bluuebunny/crossref_metadata_2025 huggingface dataset:
qMRI-BIDS: an extension to the brain imaging data structure for quantitative magnetic resonance imaging data
Authors: Karakuzu Agah , Appelhoff Stefan , Auer Tibor , Boudreau Mathieu , Feingold Franklin , Khan Ali R. , Lazari Alberto , Markiewicz Christopher J. , Mulder Martijn J. , Phillips Christophe , Salo Taylor , Stikov Nikola , Whitaker Kirstie , de Hollander Gilles
Published: October 2021

The Brain Imaging Data Structure (BIDS) established community consensus on the organization of data and metadata for several neuroimaging modalities. Traditionally, BIDS had a strong focus on functional magnetic resonance imaging (MRI) datasets and lacked guidance on how to store multimodal structural MRI datasets. Here, we present and describe the BIDS Extension Proposal 001 (BEP001), which adds a range of quantitative MRI (qMRI) applications to the BIDS application sphere. In general, the aim of qMRI is to characterize brain microstructure by quantifying the physical MR parameters of the tissue via computational, biophysical models. By proposing this new standard, we envision standardization of qMRI which makes multicenter dissemination of interoperable data possible. As a result, BIDS can act as a catalyst of convergence between qMRI methods development and application-driven neuroimaging studies that can help develop quantitative biomarkers for neural tissue characterization. Finally, our BIDS extension offers a common ground for developers to exchange novel imaging data and tools, reducing the practical barriers to standardization that is currently lacking in the field of neuroimaging.
SPARClink: an interactive tool to visualize the impact of the SPARC program
Authors: Soundarajan Sanjay , Kuruppu Sachira , Singh Ashutosh , Kim Jongchan , Achalla Monalisa
Published: October 2021

The NIH SPARC program seeks to accelerate the development of therapeutic devices that modulate electrical activity in nerves to improve organ function. SPARC-funded researchers are generating rich datasets from neuromodulation research that are curated and shared according to FAIR (Findable, Accessible, Interoperable, and Reusable) guidelines and are accessible to the public on the SPARC data portal. Keeping track of the utilization of these datasets within the larger research community is a feature that will benefit data generating researchers in showcasing the impact of their SPARC outcomes. This will also allow the SPARC program to display the impact of the FAIR data curation and sharing practices that have been implemented. This manuscript provides the methods and outcomes of SPARClink, our web tool for visualizing the impact of SPARC, which won the 2nd prize at the 2021 SPARC FAIR Codeathon. With SPARClink, we built a system that automatically and continuously finds new published SPARC scientific outputs (datasets, publications, protocols) and the external resources referring to them. SPARC datasets and protocols are queried using publicly accessible REST APIs (provided by Pennsieve and Protocols.io) and stored in a publicly accessible database. Citation information for these resources is retrieved using the NIH reporter API and NCBI Entrez system. A novel knowledge-graph-based structure was created to visualize the results of these queries and showcase the impact that the FAIR data principles can have on the research landscape when they are adopted by a consortium.
Sex Modifies the Effect of Genetic Risk Scores for Polycystic Ovary Syndrome on Metabolic Phenotypes
Authors: Actkins Ky’Era V. , Jean-Pierre Genevieve , Aldrich Melinda C. , Velez Edwards Digna R. , Davis Lea K.
Published: October 2021

Females with polycystic ovary syndrome (PCOS), the most common endocrine disorder in women, have an increased risk of developing metabolic disorders such as insulin resistance, obesity, and type 2 diabetes (T2D). Furthermore, while only diagnosable in females, males with a family history of PCOS can also exhibit a poor cardiometabolic profile. Therefore, we aimed to elucidate the role of sex in the relationship between PCOS and its comorbidities by conducting bidirectional genetic risk score analyses in both sexes. We conducted a phenome-wide association study (PheWAS) using PCOS polygenic risk scores (PCOSPRS) to understand the pleiotropic effects of PCOS genetic liability across 1,380 medical conditions in females and males recorded in the Vanderbilt University Medical Center electronic health record (EHR) database. After adjusting for age and genetic ancestry, we found that European descent males with higher PCOSPRS were significantly more likely to develop cardiovascular diseases than females at the same level of genetic risk, while females had a higher odds of developing T2D. Based on observed significant associations, we tested the relationship between PRS for comorbid conditions (e.g., T2D, body mass index, hypertension, etc.) and found that only PRS generated for BMI and T2D were associated with a PCOS diagnosis. We then further decomposed the T2DPRS association with PCOS by adjusting the model for measured BMI and BMIresidual (enriched for the environmental contribution to BMI). Results demonstrated that genetically regulated BMI primarily accounted for the relationship between T2DPRS and PCOS. This was further supported in a mediation analysis, which only revealed clinical BMI measurements, but not BMIresidual, as a strong mediator for both sexes. Overall, our findings show that the genetic architecture of PCOS has distinct metabolic sex differences, but these associations are only apparent when PCOSPRS is explicitly modeled. It is possible that these pathways are less explained by the direct genetic risk of metabolic traits than they are by the risk factors shared between them, which can be influenced by biological variables such as sex.
The 1968 Influenza Pandemic and COVID-19 Outcomes
Authors: Taylor Charles A , Boulos Christopher , Memoli Matthew J.
Published: October 2021

Past pandemic experience can affect health outcomes in future pandemics. This paper focuses on the last major influenza pandemic in 1968 (H3N2), which killed up to 100,000 people in the US. We find that places with high influenza mortality in 1968 experienced 1-4% lower COVID-19 death rates. Our identification strategy isolates variation in COVID-19 rates across people born before and after 1968. In places with high 1968 influenza incidence, older cohorts experience lower COVID-19 death rates relative to younger ones. The relationship holds using county and patient-level data, as well as in hospital and nursing home settings. Results do not appear to be driven by systemic or policy-related factors, instead suggesting an individual-level response to prior influenza pandemic exposure. The findings merit investigation into potential biological and immunological mechanisms that account for these differences—and their implications for future pandemic preparedness.
Safety and Efficacy of Daclatasvir with Sofosbuvir and Ribavirin in Hepatitis C Virus Infection: A Real World Experience from South Punjab, Pakistan
Authors: Malghani Waseem Sarwar , Din Chaudhary Farooq Mohyud , Shahid Misbah , Tameez-ud-din Ahsan , Malik Romaisa , Tameez Ud Din Asma
Published: October 2021

Background & Objectives

Sofosbuvir (SOF) and daclatasvir (DCV) in combination with ribavirin (RBV) drastically changed the treatment scenario of chronic hepatitis C (CHC) patients, achieving remarkable efficacy and safety profile. Real world experience of SOF/DCV/RBV combination in this part of Asia was scant. This study aimed to evaluate the efficacy and safety of SOF/DCV/RBV combination to treat CHC patients at a tertiary care hospital in South Punjab.

Methods

Patients of CHC of any genotype were enrolled prospectively. They were treated with 12 weeks course of SOF/DCV/RBV combination. Effectiveness was evaluated by end of treatment response (ETR) and sustained virological response (SVR) at 12 and 24 weeks post-treatment. Adverse events were recorded for safety analysis.

Results

We analyzed data of 102 patients of CHC (40 males and 62 females). The mean age was 40.04 + 10.22 years. Mean weight was 67.24 + 11.78 kg, while mean body mass index (BMI) was 26.32 + 4.58 kg/m2. Eighty patients belonged to low socio-economic status, while 22 belonged to middle socio-economic status. Sixty-four had a rural background, while 38 were from urban background. Seventy-four patients had no co-morbid condition; 16 (15.7%) had diabetes and 12 (11.8%) patients had co-morbid hypertension. Ninety percent of the patients did not have cirrhosis; 6% had compensated liver disease, while 4 % had decompensated liver disease. All the patients achieved undetectable HCV RNA at the end of treatment and 12 weeks after completion of treatment, while SVR at 24 weeks was achieved in 98% of patients. Only 2 patients discontinued treatment as a result of side effects. The most common side effects reported include fatigue, headache and fever.

Conclusion

CHC is a grave problem in developing countries like Pakistan. The SOF/DCV/RBV combination is very effective in eradicating CHC and has a very good side effect profile as well.
MRI based Kidney Radiomics analysis during chronic lithium treatment: validation of a texture index associated with decreased kidney function
Authors: Beunon Paul , Barat Maxime , Dohan Anthony , Cheddani Lynda , Males Lisa , Fernandez Pedro , Etain Bruno , Bellivier Frank , Vrtovsnik François , Vidal-Petiot Emmanuelle , Khalil Antoine , Flamant Martin , Tabibzadeh Nahid
Published: October 2021

Background

Chronic lithium therapy is associated with an increased risk of chronic kidney disease (CKD). Lithium nephrotoxicity is slowly progressive and difficult to detect at early stages. The aim of this study was to identify specific image texture changes of kidneys as possible imaging biomarkers of decreased measured glomerular filtration rate (mGFR) using radiomic analysis of T2 weighted imaging magnetic resonance imaging.

Methods

One hundred and nine patients treated with lithium carbonate were evaluated including mGFR and Kidney MRI, with T2 weighted sequence single-shot fast spin-echo. Computed radiomic analysis was performed after a manual kidney segmentation. Significant features were selected to build a radiomic signature using multivariable Cox analysis to detect a decreased mGFR <60 ml/min/1.73m2. The texture index was internally validated using a training and a validation cohort.

Results

Texture analysis index was able to detect a decrease in mGFR, with an Area Under the Curve (AUC) of 0.85 in the training cohort and 0.71 in the validation cohort. Patients with a texture index below the median were older (59 [42-66] versus 46 [34-54] years, p=0.001), with longer treatment duration (10 [3-22] versus 6 [2-10] years, p=0.02), and a lower mGFR (66 [46-84] versus 83 [71-94] ml/min/1.73m2, p<0.001). Texture analysis index was independently and negatively associated with age (β= -0.004 ±0.001, p<0.001), serum vasopressin (−0.005 ± 0.002, p=0.02), lithium treatment duration (−0.01 ± 0.003, p=0.001), with a significant interaction between lithium treatment duration and mGFR (p=0.02).

Conclusion

A renal texture index was developed and validated among patients treated with lithium carbonate associated with a decreased mGFR. This index might be relevant in the diagnosis and prognosis of lithium-induced renal toxicity.
Double-check the zebrafish18s rRNAqPCR primers: they may be wrong
Authors: Wang Jianing , Yang Zhipeng , Xiao An
Published: October 2021

A widely used qPCR primer for zebrafish generna18s(18s rRNA, or18s), with the sequence of 5’-TCGCtaGTtGGCATCGTTTAtG-3’, is found to be incorrect. Initially designed for rainbow trout (Oncorhynchus mykiss)rna18s, the primer has four different nucleotides from the zebrafish sequence 5’-TCGCGGGTCGGCATCGTTTACG-3’ (indicated in bold/underlined, lowercase letters for rainbow trout and uppercase letters for zebrafish). Since its first use in zebrafish in 2006, this mismatched primer has been clearly stated to be used in at least 50 publications and may have affected hundreds or more in publications citing them. For a sensitive, quantitative method as qPCR, this error must be corrected as soon as possible in the zebrafish community by usingrna18sprimer sets with accurate sequences, such as those summarized and newly designed in this article.
Patient-specific analysis of bicuspid aortic valve hemodynamics using a fully coupled fluid-structure interaction (FSI) model
Authors: Qin Tongran , Caballero Andrés , Mao Wenbin , Barrett Brian , Kamioka Norihiko , Lerakis Stamatios , Sun Wei
Published: October 2021

Bicuspid aortic valve (BAV), the most common congenital heart disease, is prone to develop significant valvular dysfunction and aortic wall abnormalities. Growing evidence has suggested that abnormal BAV hemodynamics could contribute to the disease progression. In order to investigate the BAV hemodynamic, we performed 3D patient-specific fluid-structure interaction (FSI) simulations of BAV with fully coupled flow dynamics and valve motions throughout the cardiac cycle. The results showed that the flow during systole can be characterized by a systolic jet and two counter-rotating recirculation vortices. At peak systole, the jet was usually eccentric, with asymmetric recirculation vortices, and helical flow motion in the ascending aorta. The flow structure at peak systole was quantified using the vorticity, flow reversal ratio and helicity index at four locations from the aortic root to the ascending aorta. The systolic jet was evaluated using the metrics including the peak velocity, normalized flow displacement, and jet angle. It was found that both the peak velocity and normalized flow displacement (rather than jet angle) of the systolic jet showed a strong correlation with the vorticity and helicity index of the flow in the ascending aorta, which suggests that these two metrics can be used for noninvasive evaluation of abnormal flow patterns in BAV patients.
Impact of biologics and small molecules for Inflammatory Bowel Disease on COVID-19 Related Hospitalization: A Systematic Review and Meta-analysis
Authors: Alrashed Fatema , Alasfour Hajer , Shehab Mohammad
Published: October 2021

Background

The use of biological therapies and small molecules have been a concern for patients with inflammatory bowel disease (IBD) during COVID-19 pandemic. We aim to assess the association between risk of COVID-19 related hospitalization and these agents.

Method

A systematic review and meta-analysis of all published studies from December 2019 to September 2021 was performed to identify studies that reported COVID-19 related hospitalization in IBD patients receiving biological therapies or tofacitinib. The risk ratio (RR) was calculated to compare the relative risk of COVID-19 related hospitalization in patients receiving these medications to those who were not, at the time of the study.

Results

18 studies were included. The relative risk of hospitalization was significantly lower in patients with IBD and COVID-19 who were receiving biologic therapy with RR of 0.47 (95% CI: 0.42-0.52, p < 0.00001). The RR was lower in patients receiving anti-TNFs compared to those who did not [RR= 0.48 (95% CI: 0.41-0.55, p < 0.00001)]. Similar finding was observed in patients taking ustekinumab [RR= 0.55 (95% CI: 0.43-0.72, p < 0.00001)]. Combination therapy of anti-TNF and an immunomodulator did not lower the risk of COVID-19 related hospitalization [RR= 0.98 (95% CI: 0.82-1.18, p =0.84]. The use of vedolizumab [RR= 1.13 (95% CI: 0.75-1.73, p =0.56] and tofacitinib [RR= 0.81 (95% CI: 0.49-1.33, p =0.40] was not associated with lower risk of COVID-19 related hospitalization.

Conclusion

Regarding COVID-19 related hospitalization in IBD, anti-TNFs and ustekinumab were associated with favorable outcomes. In addition, vedolizumab and tofacitinib were not associated with COVID-19 related hospitalization.
Targeting the chemokine receptor CXCR4 with histamine analogue to reduce inflammation in juvenile arthritis: a proof of concept for COVID-19 therapeutic approach
Authors: Bekaddour Nassima , Smith Nikaïa , Beitz Benoit , Llibre Alba , Dott Tom , Baudry Anne , Korganow Anne-Sophie , Nisole Sébastien , Mouy Richard , Breton Sylvain , Bader-Meunier Brigitte , Duffy Darragh , Terrier Benjamin , Schneider Benoit , Quartier Pierre , Rodero Mathieu P , Herbeuval Jean-Philippe
Published: October 2021

Among immune cells, activated monocytes play a detrimental role in chronic and viral-induced inflammatory pathologies. The uncontrolled activation of monocytes and the subsequent excessive production of inflammatory factors damage bone-cartilage joints in Juvenile Idiopathic Arthritis (JIA), a childhood rheumatoid arthritis (RA) disease. Inflammatory monocytes also exert a critical role in the cytokine storm induced by SARS-CoV2 infection in severe COVID-19 patients. The moderate beneficial effect of current therapies and clinical trials highlights the need of alternative strategies targeting monocytes to treat RA and COVID-19 pathologies. Here, we show that targeting CXCR4 with small amino compound such as the histamine analogue clobenpropit (CB) inhibits spontaneous and induced-production of a set of key inflammatory cytokines by monocytes isolated from blood and synovial fluids of JIA patients. Moreover, daily intraperitoneal CB treatment of arthritic mice results in significant decrease in circulating inflammatory cytokine levels, immune cell infiltrates, joints erosion, and bone resorption leading to reduction of disease progression. Finally, we provide the prime evidence that the exposure of whole blood from hospitalized COVID-19 patients to CB significantly reduces levels of key cytokine-storm-associated factors including TNF-α, IL-6 and IL-1β. These overall data show that targeting CXCR4 with CB-like molecules may represent a promising therapeutic option for chronic and viral-induced inflammatory diseases.
On the use of facial and neck cooling to improve indoor occupant thermal comfort in warm conditions
Authors: Yang Bin , Lei Tze-Huan , Wang Faming , Yang Pengfei
Published: October 2021

Face and neck cooling has been found effective to improve thermal comfort during exercise in the heat despite the surface area of human face and neck regions accounts for only 5.5% of the entire body. Presently, very limited work in the literature has been reported on face and neck cooling to improve indoor thermal comfort. In this work, two energy-efficient wearable face and neck cooling fans were used to enhance occupants’ thermal comfort in two warm indoor conditions (30 & 32 °C). Local skin temperatures and perceptual responses while using those two wearable cooling fans were examined and compared. Results showed that both cooling fans could largely reduce local skin temperatures at the forehead, face and neck regions up to 2.1 °C. Local thermal sensation votes at the face and neck were decreased by 0.82-1.21 scale unit at two studied temperatures. Overall TSVs dropped by 1.03-1.14 and 1.34-1.66 scale unit at 30 and 32 °C temperatures, respectively. Both cooling fans could extend the acceptable HVAC temperature setpoint to 32.0 °C, resulting in an average energy saving of 45.7% as compared to the baseline HVAC setpoint of 24.5 °C. Further, the free-control cooling mode is recommended to occupants for further improving thermal comfort while using those two types of wearable cooling fans indoors. Lastly, it is concluded that those two wearable cooling fans could greatly improve thermal comfort and save HVAC energy despite some issues on dry eyes and dry lips associated with those wearable cooling fans were noted.
Single injection of very mild dose BOTOX in the vastus lateralis improves testicular spermatogenesis and sperm motility in ageing experimental mice
Authors: Radhakrishnan Risna Kanjirassery , Ravichandran Sowbarnika , Sukesh Aishwarya , Kadalmani Balamuthu , Kandasamy Mahesh
Published: October 2021

Acetylcholine (ACh), a key neurochemical messenger that plays key roles in neuroplasticity and muscle contraction. While ACh is important for the physiological function of the testis, abnormal levels of ACh cause testicular atrophy and male infertility. BOTOX is a therapeutic form of the botulinum neurotoxin that blocks the excessive release of ACh at the neuromuscular junction. Previously, repeated intracremasteric injections and slight overdose of BOTOX have been reported to induce adverse effects in the testicular parameter of experimental rodents. However, a mild dose of BOTOX is highly beneficial against skin ageing, neurological deficits, overactive urinary bladder problems, testicular pain and erectile dysfunctions. Considering the facts, the possible therapeutic benefit of BOTOX on the testis might be achieved via its minimal dose and indirect mode of action rather than repeated high quantity in the local supply. Therefore, we revisited the effect of BOTOX but with a trace amount injected into the vastus lateralis of the thigh muscle, and analyzed histological parameters of testis and quality of semen in ageing experimental mice. Experimental animals injected with 1 U/kg bodyweight of BOTOX showed enhanced spermatogenesis in associations with increased activities of key antioxidants in the testis, leading to increased total sperm count and motility. This study signifies that a mild intramuscular dose of BOTOX can be considered as a potential treatment strategy to manage and prevent male infertility.
Zebrafish airinemes optimize their shape between ballistic and diffusive search
Authors: Park Sohyeon , Kim Hyunjoong , Wang Yi , Eom Dae Seok , Allard Jun
Published: October 2021

In addition to diffusive signals, cells in tissue also communicate via long, thin cellular protrusions, such as airinemes in zebrafish. Before establishing communication, cellular protrusions must find their target cell. Here we demonstrate that the shape of airinemes in zebrafish are consistent with a finite persistent random walk model. The probability of contacting the target cell is maximized for a balance between ballistic search (straight) and diffusive search (highly curved, random). We find that the curvature of airinemes in zebrafish, extracted from live cell microscopy, is approximately the same value as the optimum in the simple persistent random walk model. We also explore the ability of the target cell to infer direction of the airineme’s source, finding that there is a theoretical trade-off between search optimality and directional information. This provides a framework to characterize the shape, and performance objectives, of non-canonical cellular protrusions in general.
The social architecture of an in-depth cellular protein interactome
Authors: Michaelis André C. , Brunner Andreas-David , Zwiebel Maximilian , Meier Florian , Strauss Maximilian T. , Bludau Isabell , Mann Matthias
Published: October 2021

Nearly all cellular functions are mediated by protein-protein interactions and mapping the interactome provides fundamental insights into the regulation and structure of biological systems. In principle, affinity purification coupled to mass spectrometry (AP-MS) is an ideal and scalable tool, however, it has been difficult to identify low copy number complexes, membrane complexes and those disturbed by protein-tagging. As a result, our current knowledge of the interactome is far from complete, and assessing the reliability of reported interactions is challenging. Here we develop a sensitive, high-throughput, and highly reproducible AP-MS technology combined with a quantitative two-dimensional analysis strategy for comprehensive interactome mapping of Saccharomyces cerevisiae. We reduced required cell culture volumes thousand-fold and employed 96-well formats throughout, allowing replicate analysis of the endogenous green fluorescent protein (GFP) tagged library covering the entire expressed yeast proteome. The 4159 pull-downs generated a highly structured network of 3,909 proteins connected by 29,710 interactions. Compared to previous large-scale studies, we double the number of proteins (nodes in the network) and triple the number of reliable interactions (edges), including very low abundant epigenetic complexes, organellar membrane complexes and non-taggable complexes interfered by abundance correlation. This nearly saturated interactome reveals that the vast majority of yeast proteins are highly connected, with an average of 15 interactors, the majority of them unreported so far. Similar to social networks between humans, the average shortest distance is 4.2 interactions. A web portal (www.yeast-interactome.org) enables exploration of our dataset by the network and biological communities and variations of our AP-MS technology can be employed in any organism or dynamic conditions.
Effect of OTR4120 on pulmonary fibrosis
Authors: Charef Said , Charef Najat Mejdoubi , Chiappini Franck , Papy-Garcia Dulce , Barritault Denis
Published: October 2021

Background

Acute respiratory distress syndrome (ARDS) can be related to airway remodeling caused by pulmonary fibrosis and systemic inflammation. Etiologies of ARDS are multifaceted such as idiopathic pulmonary fibrosis or as recently the SARS-CoV-2 infection. Antifibrotic drugs may be a better approach to slow the fibrotic process but they often have poor efficacy in patients, and the mortality rate remains high, up to 40% within 5 years of diagnosis.

Here, we tested the antifibrotic effect of a ReGeneTaring Agents named OTR4120 in a bleomycin-induced mouse model of pulmonary fibrosis.

Methods

Swiss mice were randomly divided into four experimental groups: saline-treated control group, an OTR4120 group, a bleomycin-induced fibrosis group without OTR4120, and a bleomycin-induced fibrosis groups with OTR4120 (intravenous injections every 3 days starting at day 11 post bleomycin I.P. injection). Lungs were compared using the lung/body weight index, and the extend of interstitial injury area was graded using histopathological assessment of haematoxylin & eosin-stained lung tissue sections. Lung tissue Collagen I and Collagen III levels, and blood cytokine levels were measured using a Collagen colorimetric kit and a Cytokine colorimetric kit, respectively.

Results

The group treated by OTR4120 alone were used as a control. The clincal signs in all animals resoved gradually on day 17 after bleomycin injections and 6 days after OTR4120 treatment, and disappeared almost completetly at day 24 after bleomycin injections and day 13 after OTR4120 treatment. Lung/body weight index values were significantly lower in the bleomycin-OTR4120 treated group versus the bleomycin group (7.31, 9.97 and 7.63 mg/g, p-value< 0.01; respectively). Histopathological analyses suggest that OTR4120 treatment ameliorated the increased inflammatory cell infiltration, and attenuated the reduction in interstitial thickening, associated with bleomycin-induced fibrosis. Collagen III and cytokine levels were decreased in the OTR4120 group versus the fibrotic (bleomycin only) group. OTR4120-treated animals were less affected in their behavior, did not loose weight nor appetite, and recovered overall activities within 6 days of OTR4120 treatment, while none of the vehicle-treated animals recovered to normal.

Conclusion

OTR4120 is a potential candidate to reduce lung fibrosis.
The preoperative abundance of Prevotella associates with anastomotic healing after colorectal surgery
Authors: Zafeiropoulou Konstantina , Peters Emmeline G. , Brinkman Daan J. , Li Yim Andrew Y.F. , Smeets Boudewijn J.J. , Hakvoort Theodorus B.M. , Levin Evgeni , Davids Mark , Luyer Misha D.P. , de Jonge Wouter J. , Derikx Joep P.M.
Published: October 2021

Anastomotic leakage (AL) is a frequent and potentially life-threatening postoperative complication in patients undergoing colorectal surgery with a multifactorial yet unknown pathophysiology. In the present study, we aimed to unravel AL etiology and intestinal anastomotic healing (AH) physiology focusing on both host epithelial and gut microbial components. We make use of patients-related samples and two high throughput next generation sequencing analysis approaches, including anastomotic tissue-associated bulk RNA sequencing and preoperative fecal 16S rRNA gene sequencing. We find that in the absence of host epithelial gene expression differences, the preoperative fecal microbiota of patients who undergo colorectal resection with successful AH differs in the group of patients who develop AL in the abundance of Prevotella and suggests a potential beneficial role of Prevotella that may prove useful as predictive biomarker for AH.
REcovery and SURvival of patients with moderate to severe acute REspiratory distress syndrome (ARDS) due to COVID-19: a multicentre, single-arm, Phase IV Itolizumab Trial: RESURRECT
Authors: Raveendra KR , Rathod Chirag , Darnule Rahul , Loganathan Subramanian , Deodhar Sarika , Radhika A , Marwah Ashwani , Chaudhari Nitin M , Thakur Binay K , Vaidyanathan Sivakumar , Athalye Sandeep Nilkanth
Published: October 2021

Objective

To evaluate safety and efficacy of Itolizumab in hospitalized COVID-19 patients with PaO2/FiO2 ratio (PFR) ≤200 requiring oxygen therapy.

Design

A multicentre, single-arm, Phase-4 study with a treatment period of 30-Days and an extended follow-up period of 90-Days.

Methods

Hospitalized adult patients (n=300) with SARS-CoV-2 infection, with PFR ≤200; oxygen saturation ≤94% and ≥1 elevated inflammatory markers were included from 17 COVID-19-specific tertiary hospitals in India. Patients received Itolizumab infusion 1.6 mg/kg and were assessed for 1-month and then followed up to Day-90.

Results

Day-30 post-treatment safety/efficacy results and Day-90 mortality results are presented. Primary outcome measures: incidence of severe acute infusion-related reactions (IRRs) (≥Grade-3) was 1.3% and mortality rate at 1-month was 6.7% (n=20/300). Key secondary analyses: Mortality rate at Day-90 was 8.0% (24/300). 91.7% patients came off the oxygen therapy within Day-30 of treatment. By Day-7, most patients had stable/improved SpO2 without increasing FiO2. Mean PFR improved by 50% by Day-7 (p<0.001) and the trend remained consistent till Day-30. Median time of recovery was 8 days. Cumulatively, at Day-30, 260(86.7%), 256(85.3%), 132(44.0%), 113(37.6%) and 32(10.7%) patients showed >1-point, >2-point, >3-point, >4-point and 5-point improvement on the modified COVID-19 8-point ordinal scale and worsening of symptoms by >1 point, >2 points and 3-points was seen in 26(8.7%), 20(6.7%) and 6(2.0%) patients, respectively. CRP, D-dimer, LDH, and serum ferritin levels significantly decreased (p≤0.01) compared with baseline. IL-6 and TNFα levels also decreased 48-hours post-infusion. Overall, 123 treatment-emergent adverse events (TEAEs) were reported in 63 patients, most being Grades 1-3. Most common TEAEs were IRRs and lymphopenia; most common serious TEAEs were septic shock, worsening of ARDS, and respiratory failure. No deaths were attributable to Itolizumab.

Conclusion

Itolizumab shows no new safety concerns and suggests a mortality and recovery benefit at 1-month in hospitalized COVID-19 patients requiring oxygen therapy.

Trial registry number

CTRI/2020/09/027941
Evaluation of the Nallasamy Formula: A Stacking Ensemble Machine Learning Method for Refraction Prediction in Cataract Surgery
Authors: Li Tingyang , Stein Joshua D. , Nallasamy Nambi
Published: October 2021

Aims

To develop a new intraocular lens (IOL) power selection method with improved accuracy for general cataract patients receiving Alcon SN60WF lenses.

Methods and Analysis

A total of 5016 patients (6893 eyes) who underwent cataract surgery at University of Michigan’ s Kellogg Eye Center and received the Alcon SN60WF lens were included in the study. A machine learning-based method was developed using a training dataset of 4013 patients (5890 eyes), and evaluated on a testing dataset of 1003 patients (1003 eyes). Each eye had a complete profile of preoperative biometry, the implanted IOL power, and postoperative refraction. The performance of our method was compared to that of Barrett Universal II, Haigis, Hoffer Q, Holladay 1, and SRK/T.

Results

MAE of the Nallasamy formula in the testing dataset was 0.312 Diopters (MedAE = 0.242 D). Performance of existing methods were as follows: Barrett Universal II MAE = 0.328 D (MedAE = 0.256 D), Haigis MAE = 0.363 D (MedAE = 0.289 D), Hoffer Q MAE = 0.404 D (MedAE = 0.331 D), Holladay 1 MAE = 0.371 D (MedAE = 0.298 D) and SRK/T MAE = 0.376 D (MedAE = 0.300 D). The Nallasamy formula performed significantly better than all five existing methods based on the paired Wilcoxon test with Bonferroni correction (p-value < 0.05).

Conclusions

Nallasamy formula outperformed the five methods studied (including Barrett Universal II) on overall MAE and MedAE, percentage of eyes within 0.5 D of prediction, as well as MAE in short, medium, and long axial length eyes.

SYNOPSIS

Nallasamy formula, a novel machine learning-based IOL power calculation formula developed based on a dataset of 6893 eyes, achieved significantly better prediction accuracy than five traditional IOL power formulas including Barrett Universal II.
Aldehyde dehydrogenase 3A1 deficiency leads to mitochondrial dysfunction and impacts salivary gland stem cell self-renewal, differentiation and survival
Authors: Viswanathan Vignesh , Cao Hongbin , Saiki Julie , Jiang Dadi , Mattingly Aaron , Nambiar Dhanya , Bloomstein Joshua , Li Yang , Jiang Sizun , Chamoli Manish , Sirjani Davud , Kaplan Michael , Christopher Holsinger F , Liang Rachel , Von Eyben Rie , Jiang Haowen , Guan Li , Lagory Edward , Feng Zhiping , Nolan Garry , Ye Jiangbin , Denko Nicholas , Knox Sarah , Rosen Daria-Mochly , Le Quynh-Thu
Published: October 2021

Adult salivary stem/progenitor cells (SSPC) have an intrinsic property to self-renew in order to maintain tissue architecture and homeostasis. Adult salivary glands have been documented to harbor SSPC, which have been shown to play a vital role in the regeneration of the glandular structures post radiation damage. We have previously demonstrated that activation of aldehyde dehydrogenase 3A1 (ALDH3A1) after radiation reduced aldehyde accumulation in SSPC, leading to less apoptosis and improved salivary function. We subsequently found that sustained pharmacological ALDH3A1 activation is critical to enhance regeneration of murine submandibular gland after radiation damage. Further investigation shows that ALDH3A1 function is crucial for SSPC self-renewal and differentiation even in the absence of radiation stress. Salivary glands from Aldh3a1-null mice have fewer acinar structures than wildtype mice. ALDH3A1 deletion or pharmacological inhibition in SSPC leads to a decrease in mitochondrial DNA copy number, lower expression of mitochondrial specific genes and proteins, structural abnormalities, lower membrane potential, and reduced cellular respiration. Loss or inhibition of ALDH3A1 also elevates ROS levels and accumulation of ALDH3A1 substrate 4-hydroxynonenal (4-HNE, a lipid peroxidation product), leading to decreased survival of murine SSPC that can be rescued by treatment with 4-HNE specific carbonyl scavengers. Our data indicate that ALDH3A1 activity protects mitochondrial function and is important for the development and regeneration activity of SSPC. This knowledge will help to guide our translational strategy of applying ALDH3A1 activators in the clinic to prevent radiation-related hyposalivation in head and neck cancer patients.
Clarifying intercellular signalling in yeast: Saccharomyces cerevisiae does not undergo a quorum sensing-dependent switch to filamentous growth
Authors: Winters Michela , Aru Violetta , Howell Kate , Arneborg Nils
Published: October 2021

Saccharomyces cerevisiae can alter its morphology to a filamentous form associated with unipolar budding in response to environmental stressors. Induction of filamentous growth is suggested under nitrogen deficiency in response to alcoholic signalling molecules through a quorum sensing mechanism. To investigate this claim, we analysed the budding pattern of S. cerevisiae cells over time under low nitrogen while concurrently measuring cell density and extracellular metabolite concentration. We found that the proportion of cells displaying unipolar budding increased between local cell densities of 4.8×106 and 5.3×107 cells/ml. However, the observed increase in unipolar budding could not be reproduced when cells were prepared at the critical cell density and in conditioned media. Removing the nutrient restriction by growth under high nitrogen conditions also resulted in an increase in unipolar budding between local cell densities of 5.2×106 and 8.2×107 cells/ml, but there were differences in metabolite concentration compared to the low nitrogen conditions. This suggests that neither cell density, metabolite concentration, nor nitrogen deficiency were necessary or sufficient to increase the proportion of unipolar budding cells. It is therefore unlikely that quorum sensing is the mechanism controlling the switch to filamentous growth in S. cerevisiae. Only a high concentration of the putative signalling molecule, 2-phenylethanol resulted in an increase in unipolar budding, but this concentration was not physiologically relevant. We suggest that the compound 2-phenylethanol acts through a toxicity mechanism, rather than quorum sensing, to induce filamentous growth.

IMPORTANCE

Investigating dimorphism in the model organism Saccharomyces cerevisiae has been instrumental in understanding the signalling pathways that control hyphal growth and virulence in human pathogenic fungi. Quorum sensing was proposed to signal morphogenesis in S. cerevisiae populations. This mechanism requires the switch to filamentous growth to occur at a critical quorum sensing molecule concentration corresponding to a critical cell density. However, evidence for this mechanism is sparse and limited by the use of non-physiologically relevant concentrations of signalling metabolites. Our study designed a methodology to address this gap and may be applied to further studies of dimorphism in other types of yeasts. A significant implication of our findings is that morphogenesis does not occur in S. cerevisiae via a quorum sensing mechanism, and this important definition needs to be corrected. Mechanistic studies to understand dimorphism in yeasts, by considering metabolite concentrations, will further shed light onto this important cellular behaviour.
Decoding the transcriptome of denervated muscle at single-nucleus resolution
Authors: Lin Hongchun , Ma Xinxin , Sun Yuxiang , Peng Hui , Wang Yanlin , Thomas Sandhya Sara , Hu Zhaoyong
Published: October 2021

Background

Skeletal muscle exhibits remarkable plasticity under both physiological and pathological conditions. One major manifestation of this plasticity is muscle atrophy that is an adaptive response to catabolic stimuli. Since the heterogeneous transcriptome responses to catabolism in different types of muscle cells are not fully characterized, we applied single-nucleus RNA sequencing (snRNA-seq) to unveil muscle atrophy related transcriptional changes at single nucleus resolution.

Methods

Using a sciatic denervation mouse model of muscle atrophy, snRNA-seq was performed to generate single-nucleus transcriptional profiles of the gastrocnemius muscle from normal and denervated mice. Various bioinformatics analyses, including unsupervised clustering, functional enrichment analysis, trajectory analysis, regulon inference, metabolic signature characterization and cell-cell communication prediction, were applied to illustrate the transcriptome changes of the individual cell types.

Results

A total of 29,539 muscle nuclei (normalvsdenervation: 15,739vs13, 800) were classified into 13 nuclear types according to the known cell markers. Among these, the type IIb myonuclei were further divided into two subgroups, which we designated as type IIb1 and type IIb2 myonuclei. In response to denervation, the proportion of type IIb2 myonuclei increased sharply (78.12%vs38.45%,p<0.05). Concomitantly, trajectory analysis revealed that denervated type IIb2 myonuclei clearly deviated away from the normal type IIb2 myonuclei, indicating that this subgroup underwent robust transcriptional reprogramming upon denervation. Signature genes in denervated type IIb2 myonuclei includedRunx1,Gadd45a,Igfn1,Robo2,Dlg2, andSh3d19(p<0.001). The gene regulatory network analysis captured a group of atrophy-related regulons (Foxo3, Runx1, Elk4, Bhlhe40) whose activities were enhanced (p<0.01), especially in the type IIb2 myonuclei. The metabolic landscape in the myonuclei showed that most of the metabolic pathways were downregulated by denervation (p<0.001), while some of the metabolic signaling, such as glutathione metabolism, was specifically activated in the denervated type IIb2 myonulei. We also investigated the transcriptomic alterations in the type I myofibers, muscle stem cells, fibro-adipogenic progenitors, macrophages, endothelial cells and pericytes and characterized their signature responses to denervation. By predicting the cell-cell interactions, we observed that the communications between myofibers and muscle resident cells were diminished by denervation.

Conclusion

Our results define the myonuclear transition, metabolic remodeling and gene regulation networks reprogramming associated with denervation-induced muscle atrophy and illustrate the molecular basis of the heterogeneity and plasticity of muscle cells in response to catabolism. These results provide a useful resource for exploring the molecular mechanism of muscle atrophy.
A Cytoskeletal Vortex Drives Phage Nucleus Rotation During Jumbo Phage Replication in E. coli
Authors: Birkholz Erica A. , Laughlin Thomas G. , Suslov Sergey , Armbruster Emily , Lee Jina , Wittmann Johannes , Corbett Kevin D. , Villa Elizabeth , Pogliano Joe
Published: October 2021

Vortex-like arrays of cytoskeletal filaments that drive cytoplasmic streaming and nucleus rotation have been identified in eukaryotes, but similar structures have not been described in prokaryotes. The only known example of a rotating intracellular body in prokaryotic cells occurs when nucleus-forming jumbo phages infect Pseudomonas. During infection, a bipolar spindle of PhuZ filaments drives intracellular rotation of the phage nucleus, a key aspect of the replication cycle. Here we show the E. coli jumbo phage Goslar assembles a phage nucleus surrounded by an array of PhuZ filaments resembling a vortex instead of a bipolar spindle. Expression of mutant PhuZ strongly reduces Goslar phage nucleus rotation, demonstrating that the PhuZ cytoskeletal vortex is necessary for rotating the phage nucleus. While vortex-like cytoskeletal arrays are important in eukaryotes, this work identifies the first known example of a coherent assembly of filaments into a vortex-like structure driving intracellular rotation within the prokaryotic cytoplasm.
Individual-based modeling of genome evolution in haplodiploid organisms
Authors: Pracana Rodrigo , Burns Richard , Hammond Robert L. , Haller Benjamin C. , Wurm Yannick
Published: October 2021

Ants, bees, wasps, bark beetles, and other species have haploid males and diploid females. Although such haplodiploid species play key ecological roles and are threatened by environmental changes, no general framework exists for simulating their genetic evolution. Here, we use the SLiM simulation environment to build a novel model for individual-based forward simulation of genetic evolution in haplodiploid populations. We compare the fates of adaptive and deleterious mutations and find that selection is more effective in haplodiploid species than in diploid species. Our open-source model will help understand the evolution of sociality and how ecologically important species may adapt to changing environments.
Identification of the Park Grass Experiment soil metaproteome
Authors: Quinn Gerry A. , Abdelhameed Alyaa , Banat Ibrahim M. , Berrar Daniel , Doerr Stefan H. , Dudley Ed , Francis Lewis W. , Gazze Salvatore A. , Hallin Ingrid , Matthews G. Peter , Swain Martin T. , Whalley W. Richard , van Keulen Geertje
Published: October 2021

The Park Grass Experiment, is an international reference soil with an impressive repository of temperate grassland (meta)data, however, it still lacks documentation of its soil metaproteome. The identification of these proteins is crucial to our understanding of soil ecology and their role in major biogeochemical processes. However, protein extraction can be fraught with technical difficulties including co-extraction of humic material and lack of a compatible databases to identify proteins. To address these issues, we used two compatible soil protein extraction techniques on Park Grass soil, one that removed humic material, namely a modified freeze-dry, heat/thaw/phenol/chloroform (HTPC) method and another which co-extracted humic material, namely an established surfactant method. Proteins were identified by matching mass spectra against a tailored Park Grass metagenome database. We identified a broad range of proteins from Park Grass soil, mainly in “protein metabolism”, “membrane transport”, “carbohydrate metabolism”, “respiration” and “ribosome associated” categories, enabling reconstitution of specific processes active in grassland soil. The soil microbiome was dominated by Proteobacteria, Actinobacteria, Acidobacteria and Firmicutes at phyla level and Bradyrhizobium, Rhizobium, Acidobacteria, Streptomyces and Pseudolabrys at genus level. Further functional enrichment analysis enabled us to identify many proteins in regulatory and signalling networks of key biogeochemical cycles such as the nitrogen cycle. The combined extraction methods connected previous Park Grass metadata with the metaproteome, biogeochemistry and soil ecology. This could provide a base on which future targeted studies of important soil processes and their regulation can be built.

Highlights

Parallel protein extraction methods identified 1266 proteins from Park Grass soil

Proteome was enriched in ribosomal and respiration proteins for the surfactant extraction method and nitrogen associated proteins for the modified phenol/chloroform method

Identification of regulatory and signalling proteins in key biogeochemical cycles

Links metaproteome to microbiome, biogeochemical cycles and Park Grass metadata

Provides baseline for future targeted studies
Cancer malignancy is correlated with up-regulation of PCYT2-mediated glycerol phosphate modification of α-dystroglycan
Authors: Umezawa Fumiko , Natsume Makoto , Fukusada Shigeki , Nakajima Kazuki , Yamasaki Fumiya , Kawashima Hiroto , Kuo Chu-Wei , Khoo Kay-Hooi , Shimura Takaya , Yagi Hirokazu , Kato Koichi
Published: October 2021

The dystrophin-glycoprotein complex connects the cytoskeleton with base membrane components such as laminin through unique O-glycans displayed on α-dystroglycan (α-DG). Genetic impairment of elongation of these glycans causes congenital muscular dystrophies. We previously identified that glycerol phosphate (GroP) can cap the core part of the α-DG O-glycans and terminate their further elongation. This study examined the possible roles of the GroP modification in cancer malignancy, focusing on colorectal cancer. We found that the GroP modification critically depends on PCYT2, which serves as CDP-Gro synthase. Furthermore, we identified a significant positive correlation between cancer progression and GroP modification, which also correlated positively with PCYT2 expression. Moreover, we demonstrate that GroP modification promotes the migration of cancer cells. Based on these findings, we propose that the GroP modification by PCYT2 disrupts the glycan-mediated cell adhesion to the extracellular matrix and thereby enhances cancer metastasis. Thus, the present study suggests the possibility of novel approaches for cancer treatment by targeting the PCYT2-mediated GroP modification.