bluuebunny/crossref_metadata_2025 huggingface dataset:
Depletion of m-type thioredoxin impairs photosynthesis, carbon fixation, and oxidative stress in cyanobacteria
Authors: Mallén-Ponce Manuel J , Huertas María José , Sánchez-Riego Ana María , Florencio Francisco J
Published: July 2021

Thioredoxins (Trxs) are disulfide oxidoreductases that regulate many biological processes. The m-type thioredoxin (TrxA) is the only Trx present in all oxygenic photosynthetic organisms. Extensive biochemical and proteomic analyses have identified many TrxA target proteins in different photosynthetic organisms. However, the precise function of this essential protein in vivo is still poorly known. In this study, we generated a conditional Synechocystis sp. PCC 6803 mutant strain (STXA2) using an on-off promoter that is able to survive with only 2% of the TrxA level of the wild-type (WT) strain. STXA2 characterization revealed that TrxA depletion results in growth arrest and pronounced impairment of photosynthesis and the Calvin–Benson–Bassham (CBB) cycle. Analysis of the in vivo redox state of the bifunctional enzyme fructose-1,6-bisphosphatase/sedoheptulose-1,7-bisphosphatase showed higher levels of oxidation that affected enzyme activity in STXA2. This result implies that TrxA-mediated redox regulation of the CBB cycle is conserved in both cyanobacteria and chloroplasts, although the targets have different evolutionary origins. The STXA2 strain also accumulated more reactive oxygen species and was more sensitive to oxidative stress than the WT. Analysis of the in vivo redox state of 2-Cys peroxiredoxin revealed full oxidation, corresponding with TrxA depletion. Overall, these results indicate that depletion of TrxA in STXA2 greatly alters the cellular redox state, interfering with essential processes such as photosynthetic machinery operativity, carbon assimilation, and oxidative stress response. The TrxA regulatory role appears to be conserved along the evolution of oxygenic photosynthetic organisms.
Two-loop scalar functions with I internal lines, $I \le 5$
Authors: Guillet J Ph , Pilon E , Shimizu Y , Zidi M S
Published: July 2021

This article displays a proof of concept of the mixed analytical/numerical method, presented in previous publications, to compute two-loop functions with up to five massive propagators in a scalar theory having three- and four-leg vertices as the Higgs sector of the Standard Model. Several amplitudes are considered with two, three, and four external legs. Some of them diverge in the ultraviolet region and we demonstrate that the method works in that case. It is shown that all these classes of amplitudes can be generated by four master topologies. The results of a numerical evaluation for some kinematics are presented; they are compared to public software and agree well within the error bars quoted by the different programs.
Intermediaries and Asset Prices: International Evidence since 1870
Authors: Baron Matthew , Muir Tyler
Published: July 2021

We study data on commercial banks and securities firms across multiple countries since 1870. Balance sheet expansion of leveraged intermediaries negatively predicts returns of stocks, bonds, currencies, and housing. The predictability is stronger at shorter horizons, is robust to macroeconomic controls, and holds outside distress periods, in contrast to models featuring nonlinearities during distress. Intermediaries in global financial centers predict international equity returns. A new data set on individual stock holdings of Japanese intermediaries since 1955 shows intermediaries affect returns of stocks directly held. Our results suggest a strong universal link between intermediaries and asset returns distinct from macroeconomic channels.
Evidence and consensus-based recommendations for non-pharmacological treatment of fatigue, hand function loss, Raynaud’s phenomenon and digital ulcers in patients with systemic sclerosis
Authors: Stöcker Juliane K , Schouffoer Anne A , Spierings Julia , Schriemer Marisca R , Potjewijd Judith , de Pundert Lian , van den Hoogen Frank H J , Nijhuis-van der Sanden Maria W G , Staal J Bart , Satink Ton , Vonk Madelon C , van den Ende Cornelia H M ,   the Arthritis Research and Collaboration Hub study group
Published: July 2021

Objective

SSc is a complex CTD affecting mental and physical health. Fatigue, hand function loss, and RP are the most prevalent disease-specific symptoms of systemic sclerosis. This study aimed to develop consensus and evidence-based recommendations for non-pharmacological treatment of these symptoms.

Methods

A multidisciplinary task force was installed comprising 20 Dutch experts. After agreeing on the method for formulating the recommendations, clinically relevant questions about patient education and treatments were inventoried. During a face-to-face task force meeting, draft recommendations were generated through a systematically structured discussion, following the nominal group technique. To support the recommendations, an extensive literature search was conducted in MEDLINE and six other databases until September 2020, and 20 key systematic reviews, randomized controlled trials, and published recommendations were selected. Moreover, 13 Dutch medical specialists were consulted on non-pharmacological advice regarding RP and digital ulcers. For each recommendation, the level of evidence and the level of agreement was determined.

Results

Forty-one evidence and consensus-based recommendations were developed, and 34, concerning treatments and patient education of fatigue, hand function loss, and RP/digital ulcers-related problems, were approved by the task force.

Conclusions

These 34 recommendations provide guidance on non-pharmacological treatment of three of the most frequently described symptoms in patients with systemic sclerosis. The proposed recommendations can guide referrals to health professionals, inform the content of non-pharmacological interventions, and can be used in the development of national and international postgraduate educational offerings.
STATUS OF RADIATION DOSE LEVELS IN PAEDIATRIC CHEST RADIOGRAPHY IN A TERTIARY HOSPITAL IN GHANA
Authors: Anim-Sampong Samuel , Arthur Lawrence , Boahen Enock , Botwe Benard Ohene
Published: July 2021

Determination of appropriate radiation doses to paediatric patients in accordance with the as low as reasonably achievable (ALARA) principle is important, as it allows for effective optimization of imaging techniques. This study assessed the status of radiation dose levels in paediatric patients undergoing chest X-ray examinations at a tertiary hospital in Ghana. A population encompassing 86 paediatric patients categorised as infants (<1 y), young children (1-5 y) and older children (6–12 y) was selected using a quasi-experimental study design. The patients’ anatomical data and X-ray beam exposure parameters were used to indirectly calculate the entrance surface doses (ESDs) received during the examinations. The infants received the highest mean ESD of 196 μGy (uncertainty = 0.37) compared to 158 μGy (uncertainty = 0.46) among the older children. The risk of developing radiation-induced biological effects was therefore higher for infant patients. The ESDs were generally higher than the internationally recommended reference doses. Careful adoption of internationally accepted exposure factors (high tube voltage and low tube load) is most recommended to optimise the dose.
The association between Internet usage and sleep problems among Japanese adolescents: three repeated cross-sectional studies
Authors: Otsuka Yuichiro , Kaneita Yoshitaka , Itani Osamu , Matsumoto Yuuki , Jike Maki , Higuchi Susumu , Kanda Hideyuki , Kuwabara Yuki , Kinjo Aya , Osaki Yoneatsu
Published: July 2021

Study Objectives

Sleep problems and problematic Internet use have important implications for adolescent health; however, there have been no large-scale surveys using comprehensive measures. We examined the association between Internet use duration and sleep problems among Japanese adolescents.

Methods

We used data from the Lifestyle Survey of Adolescents collected in 2012, 2014, and 2017. We calculated the change in sleep status (insomnia, sleep duration, bedtime, and sleep quality) and Internet usage (screen time and services such as Internet surfing, social media use, streaming such as YouTube, and online gaming). A binary logistic model was estimated for insomnia. Generalized ordered logit models were employed for the ordinal outcomes (sleep duration, bedtime, sleep quality, and multidimensional sleep health). Sampling weights were constructed based on participation rate on survey years and selection rates from population statistics.

Results

We analyzed data from 248 983 adolescents. Sleep status was unchanged; however, many adolescents used more Internet services and for longer durations. The odds ratio of Internet screen time for all sleep problems (insomnia, shorter sleep duration, later bedtime, and worse sleep quality) gradually declined. Longer Internet screen time (>5 hours) was strongly associated with all sleep problems. Internet services were also associated with sleep problems; particularly, social media use and online gaming were linked to later bedtimes.

Conclusions

Despite the decreased strength in the association between Internet usage and sleep problems, longer Internet time was strongly associated with sleep problems. Public health interventions should consider Internet use as an intervention target to improve adolescents’ health.
Exploration of the Ixodes ricinus virosphere unveils an extensive virus diversity including novel coltiviruses and other reoviruses
Authors: Vanmechelen Bert , Merino Michelle , Vergote Valentijn , Laenen Lies , Thijssen Marijn , Martí-Carreras Joan , Claerebout Edwin , Maes Piet
Published: July 2021

Recent metagenomics studies have revealed several tick species to host a variety of previously undiscovered RNA viruses. Ixodes ricinus, which is known to be a vector for many viral, bacterial, and protozoan pathogens, is the most prevalent tick species in Europe. For this study, we decided to investigate the virosphere of Belgian I. ricinus ticks. High-throughput sequencing of tick pools collected from six different sampling sites revealed the presence of viruses belonging to many different viral orders and families, including Mononegavirales, Bunyavirales, Partitiviridae, and Reoviridae. Of particular interest was the detection of several new reoviruses, two of which cluster together with members of the genus Coltivirus. This includes a new strain of Eyach virus, a known causative agent of tick-borne encephalitis. All genome segments of this new strain are highly similar to those of previously published Eyach virus genomes, except for the fourth segment, encoding VP4, which is markedly more dissimilar, potentially indicating the occurrence of a genetic reassortment. Further polymerase chain reaction–based screening of over 230 tick pools for 14 selected viruses showed that most viruses could be found in all six sampling sites, indicating the wide spread of these viruses throughout the Belgian tick population. Taken together, these results illustrate the role of ticks as important virus reservoirs, highlighting the need for adequate tick control measures.
Gut Microbiota in Mexican Children With Acute Diarrhea
Authors: Toro Monjaraz Erick Manuel , Ignorosa Arellano Karen Rubí , Loredo Mayer Alejandro , Palacios-González Berenice , Cervantes Bustamante Roberto , Ramírez Mayans Jaime Alfonso
Published: July 2021

Background:

Acute diarrhea is the second leading cause of preventable mortality and morbidity in children worldwide. This study aimed to identify the main pathogens associated with acute diarrhea and to describe changes in gut microbiota in Mexican children.

Methods:

This single-center observational study included 30 children (6 months to 5 years old) with acute diarrhea who were referred to the Instituto Nacional de Pediatría of Mexico City and 15 healthy volunteers (control group). Stool samples at day 0 (D0) and day 15 (D15) were collected for identification of microorganisms (reverse transcriptase-polymerase chain reaction analyses with xTAG gastrointestinal pathogen panel multiplex assay) and microbiota analysis (16S gene amplification sequencing). Prescription decisions were made by the treating clinician.

Results:

The main pathogens identified were norovirus and Campylobacter jejuni (20% each). The majority of patients (n = 24) were prescribed Saccharomyces boulardii CNCM I-745 for treatment of acute diarrhea. Diarrheic episodes resolved within 1 week of treatment. Compared with D15 and control samples, D0 samples showed significantly lower alpha diversity and a clear shift in overall composition (beta diversity). Alpha diversity was significantly increased in S. boulardii-treated group between D0 and D15 to a level similar to that of control group.

Conclusions:

In these children, acute diarrhea was accompanied by significant alterations in gut microbiota. S. boulardii CNCM I-745 treatment may facilitate gut microbiota restoration in children with acute diarrhea, mostly through improvements in alpha diversity.
Studying Clinical, Biologic and Echocardiography Criteria to Predict a Resistant Kawasaki Disease in Children
Authors: Robert Anne-Cécile , Parmentier Anne-Laure , Schulze Olivier , Verney Cindy , Huet Frédéric , Thiriez Gérard , Anxionnat Raphaël
Published: July 2021

Background:

Resistant Kawasaki disease (KD) represents 10%–15% of KD patients and increases risk of coronary artery abnormalities (CAAs). Different scores exist to predict resistant KD but only in Japanese population, although a French team has recently proposed a new scoring system. The principal objective of this study is to establish criteria to predict resistant KD in our representative French population. The second objective is an attempt to develop a predictive score of resistant KD.

Methods:

We conducted a retrospective multicenter study including 2 universities and five secondary hospitals in Eastern France. Patients were included over a period from January 1, 2010 through December 31, 2019. Diagnosis of KD was recorded to the European Single Hub and Access point for pediatric Rheumatology in Europe (SHARE) initiative criteria.

Results:

Two hundred two eligible patients had KD and 194 patients were analyzed: 160 sensitive KD and 34 (17.5%) resistant KD. In univariate model, serum sodium <133 mmol/L (odds ratio [OR] 2.97 [1.40–6.45]), hemoglobin level <110 g/L (OR 3.17 [1.46–7.34]), neutrophils >80% (OR 2.36 [1.03–5.25]), C reactive protein level >150 mg/L (OR 4.47 [2.07–10.19]), CAA (OR 3.85 [1.67–8.79]) or myocarditis (OR 6.98 [1.47–36.95]) at the diagnosis were statistically significant, but only serum sodium was an independent factor of resistant KD.

Conclusion:

This study shows an association between resistant KD and biologic and echocardiography criteria, but only serum sodium is an independent predictive factor. A score to predict resistant KD could not yet be established.
Vitamin A in Children Hospitalized for Measles in a High-income Country
Authors: Lo Vecchio Andrea , Cambriglia Maria Donata , Bruzzese Dario , Guarino Alfredo
Published: July 2021

Background:

Worldwide medical authorities recommend vitamin A supplementation for severe measles requiring hospitalization; however, evidence supporting its use in high-income countries is lacking. A nationwide vitamin A shortage reported in concomitance with a recent measles outbreak in Italy provided an opportunity to test the effectiveness of vitamin A in a high-income setting, approximating an unbiased allocation.

Methods:

We conducted a prospective controlled cohort study involving children admitted for measles to a tertiary-care hospital in Southern Italy. The primary outcome was the duration of fever. Secondary outcomes included the length of hospitalization, rate of complications, need for antibiotic treatment and body temperature.

Results:

A total of 108 inpatient children (36% female, median age 16.3 months) were enrolled; 36 received 2 doses of oil-based vitamin A according to age, and 72 matched controls received standard care. There were no significant differences between the study groups in the duration of fever (7.03 ± 2.67 vs. 6.82 ± 3.27, P = 0.72), length of hospitalization (median, 5.0 vs. 5.0 days, P = 0.50), maximum body temperature (median, 39°C in both groups, P = 0.23), rate of organ (69.4% vs. 63.9%, P = 0.72) and hematologic complications (41.7% vs. 59.7%, P = 0.12), or need for antibiotic treatment (66.7% vs. 61.1%, P = 0.72). Overall, vitamin A supplementation did not reduce the risk of any complications (relative risk, 1.33; 95% confidence intervals: 0.59–2.96).

Conclusion:

Vitamin A does not change the clinical course of measles infection or the rate of complications in children hospitalized in a high-income country.

Study registration number:

EU PAS 31805.
Assessment of Disease-related Knowledge Among Children With Inflammatory Bowel Disease and their Family Using IBD-KID2: Evaluating Tool Generalizability
Authors: Vernon-Roberts Angharad , Lopez Robert N. , Lewindon Peter , Lemberg Daniel A. , Bowcock Nerissa L. , Alex George , Otley Anthony , Jacobson Kevan , Roberts Amin J. , Evans Helen M. , Gearry Richard B. , Day Andrew S.
Published: July 2021

Background:

Children with inflammatory bowel disease (IBD) and their families benefit from improved knowledge of their disease and treatment. Knowledge levels of individual family members are infrequently studied but may identify where education is best directed. We aimed to assess disease-specific knowledge among children with IBD, parents, and siblings, using a validated assessment tool (IBD-KID2), and to establish generalizability of IBD-KID2.

Methods:

Children with IBD and family members were recruited from tertiary IBD clinics in New Zealand, Australia, and Canada. All participants completed IBD-KID2 online at baseline, and the children with IBD again after 2 weeks to assess reliability.

Results:

Participants included 130 children with IBD, 118 mothers, 55 fathers, and 37 siblings. Children with IBD had a mean score of 9.1 (SD 2.9) (maximum 15 points), significantly lower than parents (P < 0.005) and higher than siblings (P < 0.005). Scores of children with IBD were positively associated with current age (P < 0.005), age at diagnosis (P = 0.04) and fathers education level (P = 0.02). Significant score correlations were seen between children with IBD and their mother (P < 0.005) but not father. Sibling scores were not correlated with either parent. Test–retest reliability was high. The cohorts from each country were comparable, and no difference in group scores was seen between countries.

Conclusion:

IBD-KID2 is a generalizable and reliable tool for the assessment of disease and treatment knowledge for children with IBD and their families. Score correlations between parents and children with IBD suggest transfer of knowledge, but sibling knowledge is low and targeted education may be beneficial.
Mesenteric Plexiform Neurofibroma as a Cause of Weight Loss and Chronic Diarrhea in a Patient with YPEL3 Variant
Authors: Gorbounova Irina , Lenahan Arthur , Wenger Tara Lynn , Rudzinski Erin , Tang Elizabeth Ren-Yee , Smith Caitlin A. , Wendel Danielle , Horslen Simon , Ambartsumyan Lusine
Published: July 2021

Mesenteric plexiform neurofibroma is a subtype of plexiform neurofibroma that involves the mesentery and causes a variety of gastrointestinal complaints. Plexiform neurofibroma is classically found in patients with neurofibromatosis type 1, although genetic contributions to plexiform neurofibroma pathogenesis are heterogeneous. We report the first case of mesenteric plexiform neurofibroma in a patient with a YPEL3 pathogenic variant. This patient presented with growth failure, generalized abdominal pain and chronic diarrhea. She was confirmed to have mesenteric plexiform neurofibroma on histopathology and targeted sequencing on affected tissue confirmed that there were no neurofibromatosis type 1 variants present. Given that this patient’s mesenteric plexiform neurofibroma is associated with YPEL3 dysfunction, she is unlikely to benefit from MEK inhibitors, which are the newly approved treatment for inoperable plexiform neurofibroma in patients with neurofibromatosis type 1.
CTLA-4 Haploinsufficiency Presenting as Extensive Enteropathy in a Patient With Very Early Onset Inflammatory Bowel Disease
Authors: Tran Ngoc N. , Setty Mala , Cham Elaine , Chan Alice Y. , Ali Sabina
Published: July 2021

Patients with very early onset inflammatory bowel disease (VEO-IBD) have a higher incidence of monogenic disease compared to older age groups. Age, alone, is a strong predictor for monogenic disease. We discuss a case of VEO-IBD in which the patient presented with severe and refractory enteropathy, leading to diagnosis of CTLA-4 haploinsufficiency. Genetic workup showed de novo heterozygous deletions of the CTLA-4 and ICOS genes. This case was unique, as the patient did not have the other manifestations commonly present with the disease. We advocate for early and routine genetic workup of VEO-IBD, as patients with monogenic IBD have high morbidity and mortality, if inadequately treated. Our patient did not respond to conventional treatment modalities and required targeted treatment with Abatacept, a CTLA-4 agonist.
Seizure During Infliximab Infusion in a Child With Crohn’s Disease: An Illustration of a Neurologic Adverse Event Associated With Drug Antibodies
Authors: Joseph Shelly , Reed Anna W , Cuffari Carmen
Published: July 2021

Antitumor necrosis factor (anti-TNF) therapy has proven efficacy in the induction and maintenance of remission in children with Crohn’s disease (CD). With the increased use of these medications, several adverse events have been associated, including the emergence of neurologic side effects. While demyelinating conditions and neuropathy associated with anti-TNF therapy have been reported in adults, seizures have been anecdotally described in case reports. We describe a case of an adolescent boy who experienced an infliximab-associated seizure during an infusion and the potential role that medication antibody levels may have played in this adverse event.
A Challenging Case of the Forgotten Abdominal Tuberculosis in the Developed World
Authors: Henen Sara , Denton Christine , Miller Aaron , Pappa Helen
Published: July 2021

Differentiating abdominal tuberculosis (TB) from Crohn’s disease (CD) despite the rarity of the condition remains vital to avoid catastrophic consequences of disseminated miliary TB as a result of mistakenly starting an immunosuppressive medication. We highlight a challenging pediatric abdominal TB case of a 5-year-old male that presented with failure to thrive, ascites, and diarrhea. Our case aims to shed light on a forgotten disease in our developed world by highlighting subtle clinical, endoscopic, and histologic features. Findings of caseating necrosis on biopsy, positive smear for acid-fast bacillus (AFB), AFB culture, and necrotic lymph node on imaging are diagnostic of TB but are rarely present. Clinicians should be vigilant in screening pediatric patients with elusive symptoms, history, and exam. TB should be suspected, and one should not shy away from empirical antituberculous treatment as it could be the only way of establishing the diagnosis.
A 180 Myr-old female-specific genome region in sturgeon reveals the oldest known vertebrate sex determining system with undifferentiated sex chromosomes
Authors: Kuhl Heiner , Guiguen Yann , Höhne Christin , Kreuz Eva , Du Kang , Klopp Christophe , Lopez-Roques Céline , Yebra-Pimentel Elena Santidrian , Ciorpac Mitica , Gessner Jörn , Holostenco Daniela , Kleiner Wibke , Kohlmann Klaus , Lamatsch Dunja K. , Prokopov Dmitry , Bestin Anastasia , Bonpunt Emmanuel , Debeuf Bastien , Haffray Pierrick , Morvezen Romain , Patrice Pierre , Suciu Radu , Dirks Ron , Wuertz Sven , Kloas Werner , Schartl Manfred , Stöck Matthias
Published: July 2021

Several hypotheses explain the prevalence of undifferentiated sex chromosomes in poikilothermic vertebrates. Turnovers change the master sex determination gene, the sex chromosome or the sex determination system (e.g. XY to WZ). Jumping master genes stay main triggers but translocate to other chromosomes. Occasional recombination (e.g. in sex-reversed females) prevents sex chromosome degeneration. Recent research has uncovered conserved heteromorphic or even homomorphic sex chromosomes in several clades of non-avian and non-mammalian vertebrates. Sex determination in sturgeons (Acipenseridae) has been a long-standing basic biological question, linked to economical demands by the caviar-producing aquaculture. Here, we report the discovery of a sex-specific sequence from sterlet (
Acipenser ruthenus
). Using chromosome-scale assemblies and pool-sequencing, we first identified an approximately 16 kb female-specific region. We developed a PCR-genotyping test, yielding female-specific products in six species, spanning the entire phylogeny with the most divergent extant lineages (
A. sturio, A. oxyrinchus
versus
A. ruthenus, Huso huso
), stemming from an ancient tetraploidization. Similar results were obtained in two octoploid species (
A. gueldenstaedtii, A. baerii
). Conservation of a female-specific sequence for a long period, representing 180 Myr of sturgeon evolution, and across at least one polyploidization event, raises many interesting biological questions. We discuss a conserved undifferentiated sex chromosome system with a ZZ/ZW-mode of sex determination and potential alternatives.

This article is part of the theme issue ‘Challenging the paradigm in sex chromosome evolution: empirical and theoretical insights with a focus on vertebrates (Part I)’.
Evolution of master sex determiners: TGF-β signalling pathways at regulatory crossroads
Authors: Pan Qiaowei , Kay Tomas , Depincé Alexandra , Adolfi Mateus , Schartl Manfred , Guiguen Yann , Herpin Amaury
Published: July 2021

To date, more than 20 different vertebrate master sex-determining genes have been identified on different sex chromosomes of mammals, birds, frogs and fish. Interestingly, six of these genes are transcription factors (Dmrt1- orSox3- related) and 13 others belong to the TGF-β signalling pathway (Amh,Amhr2,Bmpr1b,GsdfandGdf6). This pattern suggests that only a limited group of factors/signalling pathways are prone to become top regulators again and again. Although being clearly a subordinate member of the sex-regulatory network in mammals, the TGF-β signalling pathway made it to the top recurrently and independently. Facing this rolling wave of TGF-β signalling pathways, this review will decipher how the TGF-β signalling pathways cope with the canonical sex gene regulatory network and challenge the current evolutionary concepts accounting for the diversity of sex-determining mechanisms.

This article is part of the theme issue ‘Challenging the paradigm in sex chromosome evolution: empirical and theoretical insights with a focus on vertebrates (Part I)’.
Epigenetic mechanisms in sex determination and in the evolutionary transitions between sexual systems
Authors: Piferrer Francesc
Published: July 2021

The hypothesis that epigenetic mechanisms of gene expression regulation have two main roles in vertebrate sex is presented. First, and within a given generation, by contributing to the acquisition and maintenance of (i) the male
or
female function once during the lifetime in individuals of gonochoristic species; and (ii) the male
and
female function in the same individual, either at the same time in simultaneous hermaphrodites, or first as one sex and then as the other in sequential hermaphrodites. Second, if environmental conditions change, epigenetic mechanisms may have also a role across generations, by providing the necessary phenotypic plasticity to facilitate the transition: (i) from one sexual system to another, or (ii) from one sex-determining mechanism to another. Furthermore, if the environmental change lasts enough time, epimutations could facilitate assimilation into genetic changes that stabilize the new sexual system or sex-determining mechanism. Examples supporting these assertions are presented, caveats or difficulties and knowledge gaps identified, and possible ways to test this hypothesis suggested.

This article is part of the theme issue ‘Challenging the paradigm in sex chromosome evolution: empirical and theoretical insights with a focus on vertebrates (Part I)’.
Viscoelastic Parameterization of Human Skin Cells to Characterize Material Behavior at Multiple Timescales
Authors: Parvini Cameron H. , Cartagena-Rivera Alexander X. , Solares Santiago D.
Published: July 2021

Countless biophysical studies have sought distinct markers in the cellular mechanical response that could be linked to morphogenesis, homeostasis, and disease. Here, a novel iterative-fitting methodology is used to investigate the viscoelastic behavior at multiple relaxation times of human skin cells under physiologically relevant conditions. Past investigations often involved parameterizing linear elastic relationships and assuming purely Hertzian contact mechanics. However, linear elastic treatment fails to capture and properly account for the rich temporal information available in datasets. We demonstrate the performance superiority of the proposed iterative viscoelastic characterization method over standard open-search approaches. Our viscoelastic measurements revealed that 2D adherent metastatic melanoma cells exhibit reduced elasticity compared to normal counterparts—melanocytes and fibroblasts, whereas are significantly less viscous than only fibroblasts over timescales spanning three orders of magnitude. Interestingly, melanocytes are stiffer than melanoma cells, while being the less viscous cells measured. The measured loss angle indicates clear differential viscoelastic responses across multiple timescales between the measured cells. We propose the use of viscoelastic properties at multiple timescales as a mechanical biomarker of diseases. Altogether, this method provides new insight into the complex viscoelastic behavior of metastatic melanoma cells relevant to better understanding cancer metastasis aggression.
A patient-driven clinicogenomic partnership through the Metastatic Prostate Cancer Project
Authors: Crowdis Jett , Balch Sara , Sterlin Lauren , Thomas Beena S. , Camp Sabrina Y. , Dunphy Michael , Anastasio Elana , Shah Shahrayz , Damon Alyssa L. , Ramos Rafael , Sosa Delia M. , Small Ilan K. , Tomson Brett , Nguyen Colleen M. , McGillicuddy Mary , Chastain Parker S. , He Meng Xiao , Cheung Alexander T.M. , Wankowicz Stephanie , Tewari Alok K. , Kim Dewey , AlDubayan Saud H. , Dowdye Ayanah , Zola Benjamin , Nowak Joel , Manarite Jan , Gunn Major Idola Henry , Olson Bryce , Lander Eric S. , Painter Corrie A. , Wagle Nikhil , Van Allen Eliezer M.
Published: July 2021

Molecular profiling studies have enabled numerous discoveries for metastatic prostate cancer (MPC), but they have mostly occurred in academic medical institutions focused on select patient populations. We developed the Metastatic Prostate Cancer Project (MPCproject, mpcproject.org), a patient-partnered initiative to empower MPC patients living anywhere in the U.S. and Canada to participate in molecular research and contribute directly to translational discovery. Here we present clinicogenomic results from our partnership with the first 706 MPCproject participants. We found that a patient-centered and remote research strategy enhanced engagement with patients in rural and medically underserved areas. Furthermore, patient-reported data achieved 90% consistency with abstracted health records for therapies and provided a mechanism for patient-partners to share information about their cancer experience not documented in medical records. Among the molecular profiling data from 333 patient-partners (n = 573 samples), whole exome sequencing of 63 tumor samples obtained from hospitals across the U.S. and Canada and 19 plasma cell-free DNA (cfDNA) samples from blood donated remotely recapitulated known findings in MPC and enabled longitudinal study of prostate cancer evolution. Inexpensive ultra-low coverage whole genome sequencing of 318 cfDNA samples from donated blood revealed clinically relevant genomic changes like AR amplification, even in the context of low tumor burden. Collectively, this study illustrates the power of a longitudinal partnership with patients to generate a more representative clinical and molecular understanding of MPC.

Note

To assist our patient-partners and the wider MPC community interpret the results of this study, we have included a glossary of terms in the Supplementary Materials.
Protein-Protein Interaction Site Prediction Based on Attention Mechanism and Convolutional Neural Networks
Authors: Lu Shuai , Li Yuguang , Ma Qiang , Nan Xiaofei , Zhang Shoutao
Published: July 2021

Proteins usually perform their cellular functions by interacting with other proteins. Accurate identification of protein-protein interaction sites (PPIs) from sequence is import for designing new drugs and developing novel therapeutics. A lot of computational models for PPIs prediction have been developed because experimental methods are slow and expensive. Most models employ a sliding window approach in which local neighbors are concatenated to present a target residue. However, those neighbors are not been distinguished by pairwise information between a neighbor and the target. In this study, we propose a novel PPIs prediction model AttCNNPPISP, which combines attention mechanism and convolutional neural networks (CNNs). The attention mechanism dynamically captures the pairwise correlation of each neighbor-target pair within a sliding window, and therefore makes a better understanding of the local environment of target residue. And then, CNNs take the local representation as input to make prediction. Experiments are employed on several public benchmark datasets. Compared with the state-of-the-art models, AttCNNPPISP significantly improves the prediction performance. Also, the experimental results demonstrate that the attention mechanism is effective in terms of constructing comprehensive context information of target residue.
Remodeling of organelles and microtubules during spermiogenesis in the liverwort Marchantia polymorpha
Authors: Minamino Naoki , Norizuki Takuya , Mano Shoji , Ebine Kazuo , Ueda Takashi
Published: July 2021

Gametogenesis is an essential biological event for sexual reproduction in various organisms. Bryophytes and some other plants employ motile sperms (spermatozoids) as male gametes, which self-locomote to the egg cells to accomplish fertilization. Spermatozoids of bryophytes harbor distinctive morphological characteristics, including the cell body with a helical slender shape and two motile flagella at the anterior edge. During transformation from a spermatid to spermatozoid (spermiogenesis), the shape and cellular contents of spermatids are dynamically reorganized. However, how each organelle is reorganized during plant spermiogenesis remains obscure. In this study, we classified the developmental processes during spermiogenesis in the liverwort Marchantia polymorpha according to cellular and nuclear shapes and flagella development. We then examined the remodeling of microtubules and reorganization of endomembrane organelles during spermiogenesis. The results indicate that the state of post-translational modification of tubulin is dynamically changed during the formation of the flagella and spline, and the plasma membrane and endomembrane organelles are drastically reorganized in a precisely regulated manner during spermiogenesis. These findings are expected to provide useful indexes to classify developmental and subcellular processes of spermiogenesis in bryophytes.

Summary statement

We classified developmental processes of spermatozoids into 1 + 5 stages and characterized remodeling of organelles and microtubules during spermiogenesis in the liverwort Marchantia polymorpha.
Ancient Darwinian replicators nested within eubacterial genomes
Authors: Bertels Frederic , Rainey Paul B.
Published: July 2021

Integrative mobile genetic elements (MGEs), such as transposons and insertion sequences, propagate within bacterial genomes, but persistence times in individual lineages are short. For long-term survival, MGEs must continuously invade new hosts by horizontal transfer. Theoretically, MGEs that persist for millions of years in single lineages, and are thus subject to vertical inheritance, should not exist. Here we draw attention to an exception — a class of MGE termed REPIN. REPINs are non-autonomous MGEs whose duplication depends on non-jumping RAYT transposases. Comparisons of REPINs and typical MGEs show that replication rates of REPINs are orders of magnitude lower, REPIN population size fluctuations correlate with changes in available genome space, REPIN conservation depends on RAYT function, and REPIN diversity accumulates within host lineages. These data lead to the hypothesis that REPINs form enduring, beneficial associations with eubacterial chromosomes. Given replicative nesting, our hypothesis predicts conflicts arising from the diverging effects of selection acting simultaneously on REPINs and host genomes. Evidence in support comes from patterns of REPIN abundance and diversity in two distantly related bacterial species. Together this bolsters the conclusion that REPINs are the genetic counterpart of mutualistic endosymbiotic bacteria.
The functional form of specialized predation dramatically affects whether Janzen-Connell effects can prevent competitive exclusion
Authors: Smith Daniel J. B.
Published: July 2021

Janzen Connell Effects (JCEs), specialized predation of seeds and seedlings near conspecific trees, are hypothesized to promote high species richness. While past modeling studies show JCEs can maintain higher diversity than a neutral community, recent theoretical work indicates JCEs may weakly inhibit competitive exclusion when species exhibit interspecific fitness variation. However, recent models make somewhat restrictive assumptions about the functional form of specialized predation – that JCEs occur at a fixed rate when seeds/seedlings are within a fixed distance of a conspecific tree. Using a theoretical model, I show that the functional form of JCEs largely impacts their ability to promote coexistence. If specialized predation pressure increases additively with adult tree density and decays exponentially with distance, JCEs maintain considerably higher diversity than predicted by recent models. Parameterizing the model with values from a Panamanian tree community indicates JCEs can maintain high diversity in communities exhibiting high interspecific fitness variation.
Bacteria are everywhere, even in your COI marker gene data!
Authors: Zafeiropoulos Haris , Gargan Laura , Hintikka Sanni , Pavloudi Christina , Carlsson Jens
Published: July 2021

The mitochondrial cytochrome C oxidase subunit I gene (COI) is commonly used in eDNA metabarcoding studies, especially for assessing metazoan diversity. Yet, a great number of COI operational taxonomic units or/and amplicon sequence variants are retrieved from such studies and referred to as “dark matter”, and do not get a taxonomic assignment with a reference sequence. For a thorough investigation of this dark matter, we have developed the Dark mAtteR iNvestigator (DARN) software tool. A reference COI-oriented phylogenetic tree was built from 1,240 consensus sequences covering all the three domains of life, with more than 80% of those representing eukaryotic taxa. With respect to eukaryotes, consensus sequences at the family level were constructed from 183,330 retrieved from the Midori reference 2 database. Similarly, sequences from 559 bacterial genera and 41 archaeal were retrieved from the BOLD database. DARN makes use of the phylogenetic tree to investigate and quantify pre-processed sequences of amplicon samples to provide both a tabular and a graphical overview of phylogenetic assignments. To evaluate DARN, both environmental and bulk metabarcoding samples from different aquatic environments using various primer sets were analysed. We demonstrate that a large proportion of non-target prokaryotic organisms such as bacteria and archaea are also amplified in eDNA samples and we suggest bacterial COI sequences to be included in the reference databases used for the taxonomy assignment to allow for further analyses of dark matter. DARN source code is available on GitHub at https://github.com/hariszaf/darn and you may find it as a Docker at https://hub.docker.com/r/hariszaf/darn.

Author summary

DARN is a software approach aiming to provide further insight in the COI amplicon data coming from environmental samples. Building a COI-oriented reference phylogeny tree is a challenging task especially considering the small number of microbial curated COI sequences deposited in reference databases; e.g ~4,000 bacterial and ~150 archaeal in BOLD. Apparently, as more and more such sequences are collated, the DARN approach improves. To provide a more interactive way of communicating both our approach and our results, we strongly suggest the reader to visit this Google Collab notebook where all steps are described step by step and also this GitHub page where our results are demonstrated. Our approach corroborates the known presence of microbial sequences in COI environmental sequencing samples and highlights the need for curated bacterial and archaeal COI sequences and their integration into reference databases (i.e. Midori, BOLD, etc). We argue that DARN will benefit researchers as a quality control tool for their sequenced samples in terms of distinguishing eukaryotic from non-eukaryotic OTUs/ASVs, but also in terms of understanding the unknown unknowns.
A statistical framework for differential pseudotime analysis with multiple single-cell RNA-seq samples
Authors: Hou Wenpin , Ji Zhicheng , Chen Zeyu , Wherry E. John , Hicks Stephanie C. , Ji Hongkai
Published: July 2021

Pseudotime analysis with single-cell RNA-sequencing (scRNA-seq) data has been widely used to study dynamic gene regulatory programs along continuous biological processes. While many computational methods have been developed to infer the pseudo-temporal trajectories of cells within a biological sample, methods that compare pseudo-temporal patterns with multiple samples (or replicates) across different experimental conditions are lacking. Lamian is a comprehensive and statistically-rigorous computational framework for differential multi-sample pseudotime analysis. It can be used to identify changes in a biological process associated with sample covariates, such as different biological conditions, and also to detect changes in gene expression, cell density, and topology of a pseudotemporal trajectory. Unlike existing methods that ignore sample variability, Lamian draws statistical inference after accounting for cross-sample variability and hence substantially reduces sample-specific false discoveries that are not generalizable to new samples. Using both simulations and real scRNA-seq data, including an analysis of differential immune response programs between COVID-19 patients with different disease severity levels, we demonstrate the advantages of Lamian in decoding cellular gene expression programs in continuous biological processes.
High rate of mutational events in SARS-CoV-2 genomes across Brazilian geographical regions, February 2020 to June 2021
Authors: Souza U.J.B. , Santos R.N. , Campos F.S. , Lourenço K.L. , Fonseca F.G. , Spilki F.R. ,   Corona-ômica.BR/MCTI Network
Published: July 2021

Brazil has been considered as one of the emerging epicenters of the coronavirus pandemic in 2021, experiencing over 3,000 daily deaths caused by the virus at the peak of the second wave. In total, the country has more than 19.2 million confirmed cases of Covid-19, including over 533,509 fatalities. A set of emerging variants arose in the country, some of them posing new challenges for COVID-19 control. The goal of this study was to describe mutational events across samples from Brazilian SARS-CoV-2 sequences openly publicly obtainable on the Global Initiative on Sharing Avian Influenza Data-EpiCoV (GISAID-EpiCoV) platform and generate an index of new mutant by each genome. A total of 16,953 SARS-CoV-2 genomes were obtained and are not proportionally representative of the five Brazilian geographical regions. A comparative sequence analysis was conducted to identify common mutations located at 42 positions of the genome (38 were in coding regions whereas two in 5’ and two in 3’ UTR). Moreover, 11 were synonymous and 27 missense variants, and more than 44.4% were located in the spike gene. Across the total of single nucleotide variations (SNVs) identified, 32 were found in genomes obtained from all five Brazilian regions. While a high genomic diversity is reported in Europe given the large number of sequenced genomes, Africa is emerging as a hotspot for new variants. In South America, Brazil and Chile, rates are similar to those found in South Africa and India, giving enough space to generate new viral mutations. Genomic surveillance is the central key to identifying the emerging variants of SARS-CoV-2 in Brazil and has shown that the country is one of the “hotspots” in the generation of new variants.
Dynamics of glioma-associated microglia and macrophages reveals their divergent roles in the immune response of brain
Authors: Qian Jiawen , Wang Chen , Wang Bo , Li Congwen , Fu Kaiyi , Wang Yuedi , Gao Yiyuan , Niu Congyi , Zhao Chujun , Liu Jun , Wang Luman , Liu Ronghua , Luo Feifei , Lu Mingfang , Liu Yun , Chu Yiwei
Published: July 2021

Glioma microenvironment contains numerous myeloid cells, including brain-resident microglia and recruited monocytes and macrophages (Mo/Mφ). When studied collectively, these cells presented pro-tumor effects. Yet, little is known about the differences among these myeloid populations. Using single-cell sequencing analysis, we studied the phenotypic characteristics, spatial variances, and dynamic changes of these relatively heterogeneous cell populations. Microglia populations with distinct spatial distribution presented different functional states, including tumor-associated subsets with phagocytic and lipid metabolism signature. Notably, this subset of glioma-associated microglia shared similar trait in a diverse spectrum of neuropathogenesis. In contrast, Mo/Mφ highly expressed genes related to angiogenesis, tumor invasion, and immune evasion. Moreover, identifying the Mo/Mφ subsets had prognostic and classificatory value in clinical application. These results thus eliminate the long-existing ambiguity about the role of microglia and Mo/Mφ in glioma pathogenesis, and reveal their prognostic and therapeutic value for glioma patients.
Niclosamide reverses SARS-CoV-2 control of lipophagy
Authors: Garrett Timothy J. , Coatsworth Heather , Mahmud Iqbal , Hamerly Timothy , Stephenson Caroline J. , Yazd Hoda S. , Ayers Jasmine , Miller Megan R. , Lednicky John A. , Dinglasan Rhoel R.
Published: July 2021

The global effort to combat COVID-19 rapidly produced a shortlist of approved drugs with anti-viral activities for clinical repurposing. However, the jump to clinical testing was lethal in some cases as a full understanding of the mechanism of antiviral activity as opposed to pleiotropic activity/toxicity for these drugs was lacking. Through parallel lipidomic and transcriptomic analyses we observed massive reorganization of lipid profiles of infected Vero E6 cells, especially plasmalogens that correlated with increased levels of virus replication. Niclosamide (NIC), a poorly soluble anti-helminth drug identified for repurposed treatment of COVID-19, reduced the total lipid profile that would otherwise amplify during virus infection. NIC treatment reduced the abundance of plasmalogens, diacylglycerides, and ceramides, which are required for virus production. Future screens of approved drugs may identify more druggable compounds than NIC that can safely but effectively counter SARS-CoV-2 subversion of lipid metabolism thereby reducing virus replication. However, these data support the consideration of niclosamide as a potential COVID-19 therapeutic given its modulation of lipophagy leading to the reduction of virus egress and the subsequent regulation of key lipid mediators of pathological inflammation.