bluuebunny/crossref_metadata_2025 huggingface dataset:
The ubiquitin E3 ligase SR1 modulates the submergence response by degrading phosphorylated WRKY33 in Arabidopsis
Authors: Liu Bao , Jiang Yuanzhong , Tang Hu , Tong Shaofei , Lou Shangling , Shao Chen , Zhang Junlin , Song Yan , Chen Ningning , Bi Hao , Zhang Han , Li Junhua , Liu Jianquan , Liu Huanhuan
Published: February 2021

Oxygen deprivation caused by flooding activates acclimation responses to stress and restricts plant growth. After experiencing flooding stress, plants must restore normal growth; however, which genes are dynamically and precisely controlled by flooding stress remains largely unknown. Here, we show that the Arabidopsis thaliana ubiquitin E3 ligase SUBMERGENCE RESISTANT1 (SR1) regulates the stability of the transcription factor WRKY33 to modulate the submergence response. SR1 physically interacts with WRKY33 in vivo and in vitro and controls its ubiquitination and proteasomal degradation. Both the sr1 mutant and WRKY33 overexpressors exhibited enhanced submergence tolerance and enhanced expression of hypoxia-responsive genes. Genetic experiments showed that WRKY33 functions downstream of SR1 during the submergence response. Submergence induced the phosphorylation of WRKY33, which enhanced the activation of RAP2.2, a positive regulator of hypoxia-response genes. Phosphorylated WRKY33 and RAP2.2 were degraded by SR1 and the N-degron pathway during reoxygenation, respectively. Taken together, our findings reveal that the on-and-off module SR1-WRKY33-RAP2.2 is connected to the well-known N-degron pathway to regulate acclimation to submergence in Arabidopsis. These two different but related modulation cascades precisely balance submergence acclimation with normal plant growth.
Prospects for Reengineering Agrobacterium tumefaciens for T-DNA Delivery to Chloroplasts
Authors: Matsuoka Aki , Maliga Pal
Published: February 2021

Targeting the phiC31 phage integrase for direct export from Agrobacterium to chloroplasts reveals the feasibility of retargeting the Agrobacterium Vir proteins for T-DNA delivery to chloroplasts.
Parental variation in CHG methylation is associated with allelic-specific expression in elite hybrid rice
Authors: Ma Xuan , Xing Feng , Jia Qingxiao , Zhang Qinglu , Hu Tong , Wu Baoguo , Shao Lin , Zhao Yu , Zhang Qifa , Zhou Dao-Xiu
Published: February 2021

Heterosis refers to the superior performance of hybrid lines over inbred parental lines. Besides genetic variation, epigenetic differences between parental lines are suggested to contribute to heterosis. However, the precise nature and extent of differences between the parental epigenomes and the reprograming in hybrids that govern heterotic gene expression remain unclear. In this work, we analyzed DNA methylomes and transcriptomes of the widely cultivated and genetically studied elite hybrid rice (Oryza sativa) SY63, the reciprocal hybrid, and the parental varieties ZS97 and MH63, for which high-quality reference genomic sequences are available. We showed that the parental varieties displayed substantial variation in genic methylation at CG and CHG (H = A, C, or T) sequences. Compared with their parents, the hybrids displayed dynamic methylation variation during development. However, many parental differentially methylated regions (DMRs) at CG and CHG sites were maintained in the hybrid. Only a small fraction of the DMRs displayed non-additive DNA methylation variation, which, however, showed no overall correlation relationship with gene expression variation. In contrast, most of the allelic-specific expression (ASE) genes in the hybrid were associated with DNA methylation, and the ASE negatively associated with allelic-specific methylation (ASM) at CHG. These results revealed a specific DNA methylation reprogramming pattern in the hybrid rice and pointed to a role for parental CHG methylation divergence in ASE, which is associated with phenotype variation and hybrid vigor in several plant species.
A Randomized, Controlled, Crossover Trial of Virtual Reality in Maintenance Cardiovascular Rehabilitation in a Low-Resource Setting: Impact on Adherence, Motivation, and Engagement
Authors: da Cruz Mayara Moura Alves , Ricci-Vitor Ana Laura , Borges Giovanna Lombardi Bonini , da Silva Paula Fernanda , Turri-Silva Natália , Takahashi Carolina , Grace Sherry L , Vanderlei Luiz Carlos Marques
Published: February 2021

Objective

The purpose of this study was to investigate the effects of adding virtual reality (VR) to maintenance cardiac rehabilitation (CR); it was hypothesized VR would increase adherence, motivation, and engagement.

Methods

This study was a randomized, 1:1 concealed-allocation, single-blinded, 2 parallel-arm, crossover trial. Blinded assessments were undertaken at baseline (midprogram), 12 weeks, and 24 weeks after baseline. The setting was a single CR program of unlimited duration in Brazil. Participants were patients with cardiovascular diseases or risk factors who had been in the program for 3 months or longer. The CR program consisted of 3 supervised exercise sessions per week. In the VR arm, participants had 1 VR session of the 3 per week during the initial 12 weeks of the trial; this was withdrawn the subsequent 12 weeks. Measures were program adherence (% of 3 sessions/week over 12 weeks, ascertained in all participants), motivation (Behavioral Regulation in Exercise Questionnaire 3), and engagement (User Engagement Scale, adapted; vigor, dedication, and absorption subscales); all 3 were primary outcomes.

Results

Sixty-one (83.6%) patients were randomly assigned (n = 30 to CR + VR); 54 (88.5%) were retained at 12 and 24 weeks. At baseline, participants had been in CR on average 7 years and had high engagement and motivation. CR + VR resulted in a significant increase in adherence at 12 weeks (baseline = 72.87%; 12 weeks = 82.80%), with significant reductions at 24 weeks when VR was withdrawn (65.48%); in the usual CR care arm, there were no changes over time. There was a significant effect for arm, with significantly higher adherence in the CR + VR arm than usual CR at 12 weeks (73.51%). Motivation decreased significantly from baseline to 12 weeks (4.32 [SD = 0.37] vs 4.02 [SD = 0.76]) and significantly increased from 12 to 24 weeks in the CR + VR arm (4.37 [SD = 0.36]). Absorption was significantly lower at 12 weeks in the CR + VR arm (6.79 [SD = 0.37] vs 6.20 [SD = 1.01]).

Conclusion

Although VR increased program adherence, interspersing it with usual CR sessions actually decreased patient motivation and absorption.

Impact

Supplementing a maintenance CR program with VR using “exergames” resulted in significantly greater adherence (8% increase or 3 of 36 sessions), and this was quite a robust effect given it was extinguished with the removal of VR. However, contrary to the hypotheses, offering 1 session of VR per week and 2 of usual CR exercise was related to lower motivation and absorption, which has implications for how clinicians design programs for this patient population.
Do Index Funds Monitor?
Authors: Heath Davidson , Macciocchi Daniele , Michaely Roni , Ringgenberg Matthew C
Published: February 2021

Passively managed index funds now hold over 30$\%$ of U.S. equity fund assets; this shift raises fundamental questions about monitoring and governance. We show that, relative to active funds, index funds are less effective monitors: (a) they are less likely to vote against firm management on contentious governance issues; (b) there is no evidence they engage effectively publicly or privately; and (c) they promote less board independence and worse pay-performance sensitivity at their portfolio companies. Overall, the rise of index funds decreases the alignment of incentives between beneficial owners and firm management and shifts control from investors to managers.
Induction of narcolepsy-like symptoms by orexin receptor antagonists in mice
Authors: Kaushik Mahesh K , Aritake Kosuke , Cherasse Yoan , Imanishi Aya , Kanbayashi Takashi , Urade Yoshihiro , Yanagisawa Masashi
Published: February 2021

Orexins/hypocretins are hypothalamic neuropeptides that promote and stabilize wakefulness by binding to the orexin receptor type-1 (OX1R) and type-2 (OX2R). Disruption of orexinergic signaling results in the sleep disorder narcolepsy in mice, rats, dogs, and humans. The orexin receptor antagonist suvorexant promotes sleep by blocking both OX1R and OX2R. Whereas suvorexant has been clinically approved for the treatment of insomnia because it is well tolerated in experimental animals as well as in human patients, a logical question remains as to why orexin receptor antagonists do not induce overt narcolepsy-like symptoms. Here we show that acute and chronic suvorexant promotes both rapid eye movement (REM) and non-rapid eye movement (NREM) sleep without inducing cataplexy in mice. Interestingly, chronic suvorexant increases OX2R mRNA and decreases orexin mRNA and peptide levels, which remain low long after termination of suvorexant administration. When mice are chronically treated with suvorexant and then re-challenged with the antagonist after a 1-week washout, however, cataplexy and sleep-onset REM (SOREM) are observed, which are exacerbated by chocolate administration. Heterozygous orexin knockout mice, with lower brain orexin levels, show cataplexy and SOREM after acute suvorexant administration. Furthermore, we find that acute suvorexant can induce cataplexy and SOREM in wild-type mice when co-administered with chocolate under stress-free (temporally anesthetized) conditions. Taken together, these results suggest that suvorexant can inhibit orexin synthesis resulting in susceptibility to narcolepsy-like symptoms in mice under certain conditions.
Integrating Early Brain Science and Skills Into Prelicensure Nursing Curriculum to Promote Parent-Child Interaction
Authors: Brasher Susan , Becklenberg Amy , Darcy Mahoney Ashley , Ross Kimberly , Stapel-Wax Jennifer L.
Published: February 2021

Background

Research shows that the number of loving words children hear in their first 3 years of life has a tremendous impact on their health, developmental, and literacy outcomes. Early language transactions should be rich in engagement, quantity, quality, and context—a term called language nutrition.

Problem

The curriculum in most nursing programs does not emphasize the importance of early language exposure and ways to empower families to talk with their babies.

Approach

The Talk With Me Baby Curriculum for Nurses, which includes techniques to empower families to better engage conversationally with their babies, was integrated into the prelicensure nursing curriculum.

Outcomes

More than 1,300 nursing students have received knowledge and skills on early language exposure and ways nurses can promote parent-child interactions.

Conclusion

Nurses have the opportunity to empower families to engage with their babies socially, emotionally, and linguistically as a means of promoting healthy brain development.
The Therapeutic Value of Hydralazine in Reducing Inflammatory Response, Oxidative Stress, and Mortality in Animal Sepsis: Involvement of the PI3K/AKT Pathway
Authors: Santos Danillo Menezes dos , Da Silva Eric Aian Pereira , Oliveira Jeferson Yuri Santos , Marinho Yandra Yssa de Menezes , Santana Izabel Rodrigues de , Heimfarth Luana , Pereira Erik Willyame Menezes , Júnior Lucindo José Quintans , Assreuy Jamil , Menezes Igor Alexandre Cortes , Santos Márcio Roberto Viana dos
Published: February 2021

Sepsis is an amplified systemic immune-inflammatory response produced by a microorganism, which involves activation of inflammatory cytokine signaling pathways and oxidative stress. A variety of studies have shown that hydralazine (HDZ) has potent antioxidant and anti-inflammatory proprieties. Therefore, we hypothesize that HDZ can improve the clinical outcome of sepsis. Thus, this work aimed to evaluate therapeutic value of HDZ in reducing inflammatory response, oxidative stress, and mortality in animal sepsis, and to investigate its possible mechanism of action. Sepsis was induced by the cecal ligation and puncture (CLP) method in Wistar rats. After surgery, the animals were randomly divided into three groups: sham, sepsis, and sepsis + HDZ (1 mg/kg, s.c.). All groups were monitored for 48 h to assess survival rate, and clinical, hemodynamic, biochemical, and cellular parameters. After euthanasia, blood, spleen, liver, and kidneys were collected for analysis. Blood serum cytokines, tissue myeloperoxidase (MPO) activity, and oxidative stress parameters were assessed. Involvement of the PI3K/Akt pathway was also investigated. Sepsis was successfully induced by the CLP technique. HDZ treatment increased the survival rate (from 50% to 90%), improved glycemia control, reduced the clinical severity sepsis and mean arterial pressure; and prevented increased MPO activity, TNF-α, IL-1β, IL-10 levels, and oxidative damage markers. Additionally, HDZ significantly prevented the increase of Akt activation in the liver and kidney. HDZ largely mitigated the effects of sepsis by suppressing inflammatory and antioxidant responses via the PI3K/Akt pathway. These findings provide evidence that HDZ can be a new therapeutic alternative for treating sepsis.
Evaluation of rapid antibody test and chest computed tomography results of COVID-19 patients: A retrospective study
Authors: Ozturk Ali , Bozok Taylan , Bozok Tugce Simsek
Published: February 2021

Background

The coronavirus disease 2019 (COVID-19) continues to spread around the world. Therefore, rapid, simpler, and more accurate diagnostic tests are urgently needed to diagnose the Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) infection. The purpose of this study was to evaluate the SARS-CoV-2 IgM/ IgG rapid antibody test results in symptomatic patients with COVID-19 and their chest computed tomography (CT) data.

Methods

A total of 320 patients admitted to our hospital for different durations due to COVID-19 were included in the study. Serum samples were obtained within 0 to 7 days from COVID-19 patients confirmed by RT-PCR and chest CT scan. According to the SARS-CoV-2 RT-PCR results, the patients included in the study were divided into two groups: PCR positive group (n=46), and PCR negative group (n=274).

Results

Of the 320 COVID-19 serum samples, IgM, IgG, and IgM/IgG were detected in 9.4%, 3.1%, and 17.8% within one week respectively. IgG/IgM antibodies were not detected in 69.7% of the patients. In the study, it was determined that 249 (77.8%) of 320 patients had positive chest CT scans. Four (5.6%) of 100 patients with negative chest CT scan had IgM positive and 2 (2.8%) had both IgM/ IgG positive. IgM was detected in 23 (9.2%), IgG in 1 (0.4%) and IgM/IgG in 35 (14%) of chest CT scan positive patients. The rate of CT findings in patients with antibody positivity (n=97) was found to be significantly higher than those with antibody negativity.

Conclusions

The results of the present study show the accurate and equivalent performance of serological antibody assays and chest CT in detecting SARS-CoV-2 0 to 7 days from the onset of COVID19 symptoms. When the RT-PCR is not available, we believe that the combination of immunochromatographic test and chest CT scan can increase diagnostic sensitivity for COVID-19.
Viral genetic sequencing identifies staff transmission of COVID-19 is important in a community hospital outbreak
Authors: Masoli Jane A.H. , Jeffries Aaron , Temperton Ben , Auckland Cressida , Michelsen Michelle , Warwick-Dugdale Joanna , Manley Robyn , Farbos Audrey , Ellard Sian , Knight Beatrice , Bewshea Claire , Sambles Christine , Harrison James , Bunce Ben , Carr Alexis , Hattersley Andrew T. , Michell Stephen Ll. , Studholme David J.
Published: February 2021

Background

We have successfully used whole-genome sequencing to provide additional information for transmission pathways in infectious spread. We report and interpret genomic sequencing results in clinical context from a large outbreak of COVID-19 with 46 cases across staff and patients in a community hospital in the UK.

Methods

Following multiple symptomatic cases within a two-week period, all staff and patients were screened by RT-PCR and staff subsequently had serology tests.

Results

Thirty staff (25%) and 16 patients (62%) tested positive for COVID-19. Genomic sequencing data showed significant overlap of viral haplotypes in staff who had overlapping shift patterns. Patient haplotypes were more distinct from each other but had overlap with staff haplotypes.

Conclusions

This study includes clinical and genomic epidemiological detail that demonstrates the value of a combined approach. Viral genetic sequencing has identified that staff transmission of COVID-19 was important in this community hospital outbreak.

Key points

Detailed analysis of a large community hospital outbreak in older adults and staff with concurrent clinical and genomic data, including working patterns.

Staff transmission was important in this community hospital outbreak.

We found plausible associations between staff and patient cases.
Delivery of recombinant SARS-CoV-2 envelope protein into human cells
Authors: Hutchison James M. , Capone Ricardo , Luu Dustin D. , Hadziselimovic Arina , Van Horn Wade D. , Sanders Charles R.
Published: February 2021

SARS-CoV-2 envelope protein (S2-E) is a conserved membrane protein that is essential to coronavirus assembly and budding. Here, we describe the recombinant expression and purification of S2-E into amphipol-class amphipathic polymer solutions. The physical properties of amphipols underpin their ability to solubilize and stabilize membrane proteins without disrupting membranes. Amphipol delivery of S2-E to pre-formed planar bilayers results in spontaneous membrane integration and formation of viroporin ion channels. Amphipol delivery of the S2-E protein to human cells results in membrane integration followed by retrograde trafficking to a location adjacent to the endoplasmic reticulum-to-Golgi intermediate compartment (ERGIC) and the Golgi, which are the sites of coronavirus replication. Delivery of S2-E to cells enables both chemical biological approaches for future studies of SARS-CoV-2 pathogenesis and development of “Trojan Horse” anti-viral therapies. This work also establishes a paradigm for amphipol-mediated delivery of membrane proteins to cells.
Adequate knowledge of COVID-19 impacts good practices amongst health profession students in the Philippines
Authors: Dalanon Junhel , Redoble Rhomeljustein , Belotindos Jo-Ann , Reyes Candy Delos , Fabillar Jaime , Armero Ma. Shiril , Locsin Rozzano , Suzuki Yoshitaka , Okura Kazuo , Matsuka Yoshizo
Published: February 2021

Background

The spread of the coronavirus disease 2019 (COVID-19) in the Philippines started with its first suspected case on January 22, 2020. The government reacted by imposing several measures including community quarantine, class suspensions, drug therapy and vaccine development, and travel restrictions. This online survey was done amongst Filipino health professions undergraduate students to uncover the relationship between their knowledge, attitude, and practice during this pandemic.

Methods

Cross-sectional data were obtained from an online survey done on students of medicine, dentistry, optometry, rehabilitative sciences, and pharmacy.

Results

At a response rate of 100% (n=1257), the results show that healthcare profession students in the Philippines have good knowledge (87.6%) and practices (63.6%) regarding COVID-19, yet attitude (63.6%) was just passable. This study also shows that a strong correlation exists between knowledge and practice concerning the current pandemic, r(2) = 0.08, P = 0.004.

Conclusion

Adequate knowledge of COVID-19 impacts good practices of avoiding crowded places and misuse of steam inhalation amongst health profession students in the Philippines. Knowledge and practice pertaining to the current pandemic have been found to be good, but attitude remains low.
TGF-β signaling suppresses TCA cycle metabolism in renal cancer
Authors: Nam Hyeyoung , Kundu Anirban , Karki Suman , Brinkley Garrett , Chandrashekar Darshan S. , Kirkman Richard L. , Liu Juan , Liberti Maria V. , Locasale Jason W. , Mitchell Tanecia , Varambally Sooryanarayana , Sudarshan Sunil
Published: February 2021

The Warburg effect is one of most-well studied metabolic phenomenon in cancer cells. For the most part, these studies have focused on enhanced rates of glycolysis observed in various models. The presumption has been that mitochondrial metabolism is suppressed. However, recent studies indicate that the extent of mitochondrial metabolism is far more heterogeneous in tumors than originally presumed. One tumor type with suppression of mitochondrial metabolism is renal cell carcinoma (RCC). Prior studies indicate that suppressed TCA cycle enzyme mRNA expression is associated with aggressive RCC. Yet, the mechanisms that regulate the TCA cycle in RCC remain uncharacterized. Here, we demonstrate that loss of TCA cycle enzyme expression is retained in RCC metastatic tissues. Moreover, proteomic analysis demonstrates that reduced TCA cycle enzyme expression is far more pronounced in RCC relative to other tumor types. Loss of TCA cycle enzyme expression is correlated with reduced expression of the transcription factor peroxisome proliferator-activated receptor gamma coactivator 1-alpha (PGC-1α) which is also lost in RCC tissues. PGC-1α re-expression in RCC cells restores the expression of TCA cycle enzymesin vitroandin vivoand leads to enhanced glucose carbon incorporation into TCA cycle intermediates. Mechanistically, TGF-β signaling, in concert with histone deacetylase 7 (HDAC7), suppresses TCA cycle enzyme expression. In turn, pharmacologic inhibition of TGF-β restores expression of TCA cycle enzyme expression and suppresses tumor growth in an orthotopic model of RCC. Taken together, our findings reveal a novel role for the TGF-β /HDAC7 axis in global suppression of TCA cycle enzymes in RCC and provide novel insight into the molecular basis of altered mitochondrial metabolism in this malignancy.
Direct tissue sensing reprograms TLR4+Tfh-like cells inflammatory profile in the joints of rheumatoid arthritis patients
Authors: Amaral-Silva Daniela , Torrão Rita C. , Torres Rita , Falcão Sandra , Gonçalves Maria João , Araújo Maria Paula , Martins Maria José , Lopes Carina , Neto Agna , Marona José , Costa Tiago , Castelão Walter , Silva Ana Bento , Silva Inês , Lourenço Maria Helena , Mateus Margarida , Gonçalves Nuno Pina , Manica Santiago , Costa Manuela , Pimentel-Santos Fernando , Mourão Ana Filipa , Branco Jaime C. , Soares Helena
Published: February 2021

CD4+T cells mediate rheumatoid arthritis (RA) pathogenesis through both antibody-dependent and independent mechanisms. It remains unclear how synovial microenvironment impinges on CD4+T cells pathogenic functions. Here, we identified a TLR4+follicular helper T (Tfh) cell-like population present in the blood and expanded in synovial fluid. Mechanistically, we unveiled that homotypic T-T cell interactions through non-cognate HLA-DR:TCR contacts regulate TLR4 expression on T cells. TLR4+T cells possess a two-pronged pathogenic activity. Upon TCR and ICOS engagement, TLR4+T cells produce IL-21, a cytokine known to sponsor antibody production. However, direct TLR4+engagement on T cells, by endogenous ligands in the arthritic joint, reprograms them towards an IL-17 inflammatory profile compatible with tissue damage program. Blocking TLR4 signaling with a specific inhibitor impaired IL-17 production in response to synovial fluid recognition. Ex vivo, synovial fluid TLR4+T cells produced IL-17, but not IL-21. TLR4+T cells appear to uniquely reconcile an ability to promote systemic antibody production with a local synovial driven tissue damage program. TLR4+T cells could constitute an attractive cellular target and predictive biomarker for erosive arthritis.
Using Y-chromosome capture enrichment to resolve haplogroup H2 shows new evidence for a two-Path Neolithic expansion to Western Europe
Authors: Rohrlach Adam B. , Papac Luka , Childebayeva Ainash , Rivollat Maïté , Villalba-Mouco Vanessa , Neumann Gunnar U. , Penske Sandra , Skourtanioti Eirini , van de Loosdrecht Marieke , Akar Murat , Boyadzhiev Kamen , Boyadzhiev Yavor , Deguilloux Marie-France , Dobeš Miroslav , Erdal Yilmaz S. , Ernée Michal , Frangipane Marcella , Furmanek Miroslaw , Friederich Susanne , Ghesquière Emmanuel , Hałuszko Agata , Hansen Svend , Küßner Mario , Mannino Marcello , Özbal Rana , Reinhold Sabine , Rottier Stéphane , Salazar-García Domingo Carlos , Soler Diaz Jorge , Stockhammer Philipp W. , de Togores Muñoz Consuelo Roca , Aslihan Yener K , Posth Cosimo , Krause Johannes , Herbig Alexander , Haak Wolfgang
Published: February 2021

Uniparentally-inherited markers on mitochondrial DNA (mtDNA) and the non-recombining regions of the Y chromosome (NRY), have been used for the past 30 years to investigate the history of humans from a maternal and paternal perspective.

Researchers have preferred mtDNA due to its abundance in the cells, and comparatively high substitution rate. Conversely, the NRY is less susceptible to back mutations and saturation, and is potentially more informative than mtDNA owing to its longer sequence length. However, due to comparatively poor NRY coverage via shotgun sequencing, and the relatively low and biased representation of Y-chromosome variants on capture arrays such as the 1240K, ancient DNA studies often fail to utilize the unique perspective that the NRY can yield.

Here we introduce a new DNA enrichment assay, coined YMCA (Y-mappable capture assay), that targets the “mappable” regions of the NRY. We show that compared to low-coverage shotgun sequencing and 1240K capture, YMCA significantly improves the coverage and number of sites hit on the NRY, increasing the number of Y-haplogroup informative SNPs, and allowing for the identification of previously undiscovered variants.

To illustrate the power of YMCA, we show that the analysis of ancient Y-chromosome lineages can help to resolve Y-chromosomal haplogroups. As a case study, we focus on H2, a haplogroup associated with a critical event in European human history: the Neolithic transition. By disentangling the evolutionary history of this haplogroup, we further elucidate the two separate paths by which early farmers expanded from Anatolia and the Near East to western Europe.
Selective MAP1LC3C (LC3C) autophagy requires noncanonical initiation regulators and the paralog-specific C-terminal peptide
Authors: Bischoff Megan E. , Zang Yuanwei , Chou Johnson , Price Adam D. , Ehmer Birgit , Talbot Nicholas J. , Newbold Michael J. , Paul Anurag , Guan Jun-Lin , Plas David R. , Meller Jarek , Czyzyk-Krzeska Maria F.
Published: February 2021

LC3s are canonical proteins necessary for the formation of autophagosomes. We have previously established that two paralogs, LC3B and LC3C, have opposite activities in renal cancer, with LC3B playing oncogenic role and LC3C tumor suppressing role. LC3C is an evolutionary late gene, present only in higher primates and humans. Its most distinct feature is a C-terminal 20 amino acid peptide cleaved in the process of glycine 126 lipidation. Here we investigated mechanisms of LC3C selective autophagy. LC3C autophagy requires noncanonical upstream regulatory complexes that include ULK3, UVRAG, RUBCN, PIK3C2A, and a member of ESCRT, TSG101. We established that Postdivision Midbody Rings (PDMBs) implicated in cancer stem cell regulation are direct targets of LC3C autophagy. LC3C C-terminal peptide is necessary and sufficient to mediate LC3C-dependent selective degradation of PDMBs. This work establishes a new noncanonical human-specific selective autophagic program relevant to cancer stem cells.
The effect of hydrophobic gases on the nervous system of Daphnia magna
Authors: Robledo-Sánchez K. Carlo Martín , Ruiz-Suárez J. C.
Published: February 2021

Hundreds of hydrophobic substances: alkanes, alcohols, benzodiacepines, barbiturates, ethers and even gases, can induce General Anaesthesia (GA) in mammal animals. Moreover, it has been suggested that the primary site of action of such agents is on the spinal cord. Here, we investigate a scenario that is in double measure important to understand the mechanisms behind GA: its induction under water in invertebrate animals. We evaluate the capacity of xenon, nitrous oxide and krypton to suppress harmful sensations, provoked by intense light, in the crustacean D. magna. Due to the hydrophobic characteristics of those gases, we designed a special chamber to force them to dissolve in water at pressures up to to 50 atmospheres, whereas at the same time measure in real time the motility of the animals. Surprisingly, the aquatic animals are immobilized with xenon and nitrous oxide. Under this condition, they don’t respond to a noxious stimulus. Our results are crucial to understand the action of inert gases in GA and the role of the spinal cord.
Drivers of inter-population variation in the gut microbiomes of sister species ofPhanaeusdung beetles
Authors: Winfrey Claire C. , Sheldon Kimberly S.
Published: February 2021

The microbiome plays key roles in host physiology and ecology, but how the microbiome varies among populations of hosts is not well understood. However, different abiotic and biotic selection pressures across a species’ range likely lead to variation in the microbiome. In addition, symbiotic microbiota may differ more between closely-related species in sympatry than in allopatry if selection favors the reduction of interspecific competition. We investigated variation in the maternally-transmitted, beneficial gut microbiomes ofPhanaeus vindexandP. difformis, sister species of dung beetle that compete for the same resources in sympatry and occur across diverse climatic conditions. We sampled and sequenced bacterial/archaeal 16S rDNA from guts ofP. difformisandP. vindexcollected across 17 sympatric and allopatric sites. Gut microbial communities were best predicted by temperature and precipitation, cattle present at sites, and spatial relationships among sites. Contrary to our hypotheses, we did not find that the gut microbial communities ofP. vindexandP. difformisdiffered more in sympatry than in allopatry, nor thatP. vindex, the more broadly distributed of the two species, exhibited greater microbiome turnover among populations. However, the gut microbiome ofP. vindexshifted more between sympatric and allopatric populations than did that ofP. difformis, suggesting character displacement. While more research is needed, it is possible that differences in gut microbial communities allowP. vindexandP. difformisto partition their niches in sympatry. Our work argues for further exploration of the gut microbiome’s potential role in niche partitioning and local adaptation.
Dispersal syndromes affect ecosystem functioning in ciliate microcosms
Authors: Raffard Allan , Campana Julie , Legrand Delphine , Schtickzelle Nicolas , Jacob Staffan
Published: February 2021

Dispersal is a key process mediating ecological and evolutionary dynamics. Its effects on metapopulations dynamics, population genetics or species range distribution can depend on phenotypic differences between dispersing and non-dispersing individuals (i.e., dispersal syndromes). However, scaling up to the importance of dispersal syndromes for meta-ecosystems have rarely been considered, despite intraspecific phenotypic variability is now recognised as an important factor mediating ecosystem functioning. In this study, we characterised the intraspecific variability of dispersal syndromes in twenty isolated genotypes of the ciliateTetrahymena thermophilato test their consequences for biomass productivity in communities composed of fiveTetrahymenaspecies. To do so, dispersers and residents of each genotype were introduced, each separately, in ciliate communities composed of four other competing species of the genusTetrahymenato investigate the effects of dispersal syndromes. We found that introducing dispersers led to a lower biomass compared to introducing residents. This effect was highly consistent across the twentyT. thermophilagenotypes despite their marked differences of dispersal syndromes. Finally, we found a strong genotypic effect on biomass production, confirming that intraspecific variability in general affected ecosystem functions in our system. Our study shows that intraspecific variability and the existence of dispersal syndromes can impact the functioning of spatially structured ecosystems in a consistent and therefore predictable way.
The biosynthesis of phospholipids is linked to the cell cycle in a model eukaryote
Authors: Vítová Milada , Lanta Vojtěch , Čížková Mária , Jakubec Martin , Rise Frode , Halskau Øyvind , Bišová Kateřina , Furse Samuel
Published: February 2021

The structural challenges faced by eukaryotic cells through the cell cycle are key for understanding cell viability and proliferation. In this study, we tested the hypothesis that the biosynthesis of structural lipids is linked to the cell cycle. If true, this would suggest that the cell’s structure would form part the control of the cell cycle. Lipidomics (31P NMR and MS), proteomics (Western immunoblotting) and transcriptomics (RT-qPCR) techniques were used to profile the lipid fraction and characterise aspects of its metabolism at seven stages of the cell cycle of the model eukaryote,Desmodesmus quadricauda. We found considerable, transient increases in the abundance of phosphatidylethanolamine during the G1phase (+35%, ethanolamine phosphate cytidylyltransferase increased 2·5×) and phosphatidylglycerol over the G1/pre-replication phase boundary (+100%, phosphatidylglycerol synthase increased 22×). The relative abundance of phosphatidylcholine fell by ~35% during the G1.N-Methyl transferases for the conversion of phosphatidylethanolamine into phosphatidylcholine were not found in thede novotranscriptome profile, though a choline phosphate transferase was found, suggesting that the Kennedy pathway is the principal route for the synthesis of PC. The fatty acid profiles of the four most abundant lipids suggested that these lipids were not generally converted between one another. The relative abundance of both phosphatidylinositol and its synthase remained constant despite an eightfold increase in cell volume. We conclude that the biosynthesis of the three most abundant structural phospholipids is linked to the cell cycle inD. quadricauda.
Practices and trends in last-mile delivery of poultry vaccines in rural areas in developing countries: the case of Newcastle disease vaccine delivery in Bungoma County, Kenya
Authors: Chemuliti JK. , Ogolla KO. , Mbogoh SG. , Mochabo KM. , Kibore BK
Published: February 2021

Newcastle disease (ND) is the single most important infection of village chicken in smallholder farming systems in developing countries. Vaccines for ND control are available but the delivery of safe and potent vaccines in resource-poor settings remains a big challenge due to difficulties in the maintenance of cold chain. This paper reports the results of a study that was carried out in Kenya to assess the storage and handling practices of Newcastle disease vaccines by agro-veterinary shops (agro-shops) during acquisition, storage, and sale to smallholders’ farmers. Data were collected from one hundred and thirty-two agro-shops using semi-structured questionnaires, observation sheets and actual purchase of vaccines over the counter. The results showed that the majority (82 percent) of the agro-shops had a domestic refrigerator that was connected to the electricity grid but many (61 percent) did not have power backup. Sixty percent of them only stocked thermolabile vaccines. Recurrent power outages (62 percent), high cost of electricity (62 percent), and long-distance to vaccine sources (33 percent) were the most common challenges in vaccine storage and sale. Some agro-shops switched refrigerators on and off while others removed vaccines from refrigerators for overnight stay in cool boxes to minimize electricity costs. In some cases, the sale of vaccines was restricted to market days and late afternoon when ambient temperatures were lower to minimize vaccines storage time and vaccine spoilage respectively. Thermostable vaccines were not stored as recommended by the manufacturer and few agro-shops (23 percent) sold reconstituted vaccines. Most shops adequately packaged thermolabile vaccines in improvised materials during sale. Overall, most of the ND vaccine handling and storage practices in the last mile appeared to aim at safeguarding the safety and potency of vaccines, but further research could elucidate the effects of these practices on the quality and potency of ND vaccines.
Promoting axon regeneration by enhancing the non-coding function of the injury-responsive coding geneGpr151
Authors: Lee Bohm , Lee Jinyoung , Jeon Yewon , Jang Eunsoo , Oh Yeonsoo , Kim Hyemin , Kwon Minjae , Shin Jung Eun , Cho Yongcheol
Published: February 2021

Gene expression profiling in response to nerve injury has been mainly focused on protein functions of coding genes to understand mechanisms of axon regeneration and to identify targets of potential therapeutics for nerve repair. However, the protein functions of several highly injury-induced genes includingGpr151for regulating the regenerative ability remain unclear. Here we present an alternative approach focused on non-coding functions of the coding genes, which led to the identification of the non-coding function ofGpr151RNA interacting with RNA- binding proteins such as CSDE1.Gpr151promotes axon regeneration by the function of its 5’- untranslated region (5’UTR) and expression of an engineered form of the 5’UTR improves regenerative capacity in vitro and in vivo in both sciatic nerve and optic nerve injury models. Our data suggest that searching injury-induced coding genes potentially functioning by their non- coding regions is required for the RNA-based gene therapy for improving axon regeneration.
Insights into the regulatory mechanisms ofClostridioides difficilebiofilm formation
Authors: Buckley Anthony M. , Ewin Duncan , Moura Ines B. , Wilcox Mark H. , Douce Gillian R.
Published: February 2021

Mucosal biofilms play an important role in intestinal health; however, the mucosal bacterial community has been implicated in persistent infections.Clostridioides difficileis an important nosocomial pathogen, with an unacceptable high rate of recurrence following antibiotic treatment. AsC. difficileis a known biofilm producer, a property which may contribute to this suboptimal therapeutic response, we have investigated the transcriptional changes and regulatory pathways during the transition from planktonic to biofilm mode of growth. Widespread metabolic reprogramming during biofilm formation was detected, characterised by an increased usage of glycine metabolic pathways to yield key metabolites, which are used for energy production and synthesis of short chain fatty acids. We detected the expression of 107 small non-coding RNAs that appear to, in some part, regulate these pathways; however, 25 of these small RNAs were specifically expressed during biofilm formation, indicating they may play a role in regulating biofilm-specific genes. Similar toBacillus subtilis, biofilm formation is a multi-regulatory process and SinR negatively regulates biofilm formation independently of other known mechanisms. This comprehensive analysis furthers our understanding of biofilm formation inC. difficile, identifies potential targets for anti-virulence factors, and provides evidence of the link between metabolism and virulence traits.
Gene prioritization based on random walks with restarts and absorbing states, to define gene sets regulating drug pharmacodynamics from single-cell analyses
Authors: Sales-de-Queiroz Augusto , Cruz Guilherme Sales Santa , Jean-Marie Alain , Mazauric Dorian , Roux Jérémie , Cazals Frédéric
Published: February 2021

Prioritizing genes for their role in drug sensitivity, is an important step in understanding drugs mechanisms of action and discovering new molecular targets for co-treatment. To formalize this problem, we consider two sets of genesXandPrespectively composing the predictive gene signature of sensitivity to a drug and the genes involved in its mechanism of action, as well as a protein interaction network (PPIN) containing the products ofXandPas nodes. We introduceGenetrank, a method to prioritize the genes inXfor their likelihood to regulate the genes inP.

Genetrankuses asymmetric random walks with restarts, absorbing states, and a suitable renormalization scheme. Using novel so-called saturation indices, we show that the conjunction of absorbing states and renormalization yields an exploration of the PPIN which is much more progressive than that afforded by random walks with restarts only. Using MINT as underlying network, we applyGenetrankto a predictive gene signature of cancer cells sensitivity to tumor-necrosis-factor-related apoptosis-inducing ligand (TRAIL), performed in single-cells. Our ranking provides biological insights on drug sensitivity and a gene set considerably enriched in genes regulating TRAIL pharmacodynamics when compared to the most significant differentially expressed genes obtained from a statistical analysis framework alone. We also introducegene expression radars, a visualization tool to assess all pairwise interactions at a glance.

Genetrankis made available in the Structural Bioinformatics Library (https://sbl.inria.fr/doc/Genetrank-user-manual.html). It should prove useful for mining gene sets in conjunction with a signaling pathway, whenever other approaches yield relatively large sets of genes.
Notch-Jagged signaling complex defined by an interaction mosaic
Authors: Zeronian Matthieu R. , Klykov Oleg , de Montserrat Júlia Portell i , Konijnenberg Maria J. , Gaur Anamika , Scheltema Richard A. , Janssen Bert J.C.
Published: February 2021

The Notch signaling system links cellular fate to that of its neighbors, driving proliferation, apoptosis, and cell differentiation in metazoans, whereas dysfunction leads to debilitating developmental disorders and cancers. Other than a five-by-five domain complex, it is unclear how the 40 extracellular domains of the Notch1 receptor collectively engage the 19 domains of its canonical ligand Jagged1 to activate Notch1 signaling. Here, using cross-linking mass spectrometry (XL-MS), biophysical and structural techniques on the full extracellular complex and targeted sites,we identify five distinct regions, two on Notch1 and three on Jagged1, that form an interaction network.The Notch1 membrane-proximal regulatory region individually binds to the established Notch1 epidermal growth factor (EGF) 8-13 and Jagged1 C2-EGF3 activation sites, as well as to two additional Jagged1 regions, EGF 8-11 and cysteine-rich domain (CRD). XL-MS and quantitative interaction experiments show that the three Notch1 binding sites on Jagged1 also engage intramolecularly.These interactions, together with Notch1 and Jagged1 ectodomain dimensions and flexibility determined by small-angle X-ray scattering (SAXS), support the formation of backfolded architectures. Combined, the data suggest that critical Notch1 and Jagged1 regions are not distal, but engage directly to control Notch1 signaling, thereby redefining the Notch1-Jagged1 activation mechanism and indicating new routes for therapeutic applications.
A Protein A basedStaphylococcus aureusvaccine with improved safety
Authors: Shi Miaomiao , Chen Xinhai , Sun Yan , Kim Hwan Keun , Schneewind Olaf , Missiakas Dominique
Published: February 2021

Exposure toStaphylococcus aureusdoes not lead to immunity as evidenced by the persistent colonization of one third of the human population.S. aureusimmune escape is mediated by factors that preempt complement activation, destroy phagocytes, and modify B and T cell responses. One such factor, Staphylococcal protein A (SpA) encompasses five Immunoglobulin binding domains (IgBDs) that associate with the Fcγ domain to block phagocytosis. IgBDs also associate with the Fab domain of VH3-idiotypic IgM which activates B cells with the resulting secretion of antibodies that cannot bind determinants ofS. aureus. SpA crosslinking of VH3-idiotypic IgG and IgE receptors of mast cells and basophils promotes histamine release and anaphylaxis. Previous work demonstrated the safety, immunogenicity, and protective efficacy of SpAKKAA,a variant partially defective for VH3-idiotypic Ig cross-linking, in murine models ofS. aureus. Compared to mice (10%), humans produce significantly more VH3-idiotypic B cells (50%), prompting a search for safer SpA variants that may be suitably developed as clinical-grade vaccines for efficacy testing in humans. Here, we report the identification of such variants.
The Size of the Stag Determines the Level of Cooperation
Authors: Schnell Eric , Schimmelpfennig Robin , Muthukrishna Michael
Published: February 2021

In the last 12,000 years, human societies have scaled up from small bands to large states of millions and even billions. Many modern societies and even groups of societies cooperate on large-scale projects with relatively low levels of conflict, but the scale and intensity of cooperation varies dramatically between societies. Here we attempt to formalize dynamics that may be driving this rapid increase in cooperation and the differences we see between societies. Our model extends an N-person stag hunt to include population growth dynamics, “stags” with different sized payoffs, and competition for these stags. An increasing number of cooperators is required to access larger stags. The payoff from these stags in turn increases carrying capacity, which increases competition for the stag. As population size increases, new cooperative thresholds are attainable, and as population size shrinks, previously attainable thresholds fall out of reach. Among other predictions, we show that when a new threshold is accessible to a population, the level of cooperation will increase to reach this threshold. However, when the next threshold is out of reach, cooperation decreases as individuals refrain from costly cooperation, preferring a smaller stag. This model offers a framework for understanding the rapid increase in the scale of human cooperation and decline of violence, differences between societies, and challenges to future cooperation.
Harnessing the Power of Antibodies to Fight Bone Metastasis
Authors: Tian Zeru , Wu Ling , Yu Chenfei , Chen Yuda , Xu Zhan , Bado Igor , Loredo Axel , Wang Lushun , Wang Hai , Wu Kuan-lin , Zhang Weijie , Zhang Xiang H. -F. , Xiao Han
Published: February 2021

Over the past 20 years, antibody-based therapies have proved to be of great value in cancer treatment. Despite the clinical success of these biopharmaceuticals, reaching targets in the bone micro-environment has proved to be difficult perhaps due to the relatively low vascularization of bone tissue and the presence of physical barriers that impair drug penetration. Here, we have used an innovative bone targeting (BonTarg) technology to generate a first-in-class bone-targeting anti-body. Moreover, we have used two xenograft models to demonstrate the enhanced therapeutic efficacy of this bone-targeting antibody against bone metastases, compared to the efficacy of traditional antibodies. Our strategy involves the use of pClick antibody conjugation technology to chemically couple the bone-targeting moiety bisphosphonate to the human epidermal growth factor receptor 2 (HER2)-specific antibody trastuzumab. Bisphosphonate modification of therapeutic antibodies results in delivery of higher conjugate concentrations to the bone metastatic niche, relative to other tissues. In both HER2-positive and negative xenograft mice models, this strategy provides enhanced inhibition of experimental bone metastases as well as multi-organ secondary metastases that arise from the bone lesions. Specific delivery of therapeutic antibodies to the bone therefore represents a promising strategy for the treatment of bone metastatic cancers and other bone diseases.