Randall N.
Published: March 2022

The sudden emergence of the coronavirus disease 2019 (COVID-19) pandemic in early 2020 stimulated unprecedented scientific initiatives to rapidly develop effective treatments and vaccines. One example was the development of vaccines based on messenger RNA platforms, which received emergency use authorization in the United States less than 1 year after the primary sequence of the severe acute respiratory syndrome coronavirus 2 virus was published. Novel practices arose from the collaborative efforts and inclusive clinical studies that facilitated the vaccines' rapid development and clinical testing. I describe insights gained from the experience of mRNA-1273 vaccine development that may be applied to or adapted for oncology research. These insights include clinical study design, diversity and inclusion initiatives, speed, and real-world evidence generation, as well as close partnership among regulatory agencies, government, and pharmaceutical companies.
Strategies for graded motor imagery for clients with phantom limb pain and cognitive impairment
Authors: Rich Tonya L. , Marth Lindsay A. , Brielmaier Steven M. , Kiecker Jessica E. , Vogsland Rebecca J. , Macedo Franz J. , Ferguson John E. , Hansen Andrew H.
Published: March 2022

Background:

Individuals with amputations often experience phantom limb pain (PLP) that can limit their participation in rehabilitation, prosthesis training, desired activities, and roles. One nonpharmacological rehabilitation intervention for PLP is graded motor imagery (GMI). There are several components to GMI, including right/left discrimination or laterality, motor imagery, sensory retraining, and mirror therapy. Successful implementation of GMI requires a range of cognitive skills, such as attention span, working memory, abstract reasoning, and planning. For individuals with PLP who concurrently display cognitive impairments, GMI protocols can be adapted using strategies derived from clinical practice.

Objective(s):

The purpose of this technical clinical report was to discuss the application of clinically implemented cognitive compensation techniques to GMI instruction.

Study Design:

Not applicable

Methods:

Clinical expert opinion to explore adaptations for GMI.

Technique:

Graded motor imagery can be an effective tool for pain treatment; however, some clients may need greater clinician support due to existing cognitive difficulties.

Results:

For clients to be successful, active engagement in learning about and implementing GMI techniques is necessary.

Conclusions:

When serving the lifetime amputation care needs of patients with cognitive deficits, we find that targeted learning strategies and accommodations can be helpful when introducing GMI concepts and skill development. Enhanced patient education techniques support client learning.
An Application of Kane's Validity Framework to Evaluate Formative and Summative Assessment Instruments for Telesimulations in Clinical Lactation
Authors: Chuisano Samantha A. , Anderson Olivia S. , Weirauch Katrina , Roper Rosemary , Phillips Julie , McCabe Carolyn , Sadovnikova Anna
Published: March 2022

Introduction

Health professional learners have limited exposure to breastfeeding patients from diverse backgrounds in clinical rotations. Instead, simulation-based training is used for lactation skills training. There are no validated or standardized simulations and assessment rubrics for lactation. In this pilot, breastfeeding telesimulations with standardized patients (SPs) wearing a high-fidelity breast model matching their skin tone were developed. The validity of Formative and Summative Assessment Rubrics (FAR, SAR) were assessed following Kane's validity framework. The objective was to provide initial evidence for the validity of the FAR and SAR as constructs of competence in lactation support at the entry to practice or practice level.

Methods

Three breastfeeding case scenarios, FAR, and SAR were developed and evaluated with clinical lactation specialists (evaluators, n = 17) and SPs. The FAR was used in practice telesimulations where SPs' (n = 14) performance and telesimulation feasibility were assessed. The FAR was updated in preparation for a pilot study where medical students (n = 13) completed the 3 telesimulations. In the pilot, the updated FAR was used by SPs (n = 6) to assess medical students' performance of clinical skills. After the pilot, rubrics were updated after focus groups with SPs and discussions with evaluators. Evaluators (n = 3) graded students' posttelesimulation documentations using the SAR. Cronbach ɑ level and the intraclass correlation coefficient were assessed iteratively to collect evidence for the scoring, generalizability, and extrapolation of the FAR and SAR according to Kane's framework.

Results

The FAR and SAR were found to have acceptable internal consistency and moderate to high interrater reliability (intraclass correlation coefficient, 0.55–0.94), which provided evidence for scoring and generalizability of the instruments. Evaluators agreed that SPs' performances were realistic (5.6/6), and SPs' feedback was organized (5.5/6) and helpful (5.6/6), which provided evidence for extrapolation.

Conclusions

Initial evidence for validity of scoring, generalization, and extrapolation FAR and SAR (according to Kane's framework) in assessing health professional learner's performance of clinical lactation skills has been presented. These results from a pilot study suggest that the FAR and SAR are reliable instruments for assessing learners' clinical performance in a breastfeeding-focused telesimulation where the SP wears a high-fidelity breast model matching their skin tone. Additional studies will be required to collect evidence according to all 4 categories of Kane's framework for the validity of the FAR and SAR.
Increased gene dosage and mRNA expression from chromosomal duplications in C. elegans
Authors: Ragipani Bhavana , Albritton Sarah Elizabeth , Morao Ana Karina , Mesquita Diogo , Kramer Maxwell , Ercan Sevinç
Published: March 2022

Isolation of copy number variations and chromosomal duplications at high frequency in the laboratory suggested that Caenorhabditis elegans tolerates increased gene dosage. Here we addressed if a general dosage compensation mechanism acts at the level of mRNA expression in C. elegans. We characterized gene dosage and mRNA expression in three chromosomal duplications and a fosmid integration strain using DNA-seq and mRNA-seq. Our results show that on average, increased gene dosage leads to increased mRNA expression, pointing to a lack of genome-wide dosage compensation. Different genes within the same chromosomal duplication show variable levels of mRNA increase, suggesting feedback regulation of individual genes. Somatic dosage compensation and germline repression reduce the level of mRNA increase from X chromosomal duplications. Together, our results show a lack of genome-wide dosage compensation mechanism acting at the mRNA level in C. elegans and highlight the role of epigenetic and individual gene regulation contributing to the varied consequences of increased gene dosage.
Adherence to 24h movement recommendations and health indicators in the ABCD study: Cross-sectional and longitudinal associations with cognition, psychosocial health, BMI and brain structure
Authors: Fung Hoki , Yeo B.T. Thomas , Chen Christina , Lo June C. , Chee Michael W.L. , Ong Ju Lynn
Published: March 2022

Adherence to 24h movement guidelines of ≥60min of physical activity, ≤2h of screen time, and 9-11h of sleep has been shown to benefit cognition, physical and psychosocial health in children aged 5-13y. However, these findings are largely based on cross-sectional studies or small samples. Here we utilize data from the Adolescent Brain Cognitive Development (ABCD) study of 10000+ children aged 9-11y to examine whether adherence to 24h movement guidelines benefit cognition, BMI, psychosocial health and brain morphometric measures at baseline (T1) and 2 years later (T2). After adjustment for sociodemographic confounders in multivariable linear mixed models, we observed better cognitive scores, fewer behavioural problems, lower adiposity levels and greater gray matter volumes in children who met both sleep and screen time recommendations compared to those who met none. Longitudinal follow up further supports these findings; participants who met both recommendations at T1 and T2 evidenced better outcome measures than those who met none, even after controlling for T1 measures. These findings support consideration of integrated rather than isolated movement recommendations across the day for better cognitive, physical, psychosocial and brain health.
Systematic review and meta-analysis of yellow fever vaccine in elderly population
Authors: de Jesus Lopes de Abreu Ariane , Cavalcante João Roberto , de Araújo Lagos Letícia Wigg , Caetano Rosângela , Braga José Ueleres
Published: March 2022

We conducted a systematic review and meta-analysis to assess the risk of serious adverse events in the elderly after yellow fever vaccination compared to the non-elderly population. We searched multiple databases and grey literature and selected research without language and publication date restriction. Studies were analysed in a descriptive way, meta-analysed and expressed in terms of prevalence ratio and risk ratio with a 95% confidence interval, depending on the degree of heterogeneity found. A total of 18 studies were included, of which 10 were meta-analysed. Results obtained through the meta-analysis showed that the risk of serious adverse events after yellow fever vaccination is three times higher for elderlies when compared to non-elderly population and even five times higher for persons >70 years of age. Also, in relation adverse event type a greater risk was for viscerotropic disease associated with yellow fever vaccine up to six times higher when compared to the population under 60 years. The evidence found in this review supports that the vaccine indication in individuals over 60 years of age should be based on a careful analysis of the individual benefit-risk assessment. Results found suggest a higher risk of SAE for individuals over 70 years, especially for viscerotropic and neurotropic disease associated with YFV contraindicating the use of the YFV in this age group.
SPACA6 structure reveals a conserved superfamily of gamete fusion-associated proteins
Authors: Vance Tyler D.R. , Yip Patrick , Jiménez Elisabet , Li Sheng , Gawol Diana , Byrnes James , Usón Isabel , Ziyyat Ahmed , Lee Jeffrey E.
Published: March 2022

SPACA6 is a sperm-expressed surface protein that is critical for gamete fusion during mammalian sexual reproduction. Despite this fundamental role, little is known about how SPACA6 specifically functions. We elucidated the crystal structure of SPACA6 at 2.2-Å resolution, revealing a two-domain protein containing a four-helix bundle and Ig-like β-sandwich connected via a quasi-flexible linker. Based on the structural analysis, we propose SPACA6 is a founding member of a superfamily of gamete fusion-associated proteins, herein dubbed the IST superfamily. The IST superfamily is defined structurally by its distorted four-helix bundle and a pair of disulfide-bonded CXXC motifs. A structure-based search of the AlphaFold human proteome identified more protein members to this superfamily; remarkably, many of these proteins are linked to gamete fusion. The SPACA6 structure and its connection to other IST-superfamily members provide a missing link in our knowledge of mammalian gamete fusion.

Significance Statement

SPACA6 is a human sperm protein vital for the fusion of gametes, though its exact function remains a mystery. We present the first solved structure of SPACA6: a two-domain fold comprised of an Ig-like domain and a distorted four-helix bundle. Dali searches of the PDB and AlphaFold reveal a family of structurally related proteins, several of which are also known to play a role in gamete fusion; as such, SPACA6 is a founding member of a conserved protein superfamily, dubbed the IST superfamily. Evolutionary analysis to ascertain functionally relevant structural elements in SPACA6 show a conservation of flexibility between the two domains and several conserved surfaces that could function as protein-protein interfaces.
Unmyelinated neurons use Neuregulin signals to promote myelination of neighboring neurons in the CNS
Authors: Lysko Daniel E. , Talbot William S.
Published: March 2022

The signaling mechanisms neurons use to modulate myelination of circuits in the central nervous system (CNS) are only partly understood. Through analysis of isoform-specificneuregulin1(nrg1) mutants, we identifynrg1type II as an important regulator of myelination in the zebrafish CNS, required for normal myelination of two classes of spinal cord neurons. Surprisingly,nrg1type II reporter expression is prominent in unmyelinated Rohon-Beard (RB) sensory neurons, while myelination of interneurons controlling the escape response circuit is reduced innrg1type II mutants. Cell type-specific loss-of-function studies indicate thatnrg1type II is required in RB neurons to signal to other neurons, not oligodendrocytes, to modulate spinal cord myelination. Together, our data support a model in which unmyelinated neurons express Nrg1 type II proteins to regulate myelination of circuit partners, a mode of action that may coordinate function of circuits in the CNS involving both unmyelinated and myelinated neurons.

Summary points

nrg1type II is required for normal myelination of diverse neuronal classes in the zebrafish spinal cord

Surprisingly,nrg1type II reporter expression is prominent in unmyelinated Rohon-Beard neurons

Cell type-specific knockdown indicates that myelination of CoPA neurons requiresnrg1type II function in unmyelinated Rohon-Beard neurons

The Nrg1 receptorerbb2is required in neurons, but not oligodendrocytes, for normal myelination
Neural and cognitive correlates of performance in dynamic multi-modal settings
Authors: Dziego Chloe A. , Bornkessel-Schlesewsky Ina , Jano Sophie , Chatburn Alex , Schlesewsky Matthias , Immink Maarten A. , Sinha Ruchi , Irons Jessica , Schmitt Megan , Chen Steph , Cross Zachariah R.
Published: March 2022

The endeavour to understand human cognition has largely relied upon investigation of task-related brain activity. However, resting-state brain activity can also offer insights into individual information processing and performance capabilities. Previous research has identified electroencephalographic resting-state characteristics (most prominently: the individual alpha frequency; IAF) that predict cognitive function. However, it has largely overlooked a second component of electrophysiological signals: aperiodic 1/factivity. The current study examined how both oscillatory and aperiodic resting-state EEG measures, alongside traditional cognitive tests, can predict performance in a dynamic and complex, semi-naturalistic cognitive task. Participants’ resting-state EEG was recorded prior to engaging in a Target Motion Analysis (TMA) task in a simulated submarine control room environment (CRUSE), which required participants to integrate dynamically changing information over time. We demonstrated that the relationship between IAF and cognitive performance extends from simple cognitive tasks (e.g., digit span) to complex, dynamic measures of information processing. Further, our results showed that individual 1/fparameters (slope and intercept) differentially predicted performance across practice and testing sessions, whereby flatter slopes were associated with improved performance during learning, while higher intercepts were linked to better performance during testing. In addition to the EEG predictors, we demonstrate a link between cognitive skills most closely related to the TMA task (i.e., spatial imagery) and subsequent performance. Overall, the current study highlights (1) how resting-state metrics – both oscillatory and aperiodic - have the potential to index higher-order cognitive capacity, while (2) emphasising the importance of examining these electrophysiological components within more dynamic settings and over time.
Full-length transcriptome maps of reef-building coral illuminate the molecular basis of calcification, symbiosis, and circadian genes
Authors: Han Tingyu , Liao Xin , Zhu Yunchi , Liu Yunqing , Lu Na , Li Yixin , Guo Zhuojun , Chen J.-Y. , He Chunpeng , Lu Zuhong
Published: March 2022

Background

Reef-building corals are critical species for sustaining coral reefs and are highly threatened by global climate change. However, relevant transcriptomic data largely rely on short-read sequencing, which severely limits the understanding of coral molecular mechanisms and leaves many important biological questions unresolved.

Results

We sequenced the full-length transcriptomes of four common and frequently dominant reef-building corals, including two Robusta clade species, Pocillopora damicornis and Pocillopora verrucosa, and two Complexa clade species, Acropora muricata and Montipora foliosa, using the PacBio Sequel II platform. We obtained information on gene functions, structures and expression profiles. Among them, a comparative analysis of biomineralization-related genes provided insights into the molecular basis of coral skeletal density. The gene expression profiles of the symbiote Symbiodiniaceae were also isolated and annotated from the holobiont sequence data; these profiles showed more highly convergent traits related to gene structure and expression level than those of coral hosts. Interestingly, we observed that intracellular algal cells share some evolutionary convergence between intracellular symbiosis in corals and intracellular digestion in amphioxus. Finally, a phylogenetic analysis of key circadian clock genes among 27 evolutionarily representative species indicated that there are four key members in early metazoans, including cry genes; Clock or Npas2; cyc or Arntl; and tim, while per, as the fifth member, occurs in Bilateria.

Conclusions

Our work overcomes the incompleteness of short-read sequencing and illuminates the molecular basis of calcification, symbiosis, and circadian genes, thus providing a foundation for further work on the manipulation of skeleton production or symbiosis to promote the survival of these important organisms.
Spontaneous suppressors against debilitating transmembrane mutants of CaMdr1 disclose novel interdomain communication via Signature motifs of the Major Facilitator Superfamily
Authors: Sharma Suman , Banerjee Atanu , Moreno Alexis , Redhu Archana Kumari , Falson Pierre , Prasad Rajendra
Published: March 2022

The Major Facilitator Superfamily (MFS) includes multiple families of proteins operating as uniporters, symporters and antiporters for a wide spectrum of substrates. Among them, the multidrug resistance-1 drug:H+ antiporter CaMdr1 from Candida albicans is responsible for the efflux of structurally-diverse antifungals. MFS share a common fold of 12-14 transmembrane helices (TMHs) forming two N- and C-domains. Each domain is arranged in a pseudo symmetric fold of two tandems of 3-TMHs that alternatively expose the drug-binding site towards the inside or the outside of the yeast to promote drug binding and release. MFS show a high primary structure diversity and few conserved Signature motifs, each thought to have a common function in the superfamily, although not yet clearly established. Here, we provide new information on these motifs by having screened a library of 64 drug transport-deficient mutants and their corresponding suppressors spontaneously rescuing the deficiency. We found that five strains recovered the drug-resistance capacity by expressing CaMdr1 with a secondary mutation. The pairs of debilitating/rescuing residues are distributed either in the same TMH (T127ATMH1->G140DTMH1) or 3-TMHs repeat (F216ATMH4->G260ATMH5), at the hinge of 3-TMHs repeats tandems (R184ATMH3->D235HTMH4, L480ATMH10->A435TTMH9), and finally between the N- and C-domains (G230ATMH4->P528HTMH12). Remarkably, most of these mutants belongs to the different Signature motifs, highlighting a mechanistic role and interplay thought to be conserved among MFS. Results point also to the specific role of TMH11 in the interplay between the N- and C-domains in the inward- to outward-open conformational transition.
Mechanical activation of mitochondrial energy metabolism during cell differentiation
Authors: Wang Zong-Heng , Combs Christian , Zhao Wenjing , Knutson Jay , Lilly Mary , Xu Hong
Published: March 2022

In multicellular lives, differentiation of many types of stem and progenitor cells is often accompanied by a metabolic transition from glycolysis to mitochondrial oxidative phosphorylation. The mechanisms driving this metabolic transition in vivo are largely unknown. Here, we show that, during differentiation of the Drosophila female germline cyst, the surrounding somatic cells compress the cyst and increase the tension of cyst cells’ membranes. Transmembrane channel-like, an evolutionarily conserved ion channel involved in mechanosensation, maintains cytosolic Ca2+ levels in compressed differentiating cysts. Cytosolic Ca2+ induces transcriptional activation of oxidative phosphorylation through a CaMKI-Fray-JNK signaling relay. Our findings demonstrate a molecular link between cell mechanics and mitochondrial energy metabolism, with implications in other developmentally orchestrated metabolic transitions in mammals.

One-Sentence Summary

Mechanical forces from the surrounding tissue activate mitochondrial energy metabolism in differentiating cells in vivo.
LSMMD-MA: Scaling multimodal data integration for single-cell genomics data analysis
Authors: Meng-Papaxanthos Laetitia , Zhang Ran , Li Gang , Cuturi Marco , Noble William Stafford , Vert Jean-Philippe
Published: March 2022

Motivation

Modality matching in single-cell omics data analysis—i.e., matching cells across data sets collected using different types of genomic assays—has become an important problem, because unifying perspectives across different technologies holds the promise of yielding biological and clinical discoveries. However, single-cell dataset sizes can now reach hundreds of thousands to millions of cells, which remains out of reach for most multi-modal computational methods.

Results

We propose LSMMD-MA, a large-scale Python implementation of the MMD-MA method for multimodal data integration. In LSMMD-MA we reformulate the MMD-MA optimization problem using linear algebra and solve it with KeOps, a CUDA framework for symbolic matrix computation in Python. We show that LSMMD-MA scales to a million cells in each modality, two orders of magnitude greater than existing implementations.

Availability

LSMMD-MA is freely available at https://github.com/google-research/large_scale_mmdma

Contact

lpapaxanthos@google.com
Prevalence of Bourbon and Heartland viruses in field collected ticks at an environmental field station in St. Louis County, Missouri, USA
Authors: Aziati Ishmael D , McFarland Derek , Antia Avan , Joshi Astha , Aviles-Gamboa Anahi , Lee Preston , Harastani Houda , Wang David , Adalsteinsson Solny A. , Boon Adrianus C. M.
Published: March 2022

Heartland and Bourbon viruses are pathogenic tick-borne viruses putatively transmitted by Amblyomma americanum, an abundant tick species in Missouri. To assess the prevalence of these viruses in ticks, we collected 2778 ticks from 8 sampling sites at Tyson Research Center, an environmental field station within St. Louis County and close to the City of St. Louis, from May - July in 2019 and 2021. Ticks were pooled according to life stage and sex, grouped by year and sampling site to create 355 pools and screened by RT-qPCR for Bourbon and Heartland viruses. Overall, 14 (3.9%) and 27 (7.6%) of the pools were positive for Bourbon virus and Heartland virus respectively. In 2019, 11 and 23 pools were positive for Bourbon and Heartland viruses respectively. These positives pools were of males, females and nymphs. In 2021, there were 4 virus positive pools out of which 3 were positive for both viruses and were comprised of females and nymphs. Five out of the 8 sampling sites were positive for at least one virus. This included a site that was positive for both viruses in both years. Detection of these viruses in an area close to a relatively large metropolis presents a greater public health threat than previously thought.
First description of aYersinia pseudotuberculosisclonal outbreak in France, confirmed using a new core genome multilocus sequence typing method
Authors: Savin Cyril , Guern Anne-Sophie Le , Chereau Fanny , Guglielmini Julien , Heuzé Guillaume , Demeure Christian , Pizarro-Cerdá Javier
Published: March 2022

Yersinia pseudotuberculosisis an enteric pathogen causing mild enteritis that can lead to mesenteric adenitis and septicemia in elderly patients. Most cases are sporadic, but outbreaks have already been described in different countries. We report for the first time aY. pseudotuberculosisclonal outbreak in France, that occurred in 2020. An epidemiological investigation pointed towards the consumption of tomatoes as the likely source of contamination. TheYersiniaNational Reference Laboratory (YNRL) developed a new cgMLST scheme with 1,921 genes specific toY. pseudotuberculosisthat identified the clustering of isolates associated to the outbreak and allowed to perform molecular typing in real time. In addition, this method allowed to retrospectively identify isolates belonging to this cluster from earlier in 2020. This method, which does not require specific bioinformatic skills, is now used systematically at the YNRL and proves to display an excellent discriminatory power and is available to the scientific community.
Spatial turnover of soil viral populations and genotypes overlain by cohesive responses to moisture in grasslands
Authors: Santos-Medellín Christian , Estera-Molina Katerina , Yuan Mengting , Pett-Ridge Jennifer , Firestone Mary K. , Emerson Joanne B.
Published: March 2022

Although soil viral abundance, diversity, and potential roles in microbial community dynamics and biogeochemical cycling are beginning to be appreciated1–5, little is known about the patterns and drivers of soil viral community composition that underlie their contributions to terrestrial ecology. Here, we analyzed 43 soil viromes from a precipitation manipulation experiment in a Mediterranean grassland in California, USA. We recovered 5,315 viral population sequences (vOTUs), and viral community composition exhibited a highly significant distance-decay relationship within the 18 m long field. This pattern was recapitulated in the microheterogeneity of 130 prevalent vOTUs (detected in >=90% of the viromes), which tended to exhibit significant negative correlations between genomic similarity of their predominant allelic variants and distance. Although spatial turnover was also observed in the bacterial and archaeal communities from the same soils, the signal was dampened relative to the viromes, suggesting differences in assembly drivers at local scales for viruses and their microbial hosts and/or differences in the temporal scales captured by viromes and total DNA. Despite the overwhelming spatial signal, vOTUs responsive to a decrease in soil moisture were significantly enriched in a predicted protein-sharing subnetwork of 326 vOTUs linked to 191 known actinobacteriophages, suggesting a genomically cohesive viral response to soil moisture evocative of environmental filtering, potentially by way of actinobacterial hosts. Overall, soil viral ecological processes appear to be highly constrained in space and tightly coupled to the heterogeneous, dynamic soil environment and thus fundamentally different from those of their well-mixed and more thoroughly studied marine counterparts.
Revealing within-species diversity in uncultured human gut bacteria with single-cell long-read sequencing
Authors: Kogawa Masato , Nishikawa Yohei , Saeki Tatsuya , Yoda Takuya , Arikawa Koji , Takeyama Haruko , Hosokawa Masahito
Published: March 2022

Bacterial genome structure changes dynamically, and structural variants can change bacterial phenotype; However, obtaining the complete genome and analyzing genome structure of uncultured bacteria has been challenging. We aimed to develop a single-cell amplified genome long-read assembly (scALA) workflow to construct circular single-cell amplified genomes (cSAGs) from long-read single-cell sequencing data of targeted uncultured bacteria. In particular, scALA generated cSAGs from nanopore long-read sequencing data of SAGs by producing contiguous sequences with repeated bias reduction and assembly processes. From 12 human fecal samples, scALA generated 16 cSAGs of three specifically targeted bacterial species, Anaerostipes hadrus, Agathobacter rectalis, and Ruminococcus gnavus. A. hadrus cSAGs exhibited large, ten kbp-long, phage insertions, saccharide metabolic capacity, and frequent genomic recombination with related strains from cohabitant hosts. Noteworthy, cSAGs constructed using this method could expand bacterial genome databases and our understanding of within-species diversities in uncultured bacteria.
Recognition of copy-back defective interfering rabies virus genomes by RIG-I triggers the antiviral response against vaccine strains
Authors: Aouadi Wahiba , Najburg Valérie , Legendre Rachel , Varet Hugo , Kergoat Lauriane , Tangy Frédéric , Larrous Florence , Komarova Anastassia V. , Bourhy Hervé
Published: March 2022

Rabies virus (RABV) is a lethal neurotropic virus that causes 60,000 human deaths every year around the world. A typical feature of RABV infection is the suppression of type I and III interferon (IFN)-mediated antiviral response. However, molecular mechanisms leading to RABV sensing by RIG-I-like receptors (RLR) to initiate IFN signaling remain elusive. Here, we showed that RABV RNAs are recognized by RIG-I (retinoic acid-inducible gene I) sensor resulting in an IFN response of the infected cells but that this global feature was differently modulated according to the type of RABV used. RNAs from pathogenic RABV strain, THA, were poorly detected in the cytosol by RIG-I and therefore mediated a weak antiviral response. On the opposite, we revealed a strong interferon activity triggered by the RNAs of the attenuated RABV vaccine SAD strain mediated by RIG-I. Using next-generation sequencing (NGS) combined with bioinformatics tools, we characterized two major 5’copy-back defective interfering (5’cb DI) genomes generated during SAD replication. Furthermore, we identified a specific interaction of 5’cb DI genomes and RIG-I that correlated with a high stimulation of the type I IFN signaling. This study indicates that RNAs from a wild-type RABV poorly activate the RIG-I pathway, while the presence of 5’cb DIs in vaccine SAD strain serves as an intrinsic adjuvant that strengthens its efficiency by enhancing RIG-I detection and therefore strongly stimulates the IFN response.

Highlights

RABV pathogenic strain replication in vitro is characterized by the absence of defective interfering genomes thus induces a weak RLR-mediated innate immunity antiviral response.

RABV vaccine attenuated strain shows a high release of 5’ copy-back defective interfering genomes during replication in vitro and therefore enhances a strong antiviral response upon infection.

RIG-I is the main sensor for RABV RNA detection within cells.
Improved And Optimized Drug Repurposing For The SARS-CoV-2 Pandemic
Authors: Cohen Sarel , Hershcovitch Moshik , Taraz Martin , Kißig Otto , Issac Davis , Wood Andrew , Waddington Daniel , Chin Peter , Friedrich Tobias
Published: March 2022

The active global SARS-CoV-2 pandemic caused more than 426 million cases and 5.8 million deaths worldwide. The development of completely new drugs for such a novel disease is a challenging, time intensive process. Despite researchers around the world working on this task, no effective treatments have been developed yet. This emphasizes the importance of drug repurposing, where treatments are found among existing drugs that are meant for different diseases. A common approach to this is based on knowledge graphs, that condense relationships between entities like drugs, diseases and genes. Graph neural networks (GNNs) can then be used for the task at hand by predicting links in such knowledge graphs. Expanding on state-of-the-art GNN research, Doshi et al. recently developed the Dr-COVID model. We further extend their work using additional output interpretation strategies. The best aggregation strategy derives a top-100 ranking of 8,070 candidate drugs, 32 of which are currently being tested in COVID-19-related clinical trials. Moreover, we present an alternative application for the model, the generation of additional candidates based on a given pre-selection of drug candidates using collaborative filtering. In addition, we improved the implementation of the Dr-COVID model by significantly shortening the inference and pre-processing time by exploiting data-parallelism. As drug repurposing is a task that requires high computation and memory resources, we further accelerate the post-processing phase using a new emerging hardware — we propose a new approach to leverage the use of high-capacity Non-Volatile Memory for aggregate drug ranking.
The anti-fibrotic effects of RLN3 aggravated the pathogenesis of adolescent idiopathic scoliosis-a preliminary study
Authors: Zhang Hao , Luo Beier , Sun Fengyuan , Xu Bing , Li Ming , Wang Guokun , Yang Zongde
Published: March 2022

Previous research proposed that ligament laxity is a clinical feature that can be easily overlooked in patients with adolescent idiopathic scoliosis (AIS). Relaxin and relaxin-related peptides, which have anti-fibrosis roles in the vascular and kidney system and relax the pubic symphysis during pregnancy, may contribute to ligament laxity. The goal of this research was to evaluate the role of in AIS. We found significantly increased relaxin-3 plasma in patients with AIS, as well as a significant correlation between joint hypermobility and relaxin 3 plasma levels. In a classic mouse model (C57BL/6J) of scoliosis, which was established according to the literature, showed significantly higher relaxin-3 plasma levels compared to normal group. In the relaxin-3 knockout C57BL/6J mice model the prevalence of scoliosis was significantly decreased. An in vitro experiment showed that relaxin 3 has anti-fibrotic effects on spinal ligament fibroblasts in both humans and mice by inhibiting TGF-β via relaxin family peptide receptor 3 (RXFP3) and increasing expression of matrix metalloproteinase 2 and matrix metalloproteinase 9 via the TGF-β/Smad2 and MAPK-ERK1/2 pathway. Blocking RXFP3 function with R3(B1-22)R significantly decreased the prevalence of scoliosis in C57BL/6J mice. In summary, the anti-fibrotic effects of relaxin-3 and RXFP3 activation may aggravate the pathogenesis of AIS.
Transcriptome-wide Analyses of Adipose Tissue in Outbred Rats Reveal Genetic Regulatory Mechanisms Relevant for Human Obesity
Authors: Crouse Wesley L. , Das Swapan K , Le Thu , Keele Greg , Holl Katie , Seshie Osborne , Craddock Ann L , Sharma Neeraj K. , Comeau Mary , Langefeld Carl D , Hawkins Greg , Mott Richard , Valdar William , Solberg Woods Leah C
Published: March 2022

Transcriptomic analysis in metabolically active tissues allows a systems genetics approach to identify causal genes and networks involved in metabolic disease. Outbred heterogeneous stock (HS) rats are used for genetic mapping of complex traits, but to-date, a systems genetics analysis of metabolic tissues has not been done. We investigated whether adiposity-associated genes and gene co-expression networks in outbred heterogeneous stock (HS) rats overlap those found in humans. We analyzed RNAseq data from adipose tissue of 415 male HS rats, correlated these transcripts with body weight (BW) and compared transcriptome signatures to two human cohorts: the African American Genetics of Metabolism and Expression and Metabolic Syndrome in Men. We used weighted gene co-expression network analysis to identify adiposity-associated gene networks and mediation analysis to identify genes under genetic control whose expression drives adiposity. We identified 554 orthologous “consensus genes” whose expression correlates with BW in the rat and with body mass index (BMI) in both human cohorts. Consensus genes fell within eight co-expressed networks and were enriched for genes involved in immune system function, cell growth, extracellular matrix organization and lipid metabolic processes. We identified 19 consensus genes for which genetic variation may influence BW via their expression, including those involved in lipolysis (e.g.,Hcar1), inflammation (e.g.,Rgs1), adipogenesis (e.g.,Tmem120b) or no previously known role in obesity (e.g.,St14, Msa4a6). Strong concordance between HS rat and human BW/BMI associated transcripts demonstrates translational utility of the rat model, while identification of novel genes expands our knowledge of the genetics underlying obesity.
A CpG island-encoded mechanism protects genes from premature transcription termination
Authors: Hughes Amy L. , Szczurek Aleksander T. , Kelley Jessica R. , Lastuvkova Anna , Turberfield Anne H. , Dimitrova Emilia , Blackledge Neil P. , Klose Robert J.
Published: March 2022

Transcription must be highly controlled to regulate gene expression and development. However, our understanding of the molecular mechanisms that influence transcription and how these are coordinated in cells to ensure normal gene expression remains rudimentary. Here, we reveal that actively transcribed CpG island-associated gene promoters recruit SET1 chromatin modifying complexes to enable gene expression. Counterintuitively, this effect is independent of SET1 complex histone modifying activity, and instead relies on the capacity of these complexes to interact with the RNA Polymerase II-binding protein, WDR82. Unexpectedly, we discover that SET1 complexes sustain gene transcription by counteracting the activity of the ZC3H4/WDR82 protein complex, which we show can pervasively terminate both genic and extragenic transcription. Therefore, we discover a new gene regulatory mechanism whereby CpG island elements nucleate a protein complex that protects genic transcription from premature termination, effectively distinguishing genic from non-genic transcription to enable gene expression.
It’s raining species: Rainwash eDNA metabarcoding as a minimally invasive method to assess tree canopy invertebrate diversity
Authors: Macher Till-Hendrik , Schütz Robin , Hörren Thomas , Beermann Arne J. , Leese Florian
Published: March 2022

Forest canopies are a highly diverse ecosystem, but despite several decades of intense research, there remain substantial gaps in our knowledge of their biodiversity and ecological interactions. One fundamental challenge in canopy research is the limited accessibility of the ecosystem. Consequently, previous studies have relied on the application of either highly invasive methods such as chemical knockdown, or on time-consuming and expensive setups such as canopy walkways or cranes. Therefore, time- and cost-efficient, ideally minimally invasive yet comprehensive applications are required to help close this knowledge gap. High-throughput metabarcoding of environmental DNA (eDNA) collected from water, soil, or air provides a minimally invasive method for biodiversity assessment, yet its potential for canopy biodiversity monitoring has not been explored.

Herein, we conducted metabarcoding of eDNA washed off the canopy via rainwater to explore its monitoring potential. We placed four 1 m2 rain samplers beneath the canopies of four different tree taxa prior to a major rain event, filtered eDNA from the collected rainwater, and performed cytochrome c oxidase subunit I (COI) metabarcoding to profile the invertebrate community. Additionally, we collected and identified all specimens present in the rainwater for verification.

We detected 50 invertebrate species by eDNA metabarcoding, of which 43 were not physically present in the water sample, thus likely representing true canopy biodiversity signals. Furthermore, we observed distinct species occurrence patterns corresponding to the four tree taxa, suggesting that ecological patterns such as host specificity can be assessed using the method.

In conclusion, our study provides a proof of principle that rainwash eDNA metabarcoding offers a minimally invasive and comprehensive method for tree canopy diversity monitoring.
Overcoming leak sensitivity in CRISPRi circuits using antisense RNA sequestration and regulatory feedback
Authors: Specht David A. , Cortes Louis B. , Lambert Guillaume
Published: March 2022

The controlled binding of the catalytically-dead CRISPR nuclease (dCas) to DNA can be used to create complex, programmable transcriptional genetic circuits, a fundamental goal of synthetic biology. This approach, called CRISPR interference (CRISPRi), is advantageous over existing methods because the programmable nature of CRISPR proteins enables the simultaneous regulation of many different targets without crosstalk. However, such gene circuit elements are limited by 1) the sensitivity to leaky repression of CRISPRi logic gates and 2) retroactive effects owing to a shared pool of dCas proteins. By utilizing antisense RNAs (asRNAs) to sequester guide RNA transcripts, as well as CRISPRi feedback to self-regulate asRNA production, we demonstrate a mechanism that suppresses unwanted CRISPRi repression and improve logical gene circuit function in E. coli. This improvement is particularly pronounced during stationary expression when CRISPRi circuits do not achieve the expected regulatory dynamics. Further, the use of dual CRISPRi/asRNA inverters restores logical performance of layered circuits such as a double inverter. By studying circuit induction at the single cell level in microfluidic channels, we provide insight into the dynamics of antisense sequestration of gRNA and regulatory feedback on dCas-based repression and derepression. These results demonstrate how CRISPRi inverters can be improved for use in more complex genetic circuitry without sacrificing the programmability and orthogonality of dCas proteins.