bluuebunny/crossref_metadata_2025 huggingface dataset:
Prioritization of antimicrobial targets by CRISPR-based oligo recombineering
Authors: Benns HJ. , Storch M. , Falco J. , Fisher FR. , Alves E. , Wincott CJ. , Baum J. , Baldwin GS. , Weerapana E. , Tate EW. , Child MA.
Published: February 2021

Nucleophilic amino acids are important in covalent drug development yet underutilized as antimicrobial targets. Over recent years, several chemoproteomic technologies have been developed to mine chemically-accessible residues via their intrinsic reactivity toward electrophilic probes. However, these approaches cannot discern which reactive sites contribute to protein function and should therefore be prioritized for drug discovery. To address this, we have developed a CRISPR-based Oligo Recombineering (CORe) platform to systematically prioritize reactive amino acids according to their contribution to protein function. Our approach directly couples protein sequence and function with biological fitness. Here, we profile the reactivity of >1,000 cysteines on ~700 proteins in the eukaryotic pathogenToxoplasma gondiiand prioritize functional sites using CORe. We competitively compared the fitness effect of 370 codon switches at 74 cysteines and identify functional sites in a diverse range of proteins. In our proof of concept, CORe performed >800 times faster than a standard genetic workflow. Reactive cysteines decorating the ribosome were found to be critical for parasite growth, with subsequent target-based screening validating the apicomplexan translation machinery as a target for covalent ligand development. CORe is system-agnostic, and supports expedient identification, functional prioritization, and rational targeting of reactive sites in a wide range of organisms and diseases.
Return of a lost structure in the evolution of felid dentition revisited: A DevoEvo perspective on the irreversibility of evolution
Authors: Lynch Vincent J.
Published: February 2021

There is a longstanding interest in whether the loss of complex characters is reversible (so-called “Dollo’s law”). Reevolution has been suggested for numerous traits but among the first was Kurtén (1963), who proposed that the presence of the second lower molar (M2) of the Eurasian lynx (Lynx lynx) was a violation of Dollo’s law because all other Felids lack M2. While an early and often cited example for the reevolution of a complex trait, Kurtén (1963) and Werdelin (1987) used anad hocparsimony argument to support their proposition that M2reevolved in Eurasian lynx. Here I revisit the evidence that M2reevolved in Eurasian lynx using explicit parsimony and maximum likelihood models of character evolution and find strong evidence that Kurtén (1963) and Werdelin (1987) were correct – M2reevolved in Eurasian lynx. Next, I explore the developmental mechanisms which may explain this violation of Dollo’s law and suggest that the reevolution of lost complex traits may arise from the reevolution of cis-regulatory elements and protein-protein interactions, which have a longer half-life after silencing that protein coding genes. Finally, I present a model developmental model to explain the reevolution M2in Eurasian lynx.
Mesothelial cell-derived antigen-presenting cancer-associated fibroblasts induce expansion of regulatory T cells in pancreatic cancer
Authors: Huang Huocong , Wang Zhaoning , Zhang Yuqing , Brekken Rolf A.
Published: February 2021

Multiple recent single cell RNA sequencing (scRNA-seq) studies have identified a unique cancer-associated fibroblast (CAF) population in pancreatic ductal adenocarcinoma (PDA) called antigen-presenting CAFs (apCAFs). apCAFs are characterized by the expression of MHC II molecules, suggesting a function in regulating tumor immunity. Here we integrated multiple scRNA-seq studies and found that apCAFs are derived from mesothelial cells. Our data show that during PDA progression, mesothelial cells form apCAFs by down-regulating mesothelial features and gaining the fibroblastic features, a process induced by IL-1 and TGFβ. Moreover, apCAFs directly ligate and induce naïve CD4+T cells into regulatory T cells (Tregs) in an antigen-specific manner. Our study elucidates an important but neglected cell type in the regulation of PDA immunity and may lead to targeted therapeutic strategies that can overcome immune evasion in PDA.
Arithmetic proof of the multiplicity-weighted Euler characteristic for symmetrically arranged space-filling polyhedra
Authors: Naskręcki Bartosz , Dauter Zbigniew , Jaskolski Mariusz
Published: February 2021

The puzzling observation that the famous Euler's formula for three-dimensional polyhedra V − E + F = 2 or Euler characteristic χ = V − E + F − I = 1 (where V, E, F are the numbers of the bounding vertices, edges and faces, respectively, and I = 1 counts the single solid itself) when applied to space-filling solids, such as crystallographic asymmetric units or Dirichlet domains, are modified in such a way that they sum up to a value one unit smaller (i.e. to 1 or 0, respectively) is herewith given general validity. The proof provided in this paper for the modified Euler characteristic, χm = V
m − E
m + F
m − I
m = 0, is divided into two parts. First, it is demonstrated for translational lattices by using a simple argument based on parity groups of integer-indexed elements of the lattice. Next, Whitehead's theorem, about the invariance of the Euler characteristic, is used to extend the argument from the unit cell to its asymmetric unit components.
Synthesis, crystal structure, Hirshfeld surface analysis and energy framework calculations of trans-3,7,9,9-tetramethyl-10-(prop-2-yn-1-yl)-1,2,3,4,4a,9,9a,10-octahydroacridine
Authors: Acelas Mauricio , Dugarte-Dugarte Analio , Romero Bohórquez Arnold R. , Henao José Antonio , Delgado José Miguel , Díaz de Delgado Graciela
Published: February 2021

The title heterocyclic compound, C20H27N, has been prepared in good yield (72%) via a BiCl3-catalyzed cationic Povarov reaction between N-propargyl-4-methylaniline and (±)-citronellal. The X-ray single-crystal study indicates that the structure consists of molecules connected by C—H...π contacts to produce chains, which pack in a sandwich–herringbone fashion along the b-axis direction. Hirshfeld surface analysis indicates that H...H interactions dominate by contributing 79.1% to the total surface. Energy frameworks and DFT calculations indicate a major contribution of dispersive forces to the total interaction energy.
An agent-based model for exploring the impacts of reciprocal trust on knowledge transfer within an organization
Authors: Li Hong , Li Changhong , Wang Zhan
Published: February 2021

Purpose

The effective transfer of knowledge within an organization is critical for its sustainable competitive advantage. Based on the norm of reciprocity, it can be concluded that individuals’ primary motivation to transfer their treasured knowledge can be summarized as “trust,” that is, the individuals trust their selfless transfer behavior can be reciprocated by the recipients in the future.

Design/methodology/approach

In this study, a simulation model based on knowledge transfer behavior and reciprocal trust between individuals is built through agent-based modeling and simulation to investigate the factors that influence the efficiency of knowledge transfer within an organization.

Findings

Experiments are performed to test the impact of reciprocal trust and organizational structure on the efficiency of knowledge transfer.

Originality/value

The results indicate a significant role of key elements of reciprocal trust and organizational structure, which provides relevant practical guidance for both individuals and organization managers in the context of knowledge transfer.
Endolithic microbial composition in Helliwell Hills, a newly investigated Mars‐like area in Antarctica
Authors: Coleine Claudia , Biagioli Federico , de Vera Jean Pierre , Onofri Silvano , Selbmann Laura
Published: February 2021

The diversity and composition of Antarctic cryptoendolithic microbial communities in the Mars‐analogue site of Helliwell Hills (Northern Victoria Land, Continental Antarctica) are investigated, for the first time, applying both culture‐dependent and high‐throughput sequencing approaches. The study includes all the domains of the tree of life: Eukaryotes, Bacteria and Archaea to give a complete overview of biodiversity and community structure. Furthermore, to explore the geographic distribution of endoliths throughout the Victoria Land (Continental Antarctica), we compared the fungal and bacterial community composition and structure of endolithically colonized rocks, collected in >30 sites in 10 years of Italian Antarctic Expeditions. Compared with the fungi and other eukaryotes, the prokaryotic communities were richer in species, more diverse and highly heterogeneous. Despite the diverse community compositions, shared populations were found and were dominant in all sites. Local diversification was observed and included prokaryotes as members of Alphaproteobacteria and Crenarchaeota (Archaea), the last detected for the first time in these cryptoendolithic communities. Few eukaryotes, namely lichen‐forming fungal species as Lecidella grenii, were detected in Helliwell Hills only. These findings suggest that geographic distance and isolation in these remote areas may promote the establishment of peculiar locally diversified microorganisms.
Clinical validation of a new molecular test (Seegene Allplex™ Vaginitis) for the diagnosis of vaginitis: a cross‐sectional study
Authors: Vieira‐Baptista P , Silva AR , Costa M , Aguiar T , Saldanha C , Sousa C
Published: February 2021

Objective

To validate the use of Seegene Allplex™ Vaginitis assay in the diagnosis of candidiasis, bacterial vaginosis (BV) and trichomoniasis.

Design

Cross‐sectional, prospective study conducted in a single centre.

Setting

Outpatient clinic of a gynaecology department.

Population

Consecutive symptomatic and asymptomatic women (18–60 years of age).

Methods

Comparison of the assay test with the reference standards for the diagnosis of vaginitis (cultures for yeasts, Nugent for BV and nucleic acid amplification test for trichomoniasis).

Main outcome measures

Performance of the investigational assay, in comparison with the reference standards for the diagnosis of the presence of Candida spp., Trichomonas vaginalis and BV. Secondary objectives are the evaluation of the performance of the test in postmenopausal women and in symptomatic women.

Results

A diagnosis of vaginitis was established in 14.0%. The global prevalences of BV, Candida spp. and T. vaginalis were 22.3%, 13.2% and 2.4%, respectively. The sensitivity and specificity of the assay test for those three causes of vaginitis were as follows: BV 91.7% and 86.6%; any Candida spp. 91.1% and 95.6%; Candida albicans 88.1% and 98.2%, non‐albicans Candida 100% and 97.5%, and T. vaginalis 94.4 and 99.9%. The performance of the test was identical in the subgroup of women that reported vulvovaginal symptoms. The presence of multiple infections did not interfere with the performance of the test.

Conclusions

The Seegene Allplex™ Vaginitis assay has an excellent performance in the diagnosis of the BV and presence of Candida; the results were good for trichomoniasis, but the study was underpowered for this outcome.

Tweetable abstract

Seegene Allplex™ Vaginitis is an excellent option for screening and diagnosis of vaginitis.
Deciphering bacterial mechanisms of root colonization
Authors: Knights Hayley E. , Jorrin Beatriz , Haskett Timothy L. , Poole Philip S.
Published: February 2021

Bacterial colonization of the rhizosphere is critical for the establishment of plant–bacteria interactions that represent a key determinant of plant health and productivity. Plants influence bacterial colonization primarily through modulating the composition of their root exudates and mounting an innate immune response. The outcome is a horizontal filtering of bacteria from the surrounding soil, resulting in a gradient of reduced bacterial diversity coupled with a higher degree of bacterial specialization towards the root. Bacteria–bacteria interactions (BBIs) are also prevalent in the rhizosphere, influencing bacterial persistence and root colonization through metabolic exchanges, secretion of antimicrobial compounds and other processes. Traditionally, bacterial colonization has been examined under sterile laboratory conditions that mitigate the influence of BBIs. Using simplified synthetic bacterial communities combined with microfluidic imaging platforms and transposon mutagenesis screening approaches, we are now able to begin unravelling the molecular mechanisms at play during the early stages of root colonization. This review explores the current state of knowledge regarding bacterial root colonization and identifies key tools for future exploration.
Maternal celiac disease and the risk for long‐term infectious morbidity of the offspring
Authors: Abu‐Freha Naim , Wainstock Tamar , Philip Aerin , Sheiner Eyal
Published: February 2021

Problem

Celiac disease is an autoimmune disease, patients with celiac have increased risk for infections, and offspring of celiac mothers have increased morbidity. The aim of the study was to assess long‐term infectious morbidity among offspring of pregnant women with celiac disease.

Method of Study

A population‐based cohort study was conducted, including all singleton deliveries between the years 1991–2014 at a tertiary medical center. The offsprings were subdivided into two groups: offsprings of mothers with and without celiac disease. Data on demographics, maternal, perinatal, and long‐term hospitalizations for infectious morbidity were compared between the two groups.

Results

During the study period there were 210 (0.09%) deliveries of mothers with celiac, and they were compared to 242170 (99.91%) deliveries of non‐celiac mothers. Cumulative infectious morbidity was significantly higher in offspring of mothers with celiac compared to offspring of mothers without celiac (Kaplan‐Meier, log‐rank p = .004). Specifically, among the offspring of mothers with celiac significantly higher rates of bacteremia was noted (1.0% vs. 0.1%; p = .001), and infections of the central nervous system (1% vs. 0.2%; p = .028). In the Cox multivariable model which accounted for confounding variables, being born to mothers with celiac disease was associated with significantly increased risk for long‐term infectious morbidity of the offspring (adjusted HR = 1.6, 95% CI 1.165–2.357, p = .005).

Conclusions

Maternal celiac disease is an independent risk factor for long‐term infectious morbidity for the offspring.
Risk factors for postpartum depressive symptoms among fathers: A systematic review and meta‐analysis
Authors: Ansari Najmus Sehr , Shah Jyotsna , Dennis Cindy‐Lee , Shah Prakesh S.
Published: February 2021

Introduction

The transition to parenthood is a major life change that may affect the mental well‐being of both mothers and fathers and place them at an increased risk for depression. The objective of our study was to systematically review the literature and identify factors associated with postpartum depressive symptoms in fathers.

Material and methods

Searches were conducted in PubMed, PsychInfo, Embase, and CINAHL to identify studies published until March 2020. Studies that reported factors associated with depression among fathers were included. The data from these studies were extracted independently by two authors with disagreements resolved by a third author and consensus. The odds ratio (OR) was used as a measure of association between the risk factor and the primary outcome: depression within the first 12 months following childbirth among fathers diagnosed using any method. Summary estimates were calculated using a random effects model. The associations between the risk factors and depressive symptoms were evaluated.

Results

The search identified 1040 reports. After screening titles and abstracts, 62 full‐text articles were assessed for eligibility and 25 studies involving 13 972 fathers were included in the systematic review. Fathers with a prior mental health illness episode had higher odds of developing depressive symptoms than those with no mental health history (eight studies, n = 3515, pooled OR 6.77, 95% CI 5.07–9.04; I2 = 0%). Other significant risk factors included relationship dissatisfaction (eight studies, n = 6924, pooled OR 1.53, 95% CI 1.29–1.81; I2 = 93%), maternal depression (seven studies, n = 6661, pooled OR 1.66, 95% CI 1.27–2.17; I2 = 88%), financial instability (five studies, n = 3052, pooled OR 2.24, 95% CI 1.44–3.48; I2 = 74%), paternal unemployment (three studies, n = 1505, pooled OR 6.61, 95% CI 1.94–22.54; I2 = 59%), low education level (two studies, n = 1697, pooled OR 3.56, 95% CI 1.06–11.97; I2 = 88%), and perceived stress (two studies, n = 692, pooled OR 1.06, 95% CI 1.02–1.11; I2 = 5%). Lack of support and low parenting self‐efficacy were also associated with paternal postpartum depressive symptoms.

Conclusions

A history of paternal mental illness, maternal depression, and diverse psychosocial factors were associated with depressive symptoms among fathers postnatally. These findings can guide the development of family‐level interventions for early identification and treatment and social media campaigns to promote help‐seeking behaviors and engagement in preventive strategies.
Extremely and very preterm‐born children <1500 g show different weight development in childhood compared to their peers
Authors: Geisler Inga , Rausch Tanja Katrin , Göpel Wolfgang , Spiegler Juliane
Published: February 2021

Aim

To develop reference growth charts for body mass index (BMI), weight, length and head circumference in children born extremely preterm (EPT) or very preterm (VPT) with a birth weight <1500 g.

Methods

We analysed EPT and VPT children from the German Neonatal Network born between 2009 and 2013 without chronic diseases or medications influencing growth. These data of EPT and VPT datasets were split into a training dataset and a validation dataset. In the validation dataset, data from 385 EPT and 491 VPT children from birth to age 6 years were analysed to calculate growth charts.

Results

The percentiles of length of EPT and VPT children were comparable to German reference percentiles. The BMI peak in infancy was attenuated, and BMI was lower in all the EPT and VPT children analysed. From 2 years until 6 years of age, head circumference was lower in EPT and VPT boys and girls.

Conclusion

Deficits in height described in EPT cohorts born during the 1980 s and 1990 s were not seen in our cohort. However, EPT and VPT born children showed growth patterns that differed from national reference curves for BMI. The growth charts provided here can be used to judge the growth of EPT and VPT born children.
The effect of gluten‐free diet on body mass index in paediatric celiac disease
Authors: Anafy Adi , Cohen Shlomi , Ben Tov Amir , Amir Achiya , Weintraub Yael , Moran‐Lev Hadar , Dali Levy Margalit , Ankona Bussel Maayan , Yerushalmy Feler Anat
Published: February 2021

Aim

More normal weight and overweight children are currently diagnosed with celiac disease (CD). We aimed to describe the relation between body mass index (BMI) and the clinical characteristics of paediatric CD and to determine the effect of a gluten‐free diet (GFD) on BMI.

Methods

Data on all children diagnosed with CD during 7/2010–7/2019 with documented anthropometric data at diagnosis were retrospectively analysed. The children were divided into three groups according to BMI status at diagnosis: underweight, normal weight and overweight (BMIs <5%, 5%–85% and >85%, respectively).

Results

Of the 236 children [median age 7.87 (4.91–11) years] included in the study, 24 (10.1%) were underweight at diagnosis and 32 (13.6%) were overweight. Diarrhoea as the presenting symptom was significantly more common in the overweight group (p = 0.012), while short stature was more common in the underweight group (p = 0.002). Following a GFD had no significant effect on the children's BMI during a median follow‐up of 15.7 (0–85) months, but there was a significant shift of patients between the BMI categories (p < 0.001).

Conclusion

Although a shift of patients between the BMI categories was observed, following a GFD did not significantly affect the overall BMI in children with CD.
Prevalence of and factors influencing vitamin D deficiency in paediatric patients diagnosed with cancer at northern latitudes
Authors: Jackmann Natalja , Gustafsson Jan , Harila‐Saari Arja , Ljungman Gustaf , Nezirevic Dernroth Dzeneta , Frisk Per , Mäkitie Outi
Published: February 2021

Aim

To investigate the prevalence of vitamin D deficiency among children with non‐haematological malignancies and to explore possible causes of low vitamin D levels among these patients.

Methods

We performed a cross‐sectional study of 458 children diagnosed with solid tumours, brain tumours, non‐Hodgkin lymphoma or Hodgkin disease at the University Children's Hospital, Uppsala, Sweden. Serum 25‐hydroxyvitamin D and parathyroid hormone levels were measured in samples taken at the time of cancer diagnosis and related to clinical data. Vitamin D deficiency was defined as a 25‐hydroxyvitamin D level below 50 nmol/L.

Results

The prevalence rate of vitamin D deficiency among children with non‐haematological malignancies was 41%. There was no association between sex or diagnosis and vitamin D status. Vitamin D deficiency was more common among school children than preschool children (51% vs. 24%). Older age, season outside summer, and a more recent calendar year were significant predictors of lower 25‐hydroxyvitamin D. There was a significant, albeit weak, negative correlation between 25‐hydroxyvitamin D and parathyroid hormone.

Conclusion

Vitamin D deficiency is common among children diagnosed with cancer, particularly among school‐aged children diagnosed outside summer. The prevalence appears to be increasing, underlining the need for adequate replacement of vitamin D in these patients.
Ford's Gamma‐Gamma Village Simulation Revisited: Highlighting the Need for a New Middle‐Range Theory of Archaeological Types1
Authors: MacLeod N. , Nash B.
Published: February 2021

The long‐running controversy over typological concept use in archaeological investigations hinges on whether such procedures introduce assumptions, and channel interpretations, in ways that can equate analytical groups with bounded cultural‐historical units inappropriately. James A. Ford's writings, in reaction to the arguments of Albert Spaulding, have often been cited as the founding instance of this criticism. To illustrate his concerns, Ford drew a hypothetical village of houses and used these forms to make a number of assertions regarding the nature of artifact variability that, he felt, demonstrated inherent errors with Spaulding's artifact‐analysis approach. However, despite the intense character of this controversy, both at the time and subsequently, no one appears to have tested, or confirmed, any of Ford's assertions objectively. Morphometric analyses of Ford's simulation demonstrates all published assertions of which we are aware regarding patterns of variation exhibited by these drawn artifact forms, published in the intervening 67 years, are either wholly or substantially incorrect. Both traditional and new pattern‐recognition techniques allow for the identification of more fine‐grained structure in artifact variation patterns than is possible using qualitative approaches. These findings argue strongly for a re‐evaluation of the role of typology in archaeological research.
Expression of the novel tumour suppressor sterile alpha motif and HD domain‐containing protein 1 is an independent adverse prognostic factor in classical Hodgkin lymphoma
Authors: Xagoraris Ioanna , Vassilakopoulos Theodoros P. , Drakos Elias , Angelopoulou Maria K. , Panitsas Fotios , Herold Nikolas , Medeiros L. Jeffrey , Giakoumis Xanthoula , Pangalis Gerassimos A. , Rassidakis George Z.
Published: February 2021

The expression patterns and prognostic significance of sterile alpha motif and HD domain‐containing protein 1 (SAMHD1) protein in the neoplastic Hodgkin and Reed Sternberg (HRS) cells of Hodgkin lymphoma (HL) were investigated in a cohort of 154 patients with HL treated with standard regimens. SAMHD1 expression was assessed by immunohistochemistry using diagnostic lymph node biopsies obtained prior to treatment. Using an arbitrary 20% cut‐off, SAMHD1 was positive in HRS cells of 48/154 (31·2%) patients. SAMHD1 expression was not associated with clinicopathologic parameters, such as age, gender, stage or histologic subtype. In 125 patients with a median follow‐up of 90 months (7–401 months), SAMHD1 expression in HRS cells significantly correlated with inferior freedom from progression (FFP) (P = 0·025), disease‐specific survival (DSS) (P = 0·013) and overall survival (OS) (P = 0·01). Importantly, in multivariate models together with disease stage, histology subtype and type of treatment as covariates, SAMHD1 expression retained an independent significant association with unfavourable FFP (P = 0·005) as well as DSS (P = 0·022) and OS (P = 0·018). These findings uncover the significance of a novel, adverse prognostic factor in HL that may have therapeutic implications since SAMHD1 inhibitors are now available for clinical use.
Cost‐effectiveness analysis of multiple imaging modalities in diagnosis and follow‐up of intermediate complex cystic renal lesions
Authors: Spiesecke Paul , Reinhold Thomas , Wehrenberg Yano , Werner Sven , Maxeiner Andreas , Busch Jonas , Fischer Thomas , Hamm Bernd , Lerchbaumer Markus Herbert
Published: February 2021

Objectives

To compare health‐economic aspects of multiple imaging modalities used to monitor renal cysts, the present study evaluates costs and outcomes of patients with Bosniak IIF and III renal cysts detected and followed‐up by either contrast‐enhanced computed tomography (ceCT), contrast‐enhanced magnetic resonance imaging (ceMRI), or contrast‐enhanced ultrasonography (CEUS).

Patients and Methods

A simulation using Markov models was implemented and performed with 10 cycles of 1 year each. Proportionate cohorts were allocated to Markov models by a decision tree processing specific incidences of malignancy and levels of diagnostic performance. Costs of imaging and surgical treatment were investigated using internal data of a European university hospital. Multivariate probabilistic sensitivity analysis was performed to confirm results considering input value uncertainties. Patient outcomes were measured in quality‐adjusted life years (QALY), and costs as averages per patient including costs of imaging and surgical treatment.

Results

Compared to the ‘gold standard’ of ceCT, ceMRI was more effective but also more expensive, with a resulting incremental cost‐effectiveness ratio (ICER) >€70 000 (Euro) per QALY gained. CEUS was dominant compared to ceCT in both Bosniak IIF and III renal cysts in terms of QALYs and costs. Probabilistic sensitivity analysis confirmed these results in the majority of iterations.

Conclusion

Both ceMRI and CEUS can be used as alternatives to ceCT in the diagnosis and follow‐up of intermediately complex cystic renal lesions without compromising effectiveness, while CEUS is clearly cost‐effective. The economic results apply to a large university hospital and must be adapted for smaller hospitals.
Rostral cuneiform nucleus and the defence reaction: Direct and indirect midbrain–medullary 5‐HT mechanisms in baroreflex inhibition
Authors: Netzer Florence , Sévoz‐Couche Caroline
Published: February 2021

Background and Purpose

Activation of the defence reaction inhibits the baroreflex response via the intermediate rostro‐ventromedial medulla (B3 raphé) and nucleus tractus solitarius (NTS). Our aim was to determine whether and how baroreflex inhibition, induced by the disinhibition of the rostral cuneiform nucleus (part of the defence pathway), involves 5‐HT neurons in B3 and 5‐HT3 receptors in the NTS.

Experimental Approach

We performed immunohistochemistry and anatomical experiments to determine whether raphé 5‐HT cells expressing Fos were directly targeted by the rostral cuneiform nucleus. The effect of blocking raphé 5‐HT neurotransmission and NTS 5‐HT3 receptors on cuneiform‐induced inhibition of the baroreflex cardiac response were also analysed.

Key Results

Bicuculline, microinjected into the rostral cuneiform nucleus, induced an increase of double‐labelled Fos‐5‐HT‐IR cells in both the lateral paragigantocellular nucleus (LPGi) and raphé magnus. The anterograde tracer Phaseolus vulgaris leucoaggutinin injected into the rostral cuneiform nucleus revealed a dense projection to the LPGi but not raphé magnus. Cuneiform‐induced baroreflex inhibition was prevented by B3 injection of 8‐OH‐DPAT, a selective 5‐HT1A receptor agonist. Cuneiform disinhibition also failed to inhibit the baroreflex bradycardia after NTS microinjection of the 5‐HT3 receptor antagonist granisetron and in 5‐HT3 receptor knockout mice.

Conclusion and Implications

The rostral cuneiform nucleus participates in the defence inhibition of the baroreflex bradycardia via direct activation of the LPGi and via a projection to the raphé magnus to activate NTS 5‐HT3 receptors and inhibit second‐order baroreflex neurons. These data bring new insights in primary and secondary mechanisms involved in vital baroreflex prevention during stress.
The multigene classifiers 95GC/42GC/155GC for precision medicine in ER‐positive HER2‐negative early breast cancer
Authors: Naoi Yasuto , Tsunashima Ryo , Shimazu Kenzo , Noguchi Shinzaburo
Published: February 2021

In clinical decision‐making, to decide the indication for adjuvant chemotherapy for estrogen receptor‐positive (ER+), human epidermal growth factor receptor‐2‐negative (HER2−), and node‐negative (n0) breast cancer patients, the accurate estimation of recurrence risk is essential. Unfortunately, conventional prognostic factors, such as tumor size, histological grade and ER, progesterone receptor (PR), and HER2 status as well as Ki67 index, are not sufficiently accurate for such estimation. Therefore, several multigene assays (MGAs) based on the mRNA expression analysis of multiple genes in tumor tissue have been developed to better predict patient prognosis. These assays include Oncotype DX, MammaPrint, PAM50, GGI, EndoPredict, and BCI. We developed Curebest™ 95‐Gene Classifier Breast (95GC) classifier, which is unique in that mRNA expression data of all 20 000 human genes are secondarily obtainable, as the 95GC assay is performed using Affymetrix microarray. This can capture mRNA expression of not only 95 genes but also every gene at once, and such gene expression data can be utilized by the other MGAs that we have developed, such as the 155GC, which is used for the prognostic prediction of ER+/HER2− breast cancer patients treated with neoadjuvant chemotherapy. We also developed the 42GC for predicting late recurrence in ER+/HER2− breast cancer patients. In this mini‐review, our recent attempt at the development of various MGAs, which is expected to facilitate the implementation of precision medicine in ER+/HER2− breast cancer patients, is presented with a special emphasis on 95GC.
Forty‐seven pathogenic variants causing autosomal recessive disorders are shared by Israeli and Saudi Arabian Arabs
Authors: Zlotogora Joël
Published: February 2021

Several autosomal recessive disorders that are found among Arabs in Israel were also reported in Saudi Arabia. In a sytematic review of all the variants responsible for autosomal recessive disorders among Muslim Arabs Israel and in Saudi Arabia, 47 shared variants were found, many being known founder variants in both populations. Among the 21 shared variants that were reported among Bedouins 14 were founder variants representing 14% founder/assumed founder variants known in the Bedouins. Many of the common variants are ancient having a Bedouin origin probably linked to the migration from the Saudi Peninsula. It is probable that a similar phenomenon occurred along the route of the Bedouin migrations and indeed some of these variants are present in the corresponding populations.
Maintaining family stability in the age of digital technologies: An analysis of d/Discourse informing domestic screen media practices in three US families
Authors: Willett Rebekah , Wheeler Nathan
Published: February 2021

This article examines d/Discourses about screen media and parenting as reflected in parents' discursive construction of their decision‐making processes connected with domestic media practices. The analysis focuses on three parent interviews from a dataset of 51 parent interviews conducted in three states in the USA. The article illustrates ways d/Discourses connected with health, education, ethnicity and disability that are specific to these three households intersect with d/Discourses concerning children and media. The article argues that general categories describing parenting practices overlook the microcultures of households, erasing the emotional labour embedded in processes of decision‐making.
Evaluating institutional fit for the conservation of threatened species
Authors: Guerrero A. M. , Sporne I. , McKenna R. , Wilson K. A.
Published: February 2021

Recovery and conservation of threatened species require adequate institutional responses. We tested an approach to systematically identify and measure how an institutional framework acknowledges threats and required responses for the recovery of endangered species. We measured institutional functional fit with a drivers‐pressure‐state‐impacts‐response (DPSIR) model integrated with a quantitative text mining method and qualitative analysis of statutory instruments to examine regulatory responses that support the recovery of 2 endangered species native to Australia, the bridled nailtail wallaby (Onychogalea fraenata) and the Eastern Bristlebird (Dasyornis brachypterus). The key components of the DPSIR model were present in the institutional framework at statutory and operational levels, but some institutional gaps remained in the protection and recovery of the Eastern Bristlebird, including feral predator control, weed control, and grazing management in some locations. However, regulatory frameworks varied in their geographic scope and the application and implementation of many instruments remained optional. Quantitative text mining can be used to quickly navigate a large volume of regulatory documents, but challenges remain in selection of terms, queries of co‐occurrence, and interpretation of word frequency counts. To inform policy, we recommend that quantitative assessments of institutional fit be complemented with qualitative analysis and interpreted in light of the sociopolitical and institutional context.
Striatal cholinergic transmission. Focus on nicotinic receptors’ influence in striatal circuits
Authors: Assous Maxime
Published: February 2021

The critical role of acetylcholine (ACh) in the basal ganglia is evident from the effect of cholinergic agents in patients suffering from several related neurological disorders, such as Parkinson's disease, Tourette syndrome, or dystonia. The striatum possesses the highest density of ACh markers in the basal ganglia underlying the importance of ACh in this structure. Striatal cholinergic interneurons (CINs) are responsible for the bulk of striatal ACh, although extrinsic cholinergic afferents from brainstem structures may also play a role. CINs are tonically active, and synchronized pause in their activity occurs following the presentation of salient stimuli during behavioral conditioning. However, the synaptic mechanisms involved are not fully understood in this physiological response. ACh modulates striatal circuits by acting on muscarinic and nicotinic receptors existing in several combinations both presynaptically and postsynaptically. While the effects of ACh in the striatum through muscarinic receptors have received particular attention, nicotinic receptors function has been less studied. Here, after briefly reviewing relevant results regarding muscarinic receptors expression and function, I will focus on striatal nicotinic receptor expressed presynaptically on glutamatergic and dopaminergic afferents and postsynaptically on diverse striatal interneurons populations. I will also review recent evidence suggesting the involvement of different GABAergic sources in two distinct nicotinic‐receptor‐mediated striatal circuits: the disynaptic inhibition of striatal projection neurons and the recurrent inhibition among CINs. A better understanding of striatal nicotinic receptors expression and function may help to develop targeted pharmacological interventions to treat brain disorders such as Parkinson's disease, Tourette syndrome, dystonia, or nicotine addiction.
Pathophysiology linking depression and type 2 diabetes: Psychotherapy, physical exercise, and fecal microbiome transplantation as damage control
Authors: Subba Rhea , Sandhir Rajat , Singh Surya Pratap , Mallick Birendra Nath , Mondal Amal Chandra
Published: February 2021

Diabetes increases the likelihood of developing depression and vice versa. Research on this bidirectional association has somewhat managed to delineate the interplay among implicated physiological processes. Still, further exploration is required in this context. This review addresses the comorbidity by investigating suspected common pathophysiological mechanisms. One such factor is psychological stress which disturbs the hypothalamic–pituitary–adrenal axis causing hormonal imbalance. This includes elevated cortisol levels, a common biomarker of both depression and diabetes. Disrupted insulin signaling drives the hampered neurotransmission of serotonin, dopamine, and norepinephrine. Also, adipokine hormones such as adiponectin, leptin, and resistin and the orexigenic hormone, ghrelin, are involved in both depression and T2DM. This disarray further interferes with physiological processes encompassing sleep, the gut–brain axis, metabolism, and mood stability. Behavioral coping mechanisms, such as unhealthy eating, mediate disturbed glucose homeostasis, and neuroinflammation. This is intricately linked to oxidative stress, redox imbalance, and mitochondrial dysfunction. However, interventions such as psychotherapy, physical exercise, fecal microbiota transplantation, and insulin‐sensitizing agents can help to manage the distressing condition. The possibility of glucagon‐like peptide 1 possessing a therapeutic role has also been discussed. Nonetheless, there stands an urgent need for unraveling new correlating targets and biological markers for efficient treatment.
Arginase 1+ IL‐10+ polymorphonuclear myeloid‐derived suppressor cells are elevated in patients with active pemphigus and correlate with an increased Th2/Th1 response
Authors: Neri Davide , Carevic‐Neri Melanie , Brück Jürgen , Holstein Julia , Schäfer Iris , Solimani Farzan , Handgretinger Rupert , Hartl Dominik , Ghoreschi Kamran
Published: February 2021

Myeloid‐derived suppressor cells (MDSCs) are a heterogeneous population of immature myeloid cells, which are characterized by their capability to suppress T‐cell responses. While MDSCs have been traditionally associated with cancer diseases, their role as regulators of autoimmune diseases is emerging. Pemphigus is a chronic autoimmune blistering skin disease characterized by dysregulated T‐cell responses and autoantibody production. The role of MDSCs in pemphigus disease has not been defined yet. The aim of this study was to characterize MDSCs in pemphigus patients and to dissect their relationship with CD4+ T‐cell subsets and clinical disease assessments. For this purpose, we performed a cross‐sectional analysis of 20 patients with pemphigus. Our results indicate that a population of CD66b+CD11b+ polymorphonuclear‐like MDSCs (PMN‐MDSCs) is expanded in the peripheral blood mononuclear cell fraction of pemphigus patients compared to age‐matched healthy donors. These PMN‐MDSCs have the capability of suppressing allogeneic T‐cell proliferation in vitro and show increased expression of characteristic effector molecules such as arginase I and interleukin‐10. We further demonstrate that PMN‐MDSCs are especially expanded in patients with active pemphigus, but not in patients in remission. Moreover, MDSC frequencies correlate with an increased Th2/Th1 cell ratio. In conclusion, the identification of a functional PMN‐MDSC population suggests a possible role of these cells as regulators of Th cell responses in pemphigus.
FOXP3+ regulatory T cells and age‐related diseases
Authors: Deng Biaolong , Zhang Weiqi , Zhu Yicheng , Li Yangyang , Li Dan , Li Bin
Published: February 2021

Regulatory T (Treg) cells are critical for the maintenance of immune homeostasis. Dysregulation of Treg cells has been implicated in the pathogenesis of autoimmunity and chronic inflammation, while aging is characterized by an accumulation of inflammatory markers in the peripheral blood, a phenomenon known as ‘inflammaging’. The relationship between Treg cells and age‐related diseases remains to be further studied. Increasing evidence revealed that Treg cells’ dysfunction occurs in aged patients, suggesting that immune therapies targeting Treg cells may be a promising approach to treat diseases such as cancers and autoimmune diseases. Furthermore, drugs targeting Treg cells show encouraging results and contribute to CD8+ T‐cell‐mediated cytotoxic killing of tumor and infected cells. In general, a better understanding of Treg cell function may help us to develop new immune therapies against aging. In this review, we discuss potential therapeutic strategies to modify immune responses of relevance for aging to prevent and treat age‐related diseases, as well as the challenges posed by the translation of novel immune therapies into clinical practice.
Optimal temperature of vegetation productivity and its linkage with climate and elevation on the Tibetan Plateau
Authors: Chen Anping , Huang Ling , Liu Qiang , Piao Shilong
Published: February 2021

Vegetation productivity first increases and then decreases with temperature; and temperature corresponding to the maximum productivity is called optimal temperature (Topt). In this study, we used satellite derived near‐infrared reflectance of vegetation (NIRv) data to map Topt of vegetation productivity at the spatial resolution of 0.1° on the Tibetan Plateau (TP), one of most sensitive regions in the climate system. The average Topt of non‐forest vegetation on the TP is about 14.7°C, significantly lower than the Topt value used in current ecosystem models. A remarkable geographical heterogeneity in Topt is observed over the TP. Higher Topt values generally appear in the north‐eastern TP, while the south‐western TP has relatively lower Topt (<10°C), in line with the difference of climate conditions and topography across different regions. Spatially, Topt tends to decrease by 0.41°C per 100 m increase in elevation, faster than the elevational elapse rate of growing season temperature, implying a potential CO2 regulation of Topt in addition to temperature acclimation. Topt increases by 0.66°C for each 1°C of rising mean annual temperature as a result of vegetation acclimation to climate change. However, at least at the decadal scale, there is no significant change in Topt between 2000s and 2010s, suggesting that the Topt climate acclimation may not keep up with the warming rate. Finally, future (2091–2100) warming could be close to and even surpass Topt on the TP under different RCP scenarios without considering potential climate acclimation. Our analyses imply that the temperature tipping point when the impact of future warming shifts from positive to negative on the TP is greatly overestimated by current vegetation models. Future research needs to include varying thermal and CO2 acclimation effects on Topt across different time scales in vegetation models.
Divergent species‐specific impacts of whole ecosystem warming and elevated CO2on vegetation water relations in an ombrotrophic peatland
Authors: Warren Jeffrey M. , Jensen Anna M. , Ward Eric J. , Guha Anirban , Childs Joanne , Wullschleger Stan D. , Hanson Paul J.
Published: February 2021

Boreal peatland forests have relatively low species diversity and thus impacts of climate change on one or more dominant species could shift ecosystem function. Despite abundant soil water availability, shallowly rooted vascular plants within peatlands may not be able to meet foliar demand for water under drought or heat events that increase vapor pressure deficits while reducing near surface water availability, although concurrent increases in atmospheric CO2could buffer resultant hydraulic stress. We assessed plant water relations of co‐occurring shrub (primarilyRhododendron groenlandicumandChamaedaphne calyculata) and tree (Picea marianaandLarix laricina) species prior to, and in response to whole ecosystem warming (0 to +9°C) and elevated CO2using 12.8‐m diameter open‐top enclosures installed within an ombrotrophic bog. Water relations (water potential [Ψ], turgor loss point, foliar and root hydraulic conductivity) were assessed prior to treatment initiation, then Ψ and peak sap flow (trees only) assessed after 1 or 2 years of treatments. Under the higher temperature treatments,L. laricinaΨ exceeded its turgor loss point, increased its peak sap flow, and was not able to recover Ψ overnight. In contrast,P. marianaoperated below its turgor loss point and maintained constant Ψ and sap flow across warming treatments. Similarly,C. calyculataΨ stress increased with temperature whileR. groenlandicumΨ remained at pretreatment levels. The more anisohydric behavior ofL. laricinaandC. calyculatamay provide greater net C uptake with warming, while the more conservativeP. marianaandR. groenlandicummaintained greater hydraulic safety. These latter species also responded to elevated CO2by reduced Ψ stress, which may also help limit hydraulic failure during periods of extreme drought or heat in the future. Along withSphagnummoss, the species‐specific responses of peatland vascular communities to drier or hotter conditions will shape boreal peatland composition and function in the future.
Short‐ and long‐term carbon emissions from oil palm plantations converted from logged tropical peat swamp forest
Authors: McCalmont Jon , Kho Lip Khoon , Teh Yit Arn , Lewis Kennedy , Chocholek Melanie , Rumpang Elisa , Hill Timothy
Published: February 2021

Need for regional economic development and global demand for agro‐industrial commodities have resulted in large‐scale conversion of forested landscapes to industrial agriculture across South East Asia. However, net emissions of CO2 from tropical peatland conversions may be significant and remain poorly quantified, resulting in controversy around the magnitude of carbon release following conversion. Here we present long‐term, whole ecosystem monitoring of carbon exchange from two oil palm plantations on converted tropical peat swamp forest. Our sites compare a newly converted oil palm plantation (OPnew) to a mature oil palm plantation (OPmature) and combine them in the context of existing emission factors. Mean annual net emission (NEE) of CO2 measured at OPnew during the conversion period (137.8 Mg CO2 ha−1 year−1) was an order of magnitude lower during the measurement period at OPmature (17.5 Mg CO2 ha−1 year−1). However, mean water table depth (WTD) was shallower (0.26 m) than a typical drainage target of 0.6 m suggesting our emissions may be a conservative estimate for mature plantations, mean WTD at OPnew was more typical at 0.54 m. Reductions in net emissions were primarily driven by increasing biomass accumulation into highly productive palms. Further analysis suggested annual peat carbon losses of 24.9 Mg CO2‐C ha−1 year−1 over the first 6 years, lower than previous estimates for this early period from subsidence studies, losses reduced to 12.8 Mg CO2‐C ha−1 year−1 in the later, mature phase. Despite reductions in NEE and carbon loss over time, the system remained a large net source of carbon to the atmosphere after 12 years with the remaining 8 years of a typical plantation's rotation unlikely to recoup losses. These results emphasize the need for effective protection of tropical peatlands globally and strengthening of legislative enforcement where moratoria on peatland conversion already exist.