bluuebunny/crossref_metadata_2025 huggingface dataset:
Induction FOLFOX and PET-Directed Chemoradiation for Locally Advanced Esophageal Adenocarcinoma
Authors: Carr Rebecca A. , Hsu Meier , Harrington Caitlin A. , Tan Kay See , Bains Manjit S. , Bott Matthew J. , Ilson David H. , Isbell James M. , Janjigian Yelena Y. , Maron Steven B. , Park Bernard J. , Rusch Valerie W. , Sihag Smita , Wu Abraham J. , Jones David R. , Ku Geoffrey Y. , Molena Daniela
Published: August 2021

Objective:

To compare the efficacy and safety of induction FOLFOX followed by PET-directed nCRT, induction CP followed by PET-directed nCRT, and nCRT with CP alone in patients with EAC.

Summary of Background Data:

nCRT with CP is a standard treatment for locally advanced EAC. The results of cancer and leukemia group B 80803 support the use of induction chemotherapy followed by PET-directed chemo-radiation therapy.

Methods:

We retrospectively identified all patients with EAC who underwent the treatments above followed by esophagectomy. We assessed incidences of pathologic complete response (pCR), near-pCR (ypN0 with ≥90% response), and surgical complications between treatment groups using Fisher exact test and logistic regression; disease-free survival (DFS) and overall survival (OS) were estimated by the Kaplan–Meier method and evaluated using the log-rank test and extended Cox regression.

Results:

In total, 451 patients were included: 309 (69%) received induction chemotherapy before nCRT (FOLFOX, n = 70; CP, n = 239); 142 (31%) received nCRT with CP. Rates of pCR (33% vs. 16%, P = 0.004), near-pCR (57% vs. 33%, P < 0.001), and 2-year DFS (68% vs. 50%, P = 0.01) were higher in the induction FOLFOX group than in the induction CP group. Similarly, the rate of near-pCR (57% vs. 42%, P = 0.04) and 2-year DFS (68% vs. 44%, P < 0.001) were significantly higher in the FOLFOX group than in the no-induction group.

Conclusions:

Induction FOLFOX followed by PET-directed nCRT may result in better histopathologic response rates and DFS than either induction CP plus PET-directed nCRT or nCRT with CP alone.
Community-based Versus Traditional Research Among Older Minority Women With Urinary Incontinence
Authors: Pearson Sharee , Temple Luisa , Bishop Tonya , Ukaegbu Alice , Alden Jessica , Kwagyan John , Sanses Tatiana V.D.
Published: August 2021

Objective

The aim of this study was to evaluate research retention of older minority women with urinary incontinence (UI) using a community-based participatory research (CBPR) versus a traditional research approach.

Methods

An ancillary prospective study was conducted within an ongoing pilot randomized clinical trial to treat UI. Participants were recruited using CBPR in collaboration with a local community versus a traditional research approach at an academic center. Inclusion criteria were women 65 years and older and symptomatic UI. The primary outcome was the randomization rate defined as the proportion of women randomized into the randomized clinical trial out of screened participants. Screening and consent rates were also evaluated. Pearson χ2, Fisher exact, and t tests were used. The effect of CBPR on research retention rates was expressed as odds ratio (OR) with 95% confidence intervals (CI).

Results

There were 10 and 88 women screened in the CBPR and traditional research groups, respectively. The CBPR participants were Hispanic (n = 10, 100%) and older (78.4 ± 8.3 years; P < 0.01). Most of the traditional research participants were non-Hispanic Black (n = 55, 62.5%) and younger (71.0 ± 4.9 years). The CBPR group had higher rates of screening (76.9% vs 40.6%; P = 0.01), consent (80% vs 44.3%; P = 0.045), and randomization (50.0% vs 14.8%; P < 0.01) compared with the traditional research group. Community-based participatory research increased the odds of research retention during screening (OR, 4.9; 95% CI, 1.3–18.2), consent (OR, 5.0; 95% CI, 1.0–25.0), and randomization (OR, 5.8; 95% CI, 1.5–22.7).

Conclusion

Compared with traditional research, CBPR yielded higher research retention among older minority women with UI in a clinical study.
Steady-State Cortico-Cortical Evoked Potential
Authors: Arihara Masayasu , Enatsu Rei , Ochi Satoko , Sasagawa Ayaka , Hirano Tsukasa , Kuribara Tomoyoshi , Yamada Shoto , Kimura Yusuke , Matsuhashi Masao , Mikuni Nobuhiro
Published: August 2021

Purpose:

The present study evaluated the utility of the steady-state responses of cortico-cortical evoked potentials (SSCCEPs) and compared them with the responses of conventional CCEPs.

Methods:

Eleven patients with medically intractable focal epilepsy who underwent the implantation of subdural electrodes or stereoelectroencephalography were enrolled. Conventional CCEPs were obtained by averaging responses to alternating 1-Hz electrical stimuli, and 5-Hz stimuli were delivered for recording SSCCEPs. The distribution of SSCCEPs was assessed by a frequency analysis of fast Fourier transform and compared with conventional CCEPs.

Results:

Steady-state responses of cortico-cortical evoked potentials were successfully recorded in areas consistent with conventional CCEPs in all patients. However, SSCCEPs were more easily disturbed by the 5-Hz stimulation, and small responses had difficulty generating SSCCEPs.

Conclusions:

Steady-state responses of cortico-cortical evoked potentials may be a useful alternative to conventional CCEPs.
Aurantimonas marina sp. nov., isolated from deep-sea sediment
Authors: Song Lei , Liu Hongcan , Sun Qinglei , Dong Xiuzhu , Zhou Yuguang
Published: August 2021

A novel bacterial strain, designated SW136T, was isolated from a deep-sea sediment sample collected from the South China Sea. Cells were Gram-stain-negative, aerobic, catalase-positive and oxidase-positive. Phylogenetic analysis based on 16S rRNA gene sequences indicated that strain SW136T represented a novel member of the genus

Aurantimonas

, forming a distinct cluster with ‘

Aurantimonas litoralis

’,

Aurantimonas coralicida

and

Aurantimonas manganoxydans

(98.2, 98.1 and 97.9% sequence similarity, respectively). The predominant cellular fatty acid of strain SW136T was C18 : 1
 ω7c. Strain SW136T contained ubiquinone-10 as the dominant respiratory quinone, and diphosphatidylglycerol, phosphatidylcholine, phosphatidylethanolamine and phosphatidylglycerol as the major polar lipids. The genomic DNA G+C content was 64.3 mol%. The average nucleotide identity and digital DNA–DNA hybridization values of strain SW136T with

A. coralicida

CGMCC 1.12222T and

A. manganoxydans

CGMCC 1.12225T were 78.8 and 78.6 % and 21.5 and 25.5 %, respectively. On the basis of phylogenetic inference and phenotypic characteristics, we propose that strain SW136T represents a novel species of the genus

Aurantimonas

, with the name Aurantimonas marina sp. nov. The type strain is SW136T (=CGMCC 1.17725T=KCTC 82366T).
Identification of Haloactinobacterium kanbiaonis sp. nov. and Ruania zhangjianzhongii sp. nov., two novel species of the family Ruaniaceae isolated from faeces of bats (Hipposideros spp.)
Authors: Xu Mingchao , Dai Yan , Huang Yuyuan , Yang Jing , Lai Xin-He , Jin Dong , Lu Shan , Zhou Juan , Zhang Sihui , Bai Yibo , Jiao Yifan , Qiao Lei , Jiang Yan , Xu Jianguo
Published: August 2021

Two pairs of aerobic, Gram-stain-positive, rod-shaped strains (HY164T/HY044, HY168T/HY211) were isolated from bat faecal samples. Strains HY164T and HY044 were motile with a polar flagellum, and had 16S rRNA gene similarity of 95.1–98.6 % to

Haloactinobacterium album

YIM 93306T and

Haloactinobacterium glacieicola

T3246-1T; strains HY168T and HY211 were most similar to

Ruania albidiflava

DSM 18029T (96.6 %). Phylogenetic trees based on 16S rRNA gene and whole genome sequences revealed affiliation of strains HY164T and HY168T to the family

Ruaniaceae

, representing novel lineages in the genera

Haloactinobacterium

and

Ruania

, respectively, which was also supported by the results for average nucleotide identity (ANI) and digital DNA–DNA hybridization (dDDH). For all isolates, the principal cellular fatty acids were anteiso-C15 : 0 and iso-C14 : 0. HY164T and HY168T had MK-8(H4) as the predominant isoprenoid quinone, diphosphatidylglycerol, phosphatidylglycerol, several unidentified phospholipids and glycolipids as common polar lipids while the latter strain additionally contained one unidentified aminophospholipid and one unidentified phosphoglycolipid. Besides sharing alanine, glutamic acid and lysine with HY164T, HY168T additionally contained 2,4-diaminobutyric acid in the cell-wall peptidoglycan. The whole-cell sugars of HY164T were ribose and rhamnose, while HY168T only included the latter. The DNA G+C contents of HY164T and HY168T were 71.0 and 69.1 mol%, respectively. Combining the polyphasic taxonomic data, HY164T (=CGMCC 4.7606T=JCM 33464T) is classified as representing a novel species of the genus

Haloactinobacterium

with the proposed name Haloactinobacterium kanbiaonis sp. nov., and HY168T (=CGMCC 1.16970T=JCM 33465T) is proposed to represent a novel species of the genus

Ruania

with the name Ruania zhangjianzhongii sp. nov.
THE EFFECT OF BARICITINIB USAGE ON THE CLINICAL AND BIOCHEMICAL PROFILES OF COVID-19 PATIENTS- A RETROSPECTIVE OBSERVATIONAL STUDY
Authors: Amarnath Anoop , Das Ananya , Mutya Venakata Sai Shashank , Ibrahim Irfan
Published: August 2021

Introduction

Coronaviruses typically cause influenza like illness which progresses to ARDS along with other systemic manifestations. India is experiencing its second wave with a huge surge in the number of cases exponentially causing huge impact on health care infrastructure and the demand supply chain. As a result several new modalities have been used, one of which is the use of remdesivir and baricitinib . Hence this study is aimed at finding out the clinical and biochemical profile of the patients who have received the combination

Materials and Methods

All the patients who have received the combination meeting the inclusion and exclusion criteria have been included in the study. A total of 31 participants were included and their records were retrospectively analyzed.

Results

There was a significant reduction in the oxygen requirement, CRP and IL-6 levels with p values<0.05. However, in the non-survivors group, there was no statistically significant reduction. Serial monitoring of NLR ratio showed increase towards the fifth day, especially in the non-survivor group it was as high as 41.24. The mortality rate was found to be 10% and the cause being secondary sepsis in all of them.

Conclusion

The ACTT-2 trail has proved the efficacy of the use of the remdesivir and baricitinib combination with mortality benefit. In our study we found similar results which was well co-related with clinical and biochemical parameters like CRP and IL-6 especially in people with co-morbidites.
Emergence of SARS-CoV-2 variant B.1.575.2 containing the E484K mutation in the spike protein in Pamplona (Spain) May-June 2021
Authors: Trobajo-Sanmartín Camino , Miqueleiz Ana , Portillo María Eugenia , Fernández-Huerta Miguel , Navascués Ana , Sara Pilar Sola , Moreno Paula López , Ordoñez Gonzalo R , Castilla Jesús , Ezpeleta Carmen
Published: August 2021

With the emergence of new SARS-CoV-2 variants and the acquisition of novel mutations in exiting lineages, the need to implement methods capable of monitoring viral dynamics arises. We report the emergence and spread of a new SARS-CoV-2 variant within B.1.575 lineage containing the E484K mutation in the spike protein (named B.1.575.2) in a region of Northern Spain between May and June 2021. SARS-CoV-2 positive samples with cycle threshold value less than or equal to 30 were selected to screen of presumptive variants using the TaqPath™ COVID-19 RT-PCR kit and TaqMan™ SARS-CoV-2 Mutation Panel. Confirmation of variants was performed by whole genome sequencing. Of the 200 samples belonging to the B.1.575 lineage, 194 (97%) corresponded to the B.1.575.2 sub-lineage, which was related to the presence of the E484K mutation. Of 197 cases registered in GISAID EpiCoV database as lineage B.1.575.2 194 (99.5%) were identified in Pamplona (Spain).

This report emphasizes the importance of complementing surveillance of SARS-CoV-2 with sequencing for the rapid control of emerging viral variants.
What has changed in the experiences of people with mental health problems during the COVID-19 pandemic? Findings from follow-up interviews using a coproduced, participatory qualitative approach
Authors: Shah Prisha , Hardy Jackie , Birken Mary , Foye Una , Olive Rachel Rowan , Nyikavaranda Patrick , Dare Ceri , Stefanidou Theodora , Schlief Merle , Pearce Eiluned , Lyons Natasha , Machin Karen , Jeynes Tamar , Chipp Beverley , Chhapia Anjie , Barber Nick , Gillard Steven , Pitman Alexandra , Simpson Alan , Johnson Sonia , Lloyd-Evans Brynmor
Published: August 2021

Purpose

We sought to understand how the experiences of people in the UK with pre-existing mental health conditions had developed during the course of the COVID-19 pandemic.

Methods

In September-October 2020 we interviewed adults with mental health conditions pre-dating the pandemic, whom we had previously interviewed three months earlier. Participants had been recruited through online advertising and voluntary sector community organisations. Interviews were conducted by telephone or video-conference by researchers with lived experience of mental health difficulties, and explored changes over time in people’s experience of the pandemic.

Results

We interviewed 44 people, achieving diversity of demographic characteristics and a range of mental health conditions and service use among our sample. Three overarching themes were derived from interviews. The first theme “Spectrum of adaptation”: to difficulties in access to, or the quality of, statutory mental health services, through developing new personal coping strategies or identifying alternative sources of support. The second theme is “Accumulating pressures”: from pandemic-related anxieties and sustained disruption to social contact and support, and to mental health treatment. The third theme “Feeling overlooked”: A sense of people with pre-existing mental health conditions being overlooked during the pandemic by policy-makers at all levels. The latter was compounded for people from ethnic minority communities or with physical health problems.

Conclusion

Our study highlights the need to support marginalised groups who are at risk of increased inequalities, and to maintain crucial mental and physical healthcare and social care for people with existing mental health conditions, notwithstanding challenges of the pandemic.
Functional connectome mediates the association between sleep disturbance and mental health in preadolescence
Authors: Yang Fan Nils , Liu Tina Tong , Wang Ze
Published: August 2021

Background

Sleep disturbance is known to be associated with various mental disorders and typically precedes the onset of mental disorders in youth. Given the increasingly acknowledged bi-directional influence between sleep disturbance and mental disorders, we addressed the possibility of a shared neural mechanism that underlies sleep disturbance and mental disorders in preadolescents.

Methods

We analyzed a dataset of 9350 9-10 year-old children, among whom 8845 had one-year follow-up data, from the Adolescent Brain and Cognitive Development (ABCD) Study. Linear mixed-effects models, mediation analysis, and longitudinal mediation analysis were used.

Results

Out of 338 unique connectivities, the effect of total sleep disturbance (TSP, from Sleep Disturbance Scale) and total problems (TP, from Child Behavior Checklist) converged in the default mode network (DMN) and its anti-correlated dorsal attention network (DAN). Within- and between-network connectivities (DMN-DAN, DMN-DMN, DAN-DAN) mediated the relationship between baseline TSD and TP at one-year follow-up and the relationship between baseline TP and TSD at one-year follow-up. Moreover, the identified network connectivities (DMN-DAN, DAN-DAN) also correlated with the total cognitive composite score from the NIH toolbox.

Conclusions

The pathway model in which sleep disturbance and mental problems affect each other through two anticorrelated brain networks (DMN and DAN) suggests a common neural mechanism between sleep disturbance and mental disorders. A less segregated DMN and DAN is also associated with negative outcomes on mental well-being, sleep disturbance, and cognition. These findings have important implications for the design of prevention and neurofeedback intervention for mental disorders and sleep problems.

Highlights

The impact of sleep disturbance and mental disorders on functional connectivity converged in default mode and dorsal attention networks.

The relationship between sleep disturbance and mental disorders was mediated via a shared brain network mechanism

Sleep disturbance and mental disorders at baseline can each predict the other one year later through the identified network connectivities

A less segregated default mode and dorsal attention networks was correlated with poorer cognitive performance.
Safety Assessment of Broadband Laser Exposure in µOCT
Authors: Spicer Graham L. C. , Child Benjamin , Gardecki Joseph A. , Kumar Aditya , Wartak Andreas , Gregg Abigail , Leung Hui Min , Tearney Guillermo J.
Published: August 2021

Micro-optical coherence tomography (µOCT) improves the spatial resolution of in vivo OCT imaging by utilizing sophisticated focusing schemes and broadband illumination. This study explores the safety of coronary and trachea tissue exposure to µOCT illumination. © 2021 The Authors
Optimizing polymerase chain reaction (PCR) using machine learning
Authors: Cordaro Nicholas J. , Kavran Andrew J. , Smallegan Michael , Palacio Megan , Lammer Nickolaus , Brant Tyler S. , DuMont Vanessa , Garcia Naiara Doherty , Miller Suzannah , Jourabchi Tara , Sawyer Sara L. , Clauset Aaron
Published: August 2021

Despite substantial standardization, polymerase chain reaction (PCR) experiments frequently fail. Troubleshooting failed PCRs can be costly in both time and money. Using a crowdsourced data set spanning 290 real PCRs from six active research laboratories, we investigate the degree to which PCR success rates can be improved by machine learning. While human designed PCRs succeed at a rate of 55–63%, we find that a machine learning model can accurately predict reaction outcome 81% of the time. We validate this level of improvement by then using the model to guide the design and predict the outcome of 39 new PCR experiments. In addition to improving outcomes, the model identifies 15 features of PCRs that researchers did not optimize well compared to the learned model. These results suggest that PCR success rates can easily be improved by 17–26%, potentially saving millions of dollars and thousands of hours of researcher time each year across the scientific community. Other common laboratory methods may benefit from similar data-driven optimization effort.
RADseq data reveal a lack of admixture in a mouse lemur contact zone contrary to previous microsatellite results
Authors: Poelstra Jelmer , Montero B. Karina , Lüdemann Jan , Yang Ziheng , Rakotondranary S. Jacques , Hohenlohe Paul , Stetter Nadine , Ganzhorn Jörg U. , Yoder Anne D.
Published: August 2021

Despite being one of the most fundamental biological processes, the process of speciation remains poorly understood in many groups of organisms. Mouse lemurs are a species-rich genus of small primates endemic to Madagascar, whose diversity has only recently been uncovered using genetic data and is primarily found among morphologically cryptic, allopatric populations. To assess to what extent described species represent reproductively isolated entities, studies are needed in areas where mouse lemur taxa come into contact. Hybridization has previously been reported in a contact zone between two closely related mouse lemur species (Microcebus murinusandM. griseorufus) based on microsatellite data. Here, we revisit this system using RADseq data for populations in, near, and far from the contact zone, including many of the individuals that had previously been identified as hybrids. Surprisingly, we find no evidence for admixed nuclear ancestry in any of the individuals. Re-analyses of microsatellite data and simulations suggest that previously inferred hybrids were false positives and that the programNewHybridscan be particularly sensitive to erroneously inferring hybrid ancestry. Using coalescent-bases analyses, we also show an overall lack of recent gene flow between the two species, and low levels of ancestral gene flow. Combined with evidence for local syntopic occurrence, these data indicate thatM. murinusandM. griseorufusare reproductively isolated. Finally, we estimate that they diverged less than a million years ago, suggesting that completion of speciation is relatively rapid in mouse lemurs. Future work should focus on the underpinnings of reproductive isolation in this cryptic primate radiation, which are mostly unknown. Our study also provides a cautionary tale for the inference of hybridization with microsatellite data.
Transcriptomic and functional analysis of Aβ1-42 oligomer-stimulated human monocyte-derived microglia-like cells
Authors: Smit Tamar , Ormel Paul R. , Sluijs Jacqueline A. , Hulshof Lianne A. , Middeldorp Jinte , de Witte Lot D. , Hol Elly M. , Donega Vanessa
Published: August 2021

Dysregulation of microglial function contributes to Alzheimer’s disease (AD) pathogenesis. Several genetic and transcriptome studies have revealed microglia specific genetic risk factors, and changes in microglia expression profiles in AD pathogenesis, viz. the human-Alzheimer’s microglia/myeloid (HAM) profile in AD patients and the disease-associated microglia profile (DAM) in AD mouse models. The transcriptional changes involve genes in immune and inflammatory pathways, and in pathways associated with Aβ clearance. Aβ oligomers have been suggested to be the initial trigger of microglia activation in AD. To study the direct response to Aβ oligomers exposure, we assessed changes in gene expression in an in vitro model for microglia, the human monocyte-derived microglial-like (MDMi) cells. We confirmed the initiation of an inflammatory profile following LPS stimulation, based on increased expression of IL1B, IL6, and TNFα. In contrast, the Aβ1-42 oligomers did not induce an inflammatory profile or a classical HAM or DAM profile. Interestingly, we observed a specific increase in the expression of metallothioneins in the Aβ1-42 oligomer treated MDMi cells. Metallothioneins are involved in metal ion regulation, protection against reactive oxygen species, and have anti-inflammatory properties. In conclusion, our data suggests that Aβ1-42 oligomers may trigger a protective response both in vitro and in vivo.
Increases in multiple resources promote plant invasion
Authors: Zhang Zhijie , Liu Yanjie , Hardrath Angelina , Jin Huifei , van Kleunen Mark
Published: August 2021

Invasion by alien plants is frequently attributed to increased resource availabilities. Still, our understanding is mainly based on effects of single resources despite the fact that plants rely on multiple resources. How multiple resources affect success of alien plants remains largely unexplored. Here, with two common garden experiments, one in China and one in Germany, we tested whether nutrient and light availabilities affected the competitive outcomes between alien and native plants. We found that under low resource availabilities or with addition of only one type of resource aliens were not more competitive than natives. However, with a joint increase of nutrients and light intensity, aliens outcompeted natives. Our finding indicates that addition of multiple resources could greatly reduce the number of limiting factors (i.e. niche dimensionality), and that this favors the dominance of alien species. It also indicates that habitats experiencing multiple global changes might be more vulnerable to plant invasion.
SUMOylation of Jun fine-tunes the Drosophila gut immune response
Authors: Soory Amarendranath , Ratnaparkhi Girish
Published: August 2021

Post-translational modification by the small ubiquitin-like modifier, SUMO can modulate the activity of its conjugated proteins. The transcriptional regulator Jun, a member of the AP-1, complex is one such SUMO target. We find that Jra, the Drosophila Jun ortholog, is a regulator of the Pseudomonas entomophila induced gut immune gene regulatory network, modulating the expression of a few thousand genes, as measured by quantitative RNA sequencing. Decrease in Jra in gut enterocytes is protective, suggesting that reduction of Jra signaling favors the host over the pathogen. In Jra, lysines 29 and 190 are SUMO conjugation targets, with the JraK29R+K190R double mutant being SUMO conjugation resistant (SCR). Interestingly, a JraSCR fly line, generated by CRISPR/Cas9 based genome editing, is more sensitive to infection, with adults showing a weakened host response and increased proliferation of Pseudomonas. Transcriptome analysis of the guts of JraSCR and JraWT flies suggests that lack of SUMOylation of Jra significantly changes core elements of the immune gene regulatory network, that include antimicrobial agents, secreted ligands, feedback regulators, and transcription factors. SUMOylation attenuates Jra activity, with the master immune regulator Relish being an important transcriptional target. Our study implicates Jra as a major immune regulator, with dynamic SUMO conjugation/deconjugation modulating the kinetics of the gut transcriptional immune response.
Sphingosine 1-Phosphate Mediates Adiponectin Receptor Signaling Essential For Lipid Homeostasis And Embryogenesis
Authors: Ruiz Mario , Devkota Ranjan , Panagaki Dimitra , Bergh Per-Olof , Kaper Delaney , Henricsson Marcus , Nik Ali , Petkevicius Kasparas , Höög Johanna L. , Bohlooly-Y Mohammad , Carlsson Peter , Borén Jan , Pilon Marc
Published: August 2021

Cells and organisms require proper membrane composition to function and develop. Phospholipids are the major component of membranes and are primarily acquired through the diet. Given great variability in diet composition, cells must be able to deploy mechanisms that correct deviations from optimal membrane composition and properties. Here, using lipidomics and unbiased proteomics, we found that the embryonic lethality in mice lacking the fluidity regulators Adiponectin Receptors 1 and 2 (AdipoR1/2) is associated with aberrant high saturation of the membrane phospholipids. Using mouse embryonic fibroblasts (MEFs) derived from AdipoR1/2-KO embryos, human cell lines and the model organismC. eleganswe found that, mechanistically, AdipoR1/2-derived sphingosine 1-phosphate (S1P) signals in parallel through S1PR3-SREBP1 and PPARγ to sustain the expression of the fatty acid desaturase SCD and maintain membrane properties. Thus, our work identifies an evolutionary conserved pathway by which cells and organism achieve membrane homeostasis and adapt to a variable environment.
Heterochromatin rewiring and domain disruption-mediated chromatin compaction during erythropoiesis
Authors: Li Dong , Wu Fan , Zhou Shuo , Huang Xiao-Jun , Lee Hsiang-Ying
Published: August 2021

Development of mammalian red blood cells involves progressive chromatin compaction and subsequent enucleation in terminal stages of differentiation, but the molecular mechanisms underlying the three-dimensional chromatin reorganization and compaction remains obscure. Here, we systematically analyze the distinct features of higher-order chromatin in purified populations of primary human erythroblasts. Our results reveal that while heterochromatin regions undergo substantial compression, select transcription competent regions with active transcription signature are preferentially maintained to achieve a highly-compacted yet functional chromatin state in terminal erythropoiesis, which is about 20-30% of the nuclear volume compared to that of erythroid progenitors. While the partition of euchromatic and heterochromatic regions (compartment A and B) remain mostly unchanged, H3K9me3 marks relocalize to the nuclear periphery and a significant number of H3K9me3 long-range interactions are formed in the three-dimensional rewiring during terminal erythroid chromatin condensation. Moreover, ∼63% of the topologically associating domain (TAD) boundaries are disrupted, while certain TADs with active chromatin modification are selectively maintained during terminal erythropoiesis. The most well-maintained TADs are enriched for chromatin structural factors CTCF and SMC3, as well as factors and marks of the active transcription state. Finally, we demonstrate that the erythroid master regulator GATA1 involves in safeguarding select essential chromatin domains during terminal erythropoiesis. Our study therefore delineate the molecular characteristics of a development-driven chromatin compaction process, which reveals transcription competence as a key determinant of the select domain maintenance to ensure appropriate gene expression during immense chromatin compaction.
Temperature and nutrients drive eco-phenotypic dynamics in a microbial food web
Authors: Han Ze-Yi , Wieczynski Daniel J. , Yammine Andrea , Gibert Jean P.
Published: August 2021

Anthropogenic increases in temperature and nutrient loads will likely impact food web structure and stability. Although their independent effects have been reasonably well studied, their joint effects—particularly on coupled ecological and phenotypic dynamics—remain poorly understood. Here we experimentally manipulated temperature and nutrient levels in microbial food webs and used time-series analysis to quantify the strength of reciprocal effects between ecological and phenotypic dynamics across trophic levels. We found that i) joint –often interactive– effects of temperature and nutrients on ecological dynamics are more common at higher trophic levels, ii) temperature and nutrients interact to shift the relative strength of top-down vs. bottom-up control, and iii) rapid phenotypic change mediates observed ecological responses to changes in temperature and nutrients. Our results uncover how feedbacks between ecological and phenotypic dynamics mediate food web responses to environmental change. This suggests important but previously unknown ways that temperature and nutrients might jointly control the rapid eco-phenotypic feedbacks that determine food web dynamics in a changing world.
A GGDEF domain serves as a spatial on-switch for a phosphodiesterase by direct interaction with a polar landmark protein
Authors: Rick Tim , Kreiling Vanessa , Höing Alexander , Fiedler Svenja , Glatter Timo , Steinchen Wieland , Hochberg Georg , Bähre Heike , Seifert Roland , Bange Gert , Knauer Shirley K. , Graumann Peter L. , Thormann Kai M.
Published: August 2021

In bacteria, the monopolar localization of enzymes and protein complexes can result in a bi-modal distribution of enzyme activity between the dividing cells and heterogeneity of cellular behaviors. In Shewanella putrefaciens, the multidomain hybrid diguanylate cyclase/phosphodiesterase PdeB, which degrades the secondary messenger c-di-GMP, is located at the flagellated cell pole. Here we show how PdeB polar recruitment is mediated by direct interaction between the inactive diguanylate cyclase (GGDEF) domain of PdeB and the C-terminal FimV domain of the polar landmark protein HubP. We demonstrate that this interaction is crucial for full function of PdeB as a phosphodiesterase. Thus, the GGDEF domain serves as a spatially controlled on-switch that effectively restricts PdeBs activity to the flagellated cell pole. We further show that PdeB regulates abundance and activity of at least two crucial surface-interaction factors, the BpfA surface adhesion protein and the MSHA type IV pilus. The heterogeneity in c-di-GMP concentrations that is generated by differences in abundance and temporal polar appearance of PdeB as well as by bi-modal distribution after cell fission orchestrates the population behavior with respect to cell-surface interaction and environmental spreading.

Significance

Phenotypic heterogeneity benefits the proliferation of microbial populations in changing environments. Such heterogeneity can be created by recruitment of enzymatic activity to specific cellular compartments, e.g., the cell pole. Here we show how a GGDEF domain of a multidomain phosphodiesterase has adopted the function as a spatial on-switch that is specifically activated upon direct interaction with a polar landmark protein.
wnt16regulates spine and muscle morphogenesis through parallel signals from notochord and dermomyotome
Authors: Watson Claire J. , Tang W. Joyce , Rojas Maria F. , Fiedler Imke A.K. , de Oca Ernesto Morfin Montes , Cronrath Andrea R. , Callies Lulu K. , Swearer Avery Angell , Ahmed Ali R. , Sethuraman Visali , Addish Sumaya , Farr Gist H. , Gomez Arianna E. , Rai Jyoti , Monstad-Rios Adrian T. , Gardiner Edith M. , Karasik David , Maves Lisa , Busse Bjorn , Hsu Yi-Hsiang , Kwon Ronald Young
Published: August 2021

Bone and muscle interact through developmental, mechanical, paracrine, and autocrine signals. Genetic variants at theCPED1-WNT16locus are dually associated with bone- and muscle-related traits. WhileWnt16is necessary for bone mass and strength, this fails to explain pleiotropy at this locus. Here, we showwnt16is required for spine and muscle morphogenesis in zebrafish. In embryos,wnt16is expressed in dermomyotome and developing notochord, and contributes to larval myotome morphology and notochord elongation. Later,wnt16is expressed at the ventral midline of the notochord sheath, and contributes to spine mineralization and osteoblast recruitment. Morphological changes inwnt16mutant larvae are mirrored in adults, indicating thatwnt16impacts bone and muscle morphology throughout the lifespan. Finally, we show thatwnt16is a gene of major effect on lean mass at theCPED1-WNT16locus. Our findings indicate that Wnt16 is secreted in structures adjacent to developing bone (notochord) and muscle (dermomyotome) where it affects the morphogenesis of each tissue, thereby renderingwnt16expression into dual effects on bone and muscle morphology. This work expands our understanding ofwnt16in musculoskeletal development and supports the potential for variants to act throughWNT16to influence bone and muscle via parallel morphogenetic processes.

AUTHOR SUMMARY

In humans, genetic variants (DNA sequences that vary amongst individuals) have been identified that appear to influence bone and skeletal muscle mass. However, how single genes and genetic variants exert dual influence on both tissues is not well understood. In this study, we found a gene calledwnt16is necessary for specifying the size and shape of muscle and bone during development in zebrafish. Moreover, we disentangled howwnt16affects both tissues: distinct cellular populations adjacent to muscle and bone secrete Wnt16, where it acts as a signal this guides the size and shape of each tissue. This is important because in humans, genetic variants near theWNT16gene have effects on both bone- and muscle-related traits. This study expands our understanding of the role ofWNT16in bone and muscle development, and helps to explain how genetic variants nearWNT16affect traits for both tissues. Moreover, WNT16 is actively being explored as a target for osteoporosis therapies; our study could have implications with regard to the potential to target WNT16 to treat bone and muscle simultaneously.
Structure of benzothiadiazine at zwitterionic phospholipid cell membranes
Authors: Hu Zheyao , Martí Jordi , Lu Huixia
Published: August 2021

The use of drugs derived from benzothiadiazine, which is a bicyclic heterocyclic benzene derivative, has become a widespread treatment for diseases such as hypertension (treated with diuretics such as bendroflumethiazide or chlorothiazide), low blood sugar (treated with non-diuretic diazoxide) or the human immunodeficiency virus, among others. In this work we have investigated the interactions of benzothiadiazine with the basic components of cell membranes and solvents such as phospholipids, cholesterol, ions and water. The analysis of the mutual microscopic interactions is of central importance to elucidate the local structure of benzothiadiazine as well as the mechanisms responsible for the access of benzothiadiazine to the interior of the cell. We have performed molecular dynamics simulations of benzothiadiazine embedded in three different model zwitterionic bilayer membranes made by dimyristoilphosphatidylcholine, dioleoylphosphatidylcholine, 1,2-dioleoyl-sn-glycero-3-phosphoserine and cholesterol inside aqueous sodium-chloride solution in order to systematically examine microscopic interactions of benzothiadiazine with the cell membrane at liquid-crystalline phase conditions. From data obtained through radial distribution functions, hydrogen-bonding lengths and potentials of mean force based on reversible work calculations, we have observed that benzothiadiazine has a strong affinity to stay at the cell membrane interface although it can be fully solvated by water in short periods of time. Furthermore, benzothiadiazine is able to bind lipids and cholesterol chains by means of single and double hydrogen-bonds of different characteristic lengths.
Phylogenetic reconciliation reveals extensive ancestral recombination in Sarbecoviruses and the SARS-CoV-2 lineage
Authors: Zaman Sumaira , Sledzieski Samuel , Berger Bonnie , Wu Yi-Chieh , Bansal Mukul S.
Published: August 2021

An accurate understanding of the evolutionary history of rapidly-evolving viruses like SARS-CoV-2, responsible for the COVID-19 pandemic, is crucial to tracking and preventing the spread of emerging pathogens. However, viruses undergo frequent recombination, which makes it difficult to trace their evolutionary history using traditional phylogenetic methods. Here, we present a phylogenetic workflow, virDTL, for analyzing viral evolution in the presence of recombination. Our approach leverages reconciliation methods developed for inferring horizontal gene transfer in prokaryotes, and, compared to existing tools, is uniquely able to identify ancestral recombinations while accounting for several sources of inference uncertainty, including in the construction of a strain tree, estimation and rooting of gene family trees, and reconciliation itself. We apply this workflow to theSarbecovirussubgenus and demonstrate how a principled analysis of predicted recombination gives insight into the evolution of SARS-CoV-2. In addition to providing confirming evidence for the horseshoe bat as its zoonotic origin, we identify several ancestral recombination events that merit further study.
Lipid Tails Modulate Antimicrobial Peptide Membrane Incorporation and Activity
Authors: Walker Lawrence R. , Marty Michael T.
Published: August 2021

Antimicrobial peptides (AMPs) are cationic, amphipathic peptides that interact directly with lipid bilayers. AMPs generally interact with anionic lipid head groups, but it is less clear how the lipid tail length and saturation modulates interactions with membranes. Here we used native mass spectrometry to measure the stoichiometry of three different AMPs—LL-37, indolicidin, and magainin-2—in lipid nanodiscs. We also measured the activity of these AMPs in large unilamellar vesicle leakage assays. We found that LL-37 formed specific hexamer complexes but with different assembly pathways and affinities that depended on the bilayer thickness. LL-37 was also most active in lipid bilayers containing longer, unsaturated lipids. In contrast, indolicidin incorporated to a higher degree into more fluid lipid bilayers but was more active with thinner, less fluid bilayers. Finally, magainin-2 incorporated to a higher degree into longer, unsaturated bilayers and showed more activity in these same conditions. Together, these data show that higher amounts of peptide incorporation generally led to higher activity and that AMPs tend to incorporate more into longer unsaturated lipid bilayers. However, the activity of AMPs was not always directly related to amount of peptide incorporated.

Graphical Abstract
Temporal properties of painful contrast enhancement using repetitive stimulation
Authors: Szikszay Tibor M. , Adamczyk Waclaw M. , Lévénez Juliette L. M. , Gouverneur Philip , Luedtke Kerstin
Published: August 2021

Offset analgesia is characterized by a disproportionately large reduction in pain following a small decrease in a heat stimulus and is based on the phenomenon of temporal pain contrast enhancement (TPCE). The aim of this study is to investigate whether this phenomenon can also be induced by repetitive stimulation, i.e., by stimuli that are clearly separated in time. With this aim, the repetitive TPCE paradigm was induced in healthy, pain-free subjects (n=33) at the volar non-dominant forearm using heat stimuli. This paradigm was performed applying three different interstimulus intervals (ISIs): 5, 15, and 25 seconds. All paradigms were contrasted with a control paradigm without temperature change. Participants continuously rated the perceived pain intensity. In addition, electrodermal activity was recorded as a surrogate measure of autonomic arousal. Temporal pain contrast enhancement was confirmed for both ISI 5 seconds (p < 0.001) and ISI 15 seconds (p = 0.005), but not for ISI 25 seconds (p = 0.07), however the magnitude of TPCE did not differ between ISIs (p = 0.11). Electrodermal activity was consistent previous pain ratings, but showing significantly higher autonomic activity being measured. Thus, the phenomenon of temporal contrast enhancement of pain can also be induced by repetitive stimulation. Both the involvement of the autonomic nervous system and the involvement of habituation processes are conceivable, which consequently points to both central and peripheral mechanisms of TPCE.

The temporal contrast enhancement of pain and electrodermal activity can be provoked by stimuli that are clearly separated in time.
Identification of a MarR subfamily that regulates arsenic resistance genes
Authors: Yu Yanshuang , Feng Renwei , Chen Jichen , Li Yuanping , Liang Jinxuan , Xie Zhenchen , Alwathnani Hend A. , Rosen Barry P. , Grove Anne , Chen Jian , Rensing Christopher
Published: August 2021

Members of the family of Multiple Antibiotic Resistance Regulators (MarR) often regulate genes that encode antibiotic resistance in bacteria. In this study, comprehensive analyses were performed to determine the function of an atypical MarR homolog in Achromobacter sp. As-55. Genomic analyses showed that this marR is located in an arsenic gene island in Achromobacter sp. As-55 adjacent to an arsV gene. ArsV is a flavin-dependent monooxygenase that confers resistance to the antibiotic methylarsenite (MAs(III)), the organoarsenic compound roxarsone(III) (Rox(III)), and the inorganic antimonite (Sb(III)). Similar marR genes are widely distributed in arsenic-resistant bacteria. Phylogenetic analyses showed that these MarRs are found in operons predicted to be involved in resistance to inorganic and organic arsenic species, so the subfamily was named MarRars. MarRars orthologs have three conserved cysteine residues, which are Cys36, Cys37 and Cys157 in Achromobacter sp. As-55, mutation of which compromises the response to MAs(III)/Sb(III). GFP-fluorescent biosensor assays show that AdMarRars (MarR protein of Achromobacter deleyi As-55) responds to trivalent As(III) and Sb(III) but not to pentavalent As(V) or Sb(V). The results of RT-qPCR assays show that arsV is expressed constitutively in a marR deletion mutant, indicating that marR represses transcription of arsV. Moreover, electrophoretic mobility shift assays (EMSA) demonstrate that AdMarRars binds to the promoters of both marR and arsV in the absence of ligands and that DNA binding is relieved upon binding of As(III) and Sb(III). Our results demonstrate that AdMarRars is a novel As(III)/Sb(III)-responsive transcriptional repressor that controls expression of arsV, which confers resistance to MAs(III), Roxarsone(III) and Sb(III). AdMarRars and its orthologs form a subfamily of MarR proteins that regulate genes conferring resistance to arsenic-containing antibiotics.

IMPORTANCE

In this study, a MarR family member, AdMarRars was shown to regulate the arsV gene, which confers resistance to arsenic-containing antibiotics. It is a founding member of a distinct subfamily that we refer to as MarRars, regulating genes conferring resistance to arsenic and antimony antibiotic compounds. AdMarRars was shown to be a repressor containing conserved cysteine residues that are required to bind As(III) and Sb(III), leading to a conformational change and subsequent derepression. Here we show that members of the MarR family are involved in regulating arsenic-containing compounds.
A mathematical framework for analyzing wild tomato root architecture
Authors: Chandrasekhar Arjun , Julkowska Magdalena M
Published: August 2021

The root architecture of wild tomato, Solanum pimpinellifolium, can be viewed as a network connecting the main root to various lateral roots. Several constraints have been proposed on the structure of such biological networks, including minimizing the total amount of wire necessary for constructing the root architecture (wiring cost), and minimizing the distances (and by extension, resource transport time) between the base of the main root and the lateral roots (conduction delay). For a given set of lateral root tip locations, these two objectives compete with each other — optimizing one results in poorer performance on the other — raising the question how well S. pimpinellifolium root architectures balance this network design trade-off in a distributed manner. Here, we describe how well S. pimpinellifolium roots resolve this trade-off using the theory of Pareto optimality. We describe a mathematical model for characterizing the network structure and design trade-offs governing the structure of S. pimpinellifolium root architecture. We demonstrate that S. pimpinellifolium arbors construct architectures that are more optimal than would be expected by chance. Finally, we use this framework to quantify structural differences between arbors grown in the presence of salt stress, classify arbors into four distinct architectural ideotypes, and test for heritability of variation in root architecture structure.