bluuebunny/crossref_metadata_2025 huggingface dataset:
Treatment of anal fistula using a decellularized porcine small intestinal submucosa plug: A non-inferiority trial
Authors: Chen Zhao Wen , Zheng Yi , Zhao Rong , Wang Zhen Jun
Published: July 2022

Background:

Using small intestinal submucosa (SIS) has increasingly become the standard method for the treatment of anal fistula. The porcine SIS manufactured by Biosis Healing is a novel biological material that has several advantages for the safe and effective repair of tissues. Our study aimed to verify the efficacy and safety of the decellularized porcine SIS (VIDASIS) anal fistula plug.

Methods:

We conducted a non-inferiority multicenter, randomized, controlled clinical trial involving patients with chronic anal fistula. Patients from 3 centers across China were randomized 1:1 to Biosis SIS vs commercial SIS. The primary endpoint was the healing rate and secondary endpoints included recurrence within 6 months, rate of copracrasia, healing time, pain using a visual analog scale, and patient and doctor satisfaction.

Results:

A total of 186 patients were randomized. Of these, 82 patients in the Biosis SIS and 81 in the control (commercial) SIS completed the trial (per-protocol set). The healing rate at the 6-month follow-up (full analysis set) was 92.0% for the Biosis SIS and 89.8% for the control SIS (P = .620). The rate difference of 2.2% (full analysis set; 95% confidence interval: -6.4% and 10.7%, respectively) was within the pre-specified non-inferiority margin of -10%. There were no differences between the 2 groups with regard to the secondary endpoints. No serious adverse event or death occurred.

Conclusion:

Our study shows that the VIDASIS anal fistula plug manufactured by the company Biosis Healing is safe and effective and is not inferior to existing commercial SIS materials.
The effect of tranexamic acid in open reduction and internal fixation of pelvic and acetabular fracture: A systematic review and meta-analysis
Authors: Kim Chul-Ho , Hwang Jaeho , Lee Soong Joon , Yoon Pil Whan , Yoon Kang Sup
Published: July 2022

Background:

Pelvic bone fractures may cause extensive bleeding; however, the efficacy of tranexamic acid (TXA) usage in pelvic fracture surgery remains unclear. In this systematic review and meta-analysis, we aimed to evaluate the efficacy of TXA in open reduction and internal fixation surgery for pelvic and acetabular fracture.

Methods:

MEDLINE, Embase, and Cochrane Library databases were systematically searched for studies published before April 22, 2020, that investigated the effect of TXA in the treatment of pelvic and acetabular fracture with open reduction and internal fixation. A pooled analysis was used to identify the differences between a TXA usage group and a control group in terms of estimated blood loss (EBL), transfusion rates, and postoperative complications.

Results:

We included 6 studies involving 764 patients, comprising 293 patients who received TXA (TXA group) and 471 patients who did not (control group). The pooled analysis showed no differences in EBL between the groups (mean difference –64.67, 95% confidence interval [CI] –185.27 to –55.93, P = .29). The study period transfusion rate showed no significant difference between the groups (odds ratio [OR] 0.77, 95% CI 0.19–3.14, P = .71, I
2 = 82%), nor in venous thromboembolism incidence (OR 1.53, 95% CI 0.44–5.25, P = .50, I
2 = 0%) or postoperative infection rates (OR 1.15, 95% CI 0.13–9.98, P = .90, I
2 = 48%).

Conclusions:

Despite several studies having recommended TXA administration in orthopedic surgery, our study did not find TXA usage to be more effective than not using TXA in pelvic and acetabular fracture surgery, especially in terms of EBL reduction, transfusion rates, and the risk of postoperative complications.
Transcanal endoscopic treatment for congenital middle ear cholesteatoma in children
Authors: Zeng Nan , Liang Meng , Yan Shang , Zhang Lue , Li Shuo , Yang Qiong
Published: July 2022

To investigate the feasibility and efficacy of transcanal endoscopic treatment for congenital middle ear cholesteatoma in children.

Eleven children diagnosed with congenital middle ear cholesteatoma, who underwent total ear endoscopic surgery under general anesthesia, were included from the Huazhong University of Science and Technology Union Shenzhen Hospital between January 2016 and December 2020. We retrospectively analyzed their operation process and surgical complications through the surgical video; moreover, we compared the pre- and postoperative hearing outcomes.

One child underwent a planned second operation to reconstruct the ossicular chain. At 6 postoperative months, all 11 children underwent reexamination. There was no significant change and a significant decrease in the mean bone and air conduction hearing thresholds, respectively (P > .05 and P < .05); moreover, there was a significant reduction in the air–bone conduction difference (P < .05). Further, the air–bone conduction difference was reduced to >20 dB and >10 dB in 11 and 7 children, respectively. Follow-up of the children did not reveal sensorineural deafness, facial paralysis, and other serious complications; further, there were no cases of recurrence.

Transcanal endoscopic treatment for congenital middle ear cholesteatoma in children is feasible, minimally invasive, and functional.
Network pharmacology-based pharmacological mechanism prediction on Eucommia ulmoides against rheumatoid arthritis
Authors: Ying Yonggan , Tang Zhaopeng , Niu Feng , Xu Taotao , Xia Chenjie , Zhang Shuijun
Published: July 2022

Rheumatoid arthritis (RA) is a common chronic autoimmune disease characterized by synovial inflammation and progressive joint destruction. Eucommia ulmoides (EU) is a kidney-tonifying Chinese medicine that has been applied to treat RA for decides. The present study aims to explore pharmacological mechanisms of EU against RA using network pharmacology approach. Traditional Chinese Medicine Systems Pharmacology (TCMSP) database was used to screen active ingredients of EU, and their relative targets were fished from UniProt database. RA-related targets were screened from GeneCards database and DisGeNET database. The overlapping genes between EU and RA were identified by Venn diagram, and further analyzed for protein-protein interaction (PPI), Gene Ontology (GO), Kyoto Encyclopedia of Genes and Genomes (KEGG). Fifty active ingredients were identified in EU, and corresponded to 207 targets. Meanwhile, 499 targets were closely associated with RA development. A total of 50 overlapping genes between EU and RA were identified, which were regarded as therapeutically relevant. GO enrichment analysis indicated that EU exerted antiRA effects depending on regulating multiple biological processes including inflammatory response, oxidative stress, cell apoptosis and matrix catabolism. Several key pathways such as TNF pathway, IL-17 pathway, T cell receptor pathway, NOD-like receptor pathway and Toll-like receptor pathway, were involved in the above biological processes. Network pharmacology revealed that EU exerts therapeutic effects on RA through multi-ingredients, multi-targets and multi-pathways, which provides basis for its clinical application and promising directions for subsequent research.
Time to occurrence, predictors, and patterns of opportunistic infections incidence among HIV-positive patients attending Antiretroviral Therapy Clinic of Salale University Comprehensive Specialized Hospital: A retrospective cohort study
Authors: Girma Derara , Dejene Hiwot , Adugna Geleta Leta , Tesema Mengistu , Bati Feyiso
Published: July 2022

Opportunistic infections (OIs) in HIV patients are infections that are more common or more severe as a result of HIV-mediated immunosuppression. The advances in the capacity of antiretroviral therapy (ART) have diminished the incidence of OIs. However, even in the ART era, HIV-related OIs continue to be major causes of hospitalization and mortality. Therefore, this study aims to identify time to occurrence, predictors, and patterns of OIs incidence among HIV-positive patients attending ART clinic of Salale University Comprehensive Specialized Hospital, Ethiopia. A retrospective cohort study was conducted between 1st September 2016 and 1st September 2021. All 419 patients diagnosed during the study period were recruited. Data were extracted from both patient medical records and ART logbooks. Stata-16 was used for data analysis. Follow-up time was calculated from the date of HIV diagnosis to the date of OIs occurrence or censoring. Cox proportional hazards regression model was used to identify the predictors of OIs incidence. The total person-time of the follow-up was 8656 person-months of observation. During the follow-up time, 199 (47.49%) of the patients had developed OIs. The incidence rate of OIs was 23 (95%CI: 20, 26) per 1000 person-months of observation. The median OIs free survival time was 36 (95%CI: 31, 40) months. Predictors such as residence, cd4 category, baseline hemoglobin level, ART side effects, isoniazid preventive therapy, and chronic disease comorbidity were significantly predicted OIs incidence. The study area’s OIs incidence remained high, requiring prompt action. To reduce the morbidity and mortality associated with OIs, HIV-positive patients with the predictors of rural residence, low CD4 category, low baseline hemoglobin level, ART side effects, not taking IPT, and baseline chronic disease comorbidity necessitate close follow-up and monitoring. Thus, we recommend focused and evidence-informed strategies to address OIs burden and improve outcomes.
Breast Implant Associated Anaplastic Large Cell Lymphoma: An Updated Systematic Review and Analysis of Treatment Strategies
Authors: Naga Hani I. , Mellia Joseph A. , Basta Marten N. , Morris Martin P. , Christopher Adrienne N. , Campbell Frank M. , Sommers Katie , Levinson Howard , Nelson Jonas A. , Fischer John P.
Published: July 2022

BACKGROUND:

Although guidelines have been published on BIA-ALCL treatment, there has been no comprehensive analysis of BIA-ALCL treatment variation based on the available literature. The authors sought to assess current treatment strategies of breast implant associated anaplastic large cell lymphoma (BIA-ALCL) relative to current guidelines.

METHODS:

Database searches were conducted in June 2020. Included articles were case reports and case series with patient-level data. Collected variables included clinicopathological features, implant characteristics, diagnostic tests, ALCL characteristics, treatment, and details of follow-up and outcome. Treatment data before and after 2017 was compared with National Cancer Center Network guidelines.

RESULTS:

89 publications were included, and a total of 178 cases of BIA-ALCL were identified. Most patients presented with seroma (N=114, 70.4%), followed by a mass (N=14, 8.6%), or both (N=23, 14.2%). Treatment included en-bloc capsulectomy of the affected implant in 122 out of 126 cases with treatment details provided (96.8%). Radiation therapy was given in 38 cases (30.2%), and chemotherapy was given in 71 cases (56.3%). Practitioners used less chemotherapy for local disease after treatment guideline publication in 2017 (p<0.001), while treatment for advanced disease remained unchanged (p=0.3). There were 10 recurrences and 8 fatalities due to BIA-ALCL, which were associated with advanced presentation (29% vs. 2.1%, OR = 19.4 [3.9 - 96.3], p<0.001).

CONCLUSION:

BIA-ALCL remains a morbid but treatable condition. Current guidelines focused treatment for local disease and reduced non-surgical interventions with radiation or chemotherapy. Patients presenting with advanced BIA-ALCL experience higher rates of recurrence and mortality.
Polymorphism of mitochondrial DNA genes involved in asthenozoospermia in infertile patients of Côte d’Ivoire
Authors: Hermann Ayekoue Jules Erick , Sylvère N’zi Konan Guy , Berenger Ako Ako Aristide , N’guessan Marie-Florence , Guillaume Yayé Yapi , Amadou Coulibaly Founzégué , Joseph Djaman Allico
Published: July 2022

Objective:

The relationship between mitochondrial DNA (mtDNA) polymorphisms and abnormalities in sperm quality has been the subject of several studies, with the objective of improving the treatment of male infertility. This study, which contributes to the identification of genetic markers of sperm abnormalities, was conducted to study mtDNA mutations in the asthenozoospermia profile.

Methods:

This case-control study included 30 patients with asthenozoospermia and 28 with normospermia after spermogram and spermocytogram analyses. After the extraction of total DNA from the spermatozoa of 58 ejaculates from these individuals using the phenol-chloroform method, the amplification of genes of interest in mtDNA using specific primers was performed by conventional polymerase chain reaction, and sequencing was used to detect mutations.

Results:

Male patients with asthenozoospermia in the tertiary sector had significantly more mutant- than wild-type (P = 0.0005) MT-CO II genes. Similarly, for the same gene, males with asthenozoospermia and primary infertility had significantly more mutants than the wild-type (P = 0.001). Sequencing revealed 29 mutations that were observed only with asthenozoospermia, which could be the basis for low sperm mobility.

Conclusion:

This study identified several mutations in mtDNA genes that could be considered genetic markers of asthenozoospermia if confirmed in a deeper study.
Diagnosing Influenza Infection from Pharyngeal Images using Deep Learning: Machine Learning Approach
Authors: Okiyama Sho , Fukuda Memori , Sode Masashi , Takahashi Wataru , Ikeda Masahiro , Kato Hiroaki , Tsugawa Yusuke , Iwagami Masao
Published: July 2022

Background

Influenza is a major global burden of disease, causing annual epidemics and occasionally, pandemics. Given that influenza primarily infects the upper respiratory system, influenza infection may be able to be diagnosed by applying deep learning to pharyngeal images.

Objective

We aimed to develop a deep learning model to diagnose influenza infection using the data on pharyngeal images and clinical information.

Methods

We recruited patients who visited clinics and hospitals due to influenza-like symptoms. In the training stage, we developed a diagnostic prediction artificial intelligence (AI) model based on deep learning to predict polymerase chain reaction (PCR)-confirmed influenza from pharyngeal images and clinical information. In the validation stage, we assessed the diagnostic performance of the AI model. In the additional analysis, we compared the diagnostic performance of the AI model with that of three physicians, and also interpreted the AI model using the importance heatmaps.

Results

A total of 7,831 patients were enrolled at 64 hospitals between Nov 1, 2019 and Jan 21, 2020 in the training stage, and 659 patients (including 196 patients with PCR-confirmed influenza) at 11 hospitals between Jan 25, 2020 and Mar 13, 2020 in the validation stage. The area under the receiver operating characteristic curve of the AI model was 0.90 (95% confidence interval, 0.87–0.93), and its sensitivity and specificity were 76% (70–82%) and 88% (85–91%), respectively, outperforming three physicians. In the importance heatmaps, the AI model often focused on follicles on the posterior pharyngeal wall.

Conclusions

We developed the first AI model that can accurately diagnose influenza from pharyngeal images, which has the potential to assist physicians make timely diagnosis.
How the Malian press treated hydroxychloroquine at the beginning of the COVID-19 pandemic
Authors: Escot Fabrice FE , Zinszer Kate KZ , Abalovi Krystelle KA , Peiffer-Smadja Nathan NP , Coulibaly Abdourahmane AC , Saucier Adrien AS , Ridde Valéry VR
Published: July 2022

Background

The global debate on the efficacy of hydroxychloroquine (HCQ) on COVID-19 has gone far beyond the scientific framework and has been highly politicized. These issues immediately invested the debate on HCQ and made it an object of particular crystallization. This study analyzes, through the Malian press, the echo of this debate in the national background.

Methods

Mixed methods design, based on a review of 452 articles about COVID-19 published by six major Malian newspapers, from January 1st to July 31st 2020. Results of a content analysis with WORDSTAT8 software were further explained by a thematic qualitative analysis using and deductive-indictive approach.

Results

The debate on HCQ has had very little echo in the Malian press despite some interest, because of a lack of anchoring and thus of a “response” at the national level. The national health authorities, who adopted the treatment as part of clinical trials, and the press, stayed away from both the medical and the “ideological” components of the debate, despite these a priori directly involved a country like Mali.

Conclusions

The paper sheds light on the issues at stake in the HCQ debate based on a case study of an atypical country in terms of impacts of Covid-19. The governance of COVID helped crystallize political opposition to the presidential regime leading to a coup in August.
Mechanosensory stimulation triggers sustained local motor activity inDrosophila melanogaster
Authors: Medeiros Alexandra M. , Hobbiss Anna F. , Borges Gonçalo , Moita Marta , Mendes César S.
Published: July 2022

Most vertebrates and invertebrates such as Drosophila melanogaster are able to move in complex environments due to their ability to integrate sensory information along with motor commands. Mechanosensory structures exist along each leg to assist in motor coordination by transmitting external cues or proprioceptive information to motor centers in the central nervous system. Nevertheless, how different mechanosensory structures engage these locomotor centers and their underlying circuits remains poorly understood.

Here, we tested the role of mechanosensory structures in movement initiation by optogenetically stimulating specific classes of leg sensory structures. We found that stimulation of leg Mechanosensory Bristles (MsB) and femoral Chordotonal Organ (ChO) is sufficient to initiate forward movement in immobile animals. While the stimulation of the ChO required brain centers to induce forward movement, unexpectedly, brief stimulation of leg MsB triggered sustained cyclic motor activity dependent only on circuits within the Ventral Nerve Cord (VNC). The duration of the MsB-induced movement was dependent on the number of excited cells and specific to leg afferents, since stimulation of MsB in other segments lead to different motor outcomes. MsB-mediated movement lacked inter and intra-leg coordination, but preserved antagonistic muscle activity within joints. Our data shows that sensory stimulation can act in combination with descending commands in order to elicit a faster response to mechanical stimulation. In addition, it sheds light on the ability of specific sensory circuits to modulate motor control, including initiation of movement, presenting a new system to better understand how different levels of coordination are controlled by VNC and central brain locomotor circuits.

Significance Statement

Sensory feedback is critical to allow smooth and stable locomotion. Proprioceptors interact directly with pre-motor centers optimizing and sustaining coordinated movement. However, initiation of moment is considered to be triggered by higher-order centers in the brain. Here we took advantage of the genetic toolkit provided by the fruit fly Drosophila melanogaster to optogenetically activate different classes of leg sensory cells in immobile animals. We found that leg mechanosensory bristles can specifically trigger sustained leg activity independently of higher-order centers as headless flies could sustain prolonged leg movement upon mechanosensory stimulation. Moreover, while this sensory-evoked movement lacks intra- and inter-leg coordination, it still preserved basic antagonistic muscle activity. These findings suggest a parallel mechanism to trigger fast movement upon sensory stimulation. In addition, it provides a new model for movement initiation and a point–of-entry to define pre-motor circuits.
Disentangling the complex gene interaction networks between rice and the blast fungus identifies a new pathogen effector
Authors: Sugihara Yu , Abe Yoshiko , Takagi Hiroki , Abe Akira , Shimizu Motoki , Ito Kazue , Kanzaki Eiko , Oikawa Kaori , Kourelis Jiorgos , Langner Thorsten , Win Joe , Białas Aleksandra , Lüdke Daniel , Contreras Mauricio P. , Chuma Izumi , Saitoh Hiromasa , Kobayashi Michie , Zheng Shuan , Tosa Yukio , Banfield Mark J. , Kamoun Sophien , Terauchi Ryohei , Fujisaki Koki
Published: July 2022

Studies focused solely on single organisms can fail to identify the networks underlying host–pathogen gene-for-gene interactions. Here, we integrate genetic analyses of rice (Oryza sativa, host) and rice blast fungus (Magnaporthe oryzae, pathogen) and uncover a new pathogen recognition specificity of the rice nucleotide-binding domain and leucine-rich repeat protein (NLR) immune receptor Pik, which mediates resistance toM. oryzaeexpressing the avirulence effector geneAVR-Pik. Rice Piks-1, encoded by an allele ofPik-1, recognizes a previously unidentified effector encoded by theM. oryzaeavirulence geneAVR-Mgk1, which is found on a mini-chromosome.AVR-Mgk1has no sequence similarity to knownAVR-Pikeffectors, and is prone to deletion from the mini-chromosome mediated by repeatedInago2retrotransposon sequences. AVR-Mgk1 is detected by Piks-1 and by other Pik-1 alleles known to recognize AVR-Pik effectors; recognition is mediated by AVR-Mgk1 binding to the integrated heavy metal-associated (HMA) domain of Piks-1 and other Pik-1 alleles. Our findings highlight how complex gene-for-gene interaction networks can be disentangled by applying forward genetics approaches simultaneously to the host and pathogen. We demonstrate dynamic co-evolution between an NLR integrated domain and multiple families of effector proteins.
Spherical harmonics representation of the steady-state membrane potential shift induced by tDCS in realistic neuron models
Authors: Galan-Gadea Adrià , Salvador Ricardo , Bartolomei Fabrice , Wendling Fabrice , Ruffini Giulio
Published: July 2022

Objective

We provide a systematic framework for quantifying the effect of externally applied weak electric fields on realistic neuron compartment models as captured by physiologically relevant quantities such as the membrane potential or transmembrane current as a function of the orientation of the field.

Approach

We define a response function as the steady-state change of the membrane potential induced by a canonical external field of 1 V/m as a function of its orientation. We estimate the function values through simulations employing reconstructions of the rat somatosensory cortex from the Blue Brain Project. The response of different cell types is simulated using the NEURON simulation environment. We represent and analyze the angular response as an expansion in spherical harmonics.

Main results

We report membrane perturbation values comparable to those in the literature, extend them to different cell types, and provide their profiles as spherical harmonic coefficients. We show that at rest, responses are dominated by their dipole terms (ℓ= 1), in agreement with experimental findings and compartment theory. Indeed, we show analytically that for a passive cell, only the dipole term is nonzero. However, while minor, other terms are relevant for states different from resting. In particular, we show howℓ= 0 andℓ= 2 terms can modify the function to induce asymmetries in the response.

Significance

This work provides a practical framework for the representation of the effects of weak electric fields on different neuron types and their main regions—an important milestone for developing micro- and mesoscale models and optimizing brain stimulation solutions.
Dopamine Activates Astrocytes in Prefrontal Cortex via α1-Adrenergic Receptors
Authors: Pittolo Silvia , Yokoyama Sae , Willoughby Drew D. , Taylor Charlotte R. , Reitman Michael E. , Tse Vincent , Wu Zhaofa , Etchenique Roberto , Li Yulong , Poskanzer Kira E.
Published: July 2022

The prefrontal cortex (PFC) is a hub for cognitive control, and dopamine profoundly influences its functions. In other brain regions, astrocytes sense diverse neurotransmitters and neuromodulators and, in turn, orchestrate regulation of neuroactive substances. However, basic physiology of PFC astrocytes, including which neuromodulatory signals they respond to and how they contribute to PFC function, is lacking. Here, we characterize divergent signaling signatures in astrocytes of PFC and primary sensory cortex in mice, which are linked to differential responsivity to locomotion. We find that PFC astrocytes express receptors for dopamine, but are unresponsive through the Gs/Gi-cAMP pathway. Instead, fast calcium signals in PFC astrocytes are time-locked to dopamine release, and are mediated by α1-adrenergic receptors bothex vivoandin vivo. Further, we describe dopamine-triggered regulation of extracellular ATP at PFC astrocyte territories. Thus, we identify astrocytes as active players in dopaminergic signaling in PFC, contributing to PFC function though neuromodulator receptor crosstalk.

Graphical Abstract
A Practical Approach for Optimizing Off-axis Telecentric Digital Holographic Microscope Design
Authors: Jin Lei , Yu Ziyang , Au Aaron , Yip Christopher M.
Published: July 2022

Digital holographic microscopy (DHM) has become an attractive imaging tool for the analysis of living cells and histological tissues. The telecentric DHM (TDHM) is a configuration of DHM that lightens the computation load with a priori aberration corrections. However, TDHM requires a well-aligned optical pipeline to optimize its resolution and image quality (IQ), which has traditionally complicated the alignment process. Further deriving from the optical interference functions, we offer a set of methodologies to simplify TDHM design and alignment by determining the optimal +1 order position, which depends on the object-reference beam angle and the interference plane rotation angle. The methods are then experimentally tested and verified on a TDHM system by imaging living HeLa cells in suspension.
APOE ε4 carriage associates with improved myocardial performance in older age
Authors: Topriceanu Constantin-Cristian , Shah Mit , Webber Matthew , Chan Fiona , Moon James C , Richards Marcus , Chaturvedi Nishi , Hughes Alun D. , Schott Jonathan , O’Regan Declan P. , Captur Gabriella
Published: July 2022

Introduction

AlthoughAPOE ε4 allele carriage confers a risk of coronary disease, its persistence in human populations might be explained by certain survival advantages (antagonistic pleiotropy).

Hypothesis

Combining data from three British cohorts–1946 National Survey of Health and Development (NSHD), Southall and Brent Revised (SABRE) and UK Biobank–we explored whetherAPOE ε4 carriage associates with beneficial or unfavorable left ventricular (LV) structural and functional parameters by echocardiography and cardiovascular magnetic resonance (CMR) in older age.

Methods

Based on the presence ofAPOE ε4, genotypes were divided into:APOE ε4 (ε2ε4, ε3ε4,ε4ε4) and non-APOE ε4 carriers. Echocardiographic data included: LV ejection fraction, E/e’, systolic and diastolic posterior wall and interventricular septal thickness (LVPWTs/d, IVSs/d), LV mass and the ratio of the LV stroke volume to the LV myocardial volume called myocardial contraction fraction (MCF). CMR data additionally included longitudinal and radial peak diastolic strain rates (PDSR). Generalized linear models explored associations betweenAPOE ε4 genotypes as exposures and echocardiographic/CMR biomarkers as outcomes. As APOE genotype is a genetic instrumental variable (unconfounded), Model 1 was unadjusted; Model 2 was adjusted for factors associated with the outcome (age, sex, and socio-economic position) to yield more precise estimates; and subsequent models were individually adjusted for mediators (body mass index, cardiovascular disease [CVD], high cholesterol and hypertension) to explore mechanistic pathways.

Results

35,568 participants were included. Compared to the non-APOE ε4 group,APOE ε4 carriers had similar cardiac echocardiographic phenotypes in terms of LV EF, E/e’, LVPWTs/d, IVSs/dand LV mass but had a 4% higher MCF (95% confidence interval [CI]: 1–7%,p=0.016) which persisted in Model 2 (95% CI 1–7%,p=0.008) but was attenuated to 3% after adjustment for CVD, diabetes and hypertension (all 95% CI 0–6%; allp<0.070). This was replicated in UK Biobank using CMR data, whereAPOE ε4 carriers had a 1% higher MCF (95% CI 0-1%,p=0.020) which was attenuated only after adjusting for BMI or diabetes.

Conclusions

APOE ε4 carriage associates with improved myocardial performance in older age resulting in greater LV stroke volume generation per 1 mL of myocardium and better longitudinal strain rates compared to nonAPOE ε4 carriers. This potentially favorable cardiac phenotype adds to the growing number of reported survival advantages attributed toAPOEε4 carriage that might collectively explain its persistence in humans.
Evaluation of trace elements analysis in Pediatric Patients with COVID-19: A report from Turkey
Authors: Dalkıran Tahir , Unsal Velid , İpek Sevcan , Oncu Dogan , Mercan Mehmet , Kandur Yaşar
Published: July 2022

Introduction

This study aimed to evaluate the levels of Selenium, Copper, and Zinc in an attempt to identify the role of trace elements in pediatric patients with COVID-19 infection.

Methods

We randomly selected 29 patients who were hospitalized with the diagnosis of COVID-19. Blood serum sample was collected to study serum Se, Zn, and Cu levels at disease onset and at the time of discharge.

Results

The median age of our patients was 71.1 ± 14.4 months (range, 3-205 months); 14 (48.3%) patients were male. The mean CRP, and D-Dimer levels were significantly higher at disease onset than at discharge. On the other hand, the mean Cu, Zn, and Se levels were significantly lower at disease onset compared to the time of discharge. The patients with mild-moderate disease severity were older than the patients with severe disease although the difference did not reach statistical significance (82.2±17.7 vs 54.5± 24.7 months; p=0.374). There was no correlation between age and trace elements other than Zn.

Conclusion

We believe that, patients and other individuals under risk of COVID-19 should be supplemented with trace elements.
Extended family with an inherited pathogenic variant in polymerase delta provides strong evidence for recessive effect of proofreading deficiency in human cells
Authors: Andrianova Maria A. , Seplyarskiy Vladimir B. , Terradas Mariona , Sánchez-Heras Ana Beatriz , Mur Pilar , Soto José Luis , Aiza Gemma , Kondrashov Fyodor A. , Kondrashov Alexey S. , Bazykin Georgii A. , Valle Laura
Published: July 2022

Mutational processes in germline and in somatic cells are vastly different, and it remains unclear how the same genetic background affects somatic and transmissible mutations. Here, we estimate the impact of an inherited pathogenic variant in the exonuclease domain of polymerase delta (Polδ) on somatic and germline mutational processes and cancer development. In germline cells and in non-cancer somatic cells, thePOLD1L474P variant increases the mutation burden only slightly, contributing ∼11.8% and ∼14.7% of mutations respectively, although it strongly distorts the mutational spectra. By contrast, tumors developed by carriers of inherited pathogenic variants inPOLD1harbor a DNA rearrangement that results in a homozygous state of the pathogenic variant, leading to an extremely high mutation rate. Thus, mutations in both alleles ofPOLD1gene are required for strong increase in mutation rate suggesting recessiveness of Poldδ proofreading. These results show a similar role of Polδ in germline and somatic replication, and, together with previous findings, illustrate the important differences between Polδ and Polε in the disruption of their replication fidelity.
Integrated multi-cohort analysis of the Parkinson’s disease gut metagenome
Authors: Boktor Joseph C. , Sharon Gil , Metman Leo A. Verhagen , Hall Deborah A. , Engen Phillip A. , Zreloff Zoe , Hakim Daniel J. , Bostick John W. , Ousey James , Lange Danielle , Humphrey Gregory , Ackermann Gail , Carlin Martha , Knight Rob , Keshavarzian Ali , Mazmanian Sarkis K.
Published: July 2022

Background

The gut microbiome is altered in several neurologic disorders including Parkinson’s disease (PD).

Objectives

Profile the fecal gut metagenome in PD for alterations in microbial composition, taxon abundance, metabolic pathways, and microbial gene products, and their relationship with disease progression.

Methods

Shotgun metagenomic sequencing was conducted on 244 stool donors from two independent cohorts in the United States, including individuals with PD (n=48, n=47, respectively), environmental Household Controls (HC, n=29, n=30), and community Population Controls (PC, n=41, n=49). Microbial features consistently altered in PD compared to HC and PC subjects were identified. Data were cross-referenced to public metagenomic datasets from two previous studies in Germany and China to determine generalizable microbiome features.

Results

The gut microbiome in PD shows significant alterations in community composition. Robust taxonomic alterations include depletion of putative “beneficial” gut commensalsFaecalibacterium prausnitziiandEubacteriumandRoseburiaspecies, and increased abundance ofAkkermansia muciniphilaandBifidobacteriumspecies. Pathway enrichment analysis and metabolic potential, constructed from microbial gene abundance, revealed disruptions in microbial carbohydrate and lipid metabolism and increased amino acid and nucleotide metabolism. These global gene-level signatures indicate an increased response to oxidative stress, decreased cellular growth and microbial motility, and disrupted inter-community signaling.

Conclusions

A metagenomic meta-analysis of PD shows consistent and novel alterations in taxonomic representation, functional metabolic potential, and microbial gene abundance across four independent studies from three continents. These data reveal stereotypic changes in the gut microbiome are a consistent feature of PD, highlighting potential diagnostic and therapeutic avenues for future research.
A unified model for the surveillance of translation in diverse noncoding sequences
Authors: Kesner Jordan S , Chen Ziheng , Aparicio Alexis A , Wu Xuebing
Published: July 2022

Translation is pervasive outside of canonical coding regions, occurring in lncRNAs, UTRs, and introns. While the resulting polypeptides are often non-functional, translation in noncoding regions is nonetheless necessary for the birth of new coding regions. The mechanisms underlying the surveillance of translation in diverse noncoding regions and how escaped polypeptides evolve new functions remain unclear. Intriguingly, noncoding sequence-derived functional peptides often localize to membranes. Here, we show that the intrinsic nucleotide bias in the noncoding genome and in the genetic code frequently results in polypeptides with a hydrophobic C-terminal tail, which is captured by the ribosome-associated BAG6 membrane protein triage complex for either proteasomal degradation or membrane targeting. In contrast, canonical proteins have evolved to deplete C-terminal hydrophobic residues. Our results uncovered a fail-safe mechanism for the surveillance of unwanted translation from diverse noncoding regions and suggest a possible biochemical route for the preferential membrane localization of newly evolved proteins.

Highlights

Translation in diverse noncoding regions is mitigated by proteasomal degradation

C-terminal hydrophobicity is a hallmark of noncoding sequence derived polypeptides

A genome-wide CRISPR screen identified the BAG6 membrane protein triage pathway

Ribosome-associated BAG6 complex targets C-terminal hydrophobicity for degradation
De novo discovery of traits co-occurring with chronic obstructive pulmonary disease
Authors: Golovina E. , Fadason T. , Jaros R.K. , Kumar H. , John J. , Burrowes K. , Tawhai M. , O’Sullivan J.M.
Published: July 2022

Epidemiological research indicates that chronic obstructive pulmonary disease (COPD) is a heterogeneous group of chronic lung conditions that are typically accompanied by cardiovascular disease, depression, lung cancer and other conditions. Genome-wide association studies (GWAS) have identified single-nucleotide polymorphisms (SNPs) associated with COPD and the co-occuring conditions, suggesting common biological mechanisms underlying COPD and these co-occuring conditions. To identify them, we have integrated information across different biological levels (i.e. genetic variants, lung-specific 3D genome structure, gene expression and protein-protein interactions) to build lung-specific gene regulatory and protein-protein interaction networks. We have queried these networks using disease-associated SNPs for COPD, unipolar depression and coronary artery disease. Our results show that COPD-associated SNPs can control genes involved in the regulation of lung or pulmonary function, asthma, brain region volumes, cortical surface area, depressed affect, neuroticism, Parkinson’s disease, white matter microstructure and smoking behaviour. We describe the regulatory connections, genes and biochemical pathways that underly these co-occuring trait-SNP-gene associations. Collectively, our findings provide new avenues for the investigation of the underlying biology and diverse clinical presentations of COPD. In so doing, we identify a collection of genetic variants and genes that may aid COPD patient stratification and treatment.
Transcription of Murine Endogenous Retrovirus MERVL Is Required for Progression of Development in Early Preimplantation Embryos
Authors: Sakashita Akihiko , Kitano Tomohiro , Ishizu Hirotsugu , Guo Youjia , Masuda Harumi , Ariura Masaru , Murano Kensaku , Siomi Haruhiko
Published: July 2022

Zygotic genome activation (ZGA) is a critical post-fertilization step that promotes totipotency and allows different cell fates to emerge in the developing embryo. MERVL, murine endogenous retrovirus-L, is transiently upregulated at the 2-cell stage around the time of ZGA. Although MERVL expression is widely used as a marker of totipotency, the role of this retrotransposon in mouse embryogenesis remains elusive. Here, we develop a method for consistent knockdown of interspersed copies of MERVL and show that MERVL RNA, but not encoded retroviral proteins and their long terminal repeat (LTR) promoter, is essential for accurate regulation of the host transcriptome and chromatin state during preimplantation development. MERVL knockdown (KD) results in embryonic lethality due to defects in differentiation and genomic stability. Furthermore, transcriptome and epigenome analysis revealed that MERVL-KD embryos retained an accessible chromatin state at, and aberrant expression of, a subset of 2-cell specific genes at mid-preimplantation stages. Taken together, our results suggest a model in which an endogenous retrovirus plays a critical role in regulating host cell fate potential.
What drives prey selection? Assessment of tiger food habits across the Terai-Arc landscape, India
Authors: Biswas Suvankar , Kumar Shrewshree , Bandhopadhyay Meghna , Patel Shiv Kumari , Lyngdoh Salvador , Pandav Bivash , Mondol Samrat
Published: July 2022

Large carnivores strongly shape ecological interactions within their respective ecosystems, but experience significant conflicts with human across their range due to their specific ecological resource requirements. The tiger (Panthera tigris) typifies the challenges faced by the large carnivore communities globally. India retains majority of the global tiger population with significant numbers outside protected areas (PAs) that are involved in conflicts from livestock predation and human/tiger death. To understand the prey selection patterns and spatio-temporal patterns of livestock predation-related conflict issues we investigated tiger food habits across the Indian part of the Terai-Arc Landscape (TAL), a globally-important tiger conservation landscape in India. We used 510 genetically-confirmed tiger faeces collected across the landscape and ascertained 10 wild and livestock as major prey species. Large-bodied species (sambar, swamp deer, nilgai, chital, wild pig and livestock) comprised ~94% of tiger diet, with sambar, chital and livestock were the major prey species. Habitat-specific (Shivalik-Bhabar and Terai) analyses show significantly different pattern of prey selections determined by abundance and prey body weight. Results also suggest that PA and non-PAs of Terai habitat are more prone to livestock depredation-related conflicts, and careful management interventions and community involvements are required to reduce such threats. We suggest long-term plans including population estimation of tigers and prey outside PAs, reducing grazing pressures and cattle enumeration, detailed investigation of tiger deaths etc. to ensure future tiger sustainability across this habitat.
Candida albicans exhibits heterogeneous and adaptive cytoprotective responses to anti-fungal compounds
Authors: Dumeaux V , Massahi S , Bettauer V , Khurdia S , Costa ACBP , Omran RP , Simpson S , Xie JL , Whiteway M , Berman J , Hallett MT
Published: July 2022

Candida albicans is an opportunistic human pathogen which represents a significant threat to human health and is associated with substantial socio-economic burden. Current antifungal treatments fail at least in part because C. albicans can initiate a strong drug tolerance response, allowing cells to grow at concentrations above their minimal inhibitory concentration. Our goal is to better characterize this cytoprotective tolerance program at the molecular single cell level. We present here a nano-liter droplet-based fungal single cell transcriptomics platform capable of profiling thousands of individual C. albicans SC5314 cells in an efficient manner. Profiles of untreated cells partition into three transcriptional clusters with each highlighting a cell cycle checkpoint coupled with specific metabolic and stress responses, as perhaps expected. After just two days post-treatment with fluconazole, surviving cells bifurcate into two distinct subpopulations: the so-called α response involving upregulation of protein translation, rRNA processing and mitochondrial cellular respiration, and the β response involving processes and stress responses that assist damaged cells. By extending our time series to six days and profiling with other antifungals and bioactive compounds, we provide evidence that surviving cells transition from the α to β responses mediated by the Ribosome Assembly Stress Response (RASTR).
MAVEN: Compound mechanism of action analysis and visualisation using transcriptomics and compound structure data in R/Shiny
Authors: Hosseini-Gerami Layla , Ballesteros Rosa Hernansaiz , Liu Anika , Broughton Howard , Collier David Andrew , Bender Andreas
Published: July 2022

Background

Understanding the mechanism of action (MoA) of a compound is an often challenging but equally crucial aspect of drug discovery that can help improve both its efficacy and safety. Computational methods to aid MoA elucidation usually either aim to predict direct drug targets, or attempt to understand modulated downstream pathways or signalling proteins. Such methods usually require extensive coding experience and results are often optimised for further computational processing, making them difficult for wet-lab scientists to perform, interpret and draw hypotheses from.

Results

To address this issue, we in this work present MAVEN (Mechanism of Action Visualisation and Enrichment), an R/Shiny app which allows for GUI-based prediction of drug targets based on chemical structure, combined with causal reasoning based on causal protein-protein interactions and transcriptomic perturbation signatures. The app computes a systems-level view of the mechanism of action of the input compound. This is visualised as a sub-network linking predicted or known targets to modulated transcription factors via inferred signalling proteins. The tool includes a selection of MsigDB gene set collections to perform pathway enrichment on the resulting network, and also allows for custom gene sets to be uploaded by the researcher. MAVEN is hence a user-friendly, flexible tool for researchers without extensive bioinformatics or cheminformatics knowledge to generate interpretable hypotheses of compound Mechanism of Action.

Conclusions

MAVEN is available as a fully open-source tool at https://github.com/laylagerami/MAVEN with options to install in a Docker or Singularity container. Full documentation, including a tutorial on example data, is available at https://laylagerami.github.io/MAVEN.
Epigenetic age acceleration is associated with oligodendrocyte proportions in MSA and control brain tissue
Authors: Murthy Megha , Shireby Gemma , Miki Yasuo , Viré Emmanuelle , Lashley Tammaryn , Warner Thomas T. , Mill Jonathan , Bettencourt Conceição
Published: July 2022

Aims

Epigenetic clocks are widely applied as surrogates for biological age in different tissues and/or diseases, including several neurodegenerative diseases. Despite white matter (WM) changes often being observed in neurodegenerative diseases, no study has investigated epigenetic ageing in white matter.

Methods

We analysed the performances of two DNA methylation-based clocks, DNAmClockMulti and DNAmClockCortical, in post-mortem WM tissue from multiple subcortical regions and the cerebellum, and in oligodendrocyte-enriched nuclei. We also examined epigenetic ageing in control and multiple system atrophy (MSA) (WM and mixed WM and grey matter), as MSA is a neurodegenerative disease comprising pronounced WM changes and α-synuclein aggregates in oligodendrocytes.

Results

Estimated DNA methylation (DNAm) ages showed strong correlations with chronological ages, even in WM (e.g., DNAmClockCortical, r = [0.80-0.97], p<0.05). However, performances and DNAm age estimates differed between clocks and brain regions. DNAmClockMulti significantly underestimated ages in all cohorts except in the MSA prefrontal cortex mixed tissue, whereas DNAmClockCortica tended towards age overestimations. Pronounced age overestimations in the oligodendrocyte-enriched cohorts (e.g., oligodendrocyte-enriched nuclei, p=6.1×10-5) suggested that this cell-type ages faster. Indeed, significant positive correlations were observed between estimated oligodendrocyte proportions and DNAm age acceleration estimated by DNAmClockCortica (r>0.31, p<0.05), and similar trends with DNAmClockMulti. Although increased age acceleration was observed in MSA compared to controls, no significant differences were observed upon adjustment for possible confounders (e.g., cell-type proportions).

Conclusions

Our findings show that oligodendrocyte proportions positively influence epigenetic age acceleration across brain regions and highlight the need to further investigate this in ageing and neurodegeneration.