bluuebunny/crossref_metadata_2025 huggingface dataset:
Pediatric Nemaline Myopathy: A systematic review using individual patient data
Authors: Christophers Briana , Lopez Michael A. , Gupta Vandana A. , Baylies Mary
Published: February 2022

Context

Nemaline myopathy (NM) is a skeletal muscle disease that affects 1 in 50,000 live births.

Objective

Develop a narrative synthesis of the findings of a systematic review of the latest case descriptions of patients with nemaline myopathy.

Data Sources

A systematic search of MEDLINE, Embase, CINAHL, Web of Science, and Scopus was performed using Preferred Reporting Items for Systematic Reviews and Meta-analyses (PRISMA) guidelines using the keywords pediatric, child, nemaline myopathy, nemaline rod, rod myopathy.

Study Selection

Case studies focused on pediatric NM and published in English between January 1, 2010 and December 31, 2020 in order to represent the most recent findings.

Data Extraction

Information was collected about the age of first signs, earliest presenting neuromuscular signs and symptoms, systems affected, progression, death, pathological description, and genetic changes.

Results

Of a total of 385 records, 55 case reports or series were reviewed, covering 101 pediatric patients from 23 countries. We review varying presentations in children ranging in severity despite being caused by the same mutation, in addition to current and future clinical considerations relevant to the care of patients with nemaline myopathy.

Limitations

The results are limited by findings shared in the literature, which varied in their detail and sometimes lacked histological or genetic results. Trends and correlations may be altered by information available.

Conclusions

This review synthesizes genetic, histopathologic, and disease presentation findings from pediatric nemaline myopathy case reports. These data strengthen our understanding of the wide spectrum of disease seen in nemaline myopathy. Future studies are needed to identify the underlying molecular mechanism of pathology, to improve diagnostics, and to develop better methods to improve quality of life for these patients.
High-Throughput Clinical Trial Emulation with Real World Data and Machine Learning: A Case Study of Drug Repurposing for Alzheimer’s Disease
Authors: Zang Chengxi , Zhang Hao , Xu Jie , Zhang Hansi , Fouladvand Sajjad , Havaldar Shreyas , Cheng Feixiong , Chen Kun , Chen Yong , Glicksberg Benjamin S. , Chen Jin , Bian Jiang , Wang Fei
Published: February 2022

Clinical trial emulation, which is the process of mimicking targeted randomized controlled trials (RCT) with real-world data (RWD), has attracted growing attention and interest in recent years from the pharmaceutical industry. Different from RCTs which have stringent eligibility criteria for recruiting participants, RWD are more representative of real-world patients to whom the drugs will be prescribed. One technical challenge for trial emulation is how to conduct effective confounding control with complex RWD so that the treatment effects can be objectively derived. Recently many approaches, including deep learning algorithms, have been proposed for this goal, but there is still no systematic evaluation and practical guidance on them. In this paper, we emulate 430, 000 trials from two large-scale RWD warehouses, covering both electronic health records (EHR) and general claims, over 170 million patients spanning more than 10 years, aiming to identify new indications of approved drugs for Alzheimer’s disease (AD). We have investigated the behaviors of multiple different approaches including logistic regression and deep learning models, and propose a new model selection strategy that can significantly improve the performance of confounding balance of the participants in different arms of emulated trials. We demonstrate that regularized logistic regression-based propensity score (PS) model outperforms the deep learning-based PS model and others, which contradicts with our intuitions to a certain extent. Finally, we identified 8 drugs whose original indications are not AD (pantoprazole, gabapentin, acetaminophen, atorvastatin, albuterol, fluticasone, amoxicillin, and omeprazole), hold great potential of being beneficial to AD patients.
The benefits and harms of adjuvant chemotherapy for non-small cell lung cancer in patients with major comorbidities: A simulation study
Authors: Leiter Amanda , Kong Chung Yin , Gould Michael K. , Kale Minal S. , Veluswamy Rajwanth R. , Smith Cardinale B. , Mhango Grace , Huang Brian Z. , Wisnivesky Juan P. , Sigel Keith
Published: February 2022

Background

Randomized controlled trials (RCTs) have demonstrated a survival benefit for adjuvant platinum-based chemotherapy after resection of stage IB-IIIA non-small cell lung cancer (NSCLC). The relative benefits and harms and optimal approach to treatment for NSCLC patients who have major comorbidities (chronic obstructive pulmonary disease [COPD], coronary artery disease [CAD], and congestive heart failure [CHF]) are unclear, however.

Methods

We used a simulation model to run in-silico comparative trials of adjuvant chemotherapy versus observation in stage IB-IIIA NSCLC in patients with comorbidities. The model estimated quality-adjusted life years (QALYs) gained by each treatment strategy stratified by age, comorbidity, and stage. The model was parameterized using outcomes and quality-of-life data from RCTs and primary analyses from large cancer databases.

Results

Adjuvant chemotherapy was associated with clinically significant QALY gains for all patient age/stage combinations with COPD except for patients >80 years old with stage IB cancers. For patients with CHF and stage IB disease, adjuvant chemotherapy was not advantageous; in contrast, it was associated with QALY gains for stages II-IIIA for younger patients with CHF. In general, patients with multiple comorbidities benefited less from adjuvant chemotherapy than those with single comorbidities and women with comorbidities in older age categories benefited more from adjuvant chemotherapy than their male counterparts.

Conclusions

Older, multimorbid patients may derive QALY gains from adjuvant chemotherapy after NSCLC surgery. These results help extend existing clinical trial data to specific unstudied, high-risk populations and may reduce the uncertainty regarding adjuvant chemotherapy use in these patients.
Blood transcriptomes of SARS-CoV-2 infected kidney transplant recipients demonstrate immune insufficiency
Authors: Sun Zeguo , Zhang Zhongyang , Banu Khadija , Azzi Yorg Al , Reghuvaran Anand , Fredericks Samuel , Planoutene Marina , Hartzell Susan , Pell John , Tietjen Gregory , Asch William , Kulkarni Sanjay , Formica Richard , Rana Meenakshi , Zhang Weijia , Akalin Enver , Cravedi Paolo , Heeger Peter S. , Menon Madhav C.
Published: February 2022

Background

Kidney transplant recipients (KTRs) with COVID-19 have poor outcomes compared to non-KTRs. To provide insight into management of immunosuppression during acute illness, we studied immune signatures from the peripheral blood during and after COVID-19 infection from a multicenter KTR cohort.□

Methods

Clinical data were collected by chart review. PAXgene blood RNA was poly-A selected and RNA sequencing was performed to evaluate transcriptome changes.

Results

A total of 64 cases of COVID-19 in KTRs were enrolled, including 31 acute cases (< 4 weeks from diagnosis) and 33 post-acute cases (>4 weeks). In the blood transcriptome of acute cases, we identified differentially expressed genes (DEGs) in positive or negative association COVID-19 severity scores. Functional enrichment analyses showed upregulation of neutrophil and innate immune pathways, but downregulation of T-cell and adaptive immune-activation pathways proportional to severity score. This finding was independent of lymphocyte count and despite reduction in immunosuppression (IS) in most KTRs. Comparison with post-acute cases showed “normalization” of these enriched pathways after >4 weeks, suggesting recovery of adaptive immune system activation despite reinstitution of IS. The latter analysis was adjusted for COVID-19 severity score and lymphocyte count. DEGs associated with worsening disease severity in a non-KTR cohort with COVID-19 (GSE152418) showed significant overlap with KTRs in these identified enriched pathways.

Conclusion

Blood transcriptome of KTRs affected by COVID-19 shows decrease in T-cell and adaptive immune activation pathways during acute disease that associate with severity despite IS reduction and show recovery after acute illness.

Significance statement

Kidney transplant recipients (KTRs) are reported to have worse outcomes with COVID-19, and empiric reduction of maintenance immunosuppression is pursued. Surprisingly, reported rates of acute rejection have been low despite reduced immunosuppression. We evaluated the peripheral blood transcriptome of 64 KTRs either during or after acute COVID-19. We identified transcriptomic signatures consistent with suppression of adaptive T-cell responses which significantly associated with disease severity and showed evidence of recovery after acute disease, even after adjustment for lymphocyte number. Our transcriptomic findings of immune-insufficiency during acute COVID-19 provide an explanation for the low rates of acute rejection in KTRs despite reduced immunosuppression. Our data support the approach of temporarily reducing T –cell-directed immunosuppression in KTRs with acute COVID-19.
Prognostic peripheral blood biomarkers at ICU admission predict COVID-19 clinical outcomes
Authors: Messing Melina , Sekhon Mypinder S. , Hughes Michael R. , Stukas Sophie , Hoiland Ryan L. , Cooper Jennifer , Ahmed Nyra , Hamer Mark , Li Yicong , Shin Samuel B. , Tung Lin Wei , Wellington Cheryl , Sin Don D. , Leslie Kevin B. , McNagny Kelly M.
Published: February 2022

The COVID-19 pandemic continues to challenge the capacities of hospital ICUs which currently lack the ability to identify prospectively those patients who may require extended management. In this study of 90 ICU COVID-19 patients, we evaluated serum levels of four cytokines (IL-1β, IL-6, IL-10 and TNFα) as well as standard clinical and laboratory measurements. On 42 of these patients (binned into Initial and Replication Cohorts), we further performed CyTOF-based deep immunophenotyping of peripheral blood mononuclear cells with a panel of 38 antibodies. All measurements and patient samples were taken at time of ICU admission and retrospectively linked to patient clinical outcomes through statistical approaches. These analyses resulted in the definition of a new measure of patient clinical outcome: patients who will recover after short ICU stays (< 6 days) and those who will subsequently die or recover after long ICU stays (> 6 days). Based on these clinical outcome categories, we identified blood prognostic biomarkers that, at time of ICU admission, prospectively distinguish, with 91% sensitivity and 91% specificity (positive likelihood ratio 10.1), patients in the two clinical outcome groups. This is achieved through a tiered evaluation of serum IL-10 and targeted immunophenotyping of monocyte subsets, specifically, CD11clow classical monocytes. Immunophenotyping revealed clear predictors of clinical outcome in COVID-19 providing a highly sensitive and specific prognostic test that could prove useful in guiding clinical resource allocation.

Graphical Abstract
Three decades of hospital evacuations in the Netherlands: a scoping review
Authors: Barten Dennis G. , Fijten Marjolein H.M. , Gaakeer Menno I. , Klokman Vincent W. , Mortelmans Luc J. , van Osch Frits , Peters Nathalie A.L.R. , Wijnands Jaap J.J. , Tan Edward C.T.H. , Boin Arjen
Published: February 2022

Background

Hospitals are expected to provide their essential services under all circumstances, including disasters and crisis situations. However, crises and disasters may disrupt essential hospital functions, and necessitate evacuation of the facility. Data on the prevalence and causes of hospital evacuations is limited, whilst realistic evacuation planning will make hospitals more resilient during future crises and disasters. The aim of this study was to develop a systematic understanding of hospital evacuation frequency, causes and characteristics in the Netherlands.

Methods

A systematic scoping review of news articles retrieved from the LexisNexis database, Google, Google News, PubMed and EMBASE between 1990 and 2020. All articles mentioning a hospital evacuation in the Netherlands were analyzed.

Results

A total of 67 hospital evacuations were identified in a 30-year time period. The most common primary incidents were internal fire (33%), technological failure (21%) and hazardous materials (12%). Cascading events transpired in 37% of all events. As a result, internal fire (34%), internal power failure (19%) and hazardous materials (16%) were the most important reasons to evacuate a medical facility. The number of evacuees ranged from 1 to 339 patients (median 10.5, interquartile range 36), and there were 13 (19%) complete hospital evacuations. The frequency of hospital evacuations increased over time, with a more diverse etiology during later years.

Conclusions

Hospital evacuations do occur, and hospitals are vulnerable to both internal and external hazards. Internal fire, internal power failure, hazardous materials and flooding incidents were the most important reasons to (partly) evacuate a hospital. Our findings suggest that facility-specific evacuation guidelines are necessary, and that evacuation preparedness will benefit if the most relevant evacuation scenarios are planned and practiced.
Syllable-PBWT for space-efficient haplotype long-match query
Authors: Wang Victor , Naseri Ardalan , Zhang Shaojie , Zhi Degui
Published: February 2022

The positional Burrows-Wheeler transform (PBWT) has led to tremendous strides in haplotype matching on biobank-scale data. For genetic genealogical search, PBWT-based methods have optimized the asymptotic runtime of finding long matches between a query haplotype and a predefined panel of haplotypes. However, to enable fast query searches, the full-sized panel and PBWT data structures must be kept in memory, preventing existing algorithms from scaling up to modern biobank panels consisting of millions of haplotypes. In this work, we propose a space-efficient variation of PBWT named Syllable-PBWT, which divides every haplotype into syllables, builds the PBWT positional prefix arrays on the compressed syllabic panel, and leverages the polynomial rolling hash function for positional substring comparison. With the Syllable-PBWT data structures, we then present a long match query algorithm named Syllable-Query. Compared to Algorithm 3 of Sanaullah et al. (2021), the most time- and space-efficient previously published solution to the long match query problem, Syllable-Query reduced the memory use by a factor of over 100 on both the UK Biobank genotype data and the 1000 Genomes Project sequence data. Surprisingly, the smaller size of our syllabic data structures allows for more efficient iteration and CPU cache usage, granting Syllable-Query even faster runtime than existing solutions. The implementation of our algorithm is available athttps://github.com/ZhiGroup/Syllable-PBWT.
Selective inhibitors of JAK1 targeting a subtype-restricted allosteric cysteine
Authors: Kavanagh Madeline E. , Horning Benjamin D. , Khattri Roli , Roy Nilotpal , Lu Justine P. , Whitby Landon R. , Brannon Jaclyn C. , Parker Albert , Chick Joel M. , Eissler Christie L. , Wong Ashley , Rodriguez Joe L. , Rodiles Socorro , Masuda Kim , Teijaro John R. , Simon Gabriel M. , Patricelli Matthew P. , Cravatt Benjamin F.
Published: February 2022

The JAK family of non-receptor tyrosine kinases includes four subtypes (JAK1, JAK2, JAK3, and TYK2) and is responsible for signal transduction downstream of diverse cytokine receptors. JAK inhibitors have emerged as important therapies for immuno(onc)ological disorders, but their use is limited by undesirable side effects presumed to arise from poor subtype selectivity, a common challenge for inhibitors targeting the ATP-binding pocket of kinases. Here, we describe the chemical proteomic discovery of a druggable allosteric cysteine present in the non-catalytic pseudokinase domain of JAK1 (C817) and TYK2 (C838), but absent from JAK2 or JAK3. Electrophilic compounds selectively engaging this site block JAK1-dependent transphosphorylation and cytokine signaling, while appearing to act largely as “silent” ligands for TYK2. Importantly, the allosteric JAK1 inhibitors do not impair JAK2-dependent cytokine signaling and are inactive in cells expressing a C817A JAK1 mutant. Our findings thus reveal an allosteric approach for inhibiting JAK1 with unprecedented subtype selectivity.
Cellular genome wide association study identifies common genetic variation influencing lithium induced neural progenitor proliferation
Authors: Wolter Justin M. , Le Brandon D. , Matoba Nana , Lafferty Michael J. , Aygün Nil , Liang Dan , Courtney Kenan , Piven Joseph , Zylka Mark J. , Stein Jason L.
Published: February 2022

Lithium is used in the treatment of bipolar disorder (BD) and is known to increase neural progenitor cell (NPC) proliferation. Though the mechanism of lithium’s therapeutic effect is not understood, evidence suggests that genetic variation influences response to treatment. Here, we used a library of genetically diverse human NPCs to identify common genetic variants that modulate lithium induced proliferation. We identified a locus on chr3p21.1 associated with lithium induced proliferation that colocalizes with BD risk. One lithium responsive gene, GNL3, was detected within the locus. The allele associated with increased baseline and lithium-induced GNL3 expression was also associated with increased lithium-induced NPC proliferation. Experimental manipulation of GNL3 expression using CRISPRa/i in NPCs showed that GNL3 was necessary for lithium’s full proliferative effects, and sufficient to induce proliferation without lithium treatment. In all, our data suggest that GNL3 expression sensitizes NPCs for a stronger proliferative response to lithium.
Cilia stimulatory and antibacterial activities of bitter receptor agonist diphenhydramine: insights into potential complimentary strategies for CF nasal infections
Authors: Kuek L. E. , McMahon D.B. , Ma R.Z. , Miller Z.A. , Jolivert J.F. , Adappa N.D. , Palmer J.N. , Lee R.J
Published: February 2022

BACKGROUND

Bitter compounds increase ciliary beating and nitric oxide (NO) production in nasal epithelial cells through T2Rs in motile cilia. We examined expression of cilia T2Rs and both host and bacterial responses to T2R14 agonist diphenhydramine.

METHOD

Using cultured human nasal epithelial cells grown at air liquid interface, we measured expression of T2Rs via qPCR. We measured effects of diphenhydramine on ciliary beat frequency via high-speed imaging and nitric oxide production via fluorescent dye DAF-FM. We measured effects of diphenhydramine on growth of lab and clinical strains of Pseudomonas aeruginosa. We measured biofilm formation of P. aeruginosa using crystal violet staining and surface attachment of P. aeruginosa to cystic fibrosis bronchial epithelial (CBFE41o-) cells using CFU counting.

RESULTS

T2R expression increased with mucocilliary differentiation and did not vary between CF and non-CF ALIs. Treatment with P. aeruginosa flagellin decreased expression of diphenhydramine-responsive T2R14 and 40, among other isoforms. Diphenhydramine increased both NO and CBF. Increases in CBF were disrupted after flagellin treatment. Diphenhydramine impaired growth, biofilm production, and surface attachment of P. aeruginosa.

CONCLUSIONS

T2R expression is similar between normal and CF cells but decreases with flagellin treatment. Utilizing T2R agonists as therapeutics within the context of CF, P. aeruginosa infections may require co-treatment with anti-inflammatories to prevent the reduction of T2R expression with TLR activation. T2R agonist diphenhydramine increases NO production and CBF while also decreasing bacterial growth and biofilm production, and thus diphenhydramine or derivate compounds may have potential clinical usefulness in CF infections as a topical therapy.

HIGHLIGHTS

T2R14 agonist diphenhydramine increases nitric oxide production and cilia beating

Flagellin decreases T2R14 expression in primary airway epithelial cells

T2R14 agonist Diphenhydramine inhibits Pseudomonas growth and biofilm formation
Toward Atomistic Models of Intact SARS-CoV-2 via Martini Coarse-Grained Molecular Dynamics Simulations
Authors: Wang Dali , Li Jiaxuan , Wang Lei , Cao Yipeng , Li Sai , Song Chen
Published: February 2022

The causative pathogen of Coronavirus disease 2019 (COVID-19), severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), is an enveloped virus assembled by a lipid envelope and multiple structural proteins. In this study, by integrating experimental data, structural modeling, and coarse-grained molecular dynamics simulations, we constructed multiscale models of SARS-CoV-2. Our 500-ns coarse-grained simulation of the intact virion allowed us to investigate the dynamic behavior of the membrane-embedded proteins and the surrounding lipid moleculesin situ. Our results indicated that the membrane-embedded proteins are highly dynamic, and certain types of lipids exhibit various binding preferences to specific sites of the membrane-embedded proteins. The equilibrated virion model was transformed into atomic resolution, which provided a 3D structure for scientific demonstration and can serve as a framework for future exascale all-atom MD simulations.
Transcription Factor-Centric Approach to Identify Non-Recurring Putative Regulatory Drivers in Cancer
Authors: Zhao Jingkang , Martin Vincentius , Gordân Raluca
Published: February 2022

Recent efforts to sequence the genomes of thousands of matched normal-tumor samples have led to the identification of millions of somatic mutations, the majority of which are non-coding. Most of these mutations are believed to be passengers, but a small number of non-coding mutations could contribute to tumor initiation or progression, e.g. by leading to dysregulation of gene expression. Efforts to identify putative regulatory drivers rely primarily on information about the recurrence of mutations across tumor samples. However, in regulatory regions of the genome, individual mutations are rarely seen in more than one donor. Instead of using recurrence information, here we present a method to identify putative regulatory driver mutations based on the magnitude of their effects on transcription factor-DNA binding. For each gene, we integrate the effects of mutations across all its regulatory regions, and we ask whether these effects are larger than expected by chance, given the mutation spectra observed in regulatory DNA in the cohort of interest. We applied our approach to analyze mutations in a liver cancer data set with ample somatic mutation and gene expression data available. By combining the effects of mutations across all regulatory regions of each gene, we identified dozens of genes whose regulation in tumor cells is likely to be significantly perturbed by non-coding mutations. Overall, our results show that focusing on the functional effects of non-coding mutations, rather than their recurrence, has the potential to identify putative regulatory drivers and the genes they dysregulate in tumor cells.
A New Classification Method Based on Dynamic Ensemble Selection and its Application to Predict Variance Patterns in HIV-1 Env
Authors: Fili Mohammad , Hu Guiping , Han Changze , Kort Alexa , Trettin John , Haim Hillel
Published: February 2022

Therapeutics that target the envelope glycoproteins (Envs) of human immunodeficiency virus type 1 (HIV-1) effectively reduce virus levels in patients. However, due to mutations, new Env variants are frequently generated, which may be resistant to the treatments. The appearance of such sequence variance at any Env position is seemingly random. A better understanding of the spatiotemporal patterns of variance across Env may lead to the development of new therapeutic strategies. We hypothesized that, at any time point in a patient, positions with sequence variance are clustered on the three-dimensional structure of Env. To test this hypothesis, we examined whether variance at any Env position can be predicted by the variance measured at adjacent positions. Sequences from 300 HIV-infected patients were applied to a new algorithm we developed. The k-best classifiers (KBC) method is a dynamic ensemble selection technique that identifies the best classifier(s) within the neighborhood of a new observation. It applies bootstrap resampling to generate out-of-bag samples that are used with the resampled set to evaluate each classifier. For many positions of Env, primarily in the CD4-binding site, KBC accurately predicted variance based on the variance at their adjacent positions. KBC improved performance compared to the initial learners, static ensemble, and other baseline models. KBC also outperformed other algorithms for predicting variance at multi-position footprints of therapeutics on Env. These understandings can be applied to refine models that predict future changes in HIV-1 Env. More generally, we propose KBC as a new high-performance dynamic ensemble selection technique.
Generating spatiotemporal patterns of linearly polarised light at high frame rates for insect vision research
Authors: Supple Jack A. , Varennes-Phillit Léandre , Gajjar-Reid Dexter , Cerkvenik Uroš , Belušič Gregor , Krapp Holger G.
Published: February 2022

Polarisation vision is commonplace among invertebrates; however, most experiments focus on determining behavioural and/or neurophysiological responses to static polarised light sources rather than moving patterns of polarised light. To this end, we designed a polarisation stimulation device based on superimposing polarised and non-polarised images from two projectors, which can display moving patterns at frame rates exceeding invertebrate flicker fusion frequencies. A linear polariser fitted to one projector enables moving patterns of polarised light to be displayed, whilst the other projector contributes arbitrary intensities of non-polarised light to yield moving patterns with a defined polarisation and intensity contrast. To test the device, we measured receptive fields of polarisation sensitive Argynnis paphia butterfly photoreceptors for both non-polarised and polarised light. We then measured local motion sensitivities of the optic flow-sensitive lobula plate tangential cell H1 in Calliphora vicina blowflies under both polarised and non-polarised light, finding no polarisation sensitivity in this neuron.
Proteomics and Functional Analysis Revealed TaGSTU6/TaCBSX3 Enhances Wheat Resistance to Powdery Mildew
Authors: Wang Qiao , Guo Jia , Jin Pengfei , Ying Guo Meng , Guo Jun , Peng Cheng , Li Qiang , Wang Baotong
Published: February 2022

Wheat stripe rust and powdery mildew are important worldwide diseases of wheat (Triticum aestivum). The wheat cultivar Xingmin318 (XM318) is resistant to both wheat stripe rust and powdery mildew, which are caused byPuccinia striiformisf. sp.tritici(Pst) andBlumeria graminisf. sp.tritici(Bgt), respectively. To explore the molecular mechanisms of wheat defenses againstPstandBgt, quantitative proteomic analyses of XM318 inoculated withPstandBgt,respectively, were performed using tandem mass tags (TMT) technology. A total of 741 proteins were identified as differentially accumulated proteins (DAPs). Bioinformatics analyses indicated that some functional categories, including antioxidant activity, exhibited obvious differences betweenPstandBgtinfections. Intriguingly, only 42 DAPs responded to bothPstandBgtinfections. Twelve DAPs were randomly selected for RT-qPCR analysis, and the mRNA expression levels of eleven were consistent with their protein expression. Furthermore, gene silencing using the virus-induced gene silencing system indicated that glutathione S-transferase (TaGSTU6) has an important role in resistance toBgtbut not toPst. TaGSTU6 was shown to interact with the cystathionine beta-synthase (CBS) domain-containing protein (TaCBSX3). Knockdown ofTaCBSX3expression only reduced wheat resistance toBgtinfection. Overexpression ofTaGSTU6andTaCBSX3in Arabidopsis (Arabidopsis thaliana) promoted plant resistance toPseudomonas syringaepv.tomatoDC3000 (PstDC3000). Our results indicated that the TaGSTU6 interacting with TaCBSX3 only confers wheat resistance toBgt, suggesting that wheat has different response mechanisms toPstandBgtstress.

One-sentence summary

Proteomics revealed a difference in the wheat resistance response toPstandBgt, and the TaGSTU6/TaCBSX3 interaction plays an important role only in wheat resistance toBgt.
Genetic mapping of flowering time and plant height in a maize Stiff Stalk MAGIC population
Authors: Michel Kathryn J. , Lima Dayane C. , Hundley Hope , Singan Vasanth , Yoshinaga Yuko , Daum Chris , Barry Kerrie , Broman Karl W. , Robin Buell C. , de Leon Natalia , Kaeppler Shawn M.
Published: February 2022

The Stiff Stalk heterotic pool is a foundation of US maize seed parent germplasm and has been heavily utilized by both public and private maize breeders since its inception in the 1930’s. Flowering time and plant height are critical characteristics for both inbred parents and their test crossed hybrid progeny. To study these traits, a six parent multiparent advanced generation intercross (MAGIC) population was developed including maize inbred lines B73, B84, PHB47 (B37 type), LH145 (B14 type), PHJ40 (novel early Stiff Stalk), and NKH8431 (B73/B14 type). A set of 779 doubled haploid lines were evaluated for flowering time and plant height in two field replicates in 2016 and 2017, and a subset of 689 and 561 doubled haploid lines were crossed to two testers, respectively, and evaluated as hybrids in two locations in 2018 and 2019 using an incomplete block design. Markers were derived from a Practical Haplotype Graph built from the founder whole genome assemblies and genotype-by-sequencing and exome capture-based sequencing of the population. Genetic mapping utilizing an update to R/qtl2 revealed differing profiles of significant loci for both traits between 636 of the DH lines and two sets of 571 and 472 derived hybrids. Genomic prediction was used to test the feasibility of predicting hybrid phenotypes based on theper sedata. Predictive abilities were highest on direct models trained using the data they would predict (0.55 to 0.63), and indirect models trained usingper sedata to predict hybrid traits had slightly lower predictive abilities (0.49 to 0.55). Overall, this finding is consistent with the overlapping and non-overlapping significant QTL found within theper seand hybrid populations and suggests that selections for phenology traits can be made effectively on doubled haploid lines before hybrid data is available.

Core Ideas

A multi-parent advanced generation intercross (MAGIC) mapping population was developed from six founder Stiff Stalk maize inbreds with commercial relevance. Genetic mapping utilizing an update to R/qtl2 was demonstrated for flowering and plant height traits.

Genetic mapping using maize inbred and hybrid information was compared and provided insight into trait expression in inbreds relative to heterotic testcross hybrids.
Injectable hydrogels with phase-separated structures that can encapsulate live cells
Authors: Ishikawa Shohei , Yoshikawa Yuki , Kamata Hiroyuki , Chung Ung-il , Sakai Takamasa
Published: February 2022

Injectable hydrogels are biomaterials that can be administered minimally invasively in liquid form, and are considered promising artificial extracellular matrix (ECM) materials. However, ordinary injectable hydrogels are synthesized from water-soluble molecules to ensure injectability, resulting in nonphase-separated structures, making them structurally different from natural ECMs with phase-separated insoluble structural proteins, such as collagen and elastin. Here, we propose a simple material design approach to impart phase-separated structures to injectable hydrogels by adding inorganic salts. Injecting a gelling solution of mutually crosslinkable tetra-arm poly(ethylene glycol)s with potassium sulfate at optimal concentrations results in the formation of a hydrogel with phase-separated structures in situ. These phase-separated structures provide up to an 8-fold increase in fracture toughness while allowing the encapsulation of live mouse chondrogenic cells without compromising their proliferative activity. Our findings highlight that the concentration of inorganic salts is an important design parameter in injectable hydrogels for artificial ECMs.
Associations between brain imaging and polygenic scores of mental health and educational attainment in children aged 9-11
Authors: Fernandez-Cabello Sara , Alnæs Dag , van der Meer Dennis , Dahl Andreas , Holm Madelene , Kjelkenes Rikka , Maximov Ivan I. , Norbom Linn B. , Pedersen Mads L. , Voldsbekk Irene , Andreassen Ole A. , Westlye Lars T.
Published: February 2022

Psychiatric disorders are highly heritable and polygenic, and many have their peak onset in late childhood and adolescence, a period of tremendous changes. Although the neurodevelopmental antecedents of mental illness are widely acknowledged, research in youth population cohorts is still scarce, preventing our progress towards the early characterization of these disorders. We included 7,124 children (9-11 years old) from the Adolescent Brain and Cognitive Development Study to map the associations of structural and diffusion brain imaging with common genetic variants and polygenic scores for psychiatric disorders and educational attainment. We used principal component analysis to derive imaging components, and calculated their heritability. We then assessed the relationship of imaging components with genetic and clinical psychiatric risk with univariate models and Canonical correlation analysis (CCA). Most imaging components had moderate heritability. Univariate models showed limited evidence and small associations of polygenic scores with brain structure at this age. CCA revealed two significant modes of covariation. The first mode linked higher polygenic scores for educational attainment with less externalizing problems and larger surface area. The second mode related higher polygenic scores for schizophrenia, bipolar disorder, and autism spectrum disorder to higher global cortical thickness, smaller white matter volumes of the fornix and cingulum, larger medial occipital surface area and smaller surface area of lateral and medial temporal regions. While cross-validation suggested limited generalizability, our results highlight the potential of multivariate models to better understand the transdiagnostic and distributed relationships between mental health and brain structure in late childhood.
Protection by 4th dose of BNT162b2 against Omicron in Israel
Authors: Bar-On Yinon M. , Goldberg Yair , Mandel Micha , Bodenheimer Omri , Amir Ofra , Freedman Laurence , Alroy-Preis Sharon , Ash Nachman , Huppert Amit , Milo Ron
Published: February 2022

BACKGROUND

On January 2, 2022, Israel began administering a fourth dose of BNT162b2 vaccine (Pfizer-BioNTech) to people aged over 60 years and at-risk populations, who had received a third dose of vaccine at least 4 months earlier. The effect of the fourth dose on confirmed coronavirus 2019 disease (Covid-19) and severe illness are still unclear.

METHODS

We extracted data for the Omicron-dominated period January 15 through January 27, 2022, from the Israeli Ministry of Health database regarding 1,138,681 persons aged over 60 years and eligible for the fourth dose. We compared the rate of confirmed Covid-19 and severe illness between those who had received a fourth dose at least 12 days earlier, those who had received only three doses, and those 3 to 7 days after receiving the fourth dose. We used Poisson regression after adjusting for possible confounding factors.

RESULTS

The rate of confirmed infection was lower in people 12 or more days after their fourth dose than among those who received only three doses and those 3 to 7 days after vaccination by factors of 2.0 (95% confidence interval [CI], 2.0 to 2.1) and 1.9 (95% CI, 1.8 to 2.0), respectively. The rate of severe illness was lower by factors of 4.3 (95% CI, 2.4 to 7.6) and 4.0 (95% CI, 2.2 to 7.5).

CONCLUSIONS

Rates of confirmed Covid-19 and severe illness were lower following a fourth dose compared to only three doses.
Ethiopian Healthcare Workers’ Experiences During the COVID-19 Pandemic
Authors: Chakrabarti Averi , Memirie Solomon Tessema , Bekele Delayehu , Kiros Mizan , Meyer Christina L. , Pham Phuong N. , Vinck Patrick , Verguet Stéphane
Published: February 2022

Background

The COVID-19 pandemic has caused widespread health and socioeconomic disruptions around the world. Understanding the impact that this crisis has had on health workers and the delivery of routine health care services within countries provides evidence on pandemic preparedness and response. Here, we conduct an investigation into these factors for the Ethiopian context.

Methods and findings

We conducted an online cross-sectional survey with Ethiopian health care professionals between August 27 and October 10, 2020 via existing research networks. The variables of interest were confidence in COVID-19 related knowledge, training and experience, the adoption of precautionary health practices, risk perceptions, and respondent concerns. The majority of surveyed health care professionals in Ethiopia reported seeing fewer patients than usual during the COVID-19 crisis, gaps in pandemic training, inadequate access to personal protective equipment (PPE) and barriers to accessing COVID-19 testing. Most health care professionals were also deeply concerned and worried about their own COVID-19 risks and the likelihood that they would transmit the disease to others.

Conclusions

Our study findings point to a possible reduction in routine health care services during the COVID-19 pandemic and gaps in pandemic preparedness in Ethiopia. The ministry of health and other stakeholders should work towards improving access to PPE and testing, and identify approaches to ensure that essential healthcare provision (such as immunizations) is not disrupted during crises akin to the COVID-19 outbreak.
Humoral response, associated symptoms and profile of patients infected by SARS-CoV-2 with taste or smell disorders in the SAPRIS multicohort study
Authors: Ramillon Julien , de Lamballerie Xavier , Robineau Olivier , Blanché Helene , Severi Gianluca , Touvier Mathilde , Zins Marie , Carrat Fabrice , Lapidus Nathanaël ,   the SAPRIS-SERO study group
Published: February 2022

Objectives

Taste or smell disorders have been reported as strongly associated with COVID-19 diagnosis. We aimed to identify subject characteristics, symptom associations, and humoral response intensity associated with taste or smell disorders.

Patients and methods

We used data from SAPRIS, a study based on a consortium of five prospective cohorts gathering 279,478 participants in the French general population. In the analysis, we selected participants who were presumably infected by SARS-CoV-2 during the first epidemic wave.

Results

The analysis included 3,439 patients with a positive ELISA-Spike. Sex (OR = 1.28 [95% CI 1.05-1.58] for women), smoking (OR = 1.54 [95% CI 1.13-2.07]), consumption of more than 2 drinks of alcohol a day (OR = 1.37 [95% CI 1.06-1.76]) were associated with a higher probability of taste or smell disorders. The relationship between age and taste or smell disorders was non-linear. Serological titers were associated with taste or smell disorders: OR = 1.31 [95% CI 1.26-1.36], OR = 1.37 [95% CI 1.33-1.42] and OR = 1.34 [95% CI 1.29-1.39] for ELISA-Spike, ELISA-Nucleocapsid and seroneutralization, respectively. Among participants with taste or smell disorders, 90% reported a wide variety of other symptoms whereas 10% reported no other symptom or only rhinorrhea.

Conclusion

Among patients with a positive ELISA-Spike test, women, smokers and people drinking more than 2 drinks a day were more likely to develop taste or smell disorders. This symptom was strongly associated with a humoral response. The overwhelming majority of patients with taste or smell disorders experienced a wide variety of symptoms.
Activity and state-dependent modulation of salt taste behavior via pharyngeal neurons inDrosophila melanogaster
Authors: Kaushik Shivam , Kumar Rahul , Kumar Sachin , Sanghi Srishti , Tanimura Teiichi , Rincon-Limas Diego E. , Kain Pinky
Published: February 2022

Sodium present in NaCl is a fundamental nutrient required for many physiological processes. In animals, includingDrosophila,low-salt concentrations induce attraction and high-salt concentrations evoke aversive behavior. Although the cellular basis of low and high salt taste detection has been described, the mechanisms regulating high salt consumption and salt taste modulation in animals remain elusive. Thus, we investigated the neural mechanisms behind high NaCl consumption in adultDrosophila, focusing on how flies adjust their acceptance of high salt based on their diet. Our findings show that long-term exposure to high salt increases the taste sensitivity of pharyngeal LSO neurons, which, in turn, enhances high salt intake. Exposing flies to a high NaCl diet for three days shows a decline in high salt aversion under starvation. Our results suggest that this modulation requires active LSO neurons and a starvation state or dopamine as genetic suppression of LSO pharyngeal neuronal activity in high NaCl-fed flies inhibit excessive salt intake. We also found that several independent taste receptor neurons and pathways are involved in such a modulation. Silencing any one of multiple LSO neuronal types inhibits excessive salt intake. Our study suggests that flies can adapt to the amount of salt ingested over several days, indicating the presence of a critical mechanism that resets the salt appetite and related neural circuits.
Metabolic predictors of phenotypic traits can replace and complement measured clinical variables in transcriptome-wide association studies
Authors: Niehues Anna , Bizzarri Daniele , Reinders Marcel J.T. , Slagboom P. Eline , van Gool Alain J. , van den Akker Erik B. , ’t Hoen Peter A.C. ,   the BBMRI-NL BIOS and Metabolomics Consortia
Published: February 2022

Transcriptome-wide association studies (TWAS) can provide valuable insights into biological and disease-underlying mechanisms. For studying clinical effects, availability of (confounding) phenotypic traits is essential. The (re)use of RNA-seq or other omics data can be limited by missing, incomplete, or inaccurate phenotypic information. A possible solution are molecular predictors inferring clinical or behavioral phenotypic traits. Such predictors have been developed based on different omics data types and are being applied in various studies.

In this study, we applied 17 metabolic predictors to infer various traits, including diabetes status or exposure to lipid medication. We evaluated whether these metabolic surrogates can be used as an alternative to reported information for studying the respective phenotypes using TWAS. Our results revealed that in most cases, the use of metabolic surrogates yields similar results compared to using reported information, making them suitable substitutes for such studies.

The application of metabolomics-derived surrogate outcomes opens new possibilities for reuse of multi-omics data sets, especially in situations where availability of clinical metadata is limited. Missing or incomplete information can be complemented by these surrogates, thereby increasing the size of available data sets. Studies would likely also benefit from the use of such surrogates to correct for potential biological confounding. This should be further investigated.

Author summary

Transcriptome-wide association studies (TWAS) can be used to associate gene expression levels with phenotypic traits. These associations can provide insights into biological mechanisms including those that underlie diseases. Such studies require molecular profiling data from a large number of individuals as well as information on the phenotypic trait of interest. Biobanks that collect samples and corresponding molecular data, also collect information on phenotypic traits or clinical information. However, this information can be heterogeneous and/or incomplete, or a certain piece of information could be missing entirely. In this study, we apply metabolic predictors to infer various traits, including diabetes status or exposure to lipid medication. We evaluate whether these metabolic surrogates can be used as an alternative to reported information for studying the respective phenotypes using TWAS. Our results reveal that in many cases, the use of metabolic surrogates yields similar results compared to using reported information, making them suitable substitutes for such studies. The possibility of using these surrogate outcomes can thus increase the size of data sets for studies where phenotypic information is incomplete or missing.
Assessing functional connectivity differences and work-related fatigue in surviving COVID-negative patients
Authors: Hafiz Rakibul , Gandhi Tapan Kumar , Mishra Sapna , Prasad Alok , Mahajan Vidur , Natelson Benjamin H. , Di Xin , Biswal Bharat B.
Published: February 2022

The Coronavirus Disease 2019 (COVID-19) has affected all aspects of life around the world. Neuroimaging evidence suggests the novel coronavirus can attack the central nervous system (CNS), causing cerebro-vascular abnormalities in the brain. This can lead to focal changes in cerebral blood flow and metabolic oxygen consumption rate in the brain. However, the extent and spatial locations of brain alterations in COVID-19 survivors are largely unknown. In this study, we have assessed brain functional connectivity (FC) using resting-state functional MRI (RS-fMRI) in 38 (25 males) COVID patients two weeks after hospital discharge, when PCR negative and 31 (24 males) healthy subjects. FC was estimated using independent component analysis (ICA) and dual regression. When compared to the healthy group, the COVID group demonstrated significantly enhanced FC in thebasal gangliaandprecuneusnetworks (family wise error (fwe) corrected,pfwe< 0.05), while, on the other hand, reduced FC in thelanguagenetwork (pfwe< 0.05). The COVID group also experienced higher fatigue levels during work, compared to the healthy group (p < 0.001). Moreover, within theprecuneusnetwork, we noticed a significant negative correlation between FC and fatigue scores across groups (Spearman’s ρ = - 0.47, p = 0.001, r2= 0.22). Interestingly, this relationship was found to be significantly stronger among COVID survivors within the leftparietal lobe, which is known to be structurally and functionally associated with fatigue in other neurological disorders.

Significance Statement

Early neuroimaging studies have mostly focused on structural MRI imaging to report brain abnormalities in acutely ill COVID-19 patients. It is not clear whether functional abnormalities co-exist with structural alterations in patients who have survived the infection and have been discharged from the hospital. A few recent studies have emerged which attempted to address the structural/functional alterations. However, further investigations across different sites are necessary for more conclusive inference. More importantly, fatigue is a highly prevalent symptom among COVID survivors, therefore, the relations of brain imaging abnormalities to fatigue should be investigated. In this study, we try to address these gaps, by collecting imaging data from COVID survivors, now PCR negative, and healthy subjects from a single site – the Indian Institute of Technology (IIT), Delhi, India. Furthermore, this is a continuation of an ongoing study. We have recently shown structural abnormalities and stronger gray matter volume (GMV) correlates of self-reported fatigue in this group of COVID survivors compared to healthy subjects (Hafiz et al., 2022).