bluuebunny/crossref_metadata_2025 huggingface dataset:
Dorsal Pigmentation and Its Association with Functional Variation inMC1Rin a Lizard from Different Elevations on the Qinghai–Tibetan Plateau
Authors: Jin Yuanting , Tong Haojie , Shao Gang , Li Jiasheng , Lv Yudie , Wo Yubin , Brown Richard P , Fu Caiyun
Published: October 2020

Identification of the role of the MC1R gene has provided major insights into variation in skin pigmentation in several organisms, including humans, but the evolutionary genetics of this variation is less well established. Variation in this gene and its relationship with degree of melanism was analyzed in one of the world’s highest-elevation lizards, Phrynocephalus theobaldi from the Qinghai–Tibetan Plateau. Individuals from the low-elevation group were shown to have darker dorsal pigmentation than individuals from a high-elevation group. The existence of climatic variation across these elevations was quantified, with lower elevations exhibiting higher air pressure, temperatures, and humidity, but less wind and insolation. Analysis of the MC1R gene in 214 individuals revealed amino acid differences at five sites between intraspecific sister lineages from different elevations, with two sites showing distinct fixed residues at low elevations. Three of the four single-nucleotide polymorphisms that underpinned these amino acid differences were highly significant outliers, relative to the generalized MC1R population structuring, suggestive of selection. Transfection of cells with an MC1R allele from a lighter high-elevation population caused a 43% reduction in agonist-induced cyclic AMP accumulation, and hence lowered melanin synthesis, relative to transfection with an allele from a darker low-elevation population. The high-elevation allele led to less efficient integration of the MC1R protein into melanocyte membranes. Our study identifies variation in the degree of melanism that can be explained by four or fewer MC1R substitutions. We establish a functional link between these substitutions and melanin synthesis and demonstrate elevation-associated shifts in their frequencies.
Interpreting k-mer–based signatures for antibiotic resistance prediction
Authors: Jaillard Magali , Palmieri Mattia , van Belkum Alex , Mahé Pierre
Published: October 2020

Background

Recent years have witnessed the development of several k-mer–based approaches aiming to predict phenotypic traits of bacteria on the basis of their whole-genome sequences. While often convincing in terms of predictive performance, the underlying models are in general not straightforward to interpret, the interplay between the actual genetic determinant and its translation as k-mers being generally hard to decipher.

Results

We propose a simple and computationally efficient strategy allowing one to cope with the high correlation inherent to k-mer–based representations in supervised machine learning models, leading to concise and easily interpretable signatures. We demonstrate the benefit of this approach on the task of predicting the antibiotic resistance profile of a Klebsiella pneumoniae strain from its genome, where our method leads to signatures defined as weighted linear combinations of genetic elements that can easily be identified as genuine antibiotic resistance determinants, with state-of-the-art predictive performance.

Conclusions

By enhancing the interpretability of genomic k-mer–based antibiotic resistance prediction models, our approach improves their clinical utility and hence will facilitate their adoption in routine diagnostics by clinicians and microbiologists. While antibiotic resistance was the motivating application, the method is generic and can be transposed to any other bacterial trait. An R package implementing our method is available at https://gitlab.com/biomerieux-data-science/clustlasso.
Increased Expression of miR-487b Is Associated With Poor Prognosis and Tumor Progression of HBV-Related Hepatocellular Carcinoma
Authors: Cao Xiangang , Yang Qian , Yu Qing
Published: October 2020

Background

Increasing evidence has demonstrated the involvement of microRNAs in the pathogenesis of hepatitis B virus (HBV)–related hepatocellular carcinoma (HCC). The aims of this study were to analyze whether miR-487b can be used as a diagnostic and prognostic biomarker for HBV-related HCC and to explore its effect on the biological function of HCC.

Methods

The expression levels of miR-487b in the serum of all subjects were measured by real-time quantitative fluorescence polymerase chain reaction. The diagnostic value of miR-487b in serum was assessed using the receiver operating characteristic (ROC) curve. The relationship between miR-487b and the clinical data of patients was analyzed using the chi-square test. The prognostic value of miR-487b in HCC was assessed by Cox regression analysis and Kaplan-Meier survival. Moreover, CCK-8 and Transwell assays were performed to investigate the effect of miR-487b on HBV-related HCC function.

Results

Our data indicated that miR-487b in HCC patients was significantly higher than in chronic hepatitis B (CHB) patients and healthy controls. Meanwhile, the ROC curve showed that miR-487b had high specificity and sensitivity in the diagnosis of HBV-related HCC. MiR-487b can significantly distinguish between HCC patients and healthy controls and can differentiate HCC patients from CHB patients. Cox regression analysis showed that miR-487b was an independent risk factor. Overexpression of miR-487b was associated with Tumor Node Metastasis stage stage and Barcelona Clinic Liver Cancer stage in HCC patients. Cell function experiments demonstrated that upregulated miR-487b promoted cell proliferation, migration, and invasion.

Conclusions

Combined the results of the current study demonstrate that the upregulation of serum miR-487b may serve as a promising noninvasive diagnostic biomarker for HBV-related HCC.
One Health for neglected tropical diseases
Authors: Laing Gabrielle , Vigilato Marco Antonio Natal , Cleaveland Sarah , Thumbi S M , Blumberg Lucille , Salahuddin Naseem , Abela-Ridder Bernadette , Harrison Wendy
Published: October 2020

The forthcoming World Health Organization road map for neglected tropical diseases (NTDs) 2021–2030 recognises the complexity surrounding control and elimination of these 20 diseases of poverty. It emphasises the need for a paradigm shift from disease-specific interventions to holistic cross-cutting approaches coordinating with adjacent disciplines. The One Health approach exemplifies this shift, extending beyond a conventional model of zoonotic disease control to consider the interactions of human and animal health systems within their shared environment and the wider social and economic context. This approach can also promote sustainability and resilience within these systems. To achieve the global ambition on NTD elimination and control, political will, along with contextualised innovative scientific strategies, is required.
Quaternary range dynamics and taxonomy of the Mediterranean collared dwarf racer,Platyceps collaris(Squamata: Colubridae)
Authors: Šmíd Jiří , Aghová Tatiana , Velenská Doubravka , Moravec Jiří , Balej Petr , Naumov Borislav , Popgeorgiev Georgi , Üzüm Nazan , Avci Aziz , Jablonski Daniel
Published: October 2020

The geological and geographical settings of the Eastern Mediterranean have resulted in complex patterns of intraspecific diversifications and phylogeographical histories that can be observed in squamates. In this study, we examined genetic differentiation of the Collared dwarf racer (Platyceps collaris) using a multilocus genetic dataset with a sampling that covered the entire range of the species. We developed distribution models in current and past climatic conditions to assess the dynamics of the species distribution through time. We sequenced a fragment of the cytochrome b mitochondrial gene of the holotype and eight paratypes of Coluber rubriceps thracius, which is considered a synonym of Platyceps collaris. Our results show that there are two distinct clades within P. collaris, one occupying the Balkans and western and southern Anatolia (termed the Balkan–Anatolian clade), the other in the Levant (termed the Levantine clade). All type specimens of C. r. thracius are genetically identical and cluster within the Balkan–Anatolian clade. Distribution models indicate the presence of two refugia during climatically challenging periods. One was in western Anatolia and served as a source for the colonization of the Balkans and southern Anatolia, and the other was in the northern Levant, from where P. collaris dispersed further south. According to our results, we revise the subspecific taxonomy of P. collaris.
Epidemiology of Autoimmune Hepatitis (AIH) in the United States Between 2014 and 2019
Authors: Tunio Nahel A. , Mansoor Emad , Sheriff Mohammed Z. , Cooper Gregory S. , Sclair Seth N. , Cohen Stanley M.
Published: October 2020

Background and Aims:

Autoimmune hepatitis (AIH) is a chronic, inflammatory disease of the liver with increasing prevalence. However, limited epidemiological data exist for the prevalence of AIH in the United States. We used a large database to describe the prevalence of AIH in the United States and the autoimmune diseases associated with it.

Approach and Results:

Data was collected from a commercial database (Explorys Inc., Cleveland, OH), an aggregate of Electronic Health Record data from 26 major integrated health care systems in the United States. We identified a cohort of patients with a diagnosis of AIH from April 2014 to April 2019 based on a Systemized Nomenclature of Medicine—Clinical Terms and calculated the prevalence of AIH. Of the 37,161,280 individuals active in the database from April 2014 to 2019, we identified 11,600 individuals with a diagnosis of AIH with an overall prevalence rate of 31.2/100,000. The prevalence of AIH was increased in females compared with males [odds ratio (OR)=3.21, P<0.0001], elderly (aged above 65 y) compared with adults (aged 18 to 65 y) and children (aged below 18 y) (OR=2.51, P<0.0001) and whites compared with African Americans, Asians, and Hispanics (OR=1.12, P<0.0001). Moreover, patients with AIH were more likely to have Sjögren syndrome, systemic lupus erythematosus, ulcerative colitis, celiac disease, rheumatoid arthritis, Crohn’s disease, and autoimmune thyroiditis as compared with patients without AIH.

Conclusions:

We found that the estimated prevalence of AIH in the United States is 31.2/100,000, which is comparable to the reported prevalence of AIH in Europe. We confirmed that AIH has a strong association with other autoimmune diseases studied in the literature.
The Correlative Factors and Probable Mechanism of Epidural Fluid Collection After Cranioplasty
Authors: Zhang Shangming , Li Songyuan , Wei Liangfeng , Chen Hongjie , Wang Shousen , Wang Wei
Published: October 2020

Objective:

Epidural fluid collection (EFC) is one of the postoperative complications of cranioplasty and is easily ignored. Not only the predictive factors of EFC formation are unknown, the pathologic mechanisms are also unknown. We determined to analyze the predictive factors and the mechanism of EFC formation.

Methods:

A total of 340 patients underwent cranioplasty were retrospectively analyzed in this study. A series of factors were compared in the EFC and none-EFC groups and farther compared in the progress epidural fluid collection (PEFC) and none-PEFC subgroups to determine the predictive factors. The t test, χ
2 test, and logistic regression analysis were used in statistical analysis.

Results:

The rate of EFC formation was 34.41%, and the size of skull defect, preoperative volume of collapse, intraoperative dura suspending, a pre- or intraoperative ventriculoperitoneal shunt (V-P shunt), and an postoperative air bubble in epidural space were predictive factors for EFC formation. Furthermore, the incidence of PEFC was 10.29%, the size of skull defects and intraoperative dura suspending were predictive factors for PEFC formation. The protein ratio and lactate dehydrogenase (LDH) ratio of effusion to serum were >0.5 and 0.6, respectively. There was no adverse prognosis.

Conclusions:

Although EFC can be treated with conservative therapy, we need to emphasize EFC incidence and development. As neurosurgeons, it is necessary to analyze the preoperative predictive factors of EFC, pay attention to the intraoperative details such as dura suspending to prevent PEFC formation, and the early intervention should be performed in the postoperative.
Perioperative Nonsteroidal Anti-inflammatory Drugs (NSAID) Administration and Acute Kidney Injury (AKI) in Major Gastrointestinal Surgery
Authors:   STARSurg Collaborative
Published: October 2020

Objective:

This study aimed to determine the relationship between early postoperative nonsteroidal anti-inflammatory drug (NSAID) administration and postoperative acute kidney injury (AKI) and anastomotic leak.

Summary Background Data:

NSAIDs have analgesic, opioid-sparing, and anti-inflammatory effects. However, their postoperative use is limited by concerns around increased risk of AKI and anastomotic leak.

Methods:

A secondary analysis of a multicenter, prospective cohort study including patients undergoing elective or emergency major gastrointestinal surgery from September to December 2015 across 173 hospitals in the United Kingdom and ireland. Exposure to early postoperative NSAIDs was defined as NSAID administration on postoperative days 0 to 3. The primary outcome was the 7-day postoperative AKI rate. Propensity score matching was used to balance treatment groups and estimate treatment effects that are presented as odds ratios, alongside the corresponding 95% confidence interval (CI).

Results:

Overall 19.8% (1039/5240) of patients received early NSAIDs. AKI rates were 10.6% in the early NSAID group and 14.9% in the no NSAID group. The anastomotic leak rate in patients who received an anastomosis was 4.8% in the NSAIDs group and 6.0% in the no NSAIDs group. Following propensity score matching, early use of NSAIDs was not significantly associated with AKI (adjusted odds ratio 0.80, 95% CI 0.63–1.00, P = 0.057). This finding was consistent in subgroup analyses by NSAID dosage and timing. In patients who had a gastrointestinal anastomosis, NSAIDs were not associated with anastomotic leak (adjusted odds ratio 0.85, 95% CI 0.58–1.21, P = 0.382).

Conclusions:

Administration of NSAIDs in the early postoperative period is safe in selected patients following major gastrointestinal surgery.
On convergence and asymptotic behaviour of semigroups of operators
Authors: Bobrowski Adam , Rudnicki Ryszard
Published: October 2020

The classical and modern theorems on convergence, approximation and asymptotic stability of semigroups of operators are presented, and their applications to recent biological models are discussed.

This article is part of the theme issue ‘Semigroup applications everywhere’.
On operator semigroups arising in the study of incompressible viscous fluid flows
Authors: Hieber Matthias
Published: October 2020

This article concentrates on various operator semigroups arising in the study of viscous and incompressible flows. Of particular concern are the classical Stokes semigroup, the hydrostatic Stokes semigroup, the Oldroyd as well as the Ericksen–Leslie semigroup. Besides their intrinsic interest, the properties of these semigroups play an important role in the investigation of the associated nonlinear equations.

This article is part of the theme issue ‘Semigroup applications everywhere’.
Maximal inequalities for stochastic convolutions in 2-smooth Banach spaces and applications to stochastic evolution equations
Authors: van Neerven Jan , Veraar Mark
Published: October 2020

This paper presents a survey of maximal inequalities for stochastic convolutions in 2-smooth Banach spaces and their applications to stochastic evolution equations.

This article is part of the theme issue ‘Semigroup applications everywhere’.
Azithromycin resistance mutations in Streptococcus pneumoniae as revealed by a chemogenomic screen
Authors: Gingras Hélène , Patron Kévin , Leprohon Philippe , Ouellette Marc
Published: October 2020

We report on the combination of chemical mutagenesis, azithromycin selection and next-generation sequencing (Mut-Seq) for the identification of small nucleotide variants that decrease the susceptibility of

Streptococcus pneumoniae

to the macrolide antibiotic azithromycin. Mutations in the 23S ribosomal RNA or in ribosomal proteins can confer resistance to macrolides and these were detected by Mut-Seq. By concentrating on recurrent variants, we could associate mutations in genes implicated in the metabolism of glutamine with decreased azithromycin susceptibility among

S. pneumoniae

mutants. Glutamine synthetase catalyses the transformation of glutamate and ammonium into glutamine and its chemical inhibition is shown to sensitize

S. pneumoniae

to antibiotics. A mutation affecting the ribosomal-binding site of a putative ribonuclease J2 is also shown to confer low-level resistance. Mut-Seq has the potential to reveal chromosomal changes enabling high resistance as well as novel events conferring more subtle phenotypes.
Prenatal Environmental Stressors Impair Postnatal Microglia Function and Adult Behavior in Males
Authors: Block Carina L. , Eroglu Oznur , Mague Stephen D. , Sriworarat Chaichontat , Blount Cameron , Malacon Karen E. , Beben Kathleen A. , Ndubuizu Nkemdilim , Talbot Austin , Gallagher Neil M. , Jo Young Chan , Nyangacha Timothy , Carlson David E. , Dzirasa Kafui , Eroglu Cagla , Bilbo Staci D.
Published: October 2020

Gestational exposure to environmental toxins and socioeconomic stressors are epidemiologically linked to neurodevelopmental disorders with strong male-bias, such as autism. We modeled these prenatal risk factors in mice, by co-exposing pregnant dams to an environmental pollutant and limited-resource stress, which robustly activated the maternal immune system. Only male offspring displayed long-lasting behavioral abnormalities and alterations in the activity of brain networks encoding social interactions. Cellularly, prenatal stressors diminished microglial function within the anterior cingulate cortex, a central node of the social coding network, in males during early postnatal development. Genetic ablation of microglia during the same critical period mimicked the impact of prenatal stressors on a male-specific behavior, indicating that environmental stressors alter neural circuit formation in males via impairing microglia function during development.
Early induction of SARS-CoV-2 specific T cells associates with rapid viral clearance and mild disease in COVID-19 patients
Authors: Tan Anthony T. , Linster Martin , Tan Chee Wah , Le Bert Nina , Chia Wan Ni , Kunasegaran Kamini , Zhuang Yan , Tham Christine Y. L. , Chia Adeline , Smith Gavin J. , Young Barnaby , Kalimuddin Shirin , Low Jenny G. H. , Lye David , Wang Lin-Fa , Bertoletti Antonio
Published: October 2020

Virus-specific humoral and cellular immunity act synergistically to protect the host from viral infection. We interrogated the dynamic changes of virological and immunological parameters in 12 patients with symptomatic acute SARS-CoV-2 infection from disease onset to convalescence or death. We quantified SARS-CoV-2 viral RNA in the respiratory tract in parallel with antibodies and circulating T cells specific for various structural (NP, M, ORF3a and spike) and non-structural proteins (ORF7/8, NSP7 and NSP13). We observed that while rapid induction and quantity of humoral responses were associated with increased disease severity, an early induction of SARS-CoV-2 specific T cells was present in patients with mild disease and accelerated viral clearance. These findings provide further support for a protective role of SARS-CoV-2 specific T cells over antibodies during SARS-CoV-2 infection with important implications in vaccine design and immune-monitoring.
A drug-screening platform based on organotypic cultures identifies vulnerabilities to prevent local relapse and treat established brain metastasis
Authors: Zhu Lucía , Yebra Natalia , Retana Diana , Miarka Lauritz , Hernández-Encinas Elena , Blanco-Aparicio Carmen , Martínez Sonia , Soffietti Riccardo , Bertero Luca , Cassoni Paola , Weiss Tobias , Muñoz Javier , Sepúlveda Juan Manuel , Pérez-Núñez Ángel , Hernández-Laín Aurelio , Ruano Yolanda , Toldos Oscar , Caleiras Eduardo , Megías Diego , Graña-Castro Osvaldo , Nör Carolina , Taylor Michael D. , Cussó Lorena , Desco Manuel , Weller Michael , Pastor Joaquín , Valiente Manuel
Published: October 2020

Exclusion of brain metastases from clinical trials is a major cause of the limited therapeutic options for this growing population of cancer patients. Here, we report a medium-throughput drug-screening platform (METPlatform) based on organotypic cultures that allows to evaluate inhibitors against metastases growingin situ. By applying this approach to brain metastasis, we identified several hits from a library of FDA approved inhibitors and others being tested in clinical trials. A blood-brain barrier permeable HSP90 inhibitor showed high potency against mouse and human brain metastases at clinically relevant stages of the disease, including a novel model of local relapse after neurosurgery. Furthermore,in situproteomic analysis applied to organotypic cultures with metastases treated with the chaperone inhibitor revealed novel biomarkers in human brain metastasis and actionable mechanisms of resistance. Our work validates METPlatform as a potent resource for metastasis research integrating drug-screening and unbiased omic approaches that is fully compatible with human samples. We envision that METPlatform could be established as a clinically relevant strategy to personalize the management of metastatic disease in the brain and elsewhere.

Systemic spread of cancer continues to be the key aspect associated with lethality. In this publication, Zhu et al. describes a drug-screening platform specifically designed to study vulnerabilities of metastasis when colonizing secondary organs and demonstrates its value in difficult-to-treat brain metastasis using new models and patient-derived samples.
Infertility due to defective sperm flagella caused by an intronic deletion in DNAH17 that perturbs splicing
Authors: Nosková Adéla , Hiltpold Maya , Janett Fredi , Echtermann Thomas , Fang Zih-Hua , Sidler Xaver , Selige Christin , Hofer Andreas , Neuenschwander Stefan , Pausch Hubert
Published: October 2020

Artificial insemination in pig (Sus scrofa domesticus) breeding involves the evaluation of the semen quality of breeding boars. Ejaculates that fulfill predefined quality requirements are processed, diluted and used for inseminations. Within short time, eight Swiss Large White boars producing immotile sperm that had multiple morphological abnormalities of the sperm flagella were noticed at a semen collection center. The eight boars were inbred on a common ancestor suggesting that the novel sperm flagella defect is a recessive trait. Transmission electron microscopy cross-sections revealed that the immotile sperm had disorganized flagellar axonemes. Haplotype-based association testing involving microarray-derived genotypes at 41,094 SNPs of six affected and 100 fertile boars yielded strong association (P=4.22 × 10−15) at chromosome 12. Autozygosity mapping enabled us to pinpoint the causal mutation on a 1.11 Mb haplotype located between 3,473,632 and 4,587,759 bp. The haplotype carries an intronic 13-bp deletion (Chr12:3,556,401-3,556,414 bp) that is compatible with recessive inheritance. The 13-bp deletion excises the polypyrimidine tract upstream exon 56 ofDNAH17(XM_021066525.1:c.8510-17_8510-5del) encoding dynein axonemal heavy chain 17. Transcriptome analysis of the testis of two affected boars revealed that the loss of the polypyrimidine tract causes exon skipping which results in the in-frame loss of 89 amino acids from DNAH17. Disruption of DNAH17 impairs the assembly of the flagellar axoneme and manifests in multiple morphological abnormalities of the sperm flagella. Direct gene testing may now be implemented to monitor the defective allele in the Swiss Large White population and prevent the frequent manifestation of a sterilizing sperm tail disorder in breeding boars.
Loss of MGA mediated Polycomb repression promotes tumor progression and invasiveness
Authors: Mathsyaraja Haritha , Catchpole Jonathen , Eastwood Emily , Babaeva Ekaterina , Geuenich Michael , Cheng Pei Feng , Freie Brian , Ayers Jessica , Yu Ming , Wu Nan , Poudel Kumud R , Koehne Amanda , Grady William , Houghton A McGarry , Shiio Yuzuru , MacPherson David P , Eisenman Robert N
Published: October 2020

MGA, a transcription factor and member of the MYC network, is mutated or deleted in a broad spectrum of malignancies. As a critical test of a tumor suppressive role, we inactivated Mga in two mouse models of non-small cell lung cancer using a CRISPR based approach. MGA loss significantly accelerated tumor growth in both models and led to de-repression of atypical Polycomb PRC1.6, E2F and MYC-MAX targets. Similarly, MGA depletion in human lung adenocarcinoma lines augmented invasive capabilities. We further show that MGA, E2F6 and L3MBTL2 co-occupy thousands of promoters and that MGA stabilizes PRC1.6 subunits. Lastly, we report that MGA loss has also a pro-growth effect in human colon organoids. Our studies establish MGA as a bona fide tumor suppressor in vivo and suggest a tumor suppressive mechanism in adenocarcinomas resulting from widespread transcriptional attenuation of MYC and E2F targets mediated by an atypical Polycomb complex containing MGA-MAX dimers.
Pre-meiotic, 21-nucleotide Reproductive PhasiRNAs Emerged in Seed Plants and Diversified in Flowering Plants
Authors: Pokhrel Suresh , Huang Kun , Bélanger Sébastien , Caplan Jeffrey L. , Kramer Elena M. , Meyers Blake C.
Published: October 2020

Plant small RNAs (sRNAs) are important regulatory elements that fine-tune gene expression and maintain genome integrity by silencing transposons. They have critical roles in most pathways involved in plant growth and reproductive development. Reproductive organs of monocots produce abundant phased, small interfering RNAs (phasiRNAs). The 21-nt reproductive phasiRNAs triggered by miR2118 are highly enriched in pre-meiotic anthers, and have not been described in eudicots. The 24-nt reproductive phasiRNAs are triggered by miR2275, and are highly enriched during meiosis in many angiosperms. Here, we describe additional variants of 21-nt reproductive phasiRNAs, including those triggered by miR11308 in wild strawberry, a eudicot, and we validate the presence of this pathway in rose. We report the widespread presence of the 21-nt reproductive phasiRNA pathway in eudicots, with novel biogenesis triggers in the basal eudicot columbine and the rosid flax. In eudicots, these 21-nt phasiRNAs are enriched in pre-meiotic stages, a spatiotemporal distribution consistent with that of monocots and suggesting a role in anther development. Although this pathway is apparently absent in well-studied eudicot families including the Brassicaceae, Solanaceae and Fabaceae, our work in eudicots supports a singular finding in spruce, indicating that the pathway of 21-nt reproductive phasiRNAs emerged in seed plants and was lost in some lineages.
Does somatosensory acuity influence the extent of internal model recalibration in young and older adults?
Authors: Vandevoorde Koenraad , de Xivry Jean-Jacques Orban
Published: October 2020

The ability to adjust movements to changes in the environment declines with aging. This age-related decline is caused by the decline of explicit adjustments. However, automatic adjustment of movement, or internal model recalibration, remains intact and might even be increased with aging. Since somatosensory information appears to be required for internal model recalibration, it might well be that an age-related decline in somatosensory acuity is linked to the increase of internal model recalibration. One possible explanation for an increased internal model recalibration is that age-related somatosensory deficits could lead to altered sensory integration with an increased weighting of the visual sensory-prediction error. Another possibility is that reduced somatosensory acuity results in an increased reliance on predicted sensory feedback. Both these explanations led to our preregistered hypothesis: we expect a relation between the decline of somatosensation and the increased internal model recalibration with aging. However, we failed to support this hypothesis. Our results question the existence of reliability-based integration of visual and somatosensory signals during motor adaptation.

New & Noteworthy

Is somatosensory acuity linked to implicit motor adaptation? The latter is larger in old compared to younger people? In light of reliability-based sensory integration, we hypothesized that this larger implicit adaptation was linked to an age-related lower reliability of somatosensation. Over two experiments and 130 participants, we failed to find any evidence for this. We discuss alternative explanations for the increase in implicit adaptation with age and the validity of our somatosensory assessment.
Relative demographic susceptibility does not explain the extinction chronology of Sahul’s megafauna
Authors: Bradshaw Corey J. A. , Johnson Christopher N. , Llewelyn John , Weisbecker Vera , Strona Giovanni , Saltré Frédérik
Published: October 2020

The causes of Sahul’s megafauna extinctions remain uncertain, although multiple, interacting factors were likely responsible. To test hypotheses regarding plausible ecological mechanisms underlying these extinctions, we constructed the first stochastic, age-structured models for 13 extinct megafauna species from five functional/taxonomic groups, as well as 8 extant species within these groups for comparison. Perturbing specific demographic rates individually, we tested which species were more demographically susceptible to extinction, and then compared these relative sensitivities to the fossil-derived extinction chronology. Here we show that the macropodiformes were the most resilient to extinction, followed by carnivores, monotremes, vombatiform herbivores, and large birds. Five of the eight extant species were as or more susceptible than were the extinct species. There was no clear relationship between extinction susceptibility and the extinction chronology for any perturbation scenario, but body mass and generation length explained much of the variation in relative risk. Our models reveal that the actual mechanisms leading to extinction were unlikely related to variation in demographic susceptibilityper se, but were driven instead by finer-scale variation in climate change and/or human prey choice and relative hunting success.
A Novel Class of Azoles with potent Anti-Leishmanial activity
Authors: Mathur Tarun , Kumar Manoj , Barman Tarani Kanta , Raj V. Samuel , Upadhyay Dilip J. , Verma Ashwani Kumar
Published: October 2020

Objectives

To investigate the anti-leishmanial activity of novel azole compounds againstLeishmania donovani, which causes deadly visceral leishmaniasis disease.

Methods

A focused azole-based library was screened both against promastigotes and amastigotes forms ofL. donovanistrains in flat-bottomed 96-well tissue-culture plates and J774A.1 macrophages infected withL. donovani. The comprehensive screening azole-based library againstL. donovanistrains provided novel hits, which can serve as a good starting point to initiate hit to lead optimization campaign.

Results

Hits identified from azole-based library exhibited potentin vitroactivity against promastigotes and amastigotes ofL. donovani.

Conclusions

These potent novel azole hits could be a good starting point to carry out for further medicinal chemistry exploration for anti-leishmania program.
The chromatin-binding domain of Ki-67 together with p53 protects human chromosomes from mitotic damage
Authors: Garwain Osama , Sun Xiaoming , Iyer Divya Ramalingam , Li Rui , Zhu Lihua Julie , Kaufman Paul D.
Published: October 2020

Vertebrate mammals express a protein called Ki-67 which is most widely known as a clinically useful marker of highly proliferative cells. Previous studies of human cells indicated that acute depletion of Ki-67 can elicit a delay at the G1/S boundary of the cell cycle, dependent on induction of the checkpoint protein p21. Consistent with those observations, we show here that acute Ki-67 depletion causes hallmarks of DNA damage, and the damage occurs even in the absence of checkpoint signaling. This damage is not observed in cells traversing S phase but is instead robustly detected in mitotic cells. The C-terminal chromatin binding domain of Ki-67 is necessary and sufficient to protect cells from this damage. We also observe synergistic effects when Ki-67 and p53 are simultaneously depleted, resulting in increased levels of chromosome bridges at anaphase, followed by the appearance of micronuclei. Therefore, these studies identify the C-terminus of Ki-67 as an important module for genome stability.
Binocular integration of retinal motion information underlies optic flow processing by the cortex
Authors: Rasmussen Rune N. , Matsumoto Akihiro , Arvin Simon , Yonehara Keisuke
Published: October 2020

Locomotion creates various patterns of optic flow on the retina, which provide the observer with information about their movement relative to the environment. However, it is unclear how these optic flow patterns are encoded by the cortex. Here we use two-photon calcium imaging in awake mice to systematically map monocular and binocular responses to horizontal motion in four areas of the visual cortex. We find that neurons selective to translational or rotational optic flow are abundant in higher visual areas, whereas neurons suppressed by binocular motion are more common in the primary visual cortex. Disruption of retinal direction selectivity inFrmd7mutant mice reduces the number of translation-selective neurons in the primary visual cortex, and translation- and rotation-selective neurons as well as binocular direction-selective neurons in the rostrolateral and anterior visual cortex, blurring the functional distinction between primary and higher visual areas. Thus, optic flow representations in specific areas of the visual cortex rely on binocular integration of motion information from the retina.
Evidence for the role of cell reprogramming in naturally occurring cardiac repair
Authors: Shults Nataliia V. , Suzuki Yuichiro J.
Published: October 2020

Pulmonary arterial hypertension (PAH) is a fatal disease without a cure. If untreated, increased pulmonary vascular resistance kills patients within several years due to right heart failure. Even with the currently available therapies, survival durations remain short. By the time patients are diagnosed with this disease, the damage to the right ventricle (RV) has already developed. Therefore, agents that repair the damaged RV have therapeutic potential. We previously reported that cardiac fibrosis that occurs in the RV of adult Sprague-Dawley rats with PAH could naturally be reversed. We herein investigated the mechanism of this remarkable cardiac repair process. Counting of cardiomyocytes showed that the elimination of cardiac fibrosis is associated with the increased RV myocyte number, suggesting that new cardiomyocytes were generated. Immunohistochemistry showed the expression of α-smooth muscle actin and Sox-2 in RV myocytes of rats with PAH. Transmission electron microscopy detected the structure that resembles maturing cardiomyocytes in both the RV of PAH rats and cultured cardiomyocytes derived from induced pluripotent stem cells. We propose that the damaged RV in PAH can be repaired by activating the cell reprogramming mechanism that converts resident cardiac fibroblasts into induced cardiomyocytes.
Genetic insights into the causal relationship between physical activity and cognitive functioning
Authors: Cheval Boris , Darrous Liza , Choi Karmel W. , Klimentidis Yann C. , Raichlen David A. , Alexander Gene E. , Cullati Stéphane , Kutalik Zoltán , Boisgontier Matthieu P.
Published: October 2020

Physical activity and cognitive functioning are strongly intertwined. However, the causal relationships underlying this association are still unclear. Physical activity can enhance brain functions, but healthy cognition may also promote engagement in physical activity. Here, we assessed the bidirectional relationships between physical activity and general cognitive functioning using Latent Heritable Confounder Mendelian Randomization (LHC-MR). Association data were drawn from two large-scale genome-wide association studies (UK Biobank and COGENT) on accelerometer-measured moderate, vigorous, and average physical activity (N = 91,084) and cognitive functioning (N = 257,841). After Bonferroni correction, we observed significant LHC-MR associations suggesting that increased fraction of both moderate (b = 0.32, CI95%= [0.17,0.47], P = 2.89e-05) and vigorous physical activity (b = 0.22, CI95%= [0.06,0.37], P = 0.007) lead to increased cognitive functioning. In contrast, we found no evidence of a causal effect of average physical activity on cognitive functioning, and no evidence of a reverse causal effect (cognitive functioning on any physical activity measures). These findings provide new evidence supporting a beneficial role of moderate and vigorous physical activity (MVPA) on cognitive functioning.
Vasa vasorum lumen narrowing in brain vascular hyalinosis in systemic hypertension patients with ischemic stroke
Authors: Gychka Sergiy G. , Shults Nataliia V. , Nikolaienko Sofia I. , Marcocci Lucia , Sariipek Nurefsan E. , Rybka Vladyslava , Malysheva Tatiana A. , Dibrova Vyacheslav A. , Suzuki Yuichiro J. , Gavrish Alexander S.
Published: October 2020

Ischemic stroke is a major cause of death among patients with systemic hypertension. The narrowing of the lumen of the brain vasculature contributes to the increased incidence of stroke. While hyalinosis represents the major pathological lesions contributing to the vascular lumen narrowing and stroke, the pathogenic mechanism of brain vascular hyalinosis has not been well characterized. Thus, the present study examined the postmortem brain vasculature of human patients who died of ischemic stroke due to systemic hypertension. Hematoxylin and eosin staining and immunohistochemistry showed the occurrence of brain vascular hyalinosis with infiltrated plasma proteins along with the narrowing of vasa vasorum and oxidative stress. Transmission electron microscopy revealed the endothelial cell bulge protrusion into the vasa vasorum lumen and the occurrence of endocytosis in the vasa vasorum endothelium. The treatment of cultured microvascular endothelial cells with adrenaline also promoted the formation of the bulge as well as endocytic vesicles. siRNA knockdown of sortin nexin-9 (a mediator of clathrin-mediated endocytosis) inhibited the adrenaline-induced endothelial cell bulge formation. Adrenaline promoted protein-protein interactions between sortin nexin-9 and neural Wiskott–Aldrich Syndrome protein (a regulator of actin polymerization). We propose that endocytosis-depending endothelial cell bulge narrows the vasa vasorum, resulting in ischemic oxidative damage to the cerebral vessels, the formation of hyalinosis, the occurrence of ischemic stroke, and death in systemic hypertension patients.
Food restriction engages prefrontal corticostriatal cells and local microcircuitry to drive the decision to run vs conserve energy
Authors: Santiago Adrienne N. , Makowicz Emily A. , Du Muzi , Aoki Chiye
Published: October 2020

Food restriction (FR) evokes running, which may promote adaptive foraging in times of food scarcity, but can become lethal if energy expenditure exceeds caloric availability. Here, we demonstrate that chemogenetic activation of either the general medial prefrontal cortex (mPFC) pyramidal cell population, or the subpopulation projecting to dorsal striatum (DS) drives running specifically during hours preceding limited food availability, and not duringad libitumfood availability. Conversely, suppression of mPFC pyramidal cells generally, or targeting mPFC-to-DS cells, reduced wheel running specifically during FR and not duringad libitumfood access. Post-mortem c-Fos analysis and electron microscopy of mPFC layer 5 revealed distinguishing characteristics of mPFC-to-DS cells, when compared to neighboring non-DS projecting pyramidal cells: 1) greater recruitment of GABAergic activity and 2) less axo-somatic GABAergic innervation. Together, these attributes position the mPFC-to-DS subset of pyramidal cells to dominate mPFC excitatory outflow, particularly during FR, revealing a specific and causal role for mPFC-to-DS control of the decision to run during food scarcity. Individual differences in GABAergic activity correlate with running response to further support this interpretation. FR enhancement of PFC-to-DS activity may influence neural circuits both in studies using FR to motivate animal behavior and in human conditions hallmarked by FR.
Mitochondrial phenotypes in purified human immune cell subtypes and cell mixtures
Authors: Rausser Shannon , Trumpff Caroline , McGill Marlon A , Junker Alex , Wang Wei , Ho Siu-hong , Mitchell Anika , Karan Kalpita R , Monk Catherine , Segerstrom Suzanne C. , Reed Rebecca G. , Picard Martin
Published: October 2020

Using a high-throughput mitochondrial phenotyping platform to quantify multiple mitochondrial features among molecularly-defined immune cell subtypes, we quantify the natural variation in citrate synthase, mitochondrial DNA copy number (mtDNAcn), and respiratory chain enzymatic activities in human neutrophils, monocytes, B cells, and naïve and memory T lymphocyte subtypes. In mixed peripheral blood mononuclear cells (PBMCs) from the same individuals, we show to what extent mitochondrial measures are confounded by both cell type distributions and contaminating platelets. Cell subtype-specific measures among women and men spanning 4 decades of life indicate potential age- and sex-related differences, including an age-related elevation in mtDNAcn, which are masked or blunted in mixed PBMCs. Finally, a proof-of-concept, repeated-measures study in a single individual validates cell type differences and also reveals week-to-week changes in mitochondrial activities. Larger studies are required to validate and mechanistically extend these findings. These mitochondrial phenotyping data build upon established immunometabolic differences among leukocyte sub-populations, and provide foundational quantitative knowledge to develop interpretable blood-based assays of mitochondrial health.
AIBP-CAV1-VEGFR3 axis dictates lymphatic cell fate and controls lymphangiogenesis
Authors: Yang Xiaojie , Kim Jun-dae , Gu Qilin , Yan Qing , Astin Jonathan , Crosier Philip S , Yu Pengchun , Rockson Stanley G , Fang Longhou
Published: October 2020

The lymphatics are essential for the maintenance of tissue fluid homeostasis. Accordingly, lymphatic dysfunction contributes to lymphedema. In development, lymphangiogenesis often requires lymphatic endothelial cell (LEC) lineage specification from the venous ECs and subsequent LEC proliferation and migration, all of which are regulated by the VEGFC/VEGFR3 signaling. Cholesterol is essential for proper cell functions and organ development, yet the molecular mechanism by which cholesterol metabolism controls lymphangiogenesis is unknown. We show that the secreted protein, ApoA1 binding protein (AIBP), dictates lymphatic vessel formation by accelerating cholesterol efflux. Loss of Aibp2, the human paralog in zebrafish, impairs LEC progenitor specification and impedes lymphangiogenesis. Mechanistically, we found that caveolin-1 (CAV-1) suppresses VEGFR3 activation in LECs, and that AIBP-regulated cholesterol efflux disrupts lipid rafts/caveolae and reduces CAV-1 bioavailability, which abolishes the CAV-1 inhibition of VEGFR3 signaling, thereby augmenting VEGFR3 activation and increasing lymphangiogenesis. Enhancement of cholesterol efflux with ApoA1 overexpression or inhibition of cholesterol biosynthesis using atorvastatin restores proper lymphangiogenesis in Aibp2 mutant zebrafish. Loss of Cav-1 increases LEC progenitor specification in zebrafish, and rescues lymphangiogenesis in Aibp2-deficient animals. Recombinant AIBP supplement confers profound LEC fate commitment in the mouse embryonic stem cells (mESC) to LEC differentiation model. Furthermore, enhancement of AIBP-CAV-1-VEGFR3 signaling axis promotes VEGFC-engaged adult lymphangiogenesis in mice. Consistent with these data, AIBP expression is reduced in the epidermis of human lymphedematous skin. These studies identify that AIBP-mediated cholesterol efflux is a critical contributor for lymphangiogenesis. Our studies will provide a new therapeutic avenue for the treatment of lymphatic dysfunctions.

One Sentence Summary

Our studies identify that AIBP-CAV-1-VEGFR3 axis enhances VEGFC-elicited lymphangiogenesis, which will guide a new therapeutic strategy for the treatment of lymphatic dysfunctions.
SKiM - A generalized literature-based discovery system for uncovering novel biomedical knowledge from PubMed
Authors: Raja Kalpana , Steill John , Ross Ian , Tsoi Lam C , Kuusisto Finn , Ni Zijian , Livny Miron , Thomson James , Stewart Ron
Published: October 2020

Literature-based discovery (LBD) uncovers undiscovered public knowledge by linking terms A to C via a B intermediate. Existing LBD systems are limited to process certain A, B, and C terms, and many are not maintained. We present SKiM (Serial KinderMiner), a generalized LBD system for processing any combination of A, Bs, and Cs. We evaluate SKiM via the rediscovery of discoveries by Don Swanson, who pioneered LBD. Using only literature from the 19th century up to a year before Swanson’s discoveries, SKiM uncovers all five discoveries. We apply SKiM to repurposing drugs for 26 conditions of high prevalence. Manual analysis confirmed 65 discoveries useful for four diseases from Swanson’s discoveries from one to 31 years prior to their first validation by clinical trials. SKiM predicts many new potential drug candidates representing prime targets for wet lab validation. SKiM can be applied to any biomedical inquiry sufficiently mentioned in the literature.
Predicting Brain Amyloid using Multivariate Morphometry Statistics, Sparse Coding, and Correntropy: Validation in 1,101 Individuals from the ADNI and OASIS Databases
Authors: Wu Jianfeng , Dong Qunxi , Gui Jie , Zhang Jie , Su Yi , Chen Kewei , Thompson Paul M. , Caselli Richard J. , Reiman Eric M. , Ye Jieping , Wang Yalin ,   for the Alzheimer’s Disease Neuroimaging Initiative
Published: October 2020

Biomarker-assisted preclinical/early detection and intervention in Alzheimer’s disease (AD) may be the key to therapeutic breakthroughs. One of the presymptomatic hallmarks of AD is the accumulation of beta-amyloid (Aβ) plaques in the human brain. However, current methods to detect Aβ pathology are either invasive (lumbar puncture) or quite costly and not widely available (amyloid PET). Our prior studies show that MRI-based hippocampal multivariate morphometry statistics (MMS) are an effective neurodegenerative biomarker for preclinical AD. Here we attempt to use MRI-MMS to make inferences regarding brain Aβ burden at the individual subject level. As MMS data has a larger dimension than the sample size, we propose a sparse coding algorithm, Patch Analysis-based Surface Correntropy-induced Sparse coding and max-pooling (PASCS-MP), to generate a low-dimensional representation of hippocampal morphometry for each subject. Then we apply these individual representations and a binary random forest classifier to predict brain Aβ positivity for each person. We test our method in two independent cohorts, 841 subjects from the Alzheimer’s Disease Neuroimaging Initiative (ADNI) and 260 subjects from the Open Access Series of Imaging Studies (OASIS). Experimental results suggest that our proposed PASCS-MP method and MMS can discriminate Aβ positivity in people with mild cognitive impairment (MCI) (Accuracy (ACC)=0.89 (ADNI)) and in cognitively unimpaired (CU) individuals (ACC=0.79 (ADNI) and ACC=0.81 (OASIS)). These results compare favorably relative to measures derived from traditional algorithms, including hippocampal volume and surface area, shape measures based on spherical harmonics (SPHARM), and our prior Patch Analysis-based Surface Sparse-coding and Max-Pooling (PASS-MP) methods.