bluuebunny/crossref_metadata_2025 huggingface dataset:
The amino acid substitution affects cellular response to mistranslation
Authors: Berg Matthew D. , Zhu Yanrui , Ruiz Bianca Y. , Loll-Krippleber Raphaël , Isaacson Joshua , Luis Bryan-Joseph San , Genereaux Julie , Boone Charles , Villén Judit , Brown Grant W. , Brandl Christopher J.
Published: May 2021

Mistranslation, the mis-incorporation of an amino acid not specified by the “standard” genetic code, occurs in all organisms. tRNA variants that increase mistranslation arise spontaneously and engineered tRNAs can achieve mistranslation frequencies approaching 10% in yeast and bacteria. Interestingly, human genomes contain tRNA variants with the potential to mistranslate. Cells cope with increased mistranslation through multiple mechanisms, though high levels cause proteotoxic stress. The goal of this study was to compare the genetic interactions and the impact on transcriptome and cellular growth of two tRNA variants that mistranslate at a similar frequency but create different amino acid substitutions inSaccharomyces cerevisiae.One tRNA variant inserts alanine at proline codons whereas the other inserts serine for arginine. Both tRNAs decreased growth rate, with the effect being greater for arginine to serine than for proline to alanine. The tRNA that substituted serine for arginine resulted in a heat shock response. In contrast, heat shock response was minimal for proline to alanine substitution. Further demonstrating the significance of the amino acid substitution, transcriptome analysis identified unique up- and downregulated genes in response to each mistranslating tRNA. Number and extent of negative synthetic genetic interactions also differed depending upon type of mistranslation. Based on the unique responses observed for these mistranslating tRNAs, we predict that the potential of mistranslation to exacerbate diseases caused by proteotoxic stress depends on the tRNA variant. Furthermore, based on their unique transcriptomes and genetic interactions, different naturally occurring mistranslating tRNAs have the potential to negatively influence specific diseases.
Phenotypic distribution and selection response for linear-product gene-environment interaction in quantitative traits
Authors: Smith Reginald D.
Published: May 2021

Gene-environment interaction is often described by linear phenotypic plasticity but has recently also been expressed as function of the product of genotype and environmental variables. While this model can be fitted in a multiple regression scenario, little has been written on the distribution of the product of breeding values and environment, GE, its expected moments, and the theoretical impact on phenotypic selection. Here we will explore these topics introducing the distribution for GE, its mean and variance, and its expected impact of lowering realized heritability due to is increasing the phenotypic variance.
Assessing antibiotic tolerance ofStaphylococcus aureusderived directly from patients by the Replica Plating Tolerance Isolation System - REPTIS
Authors: Herren Sebastian C. , Huemer Markus , Acevedo Claudio T. , Andreoni Federica , Gómez-Mejia Alejandro , Shambat Srikanth Mairpady , Hasse Barbara , Zbinden Reinhard , Brugger Silvio D. , Zinkernagel Annelies S.
Published: May 2021

Antibiotic tolerantStaphylococcus aureuspose a great challenge to clinicians as well as to microbiological laboratories and are one reason for treatment failure. Antibiotic tolerant strains survive transient antibiotic exposure despite being fully susceptiblein vitro. Thus, fast and reliable methods to detect tolerance in the routine microbiology laboratory are urgently required.

We therefore evaluated the feasibility of the replica plating tolerance isolation system (REPTIS) to detect antibiotic tolerance inS. aureusisolates derived directly from patients suffering from different types of infections and investigated possible connections to clinical presentations and patient characteristics.

One hundred twenty-fiveS. aureusisolates were included. Replica plating of the original resistance testing plate was used to assess regrowth in the zones of inhibition, indicating antibiotic tolerance. Bacterial regrowth was assessed after 24 and 48 hours of incubation and an overall regrowth score (ORS) was assigned. Regrowth scores were compared to the clinical presentation.

Bacterial regrowth was high for most antibiotics targeting protein synthesis and relatively low for antibiotics targeting other cellular functions such as DNA-replication, transcription and cell wall synthesis, with the exception of rifampicin. Isolates with a blaZ penicillinase had lower regrowth in penicillin and ampicillin. Low ORSs were more prevalent among isolates recovered from patients with immunosuppression or methicillin-resistantS. aureus(MRSA) isolates.

In conclusion, REPTIS is useful to detect antibiotic tolerance in clinical microbiological routine diagnostics. Rapid detection of antibiotic tolerance offers a new diagnostic readout that might allow more tailored treatments in the future.
Occupation, Work-Related Contact, and SARS-CoV-2 Anti-Nucleocapsid Serological Status: Findings from the Virus Watch prospective cohort study
Authors: Beale Sarah , Patel Parth , Rodger Alison , Braithwaite Isobel , Byrne Thomas , Erica Fong Wing Lam , Fragaszy Ellen , Geismar Cyril , Kovar Jana , Navaratnam Annalan MD , Nguyen Vincent , Shrotri Madhumita , Aldridge Robert W , Hayward Andrew C
Published: May 2021

Background

Workers differ in their risk of acquiring SARS-CoV-2 infection according to their occupation; however, few studies have been able to control for multiple confounders or investigate the work-related factors that drive differences in occupational risk. Using data from the Virus Watch community cohort study in England and Wales, we set out to estimate the total effect of occupation on SARS-CoV-2 serological status, whether this is mediated by frequency of close contact within the workplace, and how exposure to poorly ventilated workplaces varied across occupations.

Methods

We used data from a sub-cohort (n =3761) of adults (≥18) tested for SARS-CoV-2 anti-nucleocapsid antibodies between 01 February-28 April 2021 and responded to a questionnaire about work during the pandemic. Anti-nucleocapsid antibodies were used as a proxy of prior natural infection with COVID-19. We used logistic decomposition to estimate the total and direct effect of occupation and indirect effect of workplace contact frequency on odds of seropositivity, adjusting for age, sex, household income and region. We investigated the relationship between occupation and exposure to poorly-ventilated workplace environments using ordinal logistic regression.

Results

Seropositivity was 16.0% (113/707) amongst workers with daily close contact, compared to 12.9% (120/933) for those with intermediate-frequency contact and 9.6% (203/2121) for those with no work-related close contact. Healthcare (OR= 2.14, 95% CI 1.47,3.12), indoor trade, process and plant (2.09, 1.31,3.33), leisure and personal service (1.96, 1.004,3.84), and transport and mobile machine (2.17, 1.12,4.18) workers had elevated total odds of SARS-CoV-2 seropositivity compared to other professional and associate occupations. Frequency of workplace contact accounted for a variable part of the increased odds in different occupational groups (OR range 1.04 [1.0004,1.07] - 1.22 [1.07, 1.38]). Healthcare workers and indoor trades and process plant workers continued to have raised odds of infection after accounting for work-related contact, and also had had greater odds of frequent exposure to poorly-ventilated workplaces (respectively 2.15 [1.66, 2.79] and (1.51, [1.12, 2.04]).

Discussion

Marked variations in occupational odds of seropositivity remain after accounting for age, sex, region, and household income. Close contact in the workplace appears to contribute substantially to this variation. Reducing frequency of workplace contact is a critical part of COVID-19 control measures.
The cyclic dinucleotide 2’3’-cGAMP induces a broad anti-bacterial and anti-viral response in the sea anemone Nematostella vectensis
Authors: Margolis Shally R. , Dietzen Peter A. , Hayes Beth M. , Wilson Stephen C. , Remick Brenna C. , Chou Seemay , Vance Russell E.
Published: May 2021

In mammals, cyclic dinucleotides (CDNs) bind and activate STING to initiate an anti-viral type I interferon response. CDNs and STING originated in bacteria and are present in most animals. By contrast, interferons are believed to have emerged in vertebrates; thus, the function of CDN signaling in invertebrates is unclear. Here, we use a CDN, 2’3’-cGAMP, to activate immune responses in a model cnidarian invertebrate, the starlet sea anemone Nematostella vectensis. Using RNA-Seq, we found that 2’3’-cGAMP induces robust transcription of both anti-viral and anti-bacterial genes in N. vectensis. Many of the anti-viral genes induced by 2’3’-cGAMP are homologs of vertebrate interferon stimulated genes, implying that the interferon response predates the evolution of interferons. Knockdown experiments identified a role for NF-κB in specifically inducing anti-bacterial genes downstream of 2’3’-cGAMP. Some of these putative anti-bacterial genes were also found to be induced during Pseudomonas aeruginosa infection. We characterized the protein product of one of the putative anti-bacterial genes, the N. vectensis homolog of Dae4, and found that it has conserved anti-bacterial activity. This work suggests that a broad anti-bacterial and anti-viral transcriptional response is an evolutionarily ancestral output of 2’3’-cGAMP signaling in animals.

Significance statement

Cyclic dinucleotides are signaling molecules that originated in bacteria and were subsequently acquired and co-opted by animals for immune signaling. The major cyclic dinucleotide signaling pathway in mammals results in the production of anti-viral molecules called interferons. Invertebrates such as sea anemones lack interferons, and thus it was unclear whether cyclic dinucleotide signaling would play a role in immunity in these animals. Here we report that in the anemone Nematostella vectensis, cyclic dinucleotides activate both anti-viral and anti-bacterial immune responses, and do so through a conserved pathway. These results provide insights into the evolutionary origins of innate immunity, and suggest a broader ancestral role for cyclic dinucleotide signaling that evolved toward more specialized anti-viral functions in mammals.
High-Efficiency Pharmacogenetic Ablation of Oligodendrocyte Progenitor Cells in the Adult Mouse CNS
Authors: Xing Yao Lulu , Poh Jasmine , Chuang Bernard H.A. , Moradi Kaveh , Mitew Stanislaw , Richardson William D. , Kilpatrick Trevor J. , Osanai Yasuyuki , Merson Tobias D.
Published: May 2021

Approaches to investigate adult oligodendrocyte progenitor cells (OPCs) by targeted cell ablation in the rodent central nervous system have been limited by methodological challenges resulting in only partial and transient OPC depletion. We have developed a novel pharmacogenetic model of conditional OPC ablation, eliminating 98.6% of all OPCs throughout the brain. By combining recombinase-based transgenic and viral strategies for targeting OPCs and ventricular-subventricular zone (V-SVZ)-derived neural precursor cells (NPCs), we found new PDGFRA-expressing cells born in the V-SVZ repopulated the OPC-deficient brain starting 12 days after OPC ablation. Our data reveal that OPC depletion induces V-SVZ-derived NPCs to generate vast numbers of PDGFRA+NG2+cells with the capacity to migrate and proliferate extensively throughout the dorsal anterior forebrain. Further application of this novel approach to ablate OPCs will advance knowledge of the function of both OPCs and oligodendrogenic NPCs in health and disease.
Host transcriptional response to SARS-CoV-2 infection in COVID-19 patients
Authors: Singh Nitesh Kumar , Srivastava Surabhi , Zaveri Lamuk , Bingi Thrilok Chander , Mesipogu Rajarao , Kumar Santosh , Gaur Namami , Hajirnis Nikhil , Maccha Pratheusa , Shambhavi Sakshi , Khan Shagufta , Soujanya Mamilla , Nagabandi Tulasi , Mishra Rakesh K. , Tallapaka Karthik Bharadwaj , Sowpati Divya Tej
Published: May 2021

Background

One of the most perplexing aspects of infection with the SARS-CoV-2 virus has been the variable response elicited in its human hosts. Investigating the transcriptional changes in individuals affected by COVID-19 can help understand and predict the degree of illness and guide clinical outcomes in diverse backgrounds.

Methods

Analysis of host transcriptome variations via RNA sequencing from naso/oropharyngeal swabs of COVID-19 patients.

Results

We report strong upregulation of the innate immune response, especially type I interferon pathway, upon SARS-CoV-2 infection. Upregulated genes were subjected to a comparative meta-analysis using global datasets to identify a common network of interferon stimulated and viral response genes that mediate the host response and resolution of infection. A large proportion of mis-regulated genes showed a reduction in expression level, suggesting an overall decrease in host mRNA production. Significantly downregulated genes included those encoding olfactory, taste and neuro-sensory receptors. Many pro-inflammatory markers and cytokines were also downregulated or remained unchanged in the COVID-19 patients. Finally, a large number of non-coding RNAs were identified as down-regulated, with a few of the lncRNAs associated with functional roles in directing the response to viral infection.

Conclusions

SARS-CoV-2 infection results in the robust activation of the body’s innate immunity. Reduction of gene expression is well correlated with the clinical manifestations and symptoms of COVID-19 such as the loss of smell and taste, and myocardial and neurological complications. This study provides a critical dataset of genes that will enhance our understanding of the nature and prognosis of COVID-19.
Altered cerebellar response to somatosensory stimuli in the Cntnap2 mouse model of autism
Authors: Fernández Marta , Sánchez-León Carlos A. , Llorente Javier , Sierra-Arregui Teresa , Knafo Shira , Márquez-Ruiz Javier , Peñagarikano Olga
Published: May 2021

Atypical sensory processing is currently included within the diagnostic criteria of autism. The cerebellum is known to integrate sensory inputs of different modalities through its connectivity to the cerebral cortex. Interestingly, cerebellar malformations are among the most replicated features found in postmortem brain of individuals with autism. We studied cerebellar integration of sensory information in a mouse model of autism, knockout for the Cntnap2 gene. Cntnap2 is widely expressed in Purkinje cells and has been recently reported to regulate their morphology. Further, individuals with CNTNAP2 mutations display cerebellar malformations and CNTNAP2 antibodies are associated with a mild form of cerebellar ataxia. Previous studies in the Cntnap2 mouse model show an altered cerebellar sensory learning. However, a physiological analysis of cerebellar function has not been performed yet. We studied sensory evoked potentials in cerebellar Crus I/II region upon electrical stimulation of the whisker pad in alert mice and found striking differences between WT and Cntnap2 KO mice. In addition, single-cell recordings identified alterations in both sensory-evoked and spontaneous firing patterns of Purkinje cells. These changes were accompanied by altered intrinsic properties and morphological features of these neurons. Together, these results indicate that the Cntnap2 mouse model could provide novel insight into the pathophysiological mechanisms of ASD core sensory deficits.
A mitochondrial long-chain fatty acid oxidation defect leads to uncharged tRNA accumulation and activation of the integrated stress response in the mouse heart
Authors: Ranea-Robles Pablo , Pavlova Natalya N. , Bender Aaron , Pereyra Andrea S. , Ellis Jessica M. , Stauffer Brandon , Yu Chunli , Thompson Craig B. , Argmann Carmen , Puchowicz Michelle , Houten Sander M.
Published: May 2021

The heart relies mainly on mitochondrial fatty acid β-oxidation (FAO) for its high energy requirements. Cardiomyopathy and arrhythmias can be severe complications in patients with inherited defects in mitochondrial long-chain FAO, reinforcing the importance of FAO for cardiac health. However, the pathophysiological mechanisms that underlie the cardiac abnormalities in long-chain FAO disorders remain largely unknown. Here, we investigated the cardiac transcriptional adaptations to the FAO defect in the long-chain acyl-CoA dehydrogenase (LCAD) knockout (KO) mouse. We found a prominent activation of the integrated stress response (ISR) mediated by the eIF2α/ATF4 axis in both fed and fasted states, accompanied by a reduction in cardiac protein synthesis during a short period of food withdrawal. Notably, we found an accumulation of uncharged tRNAs in LCAD KO hearts, consistent with a reduced availability of cardiac amino acids, in particular, glutamine. We replicated the activation of the cardiac ISR in hearts of mice with a muscle-specific deletion of carnitine palmitoyltransferase 2 deletion (Cpt2M-/-). Our results show that perturbations in amino acid metabolism caused by long-chain FAO deficiency impact cardiac metabolic signaling, in particular the ISR, and may play a role in the associated cardiac pathology.
The First High-Quality Reference Genome of Sika Deer Provides Insights for High-Tannin Adaptation
Authors: Xing Xiumei , Ai Cheng , Wang Tianjiao , Li Yang , Liu Huitao , Hu Pengfei , Wang Guiwu , Liu Huamiao , Wang Hongliang , Zhang Ranran , Zheng Junjun , Wang Xiaobo , Wang Lei , Chang Yuxiao , Qian Qian , Yu Jinghua , Tang Lixin , Wu Shigang , Shao Xiujuan , Li Alun , Cui Peng , Zhan Wei , Zhao Sheng , Wu Zhichao , Shao Xiqun , Dong Yimeng , Rong Min , Tan Yihong , Cui Xuezhe , Chang Shuzhuo , Song Xingchao , Yang Tongao , Sun Limin , Ju Yan , Zhao Pei , Fan Huanhuan , Liu Ying , Wang Xinhui , Yang Wanyun , Yang Min , Wei Tao , Song Shanshan , Xu Jiaping , Yue Zhigang , Liang Qiqi , Li Chunyi , Ruan Jue , Yang Fuhe
Published: May 2021

Sika deer are known to prefer oak leaves, which are rich in tannins and toxic to most mammals; however, the genetic mechanisms underlying their unique ability to adapt to living in the jungle are still unclear. In identifying the mechanism responsible for the tolerance of a highly toxic diet, we have made a major advancement in the elucidation of the genomics of sika deer. We generated the first high-quality, chromosome-level genome assembly of sika deer and measured the correlation between tannin intake and RNA expression in 15 tissues through 180 experiments. Comparative genome analyses showed that the UGT and CYP gene families are functionally involved in the adaptation of sika deer to high-tannin food, especially the expansion of UGT genes in a subfamily. The first chromosome-level assembly and genetic characterization of the tolerance toa highly toxic diet suggest that the sika deer genome will serve as an essential resource for understanding evolutionary events and tannin adaptation. Our study provides a paradigm of comparative expressive genomics that can be applied to the study of unique biological features in non-model animals.
The effects of host availability and fitness on Aedes albopictus blood feeding patterns in New York
Authors: Fikrig Kara , Martin Elisabeth , Dang Sharon , St Fleur Kimberly , Goldsmith Henry , Qu Sophia , Rosenthal Hannah , Pitcher Sylvie , Harrington Laura C.
Published: May 2021

Aedes albopictus is a competent vector of numerous pathogens, representing a range of transmission cycles involving unique hosts. Despite the important status of this vector, variation in its feeding patterns is poorly understood. We examined the feeding patterns of Ae. albopictus utilizing resting collections in Long Island, New York, and contextualized blood meal sources with host availability measured by household interviews and camera traps. We identified 90 blood meals, including 29 human, 22 cat, 16 horse, 12 opossum, 5 dog, 2 goat, and 1 rabbit, rat, squirrel and raccoon. Our study is the first to quantitatively assess Ae. albopictus feeding patterns in the context of host availability of wild animals in addition to humans and domestic animals. Host feeding indices showed that cats and dogs were fed upon disproportionately often compared to humans. Forage ratios suggested a tendency to feed on cats and opossums and to avoid raccoons, squirrels, and birds. This feeding pattern was different from another published study from Baltimore, where Ae. albopictus fed more often on rats than humans. To understand if these differences were due to host availability or mosquito population variation, we compared the fitness of Long Island and Baltimore Ae. albopictus after feeding on rat and human blood. In addition, we examined fitness within the Long Island population after feeding on human, rat, cat, horse, and opossum blood. Together, our results do not show major mosquito fitness differences by blood hosts, suggesting that fitness benefits do not drive Northeastern Ae. albopictus feeding patterns.
Serotonergic Neurons Translate Taste Detection into Internal Nutrient Regulation
Authors: Yao Zepeng , Scott Kristin
Published: May 2021

The nervous and endocrine systems coordinately monitor and regulate nutrient availability to maintain energy homeostasis. Sensory detection of food regulates internal nutrient availability in a manner that anticipates food intake, but sensory pathways that promote anticipatory physiological changes remain unclear. Here, we identify serotonergic (5-HT) neurons as critical mediators that transform gustatory detection by sensory neurons into the activation of insulin-producing cells and enteric neurons in Drosophila. One class of 5-HT neurons responds to gustatory detection of sugars, excites insulin-producing cells and limits consumption, suggesting that they anticipate increased nutrient levels and prevent overconsumption. A second class of 5-HT neurons responds to gustatory detection of bitter compounds and activates enteric neurons to promote gastric motility, likely to stimulate digestion and increase circulating nutrients when food quality is poor. These studies demonstrate that 5-HT neurons relay acute gustatory detection to divergent pathways for longer-term stabilization of circulating nutrients.
Site-specific epigenetic marks in Trypanosoma brucei transcription termination, antigenic variation, and proliferation
Authors: Kim Hee-Sook
Published: May 2021

In Trypanosoma brucei, genes assemble into polycistronic transcription units (PTUs). Transcription termination sites (TTSs) hold deposition sites for three non-essential chromatin factors, histone variants (H3v and H4v) and a DNA modification (base J, a hydroxyl-glucosyl dT). Here, I found that H4v is a major sign for transcription termination at TTSs and readthrough transcription machineries progress until they encounter the next bidirectional transcription start site. While having a secondary function at TTSs, H3v is important for monoallelic transcription of telomeric antigen genes. The simultaneous absence of both histone variants leads to proliferation and replication defects, which are exacerbated by the J deficiency, accompanied by accumulation of sub-G1 population. Base J likely contributes to DNA replication and cell-cycle control. I propose that the coordinated actions of H3v, H4v and J function in concert for cellular fate determination and provide compensatory mechanisms for each other in chromatin organization, transcription, and replication.
Toxoplasma gondii Toxolysin 4 contributes to efficient parasite egress from host cells
Authors: Huynh My-Hang , Roiko Marijo S. , Gomes Angelica O. , Schinke Ellyn N. , Schultz Aric J. , Agrawal Swati , Oellig Christine A. , Sexton Travis R. , Beauchamp Jessica M. , Laliberté Julie , Sivaraman Komagal Kannan , Hersh Louis B. , McGowan Sheena , Carruthers Vern B.
Published: May 2021

Egress from host cells is an essential step in the lytic cycle of T. gondii and other apicomplexan parasites; however, only a few parasite secretory proteins are known to affect this process. The putative metalloproteinase Toxolysin 4 (TLN4) was previously shown to be an extensively processed microneme protein, but further characterization was impeded by the inability to genetically ablate TLN4. Herein we show that TLN4 has the structural properties of an M16 family metalloproteinase, that it possesses proteolytic activity on a model substrate, and that genetic disruption of TLN4 reduces the efficiency of egress from host cells. Complementation of the knockout strain with the TLN4 coding sequence significantly restored egress competency, affirming that the phenotype of the Δtln4 parasite was due to the absence of TLN4. This work identifies TLN4 as the first metalloproteinase and the second microneme protein to function in T. gondii egress. The study also lays a foundation for future mechanistic studies defining the precise role of TLN4 in parasite exit from host cells.

IMPORTANCE

After replicating within infected host cells, the single celled parasite Toxoplasma gondii must rupture out of such cells in a process termed egress. Although it is known that T. gondii egress is an active event that involves disruption of host-derived membranes surrounding the parasite, very few proteins that are released by the parasite are known to facilitate egress. In this study we identify a parasite secretory protease that is necessary for efficient and timely egress, thus laying the foundation for understanding precisely how this protease facilitates T. gondii exit from host cells.
Surveillance of COVID-19 vaccination in US nursing homes, December 2020-April 2021
Authors: Geller Andrew Isaac , Budnitz Daniel S. , Dubendris Heather , Gharpure Radhika , Soe Minn Minn , Wu Hsiu , Kalayil Elizabeth J. , Benin Andrea L. , Patel Suchita A. , Lindley Megan C. , Link-Gelles Ruth
Published: May 2021

Unstructured Abstract

Monitoring COVID-19 vaccination coverage among nursing home (NH) residents and staff is important to ensure high coverage and guide patient-safety policies. With the termination of the federal Pharmacy Partnership for Long-Term Care Program, another source of facility-based vaccination data is needed. We compared numbers of COVID-19 vaccinations administered to NH residents and staff reported by pharmacies participating in the temporary federal Pharmacy Partnership for Long-Term Care Program with those reported by NHs participating in new COVID-19 vaccination modules of CDC’s National Healthcare Safety Network (NHSN). Pearson correlation coefficients comparing the number vaccinated between the two approaches were 0.89, 0.96, and 0.97 for residents and 0.74, 0.90, and 0.90 for staff, in the weeks ending January 3, 10, and 17, respectively. Based on subsequent NHSN reporting, vaccination coverage with ≥1 vaccine dose reached 77% for residents and 50% for staff the week ending January 31 and plateaued through April 2021.

Three-question summary box

What is the current understanding of the subject?

Because of high risk of disease, nursing home residents and staff were prioritized for COVID-19 vaccination when doses were limited.

What does this report add to the literature?

National monitoring of nursing home residents and staff vaccination coverage through the CDC National Healthcare Safety Network (NHSN) correlated with vaccination administration reports from the federal Pharmacy Partnership for Long-Term Care Program in January 2021. NHSN-reported vaccination coverage rates plateaued from February through April 2021.

What are the implications for public health practice?

NHSN can track COVID-19 vaccination in nursing homes and help guide efforts to increase vaccine uptake in residents and staff.
Mortality in hemodialysis: Synchrony of biomarker variability indicates a critical transition
Authors: Cohen Alan A. , Leung Diana L. , Legault Véronique , Gravel Dominique , Blanchet F. Guillaume , Côté Anne-Marie , Fülöp Tamàs , Lee Sylvia Juhong , Dufour Frédérik , Liu Mingxin , Nakazato Yuichi
Published: May 2021

Critical transition theory suggests that complex systems should experience increased temporal variability just before abrupt change, such as increases in clinical biomarker variability before mortality. We tested this in the context of hemodialysis using 11 clinical biomarkers measured every two weeks in 763 patients over 2496 patient-years. We show that variability – measured by coefficients of variation – is more strongly predictive of mortality than biomarker levels. Further, variability is highly synchronized across all biomarkers, even those from unrelated systems: the first axis of a principal component analysis explains 49% of the variance. This axis then generates powerful predictions of all-cause mortality (HR95=9.7, p<0.0001, where HR95 is a scale-invariant metric of hazard ratio across the predictor range; AUC up to 0.82) and starts to increase markedly ∼3 months prior to death. Such an indicator could provide an early warning sign of physiological collapse and serve to either trigger intervention or initiate discussions around palliative care.
Isolation and characterization of SARS-CoV-2 VOC, 20H/501Y.V2, from UAE travelers
Authors: Yadav Pragya D. , Sarkale Prasad , Razdan Alpana , Gupta Nivedita , Nyayanit Dimpal A. , Sahay Rima R. , Potdar Varsha , Patil Deepak Y. , Baradkar Shreekant , Kumar Abhinendra , Aggarwal Neeraj , Shete Anita M. , Kaur Harmanmeet
Published: May 2021

Multiple SARS-CoV-2 variants have been emerged and created serious public health in the affected countries. The variant of Concern associated with high transmissibility, disease severity and escape mutations is threat to vaccination program across the globe. Travel has been important factor in spread of SARS-CoV-2 variants worldwide. India has also witnessed the dreadful effect of these SARS-CoV-2 variants. Here, we report the Isolation and characterization of SARS-CoV-2 VOC, 20H/501Y.V2 (B.1.351), from UAE travelers to India. The virus isolate would be useful to determine the efficacy of the currently available vaccines in India.
Hypoxia induces transcription of DOT1L in articular cartilage to protect against osteoarthritis
Authors: De Roover Astrid , Escribano Ana , Cornelis Frederique M. F. , Cherifi Chahrazad , Casas-Fraile Leire , Sermon An , Cailotto Frederic , Lories Rik J. , Monteagudo Silvia
Published: May 2021

Osteoarthritis is the most prevalent joint disease worldwide and a leading source of pain and disability. To date, this disease lacks curative treatment as underlying molecular mechanisms remain largely unknown. The histone methyltransferase DOT1L protects against osteoarthritis, and DOT1L-mediated H3K79 methylation is reduced in human and mouse osteoarthritic joints. Thus, restoring DOT1L function seems to be critical to preserve joint health. However, DOT1L-regulating molecules and networks remain elusive, in the joint and beyond. Here, we identify transcription factors and networks that regulate DOT1L gene expression using a novel bioinformatics pipeline. Thereby, we unravel an undiscovered link between the hypoxia pathway and DOT1L. We provide unprecedented evidence that hypoxia enhances DOT1L expression and H3K79 methylation via hypoxia-inducible factor-1 alpha (HIF-1α). Importantly, we demonstrate that DOT1L contributes to the protective effects of hypoxia in articular cartilage and osteoarthritis. Intra-articular treatment with a selective hypoxia mimetic in mice after surgical induction of osteoarthritis restores DOT1L function and stalls disease progression. Collectively, our data unravel a novel molecular mechanism that protects against osteoarthritis with hypoxia inducing DOT1L transcription in cartilage. Local treatment with a selective hypoxia mimetic in the joint restores DOT1L function and could be an attractive therapeutic strategy for osteoarthritis.
Fiberoptic Hemodynamic Spectroscopy: validation in glioma model and magnetic probe to study cerebrovascular dysregulation in freely-moving Alzheimer’s disease model mice
Authors: Gareau Daniel S. , Bamkole Michael , Snuderl Matija , Thomas Cheddhi , Bayin N. Sumru , Placantonakis Dimitris G. , Zou Julia , Yaroslavsky Anna , Dietz Michael P. , Jacques Steven L. , Strickland Sidney , Krueger James G. , Ahn Hyung Jin
Published: May 2021

Significance

Cerebral vascular reactivity is critical parameters of brain homeostasis in health and disease, but the investigational value of brain oxymetry is diminished by anesthesia and mechanical fixation of the mouse scull.

Aim

We needed to reduce the physical restrictivity of hemodynamic spectroscopy to enable Alzheimer’s disease (AD) studies in freely-moving mice.

Approach

We combined spectroscopy, spectral analysis software and a magnetic, implantable device to measure vascular reactivity in unanesthetized, freely-moving mice. We measured cerebral blood volume fraction (CBVF) and oxygen saturation (SO2).

Results

We validated that our system could detect delayed cerebrovascular recovery from hypoxia in an orthotopic xenograft glioma model under anesthetized condition and we also found increasedCBVFand impaired vascular reactivity during hypercapnia in a freely-moving mouse model of AD compared to wild-type littermates.

Conclusions

Our optomechanical approach to reproducibly getting light into and out of the brain enabled us to successfully measureCBVFandSO2during hypercapnia in unanesthetized freely-moving mice. We present hardware and software enabling oximetric analysis of metabolic activity, which provides a safe and reliable method for rapid assessment of vascular reactivity in murine disease models as well asCBVFandSO2.
Characterization of mouse Bmp5 regulatory injury element in zebrafish wound models
Authors: Heller Ian S. , Guenther Catherine A. , Meireles Ana M. , Talbot William S. , Kingsley David M.
Published: May 2021

Many key signaling molecules used to build tissues during embryonic development are re-activated at injury sites to stimulate tissue regeneration and repair. Bone morphogenetic proteins provide a classic example, but the mechanisms that lead to reactivation of BMPs following injury are still unknown. Previous studies have mapped a large “injury response element” (IRE) in the mouse Bmp5 gene that drives gene expression following bone fractures and other types of injury. Here we show that the large mouse IRE region is also activated in both zebrafish tail resection and mechanosensory hair cell injury models. Using the ability to test multiple constructs and image temporal and spatial dynamics following injury responses, we have narrowed the original size of the mouse IRE region by over 100 fold and identified a small 142 bp minimal enhancer that is rapidly induced in both mesenchymal and epithelial tissues after injury. These studies identify a small sequence that responds to evolutionarily conserved local signals in wounded tissues and suggest candidate pathways that contribute to BMP reactivation after injury.
SMCHD1 variants may induce variegated expression in Facio Scapulo Humeral Dystophy and Bosma Arhinia and microphtalmia syndrome
Authors: Laberthonnière Camille , Chevalier Raphaël , Dion Camille , Delourme Mégane , Hirst David , Adélaïde José , Chaffanet Max , Xue Shifeng , Nguyen Karine , Reversade Bruno , Déjardin Jérôme , Baudot Anais , Robin Jérôme D. , Magdinier Frédérique
Published: May 2021

An expanding number of genetic syndromes are linked to mutations in genes encoding factors that guide chromatin organization. Recently, distinct genetic syndromes have been linked to mutations in theSMCHD1gene. However, the function of this non-canonical SMC protein remains partly defined in Human tissues. To address this question, we determined its epi-signature in type 2 Facio Scapulo Humeral Dystrophy (FSHD2) and Bosma Arhinia and Microphtalmia Syndrome (BAMS) linked to heterozygous mutations in this gene. By combining RNA-Seq, DNA methylation profiling and ChIP-Seq, we showed that SMCHD1 regulates repressed chromatin but alsocis-regulatory elements and enhancers. Our results emphasize dual functions for SMCHD1, in chromatin compaction, chromatin insulation and gene regulation with variable outcomes and targets depending on tissues. We propose that altered DNA methylation and long-range chromatin organization at a number of loci required for development and tissue differentiation, trigger variegated gene expression in rare genetic diseases linked to heterozygousSMCHD1mutations.
An intranasal ASO therapeutic targeting SARS-CoV-2
Authors: Zhu Chi , Lee Justin Y. , Woo Jia Z. , Xu Lei , Nguyenla Xammy , Yamashiro Livia H. , Ji Fei , Biering Scott B. , Van Dis Erik , Gonzalez Federico , Fox Douglas , Rustagi Arjun , Pinsky Benjamin A. , Blish Catherine A. , Chiu Charles , Harris Eva , Sadreyev Ruslan I. , Stanley Sarah , Kauppinen Sakari , Rouskin Silvi , Näär Anders M.
Published: May 2021

The COVID-19 pandemic is exacting an increasing toll worldwide, with new SARS-CoV-2 variants emerging that exhibit higher infectivity rates and that may partially evade vaccine and antibody immunity1. Rapid deployment of non-invasive therapeutic avenues capable of preventing infection by all SARS-CoV-2 variants could complement current vaccination efforts and help turn the tide on the COVID-19 pandemic2. Here, we describe a novel therapeutic strategy targeting the SARS-CoV-2 RNA using locked nucleic acid antisense oligonucleotides (LNA ASOs). We identified an LNA ASO binding to the 5’ leader sequence of SARS-CoV-2 ORF1a/b that disrupts a highly conserved stem-loop structure with nanomolar efficacy in preventing viral replication in human cells. Daily intranasal administration of this LNA ASO in the K18-hACE2 humanized COVID-19 mouse model potently (98-99%) suppressed viral replication in the lungs of infected mice, revealing strong prophylactic and treatment effects. We found that the LNA ASO also represses viral infection in golden Syrian hamsters, and is highly efficacious in countering all SARS-CoV-2 “variants of concern” tested in vitro and in vivo, including B.1.427, B.1.1.7, and B.1.351 variants3. Hence, inhaled LNA ASOs targeting SARS-CoV-2 represents a promising therapeutic approach to reduce transmission of variants partially resistant to vaccines and monoclonal antibodies, and could be deployed intranasally for prophylaxis or via lung delivery by nebulizer to decrease severity of COVID-19 in infected individuals. LNA ASOs are chemically stable and can be flexibly modified to target different viral RNA sequences4, and they may have particular impact in areas where vaccine distribution is a challenge, and could be stockpiled for future coronavirus pandemics.
Public attitudes towards free-roaming dogs and dog ownership practices in Bulgaria, Italy, and Ukraine
Authors: Smith L.M. , Quinnell R.J. , Munteanu A.M. , Hartmann S. , Dalla Villa P. , Collins L.M.
Published: May 2021

Overabundant, free-roaming dog populations are associated with risks to public health, livestock losses, wildlife conservation, and dog health and welfare. Dog population management is conducted to mitigate these issues. Assessing dog population management strategies is important to determine their effectiveness, efficiency, and long-term impact. It is essential to also determine how the behaviour and outlook of local communities may influence the efficacy of dog population management. This study aimed to determine public attitudes towards free-roaming dogs and their management and describe dog ownership practices in three European countries using an online questionnaire survey. This study found that most surveyed respondents wanted to see a reduction in free-roaming dog numbers, and felt that this should be achieved through sheltering, catch-neuter-release, and by controlling the breeding of owned dogs. This questionnaire also identified significant associations between public attitudes and dog ownership practices with gender, religious beliefs, age, education level, reason for dog ownership, previous experience with free-roaming dogs, and country of residence. Respondents who identified as: (i) being male, (ii) holding religious beliefs, (iii) owning dogs for practical reasons, (iv) being young, and (v) having no schooling or primary education had a lower probability of neutering and a higher probability of allowing dogs to roam. Respondents who identified as: (i) being female, (ii) feeling threatened by free-roaming dogs, (iii) being older, and (iv) having more education had a higher probability of answering that an increase in free-roaming dog numbers should be prevented. These findings can help to inform future dog population management interventions in these countries and highlight the importance of considering local public attitudes and dog ownership practices in the development of effective dog population management approaches. Including these social factors will ensure that both the community and organisations involved in dog population management work cohesively towards a shared goal.
Deconstructing the Cortical Sources of Frequency Following Responses to Speech: A Cross-species Approach
Authors: Gnanateja G. Nike , Rupp Kyle , Llanos Fernando , Remick Madison , Pernia Marianny , Sadagopan Srivatsun , Teichert Tobias , Abel Taylor J. , Chandrasekaran Bharath
Published: May 2021

Time-varying pitch is a vital cue for human speech perception. Neural processing of time-varying pitch has been extensively assayed using scalp-recorded frequency-following responses (FFRs), an electrophysiological signal thought to reflect integrated phase-locked neural ensemble activity from subcortical auditory areas. Emerging evidence increasingly points to a putative contribution of auditory cortical ensembles to the scalp-recorded FFRs. However, the properties of cortical FFRs and precise characterization of laminar sources are still unclear. Here we used direct human intracortical recordings as well as extra- and intracranial recordings from macaques and guinea pigs to characterize the properties of cortical sources of FFRs to time-varying pitch patterns. We found robust FFRs in the auditory cortex across all species. We leveraged representational similarity analysis as a translational bridge to characterize similarities between the human and animal models. Laminar recordings in animal models showed FFRs emerging primarily from the thalamorecepient layers of the auditory cortex. FFRs arising from these cortical sources significantly contributed to the scalp-recorded FFRs via volume conduction. Our research paves the way for a wide array of studies to investigate the role of cortical FFRs in auditory perception and plasticity.

Significance Statement

Frequency following responses (FFRs) to speech are scalp-recorded neural signals that inform the fidelity of sound encoding in the auditory system. FFRs, long believed to arise from brainstem and midbrain, have shaped our understanding of sub-cortical auditory processing and plasticity. Non-invasive studies have shown cortical contributions to the FFRs, however, this is still actively debated. Here we employed direct cortical recordings to trace the cortical contribution to the FFRs and characterize the properties of these cortical FFRs. With extra-cranial and intra-cranial recordings within the same subjects we show that cortical FFRs indeed contribute to the scalp-recorded FFRs, and their response properties differ from the sub-cortical FFRs. The findings provide strong evidence to revisit and reframe the FFR driven theories and models of sub-cortical auditory processing and plasticity with careful characterization of cortical and sub-cortical components in the scalp-recorded FFRs.
Interleukin-6 mediates PSAT1 expression and serine metabolism in TSC2-deficient cells
Authors: Wang Ji , Filippakis Harilaos , Hougard Thomas , Du Heng , Ye Chenyang , Liu Heng-Jia , Zhang Long , Hindi Khadijah , Bagwe Shefali , Nijmeh Julie , Asara John M. , Shi Wei , El-Chemaly Souheil , Henske Elizabeth P. , Lam Hilaire C.
Published: May 2021

Tuberous sclerosis complex (TSC) and lymphangioleiomyomatosis (LAM) are caused by aberrant mechanistic Target of Rapamycin Complex 1 (mTORC1) activation due to loss of either TSC1 or TSC2. Cytokine profiling of TSC2-deficient LAM patient-derived cells revealed striking upregulation of Interleukin-6 (IL-6). LAM patient plasma contained increased circulating IL-6 compared with healthy controls, and TSC2-deficient cells showed upregulation of IL-6 transcription and secretion compared to wildtype cells. IL-6 blockade repressed the proliferation and migration of TSC2-deficient cells and reduced oxygen consumption and extracellular acidification. U-13C glucose tracing revealed that IL-6 knockout reduced 3-phosphoserine and serine production in TSC2-deficient cells, implicating IL-6 in de novo serine metabolism. IL-6 knockout reduced expression of phosphoserine aminotransferase 1 (PSAT1), an essential enzyme in serine biosynthesis. Importantly, recombinant IL-6 treatment rescued PSAT1 expression in the TSC2-deficient, IL-6 knockout clones selectively and had no effect on wildtype cells. Treatment with anti-IL-6 (aIL-6) antibody similarly reduced cell proliferation and migration and reduced renal tumors in Tsc2+/- mice, while reducing PSAT1 expression. These data reveal a novel mechanism through which IL-6 regulates serine biosynthesis, with potential relevance to the therapy of tumors with mTORC1 hyperactivity.

Classification

Major category: Biological Sciences Minor category: Cell Biology
Bexarotene derivatives modify responses in acute myeloid leukemia
Authors: Hadwiger Gayla , di Martino Orsola , Ferris Margaret A. , Vu Anh , Frederick Thomas E. , Bowman Gregory R. , Ruminski Peter , Wagner Carl , Welch John S.
Published: May 2021

The retinoids all-trans retinoic acid (ATRA) and bexarotene are active in acute myeloid leukemia (AML), but responses beyond acute promyelocytic leukemia (APL) have been more modest than APL responses. To determine whether chemical modification of bexarotene might augment retinoid responses in AML, we screened a series of 38 bexarotene derivatives for activity in a mouse MLL-AF9 leukemia cell line, which exhibits strong synergistic sensitivity to the combination of ATRA and bexarotene. We found that RXRA potency correlated with anti-leukemic activity and that only one compound (103-4) with dual RARA/RXRA activity was capable of ATRA-independent anti-leukemic activity. We evaluated bioisostere and cyclohexane modifications for potential resistance to P450 metabolism and found that bioisosteres reduced potency and that bezopyran, cyclopentane, and cyclohexene modifications only modestly reduced susceptibility to metabolism. Collectively, these studies provide a map of the structure-activity relationships of bexarotene with outcomes related to RXRA and RARA activity, corepressor binding, compound stability, and anti-leukemic potential.