bluuebunny/crossref_metadata_2025 huggingface dataset:
Cohesin dysfunction results in cell wall defects in budding yeast
Authors: Kothiwal Deepash , Gopinath Swagathnath , Laloraya Shikha
Published: February 2021

Cohesin is a conserved chromatin-binding multisubunit protein complex involved in diverse chromosomal transactions such as sister-chromatid cohesion, chromosome condensation, regulation of gene expression, DNA replication, and repair. While working with a budding yeast temperature-sensitive mutant, mcd1-1, defective in a cohesin subunit, we observed that it was resistant to zymolyase, indicating an altered cell wall organization. The budding yeast cell wall is a strong but elastic structure essential for maintenance of cell shape and protection from extreme environmental challenges. Here, we show that the cohesin complex plays an important role in cell wall maintenance. Cohesin mutants showed high chitin content in the cell wall and sensitivity to multiple cell wall stress-inducing agents. Interestingly, temperature-dependent lethality of cohesin mutants was osmoremedial, in a HOG1-MAPK pathway-dependent manner, suggesting that the temperature sensitivity of these mutants may arise partially from cell wall defects. Moreover, Mpk1 hyper-phosphorylation indicated activation of the cell wall integrity (CWI) signaling pathway in cohesin mutants. Genetic interaction analysis revealed that the CWI pathway is essential for survival of mcd1-1 upon additional cell wall stress. The cell wall defect was independent of the cohesion function and accompanied by misregulation of expression of several genes having cell wall-related functions. Our findings reveal a requirement of cohesin in maintenance of CWI that is independent of the CWI pathway, and that may arise from cohesin’s role in regulating the expression of multiple genes encoding proteins involved in cell wall organization and biosynthesis.
Translating insights from the seed metabolome into improved prediction for lipid-composition traits in oat (Avena sativaL.)
Authors: Campbell Malachy T , Hu Haixiao , Yeats Trevor H , Caffe-Treml Melanie , Gutiérrez Lucía , Smith Kevin P , Sorrells Mark E , Gore Michael A , Jannink Jean-Luc
Published: February 2021

Oat (Avena sativa L.) seed is a rich resource of beneficial lipids, soluble fiber, protein, and antioxidants, and is considered a healthful food for humans. Little is known regarding the genetic controllers of variation for these compounds in oat seed. We characterized natural variation in the mature seed metabolome using untargeted metabolomics on 367 diverse lines and leveraged this information to improve prediction for seed quality traits. We used a latent factor approach to define unobserved variables that may drive covariance among metabolites. One hundred latent factors were identified, of which 21% were enriched for compounds associated with lipid metabolism. Through a combination of whole-genome regression and association mapping, we show that latent factors that generate covariance for many metabolites tend to have a complex genetic architecture. Nonetheless, we recovered significant associations for 23% of the latent factors. These associations were used to inform a multi-kernel genomic prediction model, which was used to predict seed lipid and protein traits in two independent studies. Predictions for 8 of the 12 traits were significantly improved compared to genomic best linear unbiased prediction when this prediction model was informed using associations from lipid-enriched factors. This study provides new insights into variation in the oat seed metabolome and provides genomic resources for breeders to improve selection for health-promoting seed quality traits. More broadly, we outline an approach to distill high-dimensional “omics” data to a set of biologically meaningful variables and translate inferences on these data into improved breeding decisions.
Is left ventricular superior to right ventricular pacing in children with congenital or postoperative complete heart block?
Authors: Siddharth Ch Bharat , Relan Jay
Published: January 2021

A best evidence topic in cardiac surgery was written according to a structured protocol. The question addressed was ‘Is left ventricular superior to right ventricular pacing in children with congenital or postoperative complete heart block?’ Altogether, 19 papers were found using the reported search, of which 9 represented the best evidence to answer the clinical question. The authors, journal, date and country of publication, patient group studied, study type, relevant outcomes and results of these papers are tabulated. Two large multicentric showed that site of pacing was the major determinant of left ventricular (LV) function with LV pacing being superior to RV pacing, though the number of patients paced via LV was lesser in comparison to right ventricular (RV). There were 2 prospective, 2 retrospective and 1 cross-sectional studies with fewer patients that demonstrated superiority of LV over RV pacing in preserving LV function. Only 1 small-scale retrospective study showed similar results of LV and RV pacing on LV function. One cross-sectional study showed superiority of LV apical pacing on exercise tolerance. As per the existing literature, LV apex seems to be the most optimal site for epicardial pacing while RV free wall pacing has the highest risk of causing LV dysfunction over the long term. We conclude that LV pacing appears to be superior to RV pacing in terms of long-term effect on cardiac function and ventricular synchrony.
Research on feature of thermal performance of integrated composite system
Authors: Chen Lei , Li Yangluxi
Published: February 2021

The aim of this study is to explore the effect of stud on the characteristics of thermal insulation and decoration composite system. Prior research conducted has primarily focused on the insulation material performance aside from the composite system. The theoretical calculation and field measurement method are adopted in this paper to compare the insulation performance for different building envelope systems. By considering the thermal transfer coefficient as the performance indicator, thermal bridge and air cavities of integrated insulation composite system as impact factors are investigated. Firstly, the high insulation performance of the composite system is determined via comparing other systems. Secondly, the thermal bridge issue of the composite system led by stud is subsequently investigated followed by the air cavity influenced element being studied via field measurement, which is caused by stud condition. Final results indicate that the thermal insulation and decoration composite system can achieve a substantial insulation performance. In this case, the corresponding optimal size of studs and air cavity is achieved. Further, scattered layout of air cavities could apparently improve the entire thermal system’s insulated performance. All these studied conclusions can contribute designers to implement this system more accurately.
Can We Predict Armed Conflict? How the First 9 Years of Published Forecasts Stand Up to Reality
Authors: Hegre Håvard , Nygård Håvard Mokleiv , Landsverk Peder
Published: January 2021

Can we predict civil war? This article sheds light on this question by evaluating 9 years of, at the time, future predictions made by Hegre et al. (2013) in 2011. We evaluate the ability of this study to predict observed conflicts in the 2010–2018 period, using multiple metrics. We also evaluate the original performance evaluation, i.e., whether the performance measures presented by Hegre et al. hold in this new 9-year window. Overall, we conclude that Hegre et al. were able to produce meaningful and reasonably accurate predictions of armed conflict. Of course, they did not always hit the mark. We find that the model has performed worse in predicting low level incidence of conflict than in predicting major armed conflict. The model also failed to predict some important broader regional shifts. These, however, represent important insights for future research and illustrate the utility in predictive models for both testing and developing theory.
Ultrasound-Guided Fascia Iliaca Plane Block for the Treatment of Donor Site Pain in the Burn-Injured Patient: A Randomized Control Trial
Authors: Town Cienwen J , Strand Haakan , Johnson James , Brown Jason , Pelecanos Anita , Van Zundert Andre
Published: January 2021

Burn injuries requiring surgical intervention often result in split-thickness skin grafting procedures, with donor skin frequently harvested from the patient’s anterolateral thigh. The donor site is often reported as the primary site of postoperative pain due to the damage sustained to localized nociceptors. A randomized control trial was undertaken to evaluate the impact an ultrasound-guided regional nerve block would have on patient-reported pain scores in donor site wounds, and associated rescue analgesia consumption. Twenty participants requiring split-skin grafting for burn injuries of <15% total body surface area were enrolled from a tertiary burns unit and randomized to control (10 participants) or intervention group (10 participants). The intervention group received the addition of an ultrasound-guided facia iliaca plane block prior to their surgery. Primary outcome was pain score in the donor site during the postoperative phase while secondary outcome was pain on day 1 post-surgery as measured by the numeric pain score (0–10). During the postoperative phase, the intervention group had a significantly lower median donor site pain score of 0 (interquartile range [IQR] 0–0), compared to the control group median 6 (IQR 4–7) (P < .001). Day 1 post-surgery the intervention group had a median pain score of 0 (IQR 0–4) compared to control group median 4.5 (IQR 2–6) (P = .043). The study findings demonstrated that regional anesthesia was an effective way to reduce pain scores and requirement for additional analgesics during the postoperative phase.
Malignant adnexal tumour of the shoulder—a rare case report
Authors: Shanmugam Giridharan , Chidambaram Balamurugan , Princess Beulah D , Manimohan Vignesh
Published: January 2021

Malignant adnexal tumours are a very rare and highly aggressive primary skin neoplasms. Among them, malignant hidradenocarcinoma is a particularly aggressive tumour that arises from the intradermal duct of eccrine sweat glands. It more commonly arises de novo and rarely from a pre-existing hidradenoma. It is an aggressive tumour with regional lymph nodal and distant visceral metastasis. The prognosis is poor with a 5-year survival rate of 30%. Here, we present a 48-year-old female who came with a swelling over the left shoulder. On examination, it appeared to be chronic sebaceous cyst. The patient underwent wide local excision and the specimen was diagnosed as malignant nodular hidradenocarcinoma. Subsequent re-excision and sentinel lymph node biopsy was performed and margins were found to be microscopically negative for tumour. Based on the available literature wide local excision and sentinel lymph node biopsy appear to be the most common initial treatment plans.
A graph database of scholastic relationships in the Babylonian Talmud
Authors: Waxman Joshua
Published: February 2021

Envisioning the dense scholastic interactions of the Babylonian Talmud as a multi-generational social network, we built a social network graph of the Talmud. We performed Named Entity Recognition on statement-aligned Hebrew and English texts to produce graphs of rabbis (nodes) and their interactions (edges). The new graph database, currently available online, delivers visual and color-coded information about scholastic generation, teacher–student relationships, and both local (page-level) and global (Talmud-level) interactions. By making a wealth of knowledge accessible and highlighting relevant relationships, this tool can provide valuable insights into the complex dynamics of Talmudic discourse.
Semirings of Evidence
Authors: Baur Michael , Studer Thomas
Published: February 2021

In traditional justification logic, evidence terms have the syntactic form of polynomials, but they are not equipped with the corresponding algebraic structure. We present a novel semantic approach to justification logic that models evidence by a semiring. Hence justification terms can be interpreted as polynomial functions on that semiring. This provides an adequate semantics for evidence terms and clarifies the role of variables in justification logic. Moreover, the algebraic structure makes it possible to compute with evidence. Depending on the chosen semiring this can be used to model trust, probabilities, cost, etc. Last but not least the semiring approach seems promising for obtaining a realization procedure for modal fixed point logics.
In silico analysis of selenoprotein N (Gallus gallus): absence of EF-hand motif and the role of CUGS-helix domain in antioxidant protection
Authors: Zhu Shi-Yong , Liu Li-Li , Huang Yue-Qiang , Li Xiao-Wei , Talukder Milton , Dai Xue-Yan , Li Yan-Hua , Li Jin-Long
Published: February 2021

Selenoprotein N (SEPN1) is critical to the normal muscular physiology. Mutation of SEPN1 can raise congenital muscular disorder in human. It is also central to maturation and structure of skeletal muscle in chicken. However, human SEPN1 contained an EF-hand motif, which was not found in chicken. And the biochemical and molecular characterization of chicken SEPN1 remains unclear. Hence, protein domains, transcription factors, and interactions of Ca2+ in SEPN1 were analyzed in silico to provide the divergence and homology between chicken and human in this work. The results showed that vertebrates’ SEPN1 evolved from a common ancestor. Human and chicken's SEPN1 shared a conserved CUGS-helix domain with function in antioxidant protection. SEPN1 might be a downstream target of JNK pathway, and it could respond to multiple stresses. Human's SEPN1 might not combine with Ca2+ with a single EF-hand motif in calcium homeostasis, and chicken SEPN1 did not have the EF-hand motif in the prediction, indicating the EF-hand motif malfunctioned in chicken SEPN1.
Clinical features, neurologic recovery, and risk factors of postoperative posterior fossa syndrome and delayed recovery: a prospective study
Authors: Khan Raja B , Patay Zoltan , Klimo Paul , Huang Jie , Kumar Rahul , Boop Frederick A , Raches Darcy , Conklin Heather M , Sharma Richa , Simmons Andrea , Sadighi Zsila S , Onar-Thomas Arzu , Gajjar Amar , Robinson Giles W
Published: February 2021

Background

Posterior fossa syndrome (PFS) is a known consequence of medulloblastoma resection. Our aim was to clinically define PFS, its evolution over time, and ascertain risk factors for its development and poor recovery.

Methods

Children with medulloblastoma treated at St Jude Children’s Research Hospital from 6/2013 to 7/2019 received standardized neurological examinations, before and periodically after radiation therapy. Most (98.3%) were enrolled on the ongoing multi-institutional protocol (SJMB12; NCT 01878617).

Results

Sixty (34%) of 178 evaluated children had PFS. Forty (23%) had complete mutism (PFS1) and 20 (11%) had diminished speech (PFS2). All children with PFS had severe ataxia and 42.5% of PFS1 had movement disorders. By multivariable analysis, younger age (P = .0005) and surgery in a low-volume surgery center (P = .0146) increased PFS risk, while Sonic Hedgehog tumors had reduced risk (P = .0025). Speech and gait returned in PFS1/PFS2 children at a median of 2.3/0.7 and 2.1/1.5 months, respectively, however, 12 (44.4%) of 27 PFS1 children with 12 months of follow-up were nonambulatory at 1 year. Movement disorder (P = .037) and high ataxia score (P < .0001) were associated with delayed speech recovery. Older age (P = .0147) and high ataxia score (P < .0001) were associated with delayed gait return. Symptoms improved in all children but no child with PFS had normal neurologic examination at a median of 23 months after surgery.

Conclusions

Categorizing PFS into types 1 and 2 has prognostic relevance. Almost half of the children with PFS1 with 12-month follow-up were nonambulatory. Surgical experience was a major modifiable contributor to the development of PFS.
Adult Diffuse Astrocytic and Oligodendroglial Tumors
Authors: Gestrich Catherine K , Couce Marta E , Cohen Mark L
Published: January 2021

Infiltrating gliomas comprise the most common group of primary intraparenchymal brain tumors and present a level of complexity which requires careful integration of histopathology and molecular diagnostics for optimal therapy. To this end, the fourth edition of the World Health Organization (WHO) Classification of Tumors of the Central Nervous System (CNS) has been followed by a series of publications by cIMPACT-NOW (the Consortium to Inform Molecular and Practical Approaches to CNS Tumor Taxonomy) incorporating molecular signatures to propose updated diagnostic categories in anticipation of the upcoming fifth edition of CNS tumor classification. Integration of histopathology, immunophenotyping, and molecular findings is profoundly changing the practice of diagnostic surgical neuropathology and enabling a more personalized approach to treating patients with gliomas.
A Deep-Learning–Based, Fully Automated Program to Segment and Quantify Major Spinal Components on Axial Lumbar Spine Magnetic Resonance Images
Authors: Shen Haotian , Huang Jiawei , Zheng Qiangqiang , Zhu Zhiwei , Lv Xiaoqiang , Liu Yong , Wang Yue
Published: January 2021

Objective

The paraspinal muscles have been extensively studied on axial lumbar magnetic resonance imaging (MRI) for better understanding of back pain; however, the acquisition of measurements mainly relies on manual segmentation, which is time consuming. The study objective was to develop and validate a deep-learning–based program for automated acquisition of quantitative measurements for major lumbar spine components on axial lumbar MRIs, the paraspinal muscles in particular.

Methods

This study used a cross-sectional observational design. From the Hangzhou Lumbar Spine Study, T2-weighted axial MRIs at the L4–5 disk level of 120 participants (aged 54.8 years [SD = 15.0]) were selected to develop the deep-learning–based program Spine Explorer (Tulong). Another 30 axial lumbar MRIs were automatically measured by Spine Explorer and then manually measured using ImageJ to acquire quantitative size and compositional measurements for bilateral multifidus, erector spinae, and psoas muscles; the disk; and the spinal canal. Intersection-over-union and Dice score were used to evaluate the performance of automated segmentation. Intraclass coefficients and Bland–Altman plots were used to examine intersoftware agreements for various measurements.

Results

After training, Spine Explorer (Tulong) measures an axial lumbar MRI in 1 second. The intersections-over-union were 83.3% to 88.4% for the paraspinal muscles and 92.2% and 82.1% for the disk and spinal canal, respectively. For various size and compositional measurements of paraspinal muscles, Spine Explorer (Tulong) was in good agreement with ImageJ (intraclass coefficient = 0.85 to approximately 0.99).

Conclusion

Spine Explorer (Tulong) is automated, efficient, and reliable in acquiring quantitative measurements for the paraspinal muscles, the disk, and the canal, and various size and compositional measurements were simultaneously obtained for the lumbar paraspinal muscles.

Impact

Such an automated program might encourage further epidemiological studies of the lumbar paraspinal muscle degeneration and enhance paraspinal muscle assessment in clinical practice.
Complications as a Mediator of the Perioperative Frailty–Mortality Association
Authors: McIsaac Daniel I. , Aucoin Sylvie D. , Bryson Gregory L. , Hamilton Gavin M. , Lalu Manoj M.
Published: February 2021

Background

Preoperative frailty is strongly associated with postoperative complications and mortality. However, the pathways between frailty, postoperative complications, and mortality are poorly described. The authors hypothesized that the occurrence of postoperative complications would mediate a substantial proportion of the total effect of frailty on mortality after elective noncardiac surgery.

Methods

Following protocol registration, the authors conducted a retrospective cohort study of intermediate- to high-risk elective noncardiac surgery patients (2016) using National Surgical Quality Improvement Program data. The authors conducted Bayesian mediation analysis of the relationship between preoperative frailty (exposure, using the Risk Analysis Index), serious complications (mediator), and 30-day mortality (outcome), comprehensively adjusting for confounders. The authors estimated the total effect of frailty on mortality (composed of the indirect effect mediated by complications and the remaining direct effect of frailty) and estimated the proportion of the frailty–mortality association mediated by complications.

Results

The authors identified 205,051 patients; 1,474 (0.7%) died. Complications occurred in 20,211 (9.9%). A 2 SD increase in frailty score resulted in a total association with mortality equal to an odds ratio of 3.79 (95% credible interval, 2.48 to 5.64), resulting from a direct association (odds ratio, 1.76; 95% credible interval, 1.34 to 2.30) and an indirect association mediated by complications (odds ratio, 2.15; 95% credible interval, 1.58 to 2.96). Complications mediated 57.3% (95% credible interval, 40.8 to 73.8) of the frailty–mortality association. Cardiopulmonary complications were the strongest mediators among complication subtypes.

Conclusions

Complications mediate more than half of the association between frailty and postoperative mortality in elective noncardiac surgery.

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C-Reactive Protein Levels Predict Outcomes in Continuous-Flow Left Ventricular Assist Device Patients: An INTERMACS Analysis
Authors: Batra Jaya , Truby Lauren K. , Defilippis Ersilia M. , Takeda Koji , Takayama Hiroo , Naka Yoshifumi , Yuzefpolskaya Melana , Colombo Paolo C. , Sayer Gabriel , Farr Maryjane A. , Garan A. Reshad , Uriel Nir , Topkara Veli K.
Published: February 2021

CRP is an established inflammatory biomarker with prognostic value in patients with chronic heart failure, yet its role in continuous-flow left ventricular assist device (LVAD) patients is largely unknown. 5,183 patients from the INTERMACS registry who underwent durable LVAD between 2008 and 2017 and had preimplant CRP levels were included. The sample was stratified into two groups based on preimplant CRP levels: CRP of 0–10 mg/L (low) and >10 mg/L (high). Kaplan-Meier survival estimates were used to assess outcomes at 2 years after LVAD implantation, with log-rank testing used to compare groups. Cox proportional hazard models were used for multivariable adjustment. Patients with high preimplant CRP were younger, more likely to be INTERMACS class I, and had a higher need for temporary mechanical circulatory support before LVAD implant compared to those with lower CRP levels (all P < 0.001). The high CRP group had higher WBC counts and BNP levels (all P < 0.001). After adjustment, higher CRP (>10 mg/L) was associated with greater risk of mortality, RV failure, and stroke postimplant (P < 0.001). In addition, elevated postimplant CRP level at 3 months was associated with increased mortality and stroke on LVAD support (P < 0.001). CRP is a predictor of death and complications on LVAD support. Future studies are necessary to explore the mechanisms underlying this finding and the potential role of antiinflammatory therapies in this population.
Midterm Results of Minimally Invasive Left Thoracotomy Fully Magnetically Levitated Left Ventricular Assist Device Implantation
Authors: Kervan Umit , Kocabeyoglu Sinan Sabit , Emre Sert Dogan , Karahan Mehmet , Temizhan Ahmet , Demirkan Burcu , Akin Yesim , Beyazal Osman Fehmi , Akdi Mustafa , Catav Zeki
Published: February 2021

The aim of the study is to compare outcomes of the patients who underwent HeartMate3 (HM3) implantation with conventional sternotomy (CS) and minimally invasive thoracotomy technique (MILT). From June 2013 to April 2019, 50 patients who underwent isolated HM3 implantation were included. Patients were divided into two groups according to the operative technique; of 50 patients, 28 were implanted with CS and 22 with MILT. All patients were evaluated for mortality, need of inotrope, blood product transfusion, intensive care unit stay, time on mechanical ventilation, and postoperative right ventricular failure. Primary outcomes were early mortality and occurrence of adverse events. Patients characteristics were similar; preoperative central venous pressure (CVP) and the ratio of CVP to pulmonary capillary wedge pressure (CVP/PCWP) were significantly higher in the MILT group versus the CS group (p < 0.05). Intensive care unit stay was significantly shorter in the MILT group (p < 0.05). Incidence of bleeding requiring exploratory sternotomy and postoperative drainage on the first postoperative day were statistically higher in the CS group (p < 0.05). Right ventricular failure was higher in the CS group but was not statistically significant (p = 0.4). There was no significant difference in long-term adverse events. The Kaplan–Meier survival analysis showed no difference between the groups (p = 0.66). The HM3 assist system can be successfully implanted with the MILT technique, which has proved to be safe and reproducible and yields good clinical outcomes.
Membrane Lung and Blood Pump Use During Prolonged Extracorporeal Membrane Oxygenation: Trends From 2002 to 2017
Authors: Hayes McKenzie M. , Fallon Brian P. , Barbaro Ryan P. , Manusko Niki , Bartlett Robert H. , Toomasian John M.
Published: February 2021

Extracorporeal life support (ECLS) has grown in its application since its first clinical description in the 1970s. The technology has been used to support a wide variety of mechanical support modalities and diseases, including respiratory failure, cardiorespiratory failure, and cardiac failure. Over many decades and safety and efficacy studies, followed by randomized clinical trials and thousands of clinical uses, ECLS is considered as an accepted treatment option for severe pulmonary and selected cardiovascular failure. Extracorporeal life support involves the use of support artificial organs, including a membrane lung and blood pump. Over time, changes in the technology and the management of ECLS support devices have evolved. This manuscript describes the use of membrane lungs and blood pumps used during ECLS support from 2002 to 2017 in over 65,000 patients reported to the Extracorporeal Life Support Organization Registry. Device longevity and complications associated with membrane lungs and blood pump are described and stratified by age group: neonates, pediatrics, and adults.
Longitudinal analyses reveal age-specific immune correlates of COVID-19 severity
Authors: Lewis Sloan A. , Sureshchandra Suhas , Zulu Michael Z. , Doratt Brianna , Pinski Amanda , Curtis Micaila , Jankeel Allen , Ibraim Izabela , Rhoades Nicholas , Jiang Xiwen , Tifrea Delia , Zaldivar Frank , Shen Weining , Edwards Robert , Chow Daniel , Cooper Dan , Amin Alpesh , Messaoudi Ilhem
Published: January 2021

Severe COVID-19 disproportionately impacts older individuals and those with comorbidities. It is estimated that approximately 80% of COVID-19 deaths are observed among individuals >65 years of age. However, the immunological underpinnings of severe COVID-19 in the aged have yet to be defined. This study captures the longitudinal immune response to SARS-CoV-2 infection in a cohort of young and aged patients with varying disease severity. Phenotypic transcriptional and functional examination of the peripheral mononuclear cells revealed age-, time, and disease severity-specific adaptations. Gene expression signatures within memory B cells suggest qualitative differences in the antibody responses in aged patients with severe disease. Examination of T cells showed profound lymphopenia, that worsened over time and correlated with lower levels of plasma cytokines important for T cell survival in aged patients with severe disease. Single cell RNA sequencing revealed augmented signatures of activation, exhaustion, cytotoxicity, and type-I interferon signaling in memory T cells and NK cells. Although hallmarks of a cytokine storm were evident in both groups, older individuals exhibited elevated levels of chemokines that mobilize inflammatory myeloid cells, notably in those who succumbed to disease. Correspondingly, we observed a re-distribution of DC and monocytes with severe disease that was accompanied by a rewiring towards a more regulatory phenotype. Several of these critical changes, such as the reduction of surface HLA-DR on myeloid cells, were reversed in young but not aged patients over time. In summary, the data presented here provide novel insights into the impact of aging on the host response to SARS-CoV2 infection.
Predicting and simulating effects of PEEP changes with machine learning
Authors: Strodthoff Claas , Frerichs Inéz , Weiler Norbert , Bergh Björn
Published: January 2021

Background/Objectives

Choosing ventilator settings, especially positive end-expiratory pressure (PEEP), is a very common and non-trivial task in intensive care units (ICUs). Established solutions to this problem are either poorly individualised or come with high costs in terms of used material or time. We propose a novel method relying on machine learning utilising only already routinely measured data.

Methods

Using the MIMIC-III (with over 60000 ICU stays) and eICU databases (with over 200000 ICU stays) we built a deep learning model that predicts relevant success parameters of ventilation (oxygenation, carbon dioxide elimination and respiratory mechanics). We compare a random forest, individual neural networks and a multi-tasking neural network. Our final model also allows to simulate the expected effects of PEEP changes.

Results

The model predicts arterial partial pressures of oxygen and carbon dioxide and respiratory system compliance 30 minutes into the future with mean absolute percentage errors of about 22 %, 10 % and 11 %, respectively.

Conclusions

The deep learning approach to ventilation optimisation is promising and comes with low cost compared to other approaches.
Structural basis of fitness of emerging SARS-COV-2 variants and considerations for screening, testing and surveillance strategy to contain their threat
Authors: Islam Sk Ramiz , Prusty Debasish , Manna Soumen Kanti
Published: January 2021

While emergence of new SAS-COV-2 variants is posing grave challenge to efforts to deal with the COVID-19 pandemic, the structural and molecular basis of their fitness remain poorly understood. We performed in silico analysis of structures of two most frequent SARS-COV-2 mutations, namely, N501Y and E484K, to identify plausible basis of their fitness over the original strain. The analysis suggested that the N501Y mutation is associated with strengthening of intra- as well as intermolecular H-bond in the hACE2 receptor-spike protein complex, which could result in increased affinity and, therefore, higher infectivity. While E484K mutation did not seem to directly affect the binding with hACE2 receptor, it disrupted H-bonding and salt-bridge interaction associated with binding with neutralizing antibody, which could affect chance of re-infection, disease outcome. Survey of several other mutations showing reduction in antibody-mediated neutralization also revealed that similar disruption of H-bonding or salt-bridge or Van der Waals interaction might explain their phenotype. Analysis of GESS database indicated that N501Y, EK484 as well as these other mutations existed since March-April, 2020, might have evolved independently across the world and may keep accumulating, which could affect efficacy of vaccination and antibody-based therapies. Our analysis also indicated that these may spread in spite of current travel restrictions focused on few countries and evolve indigenously warranting intensification of surveillance for emerging mutations among all travellers as well as people in their dwelling zones. Meta-analysis of existing literature showed that repeat testing of travellers, contacts and others under scrutiny 7-11 days after the initial RT-PCR test may significantly help to contain the spread of emerging variants by catching false negative results. In addition, existing evidence calls for development of strain-specific tests, escalated sequencing and broadening the scope of surveillance including in hospitals and animal farms to contain the threat of emerging variants.
Trends and opportunities in tick-borne disease geography
Authors: Lippi Catherine A. , Ryan Sadie J. , White Alexis L. , Gaff Holly D. , Carlson Colin J.
Published: January 2021

Tick-borne diseases are a growing problem in many parts of the world, and their surveillance and control touches on challenging issues in medical entomology, agricultural health, veterinary medicine, and biosecurity. Spatial approaches can be used to synthesize the data generated by integrative One Health surveillance systems, and help stakeholders, managers, and medical geographers understand the current and future distribution of risk. Here, we performed a systematic review of over 8,000 studies, and identified a total of 303 scientific publications that map tick-borne diseases using data on vectors, pathogens, and hosts (including wildlife, livestock, and human cases). We find that the field is growing rapidly, with the majorIxodes-borne diseases (Lyme disease and tick-borne encephalitis in particular) giving way to monitoring efforts that encompass a broader range of threats. We find a tremendous diversity of methods used to map tick-borne disease, but also find major gaps: data on the enzootic cycle of tick-borne pathogens is severely underutilized, and mapping efforts are mostly limited to Europe and North America. We suggest that future work can readily apply available methods to track the distributions of tick-borne diseases in Africa and Asia, following a One Health approach that combines medical and veterinary surveillance for maximum impact.
Evaluating the tea bag method as a potential tool for detecting the effects of added nutrients and their interactions with climate on litter decomposition
Authors: Mori Taiki , Hashimoto Toru , Sakai Yoshimi
Published: January 2021

It is acknowledged that exogenous nutrient addition often stimulates early-stage litter decomposition in forests and late-stage decomposition is generally suppressed by nitrogen addition, whereas the interactive effects of nutrient addition and abiotic environmental factors, such as climate, on decomposition remain unclear. The tea bag method, which was developed to provide the decomposition rate constantkof early-stage decomposition and stabilization factorSof labile materials in the late stage, is a potentially useful tool for examining the impacts of nutrient addition on both early- and late-stage litter decomposition and their interactions with climate. At a long-term (38-year) continuous fertilization experimental site (anAbies sachalinensisFr. Schmidt stand) in Hokkaido, Japan, we examined whether a standard tea bag method protocol was sufficiently sensitive to reveal any impacts of nutrient addition on early- and late-stage decomposition. In addition, we tested the interactive effects of nutrient addition and climate on litter decomposition. The short incubation period of the tea bag method (ca. 90 days) enabled us to obtain decomposition data from the same location at three different times in a year, i.e., early summer, midsummer, and winter, providing an opportunity to test interactive effects. We demonstrated that the decomposition rate of rooibos tea and the decomposition rate constantkof early-stage decomposition were clearly stimulated by fertilization in midsummer, but no impacts were detected in other seasons, probably because the relative importance of nutrient availability was elevated in midsummer, during which decomposition rates were less constrained by temperature and moisture. The green tea decomposition rate and stabilization factorS, an index related to late-stage decomposition, were unaffected by fertilization. This was probably because the tea bag method does not take into account lignin degradation, which is considered a key factor controlling late-stage litter decomposition. Overall, the present study (i) successfully determined the interactive effects of nutrient addition and climate factors on litter decomposition by making full use of the tea bag method, and (ii) the results suggest that the tea bag method can be a suitable tool for examining the direct effects of nutrient addition and their interactions with environmental factors on early-stage litter decomposition, but not those on late-stage decomposition.
Somatic mutational profiles and germline polygenic risk scores in human cancer
Authors: Liu Yuxi , Gusev Alexander , Heng Yujing J. , Alexandrov Ludmil B. , Kraft Peter
Published: January 2021

The mutational profile of a cancer reflects the activity of the mutagenic processes which have been operative throughout the lineage of the cancer cell. These processes leave characteristic profiles of somatic mutations called mutational signatures. Mutational signatures, including single-based substitution (SBS) signatures, may reflect the effects of exogenous or endogenous exposures. Here, we used polygenic risk score (PRS) as proxies for exposures and examined the association between somatic mutational profiles and germline PRS in 12 cancer types from The Cancer Genome Atlas project. We found 17 statistically significant associations after Bonferroni correction (p < 3.15×10−5), including positive associations between germline inflammatory bowel disease PRS and number of somatic mutations of signature SBS1 in prostate cancer and APOBEC-related signatures in breast cancer. The age at menarche PRS was inversely associated with mutation counts of SBS1 in prostate cancer. Our analysis suggests that there are robust associations between tumor somatic mutational profiles and germline PRS. These may reflect mechanisms through hormone regulation and immunological responses that contribute to cancer etiology and drive cancer progression.
Inference of an integrative, executable network for Rheumatoid Arthritis combining data-driven machine learning approaches and a state-of-the-art mechanistic disease map
Authors: Miagoux Quentin , Singh Vidisha , de Mézquita Dereck , Chaudru Valerie , Elati Mohamed , Petit-Teixeira Elisabeth , Niarakis Anna
Published: January 2021

Rheumatoid arthritis (RA) is a multifactorial, complex autoimmune disease that involves various genetic, environmental and epigenetic factors. Systems biology approaches provide the means to study complex diseases through the integration of different layers of biological information. Combining multiple data types can help compensate for missing or conflicting information and limit the possibility of false positives. In this work, we aim to unravel mechanisms governing the regulation of key transcription factors in RA and derive patient-specific models to gain more insights into the disease heterogeneity and the response to treatment.

We first make use of publicly available transcriptomic datasets (peripheral blood) relative to RA and machine learning to create an RA specific transcription factor (TF) co-regulatory network. The TF cooperativity network is subsequently enriched in signalling cascades and upstream regulators using a state-of-the-art, RA-specific molecular map. The integrative network is then used as a template to analyze patients’ data regarding their response to anti-TNF treatment and identify master regulators and upstream cascades affected by the treatment. We use the Boolean formalism to simulate in silico subparts of the integrated network and identify combinations and conditions that can switch on or off the identified TFs, mimicking the effects of single and combined perturbations.
ATGL-dependent white adipose tissue lipolysis controls hepatocyte PPARα activity
Authors: Fougerat Anne , Schoiswohl Gabriele , Polizzi Arnaud , Régnier Marion , Wagner Carina , Smati Sarra , Fougeray Tiffany , Lippi Yannick , Lasserre Frederic , Melin Valentine , Tramunt Blandine , Alkhoury Chantal , Emile Anthony , Schupp Michael , Gourdy Pierre , Dubot Patricia , Levade Thierry , Ellero-Simatos Sandrine , Gamet-Payrastre Laurence , Panasyuk Ganna , Amri Ez-Zoubir , Postic Catherine , Wahli Walter , Loiseau Nicolas , Montagner Alexandra , Langin Dominique , Lass Achim , Guillou Hervé
Published: January 2021

Objective

In hepatocytes, peroxisome proliferator-activated receptor α (PPARα) acts as a lipid sensor that regulates hepatic lipid catabolism during fasting and orchestrates a genomic response required for whole-body homeostasis. This includes the biosynthesis of ketone bodies and the secretion of the starvation hormone fibroblast growth factor 21 (FGF21). Several lines of evidence suggest that adipose tissue lipolysis contributes to this specific process. However, whether adipose tissue lipolysis is a dominant signal for the extensive remodeling of liver gene expression dependent on PPARα has not been investigated.

Methods

First, using mice lacking adipose tissue lipolysis through adipocyte-specific deletion of adipose triglyceride lipase (ATGL), we characterized the responses dependent on adipocyte ATGL during fasting. Next, we performed liver whole genome expression analysis in fasted mice upon deletion of adipocyte ATGL or hepatocyte PPARα. Finally, we tested the consequences of hepatocyte-specific PPARα deficiency during pharmacological induction of adipocyte lipolysis with a β3-adrenergic receptor agonist.

Results

In the absence of ATGL in adipocytes, ketone body and FGF21 productions were impaired in response to starvation. Liver transcriptome analysis revealed that adipocyte ATGL is critical for regulation of hepatic gene expression during fasting and highlighted a strong enrichment in PPARα target genes in this condition. Genome expression analysis confirmed that a large set of fasting-induced genes are sensitive to both ATGL and PPARα. Adipose tissue lipolysis induced by acute activation of the β3-adrenergic receptor also triggered PPARα-dependent responses in the liver, supporting a role for adipocyte-derived fatty acids as dominant signals for hepatocyte PPARα activity. In addition, the absence of hepatocyte PPARα altered brown adipose tissue (BAT) morphology and reduced UCP1 expression upon stimulation of the β3-adrenergic receptor. In agreement with this finding, mice lacking hepatocyte PPARα showed decreased tolerance to acute cold exposure.

Conclusions

These results underscore the central role of hepatocyte PPARα in the sensing of adipocyte-derived fatty acids and reveal that its activity is essential for full activation of BAT. Intact PPARα activity in hepatocytes is required for cross-talk between adipose tissues and the liver during fat mobilization during fasting and cold exposure.
deepManReg: a deep manifold-regularized learning model for improving phenotype prediction from multi-modal data
Authors: Nguyen Nam D. , Huang Jiawei , Wang Daifeng
Published: January 2021

The biological processes from genotype to phenotype are complex involving multi-scale mechanisms. Increasing multi-modal data enables deeper understanding of underlying complex mechanisms in various phenotypes. However, integrating and interpreting such large-scale multi-modal data remains challenging, especially given highly heterogeneous, nonlinear relationships across modalities. To address this, we developed an interpretable regularized learning model, deepManReg to predict phenotypes from multi-modal data. First, deepManReg employs deep neural networks to learn cross-modal manifolds and then align multi-modal features onto a common latent space. This space aims to preserve both global consistency and local smoothness across modalities and reveal higher-order nonlinear cross-modal relationships. Second, deepManReg uses cross-modal manifolds as a feature graph to regularize the classifiers for improving phenotype predictions and also prioritizing the multi-modal features and cross-modal interactions for the phenotypes. We applied deepManReg to recent single cell multi-modal data such as Patch-seq data including transcriptomics and electrophysiology for neuronal cells in the mouse brain. We show that deepManReg significantly improves predicting cellular phenotypes and also prioritizing genes and electrophysiological features for the phenotypes. Finally, deepManReg is open-source and general for phenotype prediction from multi-modal data. deepManReg is open-source available athttps://github.com/daifengwanglab/deepManReg.
Talker discontinuity disrupts attention to speech: Evidence from EEG and pupillometry
Authors: Lim Sung-Joo , Carter Yaminah D. , Njoroge J. Michelle , Shinn-Cunningham Barbara G. , Perrachione Tyler K.
Published: January 2021

Speech is processed less efficiently from discontinuous, mixed talkers than one consistent talker, but little is known about the neural mechanisms for processing talker variability. Here, we measured psychophysiological responses to talker variability using electroencephalography (EEG) and pupillometry while listeners performed a delayed recall of digit span task. Listeners heard and recalled seven-digit sequences with both talker (single- vs. mixed-talker digits) and temporal (0- vs. 500-ms inter-digit intervals) discontinuities. Talker discontinuity reduced serial recall accuracy. Both talker and temporal discontinuities elicited P3a-like neural evoked response, while rapid processing of mixed-talkers’ speech led to increased phasic pupil dilation. Furthermore, mixed-talkers’ speech produced less alpha oscillatory power during working memory maintenance, but not during speech encoding. Overall, these results are consistent with an auditory attention and streaming framework in which talker discontinuity leads to involuntary, stimulus-driven attentional reorientation to novel speech sources, resulting in the processing interference classically associated with talker variability.
Resident Cardiac Macrophages Mediate Adaptive Myocardial Remodeling
Authors: Wong Nicole R. , Mohan Jay , Kopecky Benjamin J , Guo Shuchi , Du Lixia , Leid Jamison , Dmytrenko Oleksandr , Luehmann Hannah , Bajpai Geetika , Ewald Laura , Bell Lauren , Patel Nikhil , Lokshina Inessa , Bredemeyer Andrea , Weinheimer Carla J. , Nigro Jessica M. , Kovacs Attila , Morimoto Sachio , Bayguinov Peter O. , Fisher Max. R. , Fitzpatrick James A.J. , Epelman Slava , Kreisel Daniel , Sah Rajan , Liu Yongjian , Hu Hongzhen , Lavine Kory J.
Published: January 2021

Cardiac macrophages represent a heterogeneous cell population with distinct origins, dynamics, and functions. Recent studies have revealed that C-C Chemokine Receptor 2 positive (CCR2+) macrophages derived from infiltrating monocytes regulate myocardial inflammation and heart failure pathogenesis. Comparatively little is known about the functions of tissue resident (CCR2−) macrophages. Herein, we identify an essential role for CCR2− macrophages in the chronically failing heart. Depletion of CCR2− macrophages in mice with dilated cardiomyopathy accelerated mortality and impaired ventricular remodeling and coronary angiogenesis, adaptive changes necessary to maintain cardiac output in the setting of reduced cardiac contractility. Mechanistically, CCR2− macrophages interacted with neighboring cardiomyocytes via focal adhesion complexes and were activated in response to mechanical stretch through a transient receptor potential vanilloid 4 (TRPV4) dependent pathway that controlled growth factor expression. These findings establish a role for tissue resident macrophages in adaptive cardiac remodeling and introduce a new mechanism of cardiac macrophage activation.