bluuebunny/crossref_metadata_2025 huggingface dataset:
Mechanisms of reduced interspecific interference between territorial species
Authors: McEachin Shawn , Drury Jonathan P , Anderson Christopher N , Grether Gregory F
Published: September 2021

Interspecific territoriality has complex ecological and evolutionary consequences. Species that interact aggressively often exhibit spatial or temporal shifts in activity that reduce the frequency of costly encounters. We analyzed data collected over a 13-year period on 50 populations of rubyspot damselflies (Hetaerina spp.) to examine how rates of interspecific fighting covary with fine-scale habitat partitioning and to test for agonistic character displacement in microhabitat preferences. In most sympatric species, interspecific fights occur less frequently than expected based on the species’ relative densities. Incorporating measurements of spatial segregation and species discrimination into the calculation of expected frequencies accounted for most of the reduction in interspecific fighting (subtle differences in microhabitat preferences could account for the rest). In 23 of 25 sympatric population pairs, we found multivariate differences between species in territory microhabitat (perch height, stream width, current speed, and canopy cover). As predicted by the agonistic character displacement hypothesis, sympatric species that respond more aggressively to each other in direct encounters differ more in microhabitat use and have higher levels of spatial segregation. Previous work established that species with the lowest levels of interspecific fighting have diverged in territory signals and competitor recognition through agonistic character displacement. In the other species pairs, interspecific aggression appears to be maintained as an adaptive response to reproductive interference, but interspecific fighting is still costly. We now have robust evidence that evolved shifts in microhabitat preferences also reduce the frequency of interspecific fighting.
Translational aspects of novel findings in genetics of male infertility—status quo 2021
Authors: Laan Maris , Kasak Laura , Punab Margus
Published: September 2021

Introduction

Male factor infertility concerns 7–10% of men and among these 40–60% remain unexplained.

Sources of data

This review is based on recent published literature regarding the genetic causes of male infertility.

Areas of agreement

Screening for karyotype abnormalities, biallelic pathogenic variants in the CFTR gene and Y-chromosomal microdeletions have been routine in andrology practice for >20 years, explaining ~10% of infertility cases. Rare specific conditions, such as congenital hypogonadotropic hypogonadism, disorders of sex development and defects of sperm morphology and motility, are caused by pathogenic variants in recurrently affected genes, which facilitate high diagnostic yield (40–60%) of targeted gene panel-based testing.

Areas of controversy

Progress in mapping monogenic causes of quantitative spermatogenic failure, the major form of male infertility, has been slower. No ‘recurrently’ mutated key gene has been identified and worldwide, a few hundred patients in total have been assigned a possible monogenic cause.

Growing points

Given the high genetic heterogeneity, an optimal approach to screen for heterogenous genetic causes of spermatogenic failure is sequencing exomes or in perspective, genomes. Clinical guidelines developed by multidisciplinary experts are needed for smooth integration of expanded molecular diagnostics in the routine management of infertile men.

Areas timely for developing research

Di−/oligogenic causes, structural and common variants implicated in multifactorial inheritance may explain the ‘hidden’ genetic factors. It is also critical to understand how the recently identified diverse genetic factors of infertility link to general male health concerns across lifespan and how the clinical assessment could benefit from this knowledge.
Therapeutic reversal of Huntington’s disease by in vivo self-assembled siRNAs
Authors: Zhang Li , Wu Tengteng , Shan Yangyang , Li Ge , Ni Xue , Chen Xiaorui , Hu Xiuting , Lin Lishan , Li Yongchao , Guan Yalun , Gao Jinfeng , Chen Dingbang , Zhang Yu , Pei Zhong , Chen Xi
Published: September 2021

Huntington’s disease is an autosomal-dominant neurodegenerative disease caused by CAG expansion in exon 1 of the huntingtin (HTT) gene. Since mutant huntingtin (mHTT) protein is the root cause of Huntington’s disease, oligonucleotide-based therapeutic approaches using small interfering RNAs (siRNAs) and antisense oligonucleotides designed to specifically silence mHTT may be novel therapeutic strategies for Huntington’s disease. Unfortunately, the lack of an effective in vivo delivery system remains a major obstacle to realizing the full potential of oligonucleotide therapeutics, especially regarding the delivery of oligonucleotides to the cortex and striatum, the most severely affected brain regions in Huntington’s disease.

In this study, we present a synthetic biology strategy that integrates the naturally existing exosome-circulating system with artificial genetic circuits for self-assembly and delivery of mHTT-silencing siRNA to the cortex and striatum. We designed a cytomegalovirus promoter-directed genetic circuit encoding both a neuron-targeting rabies virus glycoprotein tag and an mHTT siRNA.

After being taken up by mouse livers after intravenous injection, this circuit was able to reprogramme hepatocytes to transcribe and self-assemble mHTT siRNA into rabies virus glycoprotein-tagged exosomes. The mHTT siRNA was further delivered through the exosome-circulating system and guided by a rabies virus glycoprotein tag to the cortex and striatum. Consequently, in three mouse models of Huntington’s disease treated with this circuit, the levels of mHTT protein and toxic aggregates were successfully reduced in the cortex and striatum, therefore ameliorating behavioural deficits and striatal and cortical neuropathologies.

Overall, our findings establish a convenient, effective and safe strategy for self-assembly of siRNAs in vivo that may provide a significant therapeutic benefit for Huntington’s disease.
Parkin interacting substrate phosphorylation by c-Abl drives dopaminergic neurodegeneration
Authors: Kim Hyojung , Shin Jeong-Yong , Jo Areum , Kim Ji Hun , Park Sangwook , Choi Jeong-Yun , Kang Ho Chul , Dawson Valina L , Dawson Ted M , Shin Joo-Ho , Lee Yunjong
Published: September 2021

Aberrant activation of the non-receptor kinase c-Abl is implicated in the development of pathogenic hallmarks of Parkinson’s disease, such as α-synuclein aggregation and progressive neuronal loss. c-Abl-mediated phosphorylation and inhibition of parkin ligase function lead to accumulation of parkin interacting substrate (PARIS) that mediates α-synuclein pathology-initiated dopaminergic neurodegeneration.

Here we show that, in addition to PARIS accumulation, c-Abl phosphorylation of PARIS is required for PARIS-induced cytotoxicity. c-Abl-mediated phosphorylation of PARIS at Y137 (within the Krüppel-associated box domain) drives its association with KAP1 and the repression of genes with diverse functions in pathways such as chromatin remodelling and p53-dependent cell death. One phosphorylation-dependent PARIS target, MDM4 (a p53 inhibitor that associates with MDM2; also known as MDMX), is transcriptionally repressed in a histone deacetylase-dependent manner via PARIS binding to insulin response sequence motifs within the MDM4 promoter. Virally induced PARIS transgenic mice develop c-Abl activity-dependent Parkinson’s disease features such as motor deficits, dopaminergic neuron loss and neuroinflammation. PARIS expression in the midbrain resulted in c-Abl activation, PARIS phosphorylation, MDM4 repression and p53 activation, all of which are blocked by the c-Abl inhibitor nilotinib. Importantly, we also observed aberrant c-Abl activation and PARIS phosphorylation along with PARIS accumulation in the midbrain of adult parkin knockout mice, implicating c-Abl in recessive Parkinson’s disease. Inhibition of c-Abl or PARIS phosphorylation by nilotinib or Y137F-PARIS expression in adult parkin knockout mice blocked MDM4 repression and p53 activation, preventing motor deficits and dopaminergic neurodegeneration. Finally, we found correlative increases in PARIS phosphorylation, MDM4 repression and p53 activation in post-mortem Parkinson’s disease brains, pointing to clinical relevance of the c-Abl-PARIS-MDM4-p53 pathway.

Taken together, our results describe a novel mechanism of epigenetic regulation of dopaminergic degeneration downstream of pathological c-Abl activation in Parkinson’s disease. Since c-Abl activation has been shown in sporadic Parkinson’s disease, PARIS phosphorylation might serve as both a useful biomarker and a potential therapeutic target to regulate neuronal loss in Parkinson’s disease.
Profile and management of hypertensive urgencies and emergencies in the emergency cardiology department of a tertiary hospital: a 12-month registry
Authors: Fragoulis Christos , Dimitriadis Kyriakos , Siafi Eirini , Iliakis Panagiotis , Kasiakogias Alexandros , Kalos Theodoros , Leontsinis Ioannis , Andrikou Ioannis , Konstantinidis Dimitrios , Nihoyannopoulos Petros , Tsivgoulis Georgios , Thomopoulos Costas , Tousoulis Dimitrios , Muiesan Maria L , Tsioufis Konstantinos P
Published: September 2021

Aims

Currently there are scarce epidemiological data regarding prevalence, clinical phenotype, and therapy of hypertensive urgencies (HU) and emergencies (HE). The aim of this article was to record the prevalence, clinical characteristics, and management of patients with HU and HE assessed in an emergency department (ED) of a tertiary hospital.

Methods and results

The population consisted of patients presenting with HE and HU in the ED (acute increase in systolic blood pressure (BP) ≥ 180 mmHg and/or diastolic BP ≥120 mmHg with and without acute target organ damage, respectively). Of the 38 589 patients assessed in the ED during a 12-month period, 353 (0.91%) had HU and HE. There were 256 (72.5%) cases presented as HU and 97 (27.5%) as HE. Primary causes for both HU and HE were stress/anxiety (44.9%), increased salt intake (33.9%), and non-adherence to medication (16.2%). Patients with HU reported mainly dizziness/headache (46.8%) and chest pain (27.4%), whereas those with HE presented dyspnoea (67%), chest pain (30.2%), dizziness/headache (10.3%), and neurological disorders (8.2%). In HE, the underlying associated conditions were pulmonary oedema (58%), acute coronary syndrome (22.6%), and neurological disorders/stroke (7.2%). All HE cases were hospitalized and received intensive healthcare, including dialysis.

Conclusion

This 1-year single-centre registry demonstrates a reasonable prevalence of HU and HE contributing to the high volume of visits to the ED. Stress, increased salt intake and non-adherence were main triggers of HE and HU. Dizziness and headache were the prevalent symptoms of HU patients while heart failure was the most common underlying disease in patients with HE.
Androgen-Binding Protein (Abp) Evolutionary History: Has Positive Selection Caused Fixation of Different Paralogs in Different Taxa of the Genus Mus?
Authors: Karn Robert C , Yazdanifar Golbahar , Pezer Željka , Boursot Pierre , Laukaitis Christina M
Published: September 2021

Comparison of the androgen-binding protein (Abp) gene regions of six Mus genomes provides insights into the evolutionary history of this large murid rodent gene family. We identified 206 unique Abp sequences and mapped their physical relationships. At least 48 are duplicated and thus present in more than two identical copies. All six taxa have substantially elevated LINE1 densities in Abp regions compared with flanking regions, similar to levels in mouse and rat genomes, although nonallelic homologous recombination seems to have only occurred in Mus musculus domesticus. Phylogenetic and structural relationships support the hypothesis that the extensive Abp expansion began in an ancestor of the genus Mus. We also found duplicated Abpa27’s in two taxa, suggesting that previously reported selection on a27 alleles may have actually detected selection on haplotypes wherein different paralogs were lost in each. Other studies reported that a27 gene and species trees were incongruent, likely because of homoplasy. However, L1MC3 phylogenies, supposed to be homoplasy-free compared with coding regions, support our paralog hypothesis because the L1MC3 phylogeny was congruent with the a27 topology. This paralog hypothesis provides an alternative explanation for the origin of the a27 gene that is suggested to be fixed in the three different subspecies of Mus musculus and to mediate sexual selection and incipient reinforcement between at least two of them. Finally, we ask why there are so many Abp genes, especially given the high frequency of pseudogenes and suggest that relaxed selection operates over a large part of the gene clusters.
Quantifying the influence of informal payments on self-rated health: evidence from 26 post-communist countries
Authors: Habibov Nazim , Auchynnikava Alena
Published: September 2021

In contrast to previous studies that have focused on proximal outcomes such as access to and the utilization of healthcare, this study establishes and quantifies the influence of informal payments (IP) directly on population self-rated health, which can be considered the ultimate outcome. More specifically, we examine how making informal payments influences self-rated health by testing several theoretically grounded explanations of the influence of making IP. Using the quasi-experimental instrumental variable technique increases the likelihood that our findings are not the result of reverse causality, omitted variable problem and measurement error. Our main finding is that overall, making informal payments have a negative influence on self-rated health. However, this influence is higher for men, those who are poorer, live in rural areas, have a university education and have lower social capital. Theoretical approaches that have stood out in explanations regarding the effects of making IP on self-rated health are Public Choice Theory, Institutional Theory, and Sociological Theories of Differences in Life Opportunities, Social Determinants of Health and Social Capital.
Estimated SARS-CoV-2 infection rate and fatality risk in Gauteng Province, South Africa: a population-based seroepidemiological survey
Authors: Mutevedzi Portia Chipo , Kawonga Mary , Kwatra Gaurav , Moultrie Andrew , Baillie Vicky , Mabena Nicoletta , Mathibe Masego Nicole , Rafuma Martin Mosotho , Maposa Innocent , Abbott Geoff , Hugo Janie , Ikalafeng Bridget , Adelekan Tsholofelo , Lukhele Mkhululi , Madhi Shabir A
Published: September 2021

Background

Limitations in laboratory testing capacity undermine the ability to quantify the overall burden of severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) infection.

Methods

We undertook a population-based serosurvey for SARS-CoV-2 infection in 26 subdistricts, Gauteng Province (population 15.9 million), South Africa, to estimate SARS-CoV-2 infection, infection fatality rate (IFR) triangulating seroprevalence, recorded COVID-19 deaths and excess-mortality data. We employed three-stage random household sampling with a selection probability proportional to the subdistrict size, stratifying the subdistrict census-sampling frame by housing type and then selecting households from selected clusters. The survey started on 4 November 2020, 8 weeks after the end of the first wave (SARS-CoV-2 nucleic acid amplification test positivity had declined to <10% for the first wave) and coincided with the peak of the second wave. The last sampling was performed on 22 January 2021, which was 9 weeks after the SARS-CoV-2 resurgence. Serum SARS-CoV-2 receptor-binding domain (RBD) immunoglobulin-G (IgG) was measured using a quantitative assay on the Luminex platform.

Results

From 6332 individuals in 3453 households, the overall RBD IgG seroprevalence was 19.1% [95% confidence interval (CI): 18.1–20.1%] and similar in children and adults. The seroprevalence varied from 5.5% to 43.2% across subdistricts. Conservatively, there were 2 897 120 (95% CI: 2 743 907–3 056 866) SARS-CoV-2 infections, yielding an infection rate of 19 090 per 100 000 until 9 January 2021, when 330 336 COVID-19 cases were recorded. The estimated IFR using recorded COVID-19 deaths (n = 8198) was 0.28% (95% CI: 0.27–0.30) and 0.67% (95% CI: 0.64–0.71) assuming 90% of modelled natural excess deaths were due to COVID-19 (n = 21 582). Notably, 53.8% (65/122) of individuals with previous self-reported confirmed SARS-CoV-2 infection were RBD IgG seronegative.

Conclusions

The calculated number of SARS-CoV-2 infections was 7.8-fold greater than the recorded COVID-19 cases. The calculated SARS-CoV-2 IFR varied 2.39-fold when calculated using reported COVID-19 deaths (0.28%) compared with excess-mortality-derived COVID-19-attributable deaths (0.67%). Waning RBD IgG may have inadvertently underestimated the number of SARS-CoV-2 infections and conversely overestimated the mortality risk. Epidemic preparedness and response planning for future COVID-19 waves will need to consider the true magnitude of infections, paying close attention to excess-mortality trends rather than absolute reported COVID-19 deaths.
IMB-BZ as an Inhibitor Targeting ESX-1 Secretion System to Control Mycobacterial Infection
Authors: Jia Pingping , Zhang Yi , Xu Jian , Zhu Mei , Peng Shize , Zhang Yongxin , Zhao Jianyuan , Li Xiaoyu , Mi Kaixia , Yan Dan , Wang Yucheng , Yu Liyan , Lu Yu , Shi Hanping , Cen Shan
Published: September 2021

Background

Resistance to anti-tuberculosis (TB) drugs is a major issue in TB control, and demands the discovery of new drugs targeting the virulence factor ESX-1.

Methods

We first established a high-throughput screen (HTS) assay for the discovery of ESX-1 secretion inhibitors. The positive hits were then evaluated for the potency of diminishing the survival of virulent mycobacteria and reducing bacterial virulence. We further investigated the probability of inducing drug resistance and the underlying mechanism using mycobacterial protein fragment complementation.

Results

A robust HTS assay was developed to identify small molecules that inhibit ESX-1 secretion without impairing bacterial growth in vitro. A hit named IMB-BZ specifically inhibits the secretion of CFP-10 and reduces virulence in an ESX-1–dependent manner, therefore resulting in significant reduction in intracellular and in vivo survival of mycobacteria. Blocking the CFP-10–EccCb1 interaction directly or indirectly underlies the inhibitory effect of IMB-BZ on the secretion of CFP-10. Importantly, our finding shows that the ESX-1 inhibitors pose low risk of drug resistance development by mycobacteria in vitro as compared with traditional anti-TB drugs, and exhibit high potency against chronic mycobacterial infection.

Conclusions

Targeting ESX-1 may lead to the development of novel therapeutics for tuberculosis. IMB-BZ holds the potential for future development into a new anti-TB drug.
The limited state of training on the social dimensions of antimicrobial resistance
Authors: Hofstraat Karlijn , Spaan Vera F , de Vries Daniel H
Published: September 2021

Background

Training is needed to increase awareness and understanding of the complex problem of antimicrobial resistance (AMR) among professionals. However, AMR capacity building often does not stretch beyond the biomedical sciences, limiting interdisciplinary collaboration.

Objectives

Considering the relevance of including the social sciences, this scoping review assesses the state of training on the social dimensions of AMR.

Methods

Twenty-eight training courses covering social dimensions of AMR were identified via a survey (n = 133), interviews (n = 6) and an additional internet search. General characteristics, quality and social science relevance indicators were extracted and analysed for each of these training courses.

Results

Because only 57% of the analysed training courses were fully focused on AMR, AMR was usually superficially covered, focusing on the biomedical basics and just mentioning some social aspects without using social science theories or experts. Only 3 of the 28 training courses covered AMR primarily from a social science perspective, while only 14% of the educators involved had social science expertise. Biomedical dimensions of AMR were covered twice as much as the social science dimensions. In the social science domain, institution and policy elements are most frequently covered, while transformations are the least covered.

Conclusions

There is a clear gap in educational resources on AMR, but moreover for social scientists wanting to engage in AMR, or for non-social scientists wanting to learn about the social dimensions of AMR from an interdisciplinary perspective. This gap needs to be bridged if we want social sciences to become a relevant partner in the struggle against AMR.
Canadian Association of Gastroenterology (CAG) Position Statement on the Use of Hyoscine-n-butylbromide (Buscopan) During Gastrointestinal Endoscopy
Authors: Forbes Nauzer , Frehlich Levi , Borgaonkar Mark , Leontiadis Grigorios I , Tse Frances
Published: September 2021

Hyoscine butylbromide, also known as hyoscyamine or scopolamine, and sold under the trade name Buscopan, is an antimuscarinic agent commonly used to induce smooth muscle relaxation and reduce spasmodic activity of the gastrointestinal (GI) tract during endoscopic procedures. However, the balance between desirable and undesirable (adverse) effects is not clear when used during GI endoscopy. The Clinical Affairs Committee of the Canadian Association of Gastroenterology (CAG) conducted systematic reviews and applied the Grading of Recommendations Assessment, Development and Evaluation (GRADE) approach to develop recommendations for the use of Buscopan during GI endoscopy. To summarize, we recommend against the use of Buscopan before or during colonoscopy (strong recommendation, high certainty of evidence). We suggest against the use of Buscopan before or during gastroscopy (conditional recommendation, very low certainty of evidence). We suggest the use of Buscopan before or during ERCP (conditional recommendation, very low certainty of evidence). More research is needed to determine whether patients undergoing advanced procedures such as endoscopic mucosal resection or endoscopic submucosal dissection benefit from its use. Buscopan should be used with caution in patients with cardiac comorbidities. According to its product monograph, Buscopan is contraindicated in patients with tachycardia, angina, and cardiac failure. Thus, Buscopan should be used very cautiously in patients with these conditions, and only when the potential benefits of its use outweigh the potential risks in a particular case. Such patients require careful cardiac monitoring in an environment where resuscitation equipment and appropriately trained staff to use it are readily available. According to its product monograph, Buscopan is also contraindicated in patients with prostatic hypertrophy with urinary retention, and therefore, should be used very cautiously in such patients as well, and only when the potential benefits of its use outweigh the potential risks in a particular case. Obtaining a preprocedural history of glaucoma is unlikely to be of value when considering Buscopan use. However, in cases where Buscopan has been used, patients should be counselled postprocedurally and told to present to an emergency facility should they experience eye pain, redness, decreased vision, nausea and vomiting or headache.
Litter age interacted with N and P addition to impact soil N2O emissions in Cunninghamia lanceolata plantations
Authors: Wang Shuli , Yuan Xi , Zhang Ling , Chen Fusheng , Fang Xiangmin , Liu Xiaojun , Deng Bangliang , Shad Nasir , Zhang Wenyuan , Hu Xiaofei , Guo Xiaomin , Siemann Evan
Published: September 2021

Litter decomposition impacts carbon (C) and nutrient cycling. Nitrogen (N) and phosphorus (P) addition as well as litter age impact litter decomposition. Effects of nutrient addition and litter age on litter decomposition may impact emissions of soil nitrous oxide (N2O), which is an important greenhouse gas. However, no study has examined the effects of interactions between litter age and nutrient addition on soil N2O emissions, and explored the underlining mechanisms simultaneously, thus limiting our evaluation of litter decomposition effects on N2O emissions. Litter with different age was collected from Cunninghamia lanceolata plantations experienced N and P addition treatments to examine the effects of nutrient addition and litter age on N2O emissions by incubation study. Litter age generally increased N2O emissions via a decrease in litter C:N ratio. While P addition decreased N2O emissions, N addition increased them mainly by positive effects on soil enzymes as indicated by microbial functional genes associated with N2O production and negative effects on litter C:N ratio. Litter age and nutrient addition interacted to impact soil N2O emissions. In future forest management, both nutrient addition and litter age should be considered in evaluation of management effects on N2O emissions, especially thinning or selectively cutting involving litter input with different age.
Integrated Behavioral Health Increases Well-Child Visits and Immunizations in the First Year
Authors: Ammerman Robert T , Herbst Rachel , Mara Constance A , Taylor Stuart , McClure Jessica M , Burkhardt Mary Carol , Stark Lori J
Published: September 2021

Objective

To assess whether integrated behavioral health (IBH) prevention encounters provided during well-child visits (WCVs) is associated with increased adherence to WCVs and timely immunizations in the first year.

Methods

Data were collected in an urban pediatric primary care clinic serving a low-income population and using the HealthySteps model. Subjects were 813 children who attended a newborn well-child visit between January 13, 2016 and August 8, 2017. Data from the electronic health record was extracted on attendance at six well-child visits in the first year of life, IBH prevention encounters by the HealthySteps specialist, completion of immunizations at 5 and 14 months, and demographics and social and clinical risk factors.

Results

After controlling for covariates, odds of attendance at 6, 9, and 12-month WCVs were significantly higher for those who had IBH prevention encounters at previous WCVs. Odds of immunization completion by 5 months was associated with number of IBH prevention encounters in the first 4 months (OR = 1.52, p = .001) but not immunization completion at 14 months (OR = 1.18, p = .059).

Conclusions

IBH prevention encounters were associated with increased adherence to WCVs in the first year and vaccine completion at 5 months of age. These findings are consistent with IBH having a broad positive effect on child health and health care through strong relational connections with families and providing value in addressing emotional and behavioral concerns in the context of WCVs.
Utilizing the Faxitron MultiRad 225 X-ray irradiation system for the construction of mouse chronic whole brain radiation model
Authors: He Yihua , Peng Yuqin , Chang Yuan , Zhu Juan , Li Zheqi , Huang Kaibin , Pan Suyue
Published: September 2021

Radiation-induced brain injury (RBI) is a common complication of radiotherapy for head and neck tumors while its mechanism is not fully understood. Animal whole-brain radiation (WBR) models are of key importance in experimental radiation research, and an appropriate radiation source is essential. Previous animal WBR models were administered by clinical linear accelerator to induce the pathophysiological changes of RBI. In the current study, we adopted Faxitron MultiRad 225 X-ray irradiation system to construct a mouse WBR model with a single dose of 30 Gy. In the acute phase of this mouse WBR model, brain edema and blood–brain barrier (BBB) damage were found mild. However, two months later, the results of immunofluorescence showed that astrocytes and microglia were activated continuously, and the number of immature neurons in dentate gyrus (DG) area of hippocampus was significantly reduced, in accordance with the features of chronic pathophysiological changes. Besides, data of MRI scans and behavior tests illustrated the structural changes of brain tissue and cognitive impairment in the chronic phase. To sum up, this mouse WBR model using the Faxitron MultiRad 225 irradiation system with a single dose of 30 Gy is feasible to simulate the RBI-related chronic pathophysiological changes.
The impact of lymphopenia during chemoradiotherapy using photons or protons on the clinical outcomes of esophageal cancer patients
Authors: Sumiya Taisuke , Ishikawa Hitoshi , Hiroshima Yuichi , Nakamura Masatoshi , Murakami Motohiro , Mizumoto Masashi , Okumura Toshiyuki , Sakurai Hideyuki
Published: September 2021

We assessed the development of lymphopenia during concurrent chemoradiotherapy (CRT) using X-ray versus proton beams and the impact on survival in patients with esophageal cancer. Among patients with esophageal cancer who were administered concurrent CRT with a curative intent at our institute from 2014 to 2018, 69 (15 receiving X-ray radiotherapy (XRT) and 54 receiving proton beam therapy [PBT]) who underwent weekly blood testing during treatment were enrolled. The absolute lymphocyte counts (ALC) at 1, 5 and 6 weeks were significantly higher in the patients who received PBT than in those who received XRT (p = 0.002, p = 0.006 and p = 0.009, respectively), and a similar trend in the neutrophil-to-lymphocyte ratio (NLR) was observed (p = 0.003 at 5 weeks). The 2-year overall survival (OS) and progression-free survival (PFS) rates tended to be higher in the patients who maintained an ALC ≥200 compared with those who did not (p = 0.083 and p = 0.053, respectively), and similar trends were observed in the NLR (p = 0.061 and p = 0.038, respectively). Dose–volume analysis revealed significant correlations between volumes of the thoracic bones irradiated by 5–50 Gy and minimum ALCs and maximum NLR. These findings suggested that PBT prevented the development of lymphopenia during CRT by reducing the irradiated volume of the thoracic bone, and the maintained lymphocyte count is possibly one of the early predictors for survival in patients with esophageal cancer.
Multiple caecal granular cell tumours—a case report
Authors: Fok Kar Yin , P’Ng Chow Heok , Mahajan Hema , Gosselink Martijn Pieter , El-Khoury Toufic
Published: September 2021

Granular cell tumours (GCTs) are generally benign neoplasms, which are believed to be of neural origin. They are uncommon in the gastrointestinal tract. They are rarely found in the colon and even more rarely found to be multiple. We present a case of a man who underwent a right hemicolectomy for a submucosal lesion and polyps and was found to have multiple nodules diagnosed as caecal GCTs with cellular atypia. While uncommon, this case shows it remains an important differential due to implications for patient management, given the often benign nature of disease.
Deflected Agreement and Verb Singular in Arabic: A Three-Stage Historical Model
Authors: Owens Jonathan
Published: September 2021

A categorical initial Vsg (verb in singular) in Classical Arabic (‘verbal sentence’) is unique among the Semitic languages, and can therefore be postulated to be innovative in it. This paper situates this phenomenon in the larger context of the development of so-called deflected agreement (FSG agreement with a plural subject). A three-stage historical model is developed whereby stage 2 in particular saw an explosion of FSG agreement among almost all categories of plural subject nouns. It is during this phase that categorical initial Vsg is argued to have emerged. However, the origin of the characteristic Arabic deflected agreement rule is tentatively suggested to have begun not among plural nouns but among collectives, comparable phenomena in Hebrew and Syriac indicating a West Semitic origin. The three stages are to be understood as being each associated with different speech communities, which explains why each of the stages is still attested in different parts of the Arabic-speaking world today.
Differential sensitivity to temperature and evaporative demand in wheat relatives
Authors: Leveau Stéphane , Parent Boris , Zaka Serge , Martre Pierre
Published: September 2021

There are potential sources of alleles and genes currently present in wheat-related species that have the potential to be introduced into wheat breeding programs targeting current and future hot and dry climates. However, to date neither the intra- nor the interspecific diversity of the responses of leaf growth and transpiration to temperature and evaporative demand have been investigated in across a significant range of wheat-related species. By analysing 12 groups of wheat-related species and subspecies, we were able to examine the multi-dimensional structure of the genetic diversity for traits linked to plant vegetative structures and their development, and to leaf expansion and transpiration, together with their responses to ‘non-stressing’ ranges of temperature and evaporative demand. In addition to providing new insights on how genome type, ploidy level, phylogeny, and breeding pressure act together to structure this genetic diversity, our study also provides new mathematical formalisms and associated parameters for trait responses across a wide range of genetic diversity in wheat-related species. This will potentially allow crop models to predict the impact of this diversity on yield, and thus to indicate potential sources of varietal improvement for modern wheat germplasms through interspecific crosses.
Transcriptional regulation of LGALS9 by HAND2 and FOXO1 in human endometrial stromal cells in women with regular cycles
Authors: Murata Hiromi , Tanaka Susumu , Hisamatsu Yoji , Tsubokura Hiroaki , Hashimoto Yoshiko , Kitada Masaaki , Okada Hidetaka
Published: September 2021

Uterine natural killer cells are regulated via surface inhibitory receptors for IL15 and galectin-9 (LGALS9) secreted by endometrial stromal cells (ESCs). However, the mechanism that regulates LGALS9 mRNA levels in ESCs is unclear. The aim of this study is to clarify the transcriptional regulation of LGALS9 in ESCs. Here, LGALS9 mRNA expression levels significantly decreased in the endometrial tissue in the early- to mid-secretory phase, and recovered in the mid- to late-secretory phase, compared to that in the proliferative phase. In ESCs, LGALS9 mRNA expression significantly decreased following estradiol + medroxyprogesterone acetate treatment for 1 day and increased after 12 days compared to that in the control. The transcriptional activity of the LGALS9 upstream region was upregulated by heart and neural crest derivatives expressed 2 (HAND2) and downregulated by forkhead box O1 (FOXO1). In ESCs, HAND2 expression significantly increased throughout the 12 days treatment with steroid hormones, whereas FOXO1 expression significantly increased on Day 1, reached a plateau, and significantly increased again after 6 days of treatment. Levels of FOXO1 phosphorylation (pFOXO1) remained unchanged after a 3-day treatment of ESCs with steroid hormones, but significantly increased following a 12-day treatment. pFOXO1 could not bind to the DNA and was thus unable to directly suppress LGALS9 transcription. Therefore, expression level of HAND2 and phosphorylation status of FOXO1 may determine LGALS9 mRNA expression. This study provides a novel molecular mechanism underlying the transcriptional regulation of LGALS9 mRNA in ESCs, which could be valuable in the treatment of diseases associated with decidualization failure.
Lipidomics reveals perturbations in the liver lipid profile of iron-overloaded mice
Authors: Ding Haoxuan , Zhang Qian , Yu Xiaonan , Chen Lingjun , Wang Zhonghang , Feng Jie
Published: September 2021

Iron overload is an important contributor to disease. The liver, the major site of iron storage in the body, is a key organ impacted by iron overload. While several studies have reported perturbations in liver lipids in iron overload, it is not clear, on a global scale, how individual liver lipid ions are altered. Here, we used lipidomics to study the changes in hepatic lipid ions in iron-overloaded mice. Iron overload was induced by daily intraperitoneal injections of 100 mg/kg body weight iron dextran for 1 week. Iron overload was verified by serum markers of iron status, liver iron quantitation, and Perls stain. Compared with the control group, the serum of iron-overload mice exhibited low levels of urea nitrogen and high-density lipoprotein (HDL), and high concentrations of total bile acid, low-density lipoprotein (LDL), aspartate aminotransferase (AST), alanine aminotransferase (ALT), and lactate dehydrogenase (LDH), suggestive of liver injury. Moreover, iron overload disrupted liver morphology, induced reactive oxygen species (ROS) production, reduced superoxide dismutase (SOD) activity, caused lipid peroxidation, and led to DNA fragmentation. Iron overload altered the overall composition of lipid ions in the liver, with significant changes in over 100 unique lipid ions. Notably, iron overload selectively increased the overall abundance of glycerolipids and changed the composition of glycerophospholipids and sphingolipids. This study, one of the first to report iron-overload induced lipid alterations on a global lipidomics scale, provides early insight into lipid ions that may be involved in iron overload-induced pathology.
UCTD and SLE patients show increased levels of oxidative and DNA damage together with an altered kinetics of DSB repair
Authors: Micheli Consuelo , Parma Alice , Tani Chiara , Di Bello Domenica , Falaschi Aurora , Chiaramonte Anna , Testi Serena , Mosca Marta , Scarpato Roberto
Published: September 2021

Immunological tolerance is a critical feature of the immune system; its loss might lead to an abnormal response of lymphocytes causing autoimmune diseases. One of the most important groups belonging to autoimmune disorders is the connective tissue diseases (CTD). CTD are classified among systemic rheumatic diseases and include pathologies such as systemic lupus erythematosus (SLE), and undifferentiated CTD (UCTD). In this study, we evaluated oxidative and genome damage in peripheral blood lymphocytes from patients with SLE and UCTD, further classified on the basis of disease activity and the presence/absence of a serological profile. Oxidative damage was evaluated in cell membrane using the fluorescent fatty acid analogue BODIPY581/591 C11. The percentage of oxidised lymphocytes in both SLE and UCTD patients was higher than in the control group, and the oxidative stress correlated positively with both disease activity and autoantibody profile. The γH2AX focus assay was used to quantify the presence of spontaneous double strand breaks (DSBs), and to assess the abilities of DSBs repair system after T cells were treated with mitomycin C (MMC). Subjects with these autoimmune disorders showed a higher number of γH2AX foci than healthy controls, but no correlation with diseases activity and presence of serological profile was observed. In addition, patients displayed an altered response to MMC-induced DSBs, which led their peripheral cells to greatly increase apoptosis. Taken together our results confirmed an interplay among oxidative stress, DNA damage and impaired DNA repair, which are directly correlated to the aggressiveness and clinical progression of the diseases. We propose the evaluation of these molecular markers to better characterise SLE and UCTD, aiming to improve the treatment plan and the quality of the patients’ life.
The IDEAL trial in Australia and New Zealand: clinical and economic impact
Authors: Dansie Kathryn B , Davies Christopher E , Morton Rachael L , Hawley Carmel M , Johnson David W , Craig Jonathan C , Chapman Jeremy R , Cooper Bruce A , Pollock Carol A , Harris David C H , McDonald Stephen P
Published: September 2021

Background

The impact of research findings on clinical practice usually remains uncertain and unmeasured. To address this problem, we examined the long-term clinical and economic impact of the Initiating Dialysis Early and Late (IDEAL) trial using data from the Australia and New Zealand Dialysis and Transplant Registry.

Methods

We performed a registry-based study including all incident adult dialysis patients in Australia and New Zealand from July 2000 to June 2018. A piecewise linear regression model was used to examine differences in mean estimated glomerular filtration rate (eGFR) at dialysis commencement for the years prior to (2000–2010) and following (2010–2018) publication of the IDEAL trial results. The return on investment (ROI) was calculated using the total cost of performing the IDEAL trial and the cost or savings accruing in Australia and New Zealand from changes in dialysis initiation practice.

Results

From July 2000 to June 2010, mean eGFR at dialysis commencement increased at a rate of 0.21 mL/min/1.73 m2/year [95% confidence interval (CI) 0.19–0.23]. After the IDEAL trial results were published, mean eGFR at dialysis commencement did not show any temporal change [−0.01 mL/min/1.73 m2/year (95% CI −0.03–0.01)]. The ROI of the IDEAL trial was AU$35.70/AU$1 spent, an estimated savings to the Australian and New Zealand health systems of up to AU$84 million/year.

Conclusions

The previous trend to higher eGFR at dialysis commencement changed following publication of the IDEAL trial results to a steady eGFR that has continued for a decade, avoiding unnecessary dialysis treatments and accruing savings to the Australian and New Zealand health systems.
The Effect of Nomenclature Revision of Streptococcus bovis to Streptococcus gallolyticus on Subsequent Colon Cancer Screening
Authors: Thind Sharanjeet K , Shibib Dena R , Gentry Chris A
Published: September 2021

Background

Lack of awareness of the taxonomic revision from the familiar Streptococcus bovis to the less familiar Streptococcus gallolyticus may be associated with a decrease in recommended colon cancer screening in patients with bacteremia from this organism. This could subsequently lead to a delay in diagnosis or underdiagnosis of colon cancer and other serious underlying gastrointestinal diseases. The aim of this study was to determine whether the nomenclature change of S. bovis to S. gallolyticus resulted in decreased colon cancer screening.

Methods

This study was a retrospective, observational, nationwide analysis of patients who had positive blood cultures for S. bovis/S. gallolyticus from any Veterans Affairs Medical Center (VAMC) between January 1, 2002, and December 31, 2017.

Results

There was no difference in the primary end point of intent for colonoscopy between the S. gallolyticus and S. bovis groups (66.5% [117/176] vs 62.1% [624/1005], respectively; P = .26). The overall mortality rate was 33.8% among 1181 patients included in the study, with a significantly lower mortality in patients with evidence of intent for colonoscopy (29.6% vs 42.5%; P ≤ .001), gastroenterology (GI) consultation (29.8% vs 41.4%; P < .001), infectious diseases (ID) consultation (29.4% vs 39.0%; P = .001), or either consultation (31.9% vs 40.7%; P = .013), compared to those that did not.

Conclusions

There was no difference in colon cancer screening rates between patients with episodes of bacteremia reported as S. bovis and those reported as S. gallolyticus. Overall mortality was lower in patients who had ID consultation, GI consultation, or evidence of colonoscopy.
Outstanding Questions on the Beneficial Role of Silicon in Crop Plants
Authors: Shivaraj S M , Mandlik Rushil , Bhat Javaid Akhter , Raturi Gaurav , Elbaum Rivka , Alexander Lux , Tripathi Durgesh Kumar , Deshmukh Rupesh , Sonah Humira
Published: September 2021

Silicon (Si) is widely accepted as a beneficial element for plants. Despite the substantial progress made in understanding Si transport mechanisms and modes of action in plants, several questions remain unanswered. In this review, we discuss such outstanding questions and issues commonly encountered by biologists studying the role of Si in plants in relation to Si bioavailability. In recent years, advances in our understanding of the role of Si-solubilizing bacteria and the efficacy of Si nanoparticles have been made. However, there are many unknown aspects associated with structural and functional features of Si transporters, Si loading into the xylem, and the role of specialized cells like silica cells and compounds preventing Si polymerization in plant tissues. In addition, despite several 1,000 reports showing the positive effects of Si in high as well as low Si-accumulating plant species, the exact roles of Si at the molecular level are yet to be understood. Some evidence suggests that Si regulates hormonal pathways and nutrient uptake, thereby explaining various observed benefits of Si uptake. However, how Si modulates hormonal pathways or improves nutrient uptake remains to be explained. Finally, we summarize the knowledge gaps that will provide a roadmap for further research on plant silicon biology, leading to an exploration of the benefits of Si uptake to enhance crop production.
In action—an early warning system for the detection of unexpected or novel pathogens
Authors: Santos Pauline Dianne , Ziegler Ute , Szillat Kevin P , Szentiks Claudia A , Strobel Birte , Skuballa Jasmin , Merbach Sabine , Grothmann Pierre , Tews Birke Andrea , Beer Martin , Höper Dirk
Published: September 2021

Proactive approaches in preventing future epidemics include pathogen discovery prior to their emergence in human and/or animal populations. Playing an important role in pathogen discovery, high-throughput sequencing (HTS) enables the characterization of microbial and viral genetic diversity within a given sample. In particular, metagenomic HTS allows the unbiased taxonomic profiling of sequences; hence, it can identify novel and highly divergent pathogens such as viruses. Newly discovered viral sequences must be further investigated using genomic characterization, molecular and serological screening, and/or invitro and invivo characterization. Several outbreak and surveillance studies apply unbiased generic HTS to characterize the whole genome sequences of suspected pathogens. In contrast, this study aimed to screen for novel and unexpected pathogens in previously generated HTS datasets and use this information as a starting point for the establishment of an early warning system (EWS). As a proof of concept, the EWS was applied to HTS datasets and archived samples from the 2018–9 West Nile virus (WNV) epidemic in Germany. A metagenomics read classifier detected sequences related to genome sequences of various members of Riboviria. We focused the further EWS investigation on viruses belonging to the families Peribunyaviridae and Reoviridae, under suspicion of causing co-infections in WNV-infected birds. Phylogenetic analyses revealed that the reovirus genome sequences clustered with sequences assigned to the species Umatilla virus (UMAV), whereas a new peribunyavirid, tentatively named ‘Hedwig virus’ (HEDV), belonged to a putative novel genus of the family Peribunyaviridae. In follow-up studies, newly developed molecular diagnostic assays detected fourteen UMAV-positive wild birds from different German cities and eight HEDV-positive captive birds from two zoological gardens. UMAV was successfully cultivated in mosquito C6/36 cells inoculated with a blackbird liver. In conclusion, this study demonstrates the power of the applied EWS for the discovery and characterization of unexpected viruses in repurposed sequence datasets, followed by virus screening and cultivation using archived sample material. The EWS enhances the strategies for pathogen recognition before causing sporadic cases and massive outbreaks and proves to be a reliable tool for modern outbreak preparedness.