bluuebunny/crossref_metadata_2025 huggingface dataset:
Preexisting opioid use disorder is associated with poor outcomes in hospitalized acute pancreatitis patients
Authors: Shaikh Abdullah S. , Al Mouslmani Mhd Yassin , Raza Shah Aun , Hassan Khan Zarak , Tausif Siddiqui Mohamed , Saraireh Hamzeh , Chandan Saurabh , Umar Shifa , Arora Sumant , Desai Madhav , Guturu Praveen , Bilal Mohammad
Published: August 2021

Introduction

Although opioids are widely used for pain management in acute pancreatitis, the impact of opioid use disorder (OUD) on outcomes in patients with acute pancreatitis remains unknown. In the current study, we aimed to evaluate the impact of the OUD on outcomes in patients hospitalized with acute pancreatitis and delineate the trends associated with OUD and acute pancreatitis using a nationally representative sample.

Methods

This is a retrospective cohort study of patients with acute pancreatitis using the combined releases of the year 2005–2014 of the National (Nationwide) Inpatient Sample (NIS) database. Patients over the age of 18 years with a principal diagnosis of acute pancreatitis were divided into cohorts of patients with opioid use disorders and those without. The primary measured outcome was in-hospital mortality and secondary outcomes were healthcare utilization measures, including length of stay (LOS) and hospitalization costs.

Results

A total of 2 593 831 hospitalizations of acute pancreatitis were included; of which, 37 849 (1.46%) had a secondary diagnosis of OUD. Total acute pancreatitis-related hospitalizations increased from 237 882 in 2005 to 274 006 in 2014. At the same time prevalence of OUD in acute pancreatitis patients also increased from 1 to 2.1%. Patients with OUD had significantly increased mortality as compared to patients without OUD (aOR: 1.4; P < 0.001). At the same time, acute pancreatitis patients with OUD were associated with 1.3 days longer LOS as compared to other acute pancreatitis patients (P < 0.001]. The mean adjusted difference in total hospitalization costs was $2353 (P < 0.001).

Conclusion

OUD is associated with a significant increase in LOS, healthcare utilization cost and in-hospital mortality in patients admitted for acute pancreatitis. Therefore, clinicians should exercise caution in prescribing opioid medications to this high-risk patient population and other modalities such as nonopioid pain medications should be tried as alternatives to opioid analgesics.
Pediatric Endoscopy Quality Improvement Network Quality Standards and Indicators for Pediatric Endoscopists and Endoscopists in Training
Authors: Walsh Catharine M. , Lightdale Jenifer R. , Leibowitz Ian H. , Lerner Diana G. , Liu Quin Y. , Mack David R. , Mamula Petar , Narula Priya , Oliva Salvatore , Riley Matthew R. , Rosh Joel R. , Tavares Marta , Utterson Elizabeth C. , Amil‐Dias Jorge , Bontems Patrick , Brill Herbert , Croft Nicholas M. , Fishman Douglas S. , Furlano Raoul I. , Gillett Peter M. , Hojsak Iva , Homan Matjaž , Huynh Hien Q. , Jacobson Kevan , Ambartsumyan Lusine , Otley Anthony R. , Kramer Robert E. , McCreath Graham A. , Connan Veronik , Thomson Mike A. ,   PEnQuIN Working Group
Published: August 2021

Introduction:

High‐quality pediatric endoscopy requires reliable performance of procedures by competent individual providers who consistently uphold all standards determined to assure optimal patient outcomes. Establishing consensus expectations for ongoing monitoring and assessment of individual pediatric endoscopists is a method for confirming the highest possible quality of care for such procedures worldwide. We aim to provide guidance to define and measure quality of endoscopic care for children.

Methods:

With support from the North American and European Societies of Pediatric Gastroenterology Hepatology and Nutrition (NASPGHAN and ESPGHAN), an international working group of the Pediatric Endoscopy Quality Improvement Network (PEnQuIN) used the methodological strategy of the Appraisal of Guidelines for REsearch and Evaluation (AGREE) II instrument to develop standards and indicators relevant for assessing the quality of endoscopists. Consensus was sought via an iterative online Delphi process and finalized at an in‐person conference. The quality of evidence and strength of recommendations were rated according to the GRADE (Grading of Recommendation Assessment, Development, and Evaluation) approach.

Results:

The PEnQuIN working group achieved consensus on 6 standards that all providers who perform pediatric endoscopy should uphold and 2 standards for pediatric endoscopists in training, with 7 corresponding indicators that can be used to identify high‐quality endoscopists. Additionally, these can inform continuous quality improvement at the provider level. Minimum targets for defining high‐quality pediatric ileocolonoscopy were set for 2 key indicators: cecal intubation rate (≥90%) and terminal ileal intubation rate (≥85%).

Discussion:

It is recommended that all individual providers performing or training to perform pediatric endoscopy initiate and engage with these international endoscopist‐related standards and indicators developed by PEnQuIN.
Extraordinarily rapid proliferation of cultured muscle satellite cells from migratory birds
Authors: Young Kevin G. , Regnault Timothy R. H. , Guglielmo Christopher G.
Published: August 2021

Migratory birds experience bouts of muscle growth and depletion as they prepare for, and undertake prolonged flight. Our studies of migratory bird muscle physiology
in vitro
led to the discovery that sanderling (
Calidris alba
) muscle satellite cells proliferate more rapidly than other normal cell lines. Here we determined the proliferation rate of muscle satellite cells isolated from five migratory species (sanderling; ruff,
Calidris pugnax
; western sandpiper,
Calidris mauri
; yellow-rumped warbler,
Setophaga coronata
; Swainson's thrush,
Catharus ustulatus
) from two families (shorebirds and songbirds) and with different migratory strategies. Ruff and sanderling satellite cells exhibited rapid proliferation, with population doubling times of 9.3 ± 1.3 and 11.4 ± 2 h, whereas the remaining species' cell doubling times were greater than or equal to 24 h. The results indicate that the rapid proliferation of satellite cells is not associated with total migration distance but may be related to flight bout duration and interact with lifespan.
Pterin-based pigmentation in animals
Authors: Andrade Pedro , Carneiro Miguel
Published: August 2021

Pterins are one of the major sources of bright coloration in animals. They are produced endogenously, participate in vital physiological processes and serve a variety of signalling functions. Despite their ubiquity in nature, pterin-based pigmentation has received little attention when compared to other major pigment classes. Here, we summarize major aspects relating to pterin pigmentation in animals, from its long history of research to recent genomic studies on the molecular mechanisms underlying its evolution. We argue that pterins have intermediate characteristics (endogenously produced, typically bright) between two well-studied pigment types, melanins (endogenously produced, typically cryptic) and carotenoids (dietary uptake, typically bright), providing unique opportunities to address general questions about the biology of coloration, from the mechanisms that determine how different types of pigmentation evolve to discussions on honest signalling hypotheses. Crucial gaps persist in our knowledge on the molecular basis underlying the production and deposition of pterins. We thus highlight the need for functional studies on systems amenable for laboratory manipulation, but also on systems that exhibit natural variation in pterin pigmentation. The wealth of potential model species, coupled with recent technological and analytical advances, make this a promising time to advance research on pterin-based pigmentation in animals.
Hubert Simon (Jim) Markl. 17 August 1938—8 January 2015
Authors: Meyer Axel , Mittelstraß Jürgen
Published: August 2021

Hubert (Jim) Markl was a zoologist and animal behavioural physiologist; but, beyond that, he was arguably the most influential figure in European science policy and the key person influencing the relationship between science and society in Germany. He uniquely served as president of both the Deutsche Forschungsgemeinschaft (German Science Foundation) and the Max Planck Gesellschaft. In these roles he was an outstanding and bold advocate for scientific research in Germany and throughout Europe, and his astute judgement, cogency and intellectual rigour commanded the respect of all his peers. His occupancy of the two most senior positions in German science policy followed from his earlier substantial scientific contributions to the emerging discipline of behavioural ecology, as well as his books on science, society and culture. Markl was a leading spokesperson in Germany on contested issues at the interface between science and society; for example, he was an eloquent advocate of stem cell research, speaking out against the political mainstream. He also strove to expose fully, and acknowledge, the Max Planck Society's responsibility for atrocities committed by the Kaiser Wilhelm Gesellschaft scientists during the Nazi era; Markl will be remembered as the president who oversaw a historical analysis of the involvement of the Kaiser Wilhelm Gesellschaft (the scientific society that legally preceded the Max Planck Gesellschaft), and in 2001 he apologized in the name of the Max Planck Society for the expulsion and deaths of Jewish scientists.
Fungal microbiomes are determined by host phylogeny and exhibit widespread associations with the bacterial microbiome
Authors: Harrison Xavier A. , McDevitt Allan D. , Dunn Jenny C. , Griffiths Sarah M. , Benvenuto Chiara , Birtles Richard , Boubli Jean P. , Bown Kevin , Bridson Calum , Brooks Darren R. , Browett Samuel S. , Carden Ruth F. , Chantrey Julian , Clever Friederike , Coscia Ilaria , Edwards Katie L. , Ferry Natalie , Goodhead Ian , Highlands Andrew , Hopper Jane , Jackson Joseph , Jehle Robert , da Cruz Kaizer Mariane , King Tony , Lea Jessica M. D. , Lenka Jessica L. , McCubbin Alexandra , McKenzie Jack , de Moraes Bárbara Lins Caldas , O'Meara Denise B. , Pescod Poppy , Preziosi Richard F. , Rowntree Jennifer K. , Shultz Susanne , Silk Matthew J. , Stockdale Jennifer E. , Symondson William O. C. , de la Pena Mariana Villalba , Walker Susan L. , Wood Michael D. , Antwis Rachael E.
Published: August 2021

Interactions between hosts and their resident microbial communities are a fundamental component of fitness for both agents. Though recent research has highlighted the importance of interactions between animals and their bacterial communities, comparative evidence for fungi is lacking, especially in natural populations. Using data from 49 species, we present novel evidence of strong covariation between fungal and bacterial communities across the host phylogeny, indicative of recruitment by hosts for specific suites of microbes. Using co-occurrence networks, we demonstrate marked variation across host taxonomy in patterns of covariation between bacterial and fungal abundances. Host phylogeny drives differences in the overall richness of bacterial and fungal communities, but the effect of diet on richness was only evident in the mammalian gut microbiome. Sample type, tissue storage and DNA extraction method also affected bacterial and fungal community composition, and future studies would benefit from standardized approaches to sample processing. Collectively these data indicate fungal microbiomes may play a key role in host fitness and suggest an urgent need to study multiple agents of the animal microbiome to accurately determine the strength and ecological significance of host–microbe interactions.
Lifetime reproductive benefits of cooperative polygamy vary for males and females in the acorn woodpecker (
Melanerpes formicivorus
)
Authors: Barve Sahas , Riehl Christina , Walters Eric L. , Haydock Joseph , Dugdale Hannah L. , Koenig Walter D.
Published: August 2021

Cooperative breeding strategies lead to short-term direct fitness losses when individuals forfeit or share reproduction. The direct fitness benefits of cooperative strategies are often delayed and difficult to quantify, requiring data on lifetime reproduction. Here, we use a longitudinal dataset to examine the lifetime reproductive success of cooperative polygamy in acorn woodpeckers (
Melanerpes formicivorus
), which nest as lone pairs or share reproduction with same-sex cobreeders. We found that males and females produced fewer young per successful nesting attempt when sharing reproduction. However, males nesting in duos and trios had longer reproductive lifespans, more lifetime nesting attempts and higher lifetime reproductive success than those breeding alone. For females, cobreeding in duos increased reproductive lifespan so the lifetime reproductive success of females nesting in duos was comparable to those nesting alone and higher than those nesting in trios. These results suggest that for male duos and trios, reproductive success alone may provide sufficient fitness benefits to explain the presence of cooperative polygamy, and the benefits of cobreeding as a duo in females are higher than previously assumed. Lifetime individual fitness data are crucial to reveal the full costs and benefits of cooperative polygamy.
Evolutionary history of quadrupedal walking gaits shows mammalian release from locomotor constraint
Authors: Wimberly Alexa N. , Slater Graham J. , Granatosky Michael C.
Published: August 2021

Vertebrates employ an impressive range of strategies for coordinating their limb movements while walking. Although this gait variation has been quantified and hypotheses for its origins tested in select tetrapod lineages, a comprehensive understanding of gait evolution in a macroevolutionary context is currently lacking. We used freely available internet videos to nearly double the number of species with quantitative gait data, and used phylogenetic comparative methods to test key hypotheses about symmetrical gait origin and evolution. We find strong support for an ancestral lateral-sequence diagonal-couplet gait in quadrupedal gnathostomes, and this mode is remarkably conserved throughout tetrapod phylogeny. Evolutionary rate analyses show that mammals overcame this ancestral constraint, resulting in a greater range of phase values than any other tetrapod lineage. Diagonal-sequence diagonal-couplet gaits are significantly associated with arboreality in mammals, though this relationship is not recovered for other tetrapod lineages. Notably, the lateral-sequence lateral-couplet gait, unique to mammals among extant tetrapods, is not associated with any traditional explanations. The complex drivers of gait diversification in mammals remain unclear, but our analyses suggest that their success was due, in part, to release from a locomotor constraint that has probably persisted in other extant tetrapod lineages for over 375 Myr.
Kinship dynamics: patterns and consequences of changes in local relatedness
Authors: Croft Darren P. , Weiss Michael N. , Nielsen Mia L. K. , Grimes Charli , Cant Michael A. , Ellis Samuel , Franks Daniel W. , Johnstone Rufus A.
Published: August 2021

Mounting evidence suggests that patterns of local relatedness can change over time in predictable ways, a process termed kinship dynamics. Kinship dynamics may occur at the level of the population or social group, where the mean relatedness across all members of the population or group changes over time, or at the level of the individual, where an individual's relatedness to its local group changes with age. Kinship dynamics are likely to have fundamental consequences for the evolution of social behaviour and life history because they alter the inclusive fitness payoffs to actions taken at different points in time. For instance, growing evidence suggests that individual kinship dynamics have shaped the evolution of menopause and age-specific patterns of helping and harming. To date, however, the consequences of kinship dynamics for social evolution have not been widely explored. Here we review the patterns of kinship dynamics that can occur in natural populations and highlight how taking a kinship dynamics approach has yielded new insights into behaviour and life-history evolution. We discuss areas where analysing kinship dynamics could provide new insight into social evolution, and we outline some of the challenges in predicting and quantifying kinship dynamics in natural populations.
Genome-based studies indicate that the Enterococcus faecium Clade B strains belong to Enterococcus lactis species and lack of the hospital infection associated markers
Authors: Belloso Daza Mireya Viviana , Cortimiglia Claudia , Bassi Daniela , Cocconcelli Pier Sandro
Published: August 2021

Enterococcus lactis

and the heterotypic synonym

Enterococcus xinjiangensis

from dairy origin have recently been identified as a novel species based on 16S rRNA gene sequence analysis.

Enterococcus faecium

type strain NCTC 7171T was used as the reference genome for determining

E. lactis

and

E. faecium

to be separate species. However, this taxonomic classification did not consider the diverse lineages of

E. faecium

, and the double nature of hospital-associated (clade A) and community-associated (clade B) isolates. Here, we investigated the taxonomic relationship among isolates of

E. faecium

of different origins and

E. lactis

, using a genome-based approach. Additional to 16S rRNA gene sequence analysis, we estimated the relatedness among strains and species using phylogenomics based on the core pangenome, multilocus sequence typing, the average nucleotide identity and digital DNA–DNA hybridization. Moreover, following the available safety assessment schemes, we evaluated the virulence profile and the ampicillin resistance of

E. lactis

and

E. faecium

clade B strains. Our results confirmed the genetic and evolutionary differences between clade A and the intertwined clade B and

E. lactis

group. We also confirmed the absence in these strains of virulence gene markers IS16, hylEfm
and esp and the lack of the PBP5 allelic profile associated with ampicillin resistance. Taken together, our findings support the reassignment of the strains of

E. faecium

clade B as

E. lactis

.
Limnohabitans radicicola sp. nov., a slow-growing bacterium isolated from rhizosphere of rice plant and emended description of the genus Limnohabitans
Authors: Chhetri Geeta , Kim Jiyoun , Kim Inhyup , Kang Minchung , Seo Taegun
Published: August 2021

In the present study, in an attempt to explore the diversity of bacteria in the roots of rice plants, a Gram-stain-negative, motile, facultatively anaerobic, non-pigmented, catalase-positive, oxidase-negative and rod-shaped bacterium with polar flagella was isolated. Phylogenetic analysis based on 16S rRNA gene sequences revealed highest sequence similarity to

Limnohabitans parvus

KCTC 42859T (98.2%) followed by

Limnohabitans curvus

KCTC 42562T (98%), Limnohabitans planktonicicus II-D5T (97.9%) and

Limnohabitans australis

MWH-BRAZ-DAM2DT (97.4%). Growth of strain JUR4T occurred at 10–37 °C (optimum, 30 °C), at pH 5.5–8.0 (optimum, 6.5–7) and in the presence of 0–0.2% NaCl (optimum, 0%, w/v). The genome size of strain JUR4T was found to be 3.34 Mb containing 3139 predicted protein-coding genes with a DNA G+C content of 61.5 mol%. The digital DNA–DNA hybridization and average nucleotide identity values between the genome sequence of strain JUR4T and closely related reference strains were 21.0–24.8% and 74.7–81.4%, respectively. Strain JUR4T contained diphosphatidylglycerol, phoshatidylethanolamine, one unidentified phosphoglycolipid, one unidentified aminophosphoglycolipid, one unidentified phospholipid and seven unidentified glycolipids. The major fatty acids were C16:0 and summed feature 3 (comprising C16:1
ω7c and/or C16:1
ω6c), and ubiquinone Q-8 was the sole isoprenoid quinone. So far, all species belonging to the genus

Limnohabitans

have been described as non-motile and devoid of flagella. All species were isolated from freshwater and are therefore denoted as planktonic bacteria. This present study introduces a novel motile member of

Limnohabitans

isolated from the root of rice plant, and introduces the genes associated with motility and methyl-accepting chemotaxis proteins. Phylogenetic, phenotypic, chemotaxonomic and genotypic data clearly indicates that strain JUR4T represents a novel species of the genus

Limnohabitans

for which the name Limnohabitans radicicola sp. nov. is proposed. The type strain is JUR4T (=KACC 21745T=NBRC 114484T).
High ESBL-E colonization rate among children in Gabon: a follow-up study
Authors: Hofmann Philipp , Alabi Abraham , Manouana Gédéon P. , Onwugamba Francis C. , Hasenauer Amelia , Agbanrin Maradona D. , Gouleu Christiane S. M. , Bingoulou Gédéon , Borrmann Steffen , McCall Matthew B. B. , Adegnika Ayola A.
Published: August 2021

A previous study conducted in Gabon, Central Africa, in 2010/11 found a high colonization rate with extended-spectrum β-lactamase-producing enterobacterales (ESBL-E) among children of ~34 %. Eight years later, we aimed to reassess the ESBL-E rate and previously identified risk factors for colonization in children from Gabon. We conducted a cross-sectional cohort study in 2018 on 92 outpatients under 5 years of age with diarrhoea in Lambaréné, Gabon, in whom a rectal swab was obtained at the initial medical encounter (baseline). Fifty-eight of these provided a further rectal swab 1 week afterwards. ESBL-E colonization was assessed [following the European Committee on Antimicrobial Susceptibility Testing (EUCAST)], and in confirmed ESBL-E isolates the susceptibility to meropenem and the prevalence of the most abundant ESBL genes, bla
CTX-M, bla
SHV, and bla
TEM, were investigated. At baseline, the ESBL-E colonization rate was 57 % (52/92; 95 % CI: 46–67). Hospitalization during the previous year, chicken consumption in the past week and young age were identified as independent risk factors for ESBL-E colonization at baseline. On day 7, the ESBL-E carriage rate was 72 % (42/58; 95 % CI: 59–83). All ESBL-E isolates (n=293) were susceptible to meropenem and bla
CTX-M was the most frequently detected β-lactamase gene. The ESBL-E colonization rate among children from Gabon is alarmingly high, with indications of further increase over recent years. While all ESBL-E strains remain currently susceptible to meropenem, in practice no adequate treatment is available locally for severe infections with such isolates. It is thus of the utmost importance to invest in improved hospital infection prevention and control measures to combat ESBL-E effectively.
The role of phenylalanine hydroxylase in lipogenesis in the oleaginous fungus Mortierella alpina
Authors: Wang Hongchao , Wang Chunmei , Yuan Weiwei , Chen Haiqin , Lu Wenwei , Zhang Hao , Chen Yong Q. , Zhao Jianxin , Chen Wei
Published: August 2021

Phenylalanine hydroxylase (PAH) catalyses the irreversible hydroxylation of phenylalanine to tyrosine, which is the rate-limiting reaction in phenylalanine metabolism in animals. A variety of polyunsaturated fatty acids can be synthesized by the lipid-producing fungus Mortierella alpina, which has a wide range of industrial applications in the production of arachidonic acid. In this study, RNA interference (RNAi) with the gene PAH was used to explore the role of phenylalanine hydroxylation in lipid biosynthesis in M. alpina. Our results indicated that PAH knockdown decreased the PAH transcript level by approximately 55% and attenuated cellular fatty acid biosynthesis. Furthermore, the level of NADPH, which is a critical reducing agent and the limiting factor in lipogenesis, was decreased in response to PAH RNAi, in addition to the downregulated transcription of other genes involved in NADPH production. Our study indicates that PAH is part of an overall enzymatic and regulatory mechanism supplying NADPH required for lipogenesis in M. alpina.
Efficacy and Safety of Ayurveda Intervention (AYUSH 64) as add-on therapy for patients with COVID-19 infections – An open labelled, Parallel Group, Randomized controlled clinical trial
Authors: bhardwaj Pankaj , Godatwar Pawan Kumar , Charan Jaykaran , Sharma Sanjeev , Shafi Shazia , Chauhan Nishant , Vyas Pratibha , Dutt Naveen , Midha Naresh , Jalandra Ramniwas , Sharma Meenakshi , Nag Vijaya Lakshmi , Sharma Suman , Singh Sarvesh Kumar , Sharma Praveen , Misra Sanjeev
Published: August 2021

The authors have withdrawn this manuscript because they found a serious issue in data-analysis which leads to wrong interpretation of the results. Therefore, the authors do not wish this work to be cited as reference for the project. If you have any questions, please contact the corresponding author.
Analysis of key genes and pathways associated with the pathogenesis of Type 2 diabetes mellitus
Authors: Alur Varun , Raju Varshita , Vastrad Basavaraj , Vastrad Chanabasayya , Kotturshetti Shivakumar
Published: August 2021

Type 2 diabetes mellitus (T2DM) is the most common endocrine disorder which poses a serious threat to human health. This investigation aimed to screen the candidate genes differentially expressed in T2DM by bioinformatics analysis. The expression profiling by high throughput sequencing of GSE81608 dataset was retrieved from the gene expression omnibus (GEO) database and analyzed to identify the differentially expressed genes (DEGs) between T2DM and normal controls. Then, Gene Ontology (GO) and pathway enrichment analysis, protein-protein interaction (PPI) network, modules, miRNA-hub gene regulatory network construction and TF-hub gene regulatory network construction, and topological analysis were performed. Receiver operating characteristic curve (ROC) analysis was also performed to verify the diagnostics value and expression of identified hub genes. A total of 927 DEGs (461 were up regulated and 466 down regulated genes) were identified in T2DM. GO and REACTOME results showed that DEGs mainly enriched in protein metabolic process, establishment of localization, metabolism of proteins and metabolism. The top centrality hub genes APP, MYH9, TCTN2, USP7, SYNPO, GRB2, HSP90AB1, UBC, HSPA5 and SQSTM1 were screened out as the critical genes among the DEGs from the PPI network, modules, miRNA-hub gene regulatory network construction and TF-hub gene regulatory network. ROC analysis provide diagnostics value of hub genes. This study identified key genes, signal pathways and therapeutic agents, which might help us, improve our understanding of the mechanisms of HGPS and identify some new therapeutic agents for T2DM.
Proteogenomic Discovery of Neoantigens Facilitates Personalized Multi-antigen Targeted T cell Immunotherapy for Brain Tumors
Authors: Rivero-Hinojosa Samuel , Grant Melanie , Panigrahi Aswini , Zhang Huizhen , Caisova Veronika , Bollard Catherine M. , Rood Brian R.
Published: August 2021

Neoantigen discovery in pediatric brain tumors is hampered by their low mutational burden and scant tissue availability. We developed a low-input proteogenomic approach combining tumor DNA/RNA sequencing and mass spectrometry proteomics to identify tumor-restricted (neoantigen) peptides arising from multiple genomic aberrations to generate a highly target-specific, autologous, personalized T cell immunotherapy. Our data indicate that novel splice junctions are the primary source of neoantigens in medulloblastoma, a common pediatric brain tumor. Proteogenomically identified tumor-specific peptides are immunogenic and generate MHC II-based T cell responses. Moreover, polyclonal and polyfunctional T cells specific for tumor-specific peptides effectively eliminated tumor cells in vitro. Targeting novel tumor-specific antigens obviates the issue of central immune tolerance while potentially providing a safety margin favoring combination with other immune-activating therapies. These findings demonstrate the proteogenomic discovery of immunogenic tumor-specific peptides and lay the groundwork for personalized targeted T cell therapies for children with brain tumors.
In silico Analysis of Transcriptomic Profiling and Affected Biological pathways in Multiple Sclerosis
Authors: Vaja Rutvi , Kaur Harpreet , Mazumder Mohit , Brodsky Elia
Published: August 2021

Multiple sclerosis (MS) is a chronic autoimmune, inflammatory neurological disease that is widely associated with Grey and white matter degradation due to the demyelination of axons. Thus exposing the underlying causes of this condition can lead to a novel treatment approach for Multiple Sclerosis. The total RNA microarray processed data from GEO for Multiple sclerotic patients was comprehensively analyzed to find out underlying differences between Grey Matter lesions (GML), Normal appearing Grey Matter (NAGM), and Control Grey matter at the transcriptomics level. Thus, in the current study, we performed various bioinformatics analyses on transcriptional profiles of 184 samples including 105 NAGM, 37 GML, and 42 Controls obtained from the NCBI-Bio project (PRJNA543111). First, exploratory data analysis based on gene expression data using principal component analysis (PCA) depicted distinct patterns between GML and CG samples. Subsequently, the Welch’s T-test differential gene expression analysis identified 15,525 significantly differentially expressed genes (p.adj value <0.05, Fold change(>=+/-1.5) between these conditions. This study reveals the genes like CREB3L2, KIF5B, WIPI1, EP300, NDUFA1, ATG101, AND TAF4 as the key features that may substantially contribute to loss of cognitive functions in Multiple sclerosis and several other neurodegenerative disorders. Further, this study also proposes genes associated with Huntington’s disease in Multiple sclerotic patients. Eventually, the results presented here reveal new insights into MS and how it affects the development of male primary sexual characteristics.
Harnessing secretory pathway differences between HEK293 and CHO to rescue production of difficult to express proteins
Authors: Malm Magdalena , Kuo Chih-Chung , Barzadd Mona Moradi , Mebrahtu Aman , Wistbacka Num , Razavi Ronia , Volk Anna-Luisa , Lundqvist Magnus , Kotol David , Edfors Fredrik , Gräslund Torbjörn , Chotteau Veronique , Field Ray , Varley Paul G. , Roth Robert G. , Lewis Nathan E. , Hatton Diane , Rockberg Johan
Published: August 2021

Biologics represent the fastest growing group of therapeutics, but many advanced recombinant protein moieties remain difficult to produce. Here, we identify bottlenecks limiting expression of recombinant human proteins through a systems biology analysis of the transcriptomes of CHO and HEK293 during recombinant overexpression. Surprisingly, one third of the challenging human proteins displayed improved secretion upon host cell swapping from CHO to HEK293. While most components of the secretory machinery showed comparable expression levels in both expression hosts, genes with significant expression variation were identified. Among these, ATF4, SRP9, JUN, PDIA3 and HSPA8 were validated as productivity boosters in CHO. Further, more heavily glycosylated products benefitted more from the elevated activities of the N- and O-glycosyltransferases found in HEK293. Collectively, our results demonstrate the utilization of HEK293 for expression rescue of human proteins and suggest a methodology for identification of secretory pathway components improving recombinant protein yield in HEK293 and CHO.
Bacterial DNA on the skin surface overrepresents the viable skin microbiome
Authors: Acosta Ellen M , Little Katherine A , Bratton Benjamin P , Lopez Jaime G , Mao Xuming , Payne Aimee , Donia Mohamed S , Devenport Danelle , Gitai Zemer
Published: August 2021

The skin microbiome provides vital contributions to human health. However, the spatial organization and viability of its bacterial components remain unclear. Here we apply culturing, imaging, and molecular approaches to human and mouse skin samples, and find that the skin surface is colonized by fewer viable bacteria than predicted by bacterial DNA levels. Instead, viable skin-associated bacteria are predominantly located in hair follicles and other cutaneous invaginations. Furthermore, we show that the skin microbiome has a uniquely low fraction of viable bacteria as compared to other human microbiome sites, indicating that most bacterial DNA on the skin surface is not associated with viable cells Additionally, a small number of bacterial families dominate each skin site and traditional sequencing methods overestimate both the richness and diversity of the skin microbiome. Finally, we performed an in-vivo skin microbiome perturbation-recovery study using human volunteers. Bacterial 16S rRNA gene sequencing revealed that, while the skin microbiome is remarkably stable even in the wake of aggressive perturbation, repopulation of the skin surface is driven by the underlying viable population. Our findings help explain the dynamics of skin microbiome perturbation, as bacterial DNA on the skin surface can be transiently perturbed but is replenished by a stable underlying viable population. These results address multiple outstanding questions in skin microbiome biology with significant implications for future efforts to study and manipulate it.

Significance statement

This study provides a crucial update to the skin microbiome paradigm by showing that viable bacteria of the skin microbiome are primarily localized to hair follicles and other sub-cutaneous structures rather than the skin surface. The native distribution of skin-associated bacteria has not been previously evaluated, and here we show that the skin surface has few intact bacteria while deeper structures are replete with bacterial contents. We used orthogonal approaches to evaluate the source of bacterial DNA and the dynamics of bacterial repopulation on the skin surface to develop an updated model of the skin microbiome. By adjusting the current understanding of the skin microbiome to match this model, we will be able to address outstanding questions in the field.
Molecular signature and target-specificity of inhibitory circuits formed by Martinotti cells in the mouse barrel cortex
Authors: Donato Cristina , Cabezas Carolina , Aguirre Andrea , Lourenço Joana , Potier Marie-Claude , de San Martin Javier Zorrilla , Bacci Alberto
Published: August 2021

In the neocortex, fast synaptic inhibition orchestrates both spontaneous and sensory-evoked activity. GABAergic interneurons (INs) inhibit pyramidal neurons (PNs) directly, modulating their output activity and thus contributing to balance cortical networks. Moreover, several IN subtypes also inhibit other INs, forming specific disinhibitory circuits, which play crucial roles in several cognitive functions. Here, we studied a homogeneous subpopulation of somatostatin (SST)-positive INs, the Martinotti cells (MCs) in layer 2/3 of the mouse barrel cortex (both sexes). MCs are a prominent IN subclass inhibiting the distal portion of PN apical dendrites, thus controlling dendrite electrogenesis and synaptic integration. Yet, it is poorly understood whether MCs inhibit other elements of the cortical circuits, and the connectivity properties with non-PN targets are unknown. We found that MCs have a strong preference for PN dendrites, but they also considerably connect with parvalbumin (PV)-positive, vasoactive intestinal peptide (VIP)-expressing and layer 1 (L1) INs. Remarkably, GABAergic synapses from MCs exhibited clear cell-type-specific short-term plasticity. Moreover, whereas the biophysical properties of MC-PN synapses were consistent with distal dendritic inhibition, MC-IN synapses exhibited characteristics of fast perisomatic inhibition. Finally, MC-PN connections used α5-containing GABAARs, but this subunit was not expressed by the other INs targeted by MCs. We reveal a specialized connectivity blueprint of MCs within different elements of superficial cortical layers. In addition, our results identify α5-GABAARs as the molecular fingerprint of MC-PN dendritic inhibition. This is of critical importance, given the role of α5-GABAARs in cognitive performance and their involvement in several brain diseases.

Significance statement

Martinotti cells (MCs) are a prominent subclass of SST-expressing GABAergic INs, specialized in controlling distal dendrites of PNs and taking part in several cognitive functions. Here we characterize the connectivity pattern of MCs with other INs in the superficial layers (L1 and L2/3) of the mouse barrel cortex. We found that the connectivity pattern of MCs with PNs as well as PV, VIP and L1 INs exhibit target-specific plasticity and biophysical properties. The stark specificity of α5-GABAARs at MC-PN synapses, and the lack or functional expression of this subunit by other cell types, define the molecular identity of MC-PN connections and the exclusive involvement of this outstanding inhibitory circuits in α5-dependent cognitive tasks.
Prediction of allosteric sites and signalling: insights from benchmarking datasets
Authors: Wu Nan , Strömich Léonie , Yaliraki Sophia N.
Published: August 2021

Abstract

Allostery is a pervasive mechanism which regulates the activity of proteins in living systems through binding of a molecule at a distant site from the orthosteric site of the protein. The universality of allosteric regulation complemented by the benefits of highly specific, potentially non-toxic and protein activity modulating allosteric drugs makes uncovering allosteric sites on proteins invaluable for drug discovery. However, there are few computational methods to effectively predict them. Bond-to-bond propensity analysis, a recently developed method, has successfully predicted allosteric sites for a diverse group of proteins with only the knowledge of the orthosteric sites and the corresponding ligands in 19 of 20 cases. The method is based on an energy-weighted atomistic protein graph and allows for computationally highly efficient analysis in atomistic detail. We here extended the analysis onto 432 structures of 146 proteins from two existing benchmarking datasets for allosteric proteins: ASBench and CASBench. We further refined the metrics to account for the cumulative effect of residues with high propensities and the crucial residues in a given site with two additional measures. The allosteric site is recovered for 95/113 proteins (99/118 structures) from ASBench and 32/33 proteins (304/314 structures) from CASBench, with the only a priori knowledge being the orthosteric site residues. Knowing the orthosteric ligands of the protein, the allosteric site is identified for 32/33 proteins (308/314 structures) from CASBench.
Controlling for variable transposition rate with an age-adjusted site frequency spectrum
Authors: Horvath Robert , Menon Mitra , Stitzer Michelle , Ross-Ibarra Jeffrey
Published: August 2021

Recognition of the important role of transposable elements (TEs) in eukaryotic genomes quickly led to a burgeoning literature modeling and estimating the effects of selection on TEs. Much of the empirical work on selection has focused on analyzing the site frequency spectrum (SFS) of TEs. But TEs differ from standard evolutionary models in a number of ways that can impact the power and interpretation of the SFS. For example, rather than mutating under a clock-like model, transposition often occurs in bursts which can inflate particular frequency categories compared to expectations under a standard neutral model. If a TE burst has been recent, the excess of low frequency polymorphisms can mimic the effect of purifying selection. Here, we investigate how transposition bursts affect the frequency distribution of TEs and the correlation between age and allele frequency. Using information on the TE age distribution, we propose an age-adjusted site frequency spectrum to compare TEs and neutral polymorphisms to more effectively evaluate whether TEs are under selective constraints. We show that our approach can minimize instances of false inference of selective constraint, but also allows for a correct identification of even weak selection affecting TEs which experienced a transposition burst and is robust to at least simple demographic changes. The results presented here will help researchers working on TEs to more reliably identify the effects of selection on TEs without having to rely on the assumption of a constant transposition rate.
Brain transcriptomic profiling reveals common alterations across neurodegenerative and psychiatric disorders
Authors: Sadeghi Iman , Gispert Juan D. , Palumbo Emilio , Muñoz-Aguirre Manuel , Wucher Valentin , D’Argenio Valeria , Santpere Gabriel , Navarro Arcadi , Guigo Roderic , Vilor-Tejedor Natàlia
Published: August 2021

Neurodegenerative and neuropsychiatric disorders (ND-NPs) are multifactorial, polygenic and complex behavioral phenotypes caused by brain abnormalities. Large-scale collaborative efforts have tried to identify the genetic architecture of these conditions. However, specific and shared underlying molecular pathobiology of brain illnesses is not clear. Here, we examine transcriptome-wide characterization of eight conditions, using a total of 2,633 post-mortem brain samples from patients with Alzheimer’s disease (AD), Parkinson’s disease (PD), Progressive Supranuclear Palsy (PSP), Pathological Aging (PA), Autism Spectrum Disorder (ASD), Schizophrenia (Scz), Major Depressive Disorder (MDD), and Bipolar Disorder (BP)–in comparison with 2,078 brain samples from matched control subjects.

Similar transcriptome alterations were observed between NDs and NPs with the top correlations obtained between Scz-BP, ASD-PD, AD-PD, and Scz-ASD. Region-specific comparisons also revealed shared transcriptome alterations in frontal and temporal lobes across NPs and NDs. Co-expression network analysis identified coordinated dysregulations of cell-type-specific modules across NDs and NPs. This study provides a transcriptomic framework to understand the molecular alterations of NPs and NDs through their shared- and specific gene expression in the brain.
Structural basis for feedforward control in the PINK1/parkin pathway
Authors: Sauvé Véronique , Sung George , MacDougall Emma , Kozlov Guennadi , Saran Anshu , Fakih Rayan , Fon Edward A. , Gehring Kalle
Published: August 2021

PINK1 and parkin constitute a mitochondrial quality control system mutated in Parkinson’s disease. PINK1, a kinase, phosphorylates ubiquitin to recruit parkin, an E3 ubiquitin ligase, to mitochondria. PINK1 controls both parkin localization and activity through phosphorylation of both ubiquitin and the ubiquitin-like (Ubl) domain of parkin. Here, we observe that phospho-ubiquitin can bind to two distinct sites on parkin, a high affinity site on RING1 that controls parkin localization, and a low affinity site on RING0 that releases parkin autoinhibition. Surprisingly, NMR titrations and ubiquitin vinyl sulfone assays show that the RING0 site has higher affinity for phospho-ubiquitin than the phosphorylated Ubl. Parkin could be activated by micromolar concentrations of tetra-phospho-ubiquitin chains that mimic a mitochondrion bearing multiple phosphorylated ubiquitins. A chimeric form of parkin with the Ubl domain replaced by ubiquitin was readily activated by PINK1 phosphorylation. In all cases, mutation of the binding site on RING0 abolished parkin activation. The feedforward mechanism of parkin activation confers robustness and rapidity to the PINK1-parkin pathway and likely represents an intermediate step in its evolutionary development.
Refutation of traumatic insemination in the Drosophila bipectinata species complex: Hypothesis fails critical tests
Authors: Polak Michal , McEvey Shane F.
Published: August 2021

Traumatic insemination (TI) is a rare reproductive behaviour characterized by the transfer of sperm to the female via puncture wounds inflicted across her body wall. Here, we challenge the claim made by Kamimura (2007) that males of species of the Drosophila bipectinata complex utilize a pair of claw-like processes (“claws”) to traumatically inseminate females: the claws are purported to puncture the female body wall and genital tract, and to inject sperm through the wounds into the genital tract, bypassing the vaginal opening, the route of sperm transfer occurring in other Drosophila. This supposed case of TI is widely cited and featured in prominent subject reviews. We examined high-resolution scanning electron micrographs of the claws and failed to discover any obvious “groove” for sperm transport. We demonstrated that sperm occurred in the female reproductive tract as a single integrated unit when mating flies were experimentally separated, inconsistent with the claim that sperm are injected via paired processes. The aedeagus in the bipectinata complex was imaged, and shown to deliver sperm through the vaginal opening. Laser ablation of the sharp terminal ends of the claws failed to inhibit insemination. The results refute the claim of TI in the Drosophila bipectinata species complex.
Sex-dependent resource defense in a nectar-feeding bat
Authors: Wintergerst Sabine , Winter York , Nachev Vladislav
Published: August 2021

Aggressive resource defense spans from the transient monopolization of a resource up to the long-term maintenance of a territory. While such interference competition is common in nectar-feeding birds, reports in nectar-feeding bats are rare.Glossophagabats have been observed to temporarily defend flowers but the extent of this monopolization, its effects on nectar intake, and underlying sexual differences have remained unknown. We investigated resource defense behavior ofGlossophaga muticain the laboratory. We presented bats with two patches of computer-controlled artificial flowers and tracked individual nectar intake. Furthermore, we established an automated method for detecting aggressive interactions at the artificial flowers. Theoretical models of interference competition predict more aggressive interactions when resources are spatially more clumped. To test this, we varied resource distribution across two patches from clumped to dispersed and monitored bats’ interactions in one male, one female, and four mixed-sex groups. Males engaged in aggressive interactions more often than females and in each group some individuals defended clumped artificial flowers against others. Subordinate males experienced a substantial decrease in nectar intake, while females were only marginally affected by male aggression. These results suggest that aggressive interactions and their effect on nectar intake are sex-dependent inG. mutica. Furthermore, aggressive interactions were more frequent and resource defense was only successful when resources were clumped. Our experimental set-up allowed us to perform an automated test of models of interference competition with a mammal under controlled laboratory conditions. This approach may pave the way for similar studies with other animals.

Lay summary

Males bully other males to get more food, but only when food is easy to defend. When flowers are spread out nectar-feeding bats rarely engage in fights. However, when there are rich flowers in one spot and no flowers elsewhere, some males start attacking others, denying them access to the nectar. Females do not seem bothered by such male bullies, but when there are no males around, some females become bullies themselves.