bluuebunny/crossref_metadata_2025 huggingface dataset:
Effect of Stromal Vascular Fractions on Angiogenesis of Injected Diced Cartilage
Authors: Yin Han , Xie Cong , Li Li , Zeng Li , Zhu Zi-Wen , Chen Nian , Xie Hong-Ju , Liao Jun-Lin
Published: January 2022

Objectives:

This study explored the effect of adipose-derived stromal vascular fractions (SVFs) on angiogenesis in injected autologous diced cartilage.

Methods:

Stromal vascular fractions were extracted by enzymatic digestion. Cartilage grafts were harvested from 1 side of the auricular cartilage of New Zealand rabbit and then diced to a size of 1.0 mm3. The grafts were divided into 2 groups. The control group was diced cartilage mixed with culture medium, and the experimental group was diced cartilage mixed with SVFs. The 2 groups of composite grafts were subcutaneously implanted on both sides of the back of each rabbit. After 4, 12 and 24 weeks, the tissue structure, number of blood vessels, and angiogenic factors in the grafts were observed.

Results:

The SVFs conformed to the current standard of the biological evaluation. Under an inverted microscope, the number of layers of chondrocytes in the experimental group was higher than that in the control group at 4 weeks. A small number of inflammatory cells and blood vessels were observed around the cartilage grafts. At 12 and 24 weeks, the volume of tissue was increased gradually by general observation. And a large number of chondrocytes were observed microscopically, whereas the number of inflammatory cells decreased. And meanwhile additional new blood vessels were observed. Immunohistochemical analysis of CD31 showed that the number of capillaries in the control group was significantly lower than that in the experimental group at 4, 12 and 24 weeks. Further, the expression of Hypoxia inducible factor-1 (HIF-1) and vascular endothelial growth factor (VEGF) mRNA and protein were measured by RT-PCR and Western bloting, respectively. The results showed that the mRNA expression of VEGF and HIF-1α in the experimental group was increased. The mRNA level remained higher than that of the control group at 24 weeks (P < 0.05). And the relative expression levels of VEGF and HIF-1α protein in the experimental group were higher than those in the control group at 4, 12 and 24 weeks (P < 0.05).

Conclusion:

Autologous diced cartilage mixed with adipose-derived SVFs can promote angiogenesis when transplanted by injection. Further research showed that SVFs could increase the expression levels of VEGF and HIF-1α in the grafts, which may be part of the mechanism that SVFs promoted the angiogenesis of diced cartilage.
Steroid Use in Palatoplasty: A Single Surgeon Comparative Retrospective Cohort Study
Authors: Lee Jessica A. , Erpenbeck Sarah P. , Egro Francesco M. , Grunwaldt Lorelei J.
Published: January 2022

Background:

Fistula rates in cleft palate repair vary by technique, surgeon, and institution. Although steroids are commonly used in airway surgery, many plastic surgeons are reluctant to use steroids because of concerns with wound healing. This study aims to assess outcomes and safety of steroid use in Furlow palatoplasty and determine its impact on fistula formation.

Methods:

A retrospective cohort study was done of all cleft palate surgeries performed by a single surgeon between 2010 and 2014. Data reviewed included demographics, type of cleft, steroid use, length of surgery, length of stay, and fistula formation rate.

Results:

One hundred thirty-five patients underwent palatoplasty, of which 101 received steroids and 34 did not. The mean age was 4.6 years. A total of 42.2% of patients underwent primary palatoplasty, 48.1% underwent submucous cleft palatoplasty, and 9.7% underwent conversion palatoplasty. The overall fistula rate was 1.5% and was comparable between the 2 groups (steroids = 2.0%, no steroids = 0.0%, P = 0.558), and all occurred in primary palatoplasty patients. The average length of stay in the hospital was shorter among patients receiving steroids (steroids = 2.0 days, no steroids = 2.5 days, P < 0.05).

Conclusions:

Steroid use in cleft palate surgery appears to be safe and likely not associated with impaired wound healing or increased fistula formation. It may also shorten length of hospitalization.
Cleft Lip and Palate Repair Training to Bridge the Gap in Low-Income Countries
Authors: Borg Tiffanie-Marie , Hong Shek , Ghanem Ali
Published: January 2022

Introduction:

There is a significant unmet need for cleft repair in low-income countries. The procedure is challenging due to limited access, small fragile flaps, and the depth at which sutures need to be placed. The aim of this analysis is to review available literature pertaining to cleft lip and palate repair training, with a focus on those applicable to low-income countries.

Methodology:

Literature searches of Medline and EMBase were performed to identify studies of cleft lip and/or palate training. Terms including “cleft,” “lip,” “palate,” and “training” were searched. Literature published in English from inception to May 2021 in which the full text was available was considered for inclusion. Studies were included on the basis that they included interventions such as virtual/online training, simulation training, courses, fellowships, and/or hospital-based training. Studies that met this criterion were further assessed using a validated scoring tool then the applicability of each training strategy for low-income countries reviewed.

Results:

Nineteen studies were included in this analysis. Of these 4 studies pertained to online training, 11 studies illustrated cleft models and simulation training, while 4 studies highlighted the role of charity led training achieved through direct hospital teaching and fellowship programs. The training strategies described have been summarised and presented herein in a narrative format. The simplicity, fidelity, and training benefit of palatoplasty models has also been described.

Conclusions:

Cleft lip and palate repair training should be accessible to surgeons in low-income countries. Direct practical experience has an important role in training to perform cleft procedures. Affordable, simple simulation models that resemble human tissue are essential so that surgeons can safely practice skills between initial training and operating on a living child.
Complication Rates From Otoplasty at a Tertiary Facial Plastic Surgery Center: A Retrospective Analysis
Authors: AlAwadh Ibrahim , Alassiry Hassan , Bogari Ahmad , Alabduljabbar Ziyad , AlDosari Badi
Published: January 2022

Prominent ears are considered the most common congenital external ear deformity among Caucasians. Affecting approximately 5% of the population, it runs in families and exhibits equal sex incidence. This study aimed to determine the complication rate from otoplasty in a tertiary facial plastic surgery center. This retrospective cross-sectional study included all patients with prominent ears deformities who underwent otoplasty at King Abdul-Aziz University Hospital between January 2019 and June 2021. The records of 116 patients who underwent otoplasty during the study period were examined and only 44 matched the inclusion and exclusion criteria. The total of 85 operated ears from 44 patients were included. Of these, 17 were pediatric patients and 25 were male patients. Forty-one patients underwent bilateral otoplasty and 3 underwent unilateral otoplasty. Complications occurred in 17/85 (20%) patients and the complications included recurrence 4 (4.70%), hypertrophic scar 3 (3.52%), keloid 2 (2.35), granuloma 2 (2.35%), infection 2 (2.35%), discomfort 1 (1.17%), wound dehiscence 1 (1.17%), hematoma 1 (1.17%), and retracted ear 1 (1.17%). The overall patient satisfaction was 38/44 (86.36%). Our study is first study conducted in middle east about otoplasty complications. It showed that the complications from otoplasty surgery varied from severe to mild, with acceptable overall satisfactory results. The most common complication was recurrence. Fortunately, serious complications, such as wound dehiscence and hematoma, were rare. However, our study’s small sample size remains a major limitation.
The impact of restorative green environment on mental health of big cities and the role of mental health professionals
Authors: Siah Chiew-Jiat Rosalind , Kua Ee Heok , Goh Yong-Shian Shawn
Published: January 2022

Purpose of review

To provide an update on insights into the effectiveness of the green environment and forest on the mental health of city dwellers; and the role of mental health professionals in advocating green restorative therapies.

Recent findings

The studies reviewed in this paper confirmed the mental health benefits on individuals who engaged in the green environment and forest. Results of studies showed that the participants reported significantly higher positive effects. However, it is difficult to compare studies because of marked differences in methodology and often lack of biological markers. With the recent global concern about climate warming, mental health professionals have a critical role to influence city planners on the importance of the green environment and the forest. In Singapore, the ’Therapeutic Garden’ project and ’Therapeutic Rainforest’ program are examples of mental health professionals working with government agencies for a ’city in nature’.

The benefits of the green environment and forest are emphasized especially on the psychological well being. In the light of the danger of climate warming, this review highlights the need for city planners to collaborate with mental health professionals to incorporate high-quality green spaces when planning the city of the future. There is an urgent need for better consultation between health agencies and local city government to create an appealing and diverse green environment within the city.
Putative host-derived insertions in the genomes of circulating SARS-CoV-2 variants
Authors: Yang Yiyan , Dufault-Thompson Keith , Fontenele Rafaela Salgado , Jiang Xiaofang
Published: January 2022

Insertions in the SARS-CoV-2 genome have the potential to drive viral evolution, but the source of the insertions is often unknown. Recent proposals have suggested that human RNAs could be a source of some insertions, but the small size of many insertions makes this difficult to confirm. Through an analysis of available direct RNA sequencing data from SARS-CoV-2 infected cells, we show that viral-host chimeric RNAs are formed through what are likely stochastic RNA-dependent RNA polymerase template switching events. Through an analysis of the publicly available GISAID SARS-CoV-2 genome collection, we identified two genomic insertions in circulating SARS-CoV-2 variants that are identical to regions of the human 18S and 28S rRNAs. These results provide direct evidence of the formation of viral-host chimeric sequences and the integration of host genetic material into the SARS-CoV-2 genome, highlighting the potential importance of host-derived insertions in viral evolution.

IMPORTANCE

Throughout the COVID-19 pandemic, the sequencing of SARS-CoV-2 genomes has revealed the presence of insertions in multiple globally circulating lineages of SARS-CoV-2, including the Omicron variant. The human genome has been suggested to be the source of some of the larger insertions, but evidence for this kind of event occurring is still lacking. Here, we leverage direct RNA sequencing data and SARS-CoV-2 genomes to show host-viral chimeric RNAs are generated in infected cells and two large genomic insertions have likely been formed through the incorporation of host rRNA fragments into the SARS-CoV-2 genome. These host-derived insertions may increase the genetic diversity of SARS-CoV-2 and expand its strategies to acquire genetic materials, potentially enhancing its adaptability, virulence, and spread.
Diurnal stomatal apertures profile and density ratios affect whole-canopy conductance, drought response, water-use efficiency and yield
Authors: Gosa Sanbon Chaka , Gebeyo Bogale Abebe , Patil Ravitejas , Mencia Ramón , Moshelion Menachem
Published: January 2022

Key physiological traits of crop plants, such as transpiration, stomatal conductance, and photosynthesis are highly related to plant productivity. However, these traits are typically studied under steady-state conditions or modeled using only a few measured data points which do not reflect the dynamic behavior of the plant in response to field conditions. In this work, we hypothesized that the plastic behavior of whole-plant water balance regulation, as previously observed in tomato WT, was partially lost in the breeding process due to selective pressure towards productivity. We also hypothesized that this plastic behavior would be observed in some members of the tomato introgression lines (ILs) population, which was created by crossing the WT and M82 lines, particularly in ILs that demonstrate improved drought response. To overcome the steady-state bottleneck, and to test our hypothesis we used a gravimetric functional-phenotyping platform and a reverse-phenotyping method to examine the dynamic whole-plant water-regulation responses of tomato ILs and compared those responses with several years of yield performance in commercial fields. Indeed, our study enabled us to identify high plasticity in a few ideotypic ILs. We found that ideotype lines with highly plastic stomatal conductance and high abaxial-adaxial stomatal density ratios had stomatal apertures that peaked early in the day, even under water-deficit conditions. These traits resulted in dynamic daily water-use efficiency, along with rapid recovery of transpiration when irrigation was resumed after a period of imposed drought. Abaxial stomatal density was also found to be strongly correlated with the expression of the stomatal-development genesSPCHandZEP. This study demonstrates how a reverse functional phenotyping approach based on field yield data, continuous and simultaneous whole-plant water-balance measurements and anatomical examination of individual leaves can help us to understand and identify dynamic and complex yield-related physiological traits.
Genomic and transcriptomic data analyses highlight KPNB1 and MYL4 as novel risk genes for congenital heart disease
Authors: Broberg Martin , Ampuja Minna , Jones Samuel , Ojala Tiina , Rahkonen Otto , Kivelä Riikka , Priest James ,   FinnGen, Ollila Hanna M. , Helle Emmi
Published: January 2022

Congenital heart defects (CHD) are structural defects of the heart affecting approximately 1% of newborns. CHDs exhibit a complex inheritance pattern. While genetic factors are known to play an important role in the development of CHD, relatively few variants have been discovered so far and very few genome-wide association studies (GWAS) have been conducted. We performed a GWAS of general CHD and five CHD subgroups in FinnGen followed by functional fine-mapping through eQTL analysis in the GTEx database, and target validation in human induced pluripotent stem cell - derived cardiomyocytes (hiPS-CM) from CHD patients. We discovered that the MYL4-KPNB1 locus (rs11570508, beta = 0.24, P = 1.2×10−11) was associated with the general CHD group. An additional four variants were significantly associated with the different CHD subgroups. Two of these, rs1342740627 associated with left ventricular outflow tract obstruction defects and rs1293973611 associated with septal defects, were Finnish population enriched. The variant rs11570508 associated with the expression of MYL4 (normalized expression score (NES) = 0.1, P = 0.0017, in the atrial appendage of the heart) and KPNB1 (NES = -0.037, P = 0.039, in the left ventricle of the heart). Furthermore, lower expression levels of both genes were observed in human induced pluripotent stem cell derived cardiomyocytes (hiPSC-CM) from CHD patients compared to healthy controls. Together, the results demonstrate KPNB1 and MYL4 as in a potential genetic risk loci associated with the development of CHD.
Developmental patterning function of GNOM ARF-GEF mediated from the plasma membrane
Authors: Adamowski Maciek , Matijević Ivana , Friml Jiří
Published: January 2022

The GNOM (GN) Guanine nucleotide Exchange Factor for ARF small GTPases (ARF-GEF) is among the best studied trafficking regulators in plants, playing crucial and unique developmental roles in patterning and polarity. The current models place GN at the Golgi apparatus (GA), where it mediates secretion/recycling, and at the plasma membrane (PM) presumably contributing to clathrin-mediated endocytosis (CME). The mechanistic basis of the developmental function of GN, distinct from the other ARF-GEFs including its homologue GNOM-LIKE1 (GNL1), remains elusive. Insights from this study redefine the current notions of GN function. We show that GN, but not GNL1, localizes to the PM at long-lived structures distinct from clathrin-coated pits, while CME and secretion proceed normally in gn knockouts. The functional GN mutant variant GNfewerroots, absent from the GA, suggests that PM is the major place of GN action responsible for its developmental function. Following inhibition by Brefeldin A, GN, but not GNL1, relocates to the PM likely on exocytic vesicles, suggesting selective molecular associations. A study of GN-GNL1 chimeric ARF-GEFs indicate that all GN domains contribute to the specific GN function in a partially redundant manner. Together, this study offers significant steps towards the elucidation of the mechanism underlying unique cellular and development functions of GN.
Pilot scale study on UV-C inactivation of bacterial endospores and virus particles in whole milk: evaluation of system efficiency and product quality
Authors: Vashisht Pranav , Pendyala Brahmaiah , Patras Ankit , Sudhir Gopisetty Vybhav Vipul , Ravi Ramasamy
Published: January 2022

UV-C processing of whole milk (WM) using a designed pilot scale Dean flow system was conducted at flow rates (11.88, 23.77, and 47.55 gph), Reynolds number ranges from 2890-11562 and the Dean number (at curved region) calculated as (648-2595) to inactivate bacterial endospores and virus particles. Biodosimetry studies were conducted to quantify the reduction equivalent fluence at selected experimental conditions. Results revealed that the fluence distribution improved as flow rate increases, attributed to increase in Dean effects and turbulence intensity. Microbial inactivation studies conducted at 47.55 gph showed 0.91 ± 0.15 and 2.14 ± 0.19 log reduction/ pass forB. cereusendospores and T1UV phage. Linear inactivation trend was observed against number of passes which clearly demonstrates equivalent fluence delivery during each pass. Lipid peroxidation value and volatiles profile did not change significantly at UV fluence of 60 mJ/cm2. Lower EEOvalue signifies the higher electrical efficiency of the system.
Assessing Comparative Microbiome Performance in Plant Cell Wall Deconstruction Using Multi-‘omics-Informed Network Analysis
Authors: Tom Lauren M. , Aulitto Martina , Wu Yu-Wei , Deng Kai , Gao Yu , Xiao Naijia , Rodriguez Beatrice Garcia , Louime Clifford , Northen Trent R. , Eudes Aymerick , Mortimer Jenny C. , Adams Paul , Scheller Henrik , Simmons Blake A. , Ceja-Navarro Javier A. , Singer Steven W.
Published: January 2022

Plant cell walls are interwoven structures recalcitrant to degradation. Both native and adapted microbiomes are particularly effective at plant cell wall deconstruction. Studying these deconstructive microbiomes provides an opportunity to assess microbiome performance and relate it to specific microbial populations and enzymes. To establish a system assessing comparative microbiome performance, parallel microbiomes were cultivated on sorghum (Sorghum bicolor L. Moench) from compost inocula. Biomass loss and biochemical assays indicated that these microbiomes diverged in their ability to deconstruct biomass. Network reconstructions from time-dependent gene expression identified key deconstructive groups within the adapted sorghum-degrading communities, including Actinotalea, Filomicrobium, and Gemmanimonadetes populations. Functional analysis of gene expression demonstrated that the microbiomes proceeded through successional stages that are linked to enzymes that deconstruct plant cell wall polymers. This combination of network and functional analysis highlighted the importance of celluloseactive Actinobacteria in differentiating the performance of these microbiomes.
Characterizing protein protonation microstates using Monte Carlo sampling
Authors: Khaniya Umesh , Mao Junjun , Wei Rongmei , Gunner M. R.
Published: January 2022

Proteins are polyelectrolytes with acidic or basic amino acids making up ≈25% of the residues. The protonation state of all Asp, Glu, Arg, Lys, His and other protonatable residues, cofactors and ligands define each protonation microstate. As all of these residues will not be fully ionized or neutral, proteins exist in a mixture of microstates. The microstate distribution changes with pH. As the protein environment modifies the proton affinity of each site the distribution may also change in different reaction intermediates or as ligands are bound. Particular protonation microstates may be required for function, while others exist simply because there are many states with similar energy. Here, the protonation microstates generated in Monte Carlo sampling in MCCE are characterized in HEW lysozyme as a function of pH and bacterial photosynthetic reaction centers (RCs) in different reaction intermediates. The lowest energy and highest probability microstates are compared. The ΔG, ΔH and ΔS between the four protonation states of Glu35 and Asp52 in lysozyme are shown to be calculated with reasonable precision. A weighted Pearson correlation analysis identifies coupling between residue protonation states in RCs and how they change when the quinone in the QBsite is reduced.
MicrogliaST: a web server for microglia spatiotemportal pattern analysis in normal and disordered brains
Authors: Zhong Xiaoling , Li Feng , Tan Guiyuan , Yi Li , Zhao Jiaxin , Mi Wanqi , Zhang Yu , Hu Congxue , Li Xia , Xu Yingqi , Zhang Chunlong
Published: January 2022

Brain is the most complex organ of living organisms, as the celebrated cells in the brain, microglia play an indispensable role in the brain’s immune microenvironment. Microglia have critical roles not only in neural development and homeostasis, but also in neurodegenerative diseases and malignant of the central nervous system. However, little is known about the dynamic characteristics of microglia during development or disease conditions. Recently, the single-cell RNA sequencing technologies have become possible to characterize the heterogeneity of immune system in brain. But it posed computational challenges on integrating and utilizing the massive published datasets to dissect the spatiotemporal characterization of microglia. Here, we present microgliaST (bio-bigdata.hrbmu.edu.cn/MST), a database consisting of single-cell microglia transcriptomes across multiple brain regions and developmental periods. Based on high-quality microglia markers collected from published papers, we annotated and constructed human and mouse transcriptomic profiles of 273,374 microglias, comprising 12 regions, 12 periods and 3 conditions (normal, disease, treatment). In addition, MicrogliaST provides multiple analytical tools to elucidate the landscape of microglia under disorder conditions, conduct personalized difference analysis and spatiotemporal dynamic analysis. More importantly, microgliaST paves an ingenious way to the study of brain environment, and also provides insights into clinical therapy assessments.
Lipid nanoparticles delivering constitutively active STING mRNA as a novel anti-cancer therapeutic approach
Authors: Liu Wei , Alameh Mohamad-Gabriel , Yang June F. , Xu Jonathan R. , Lin Paulo JC , Tam Ying K , Weissman Drew , You Jianxin
Published: January 2022

Treating immunosuppressive tumors represents a major challenge in cancer therapies. Activation of STING signaling has shown remarkable potential to invigorate the immunologically ‘cold’ tumor microenvironment (TME). However, we and others have shown that STING is silenced in many cancers, including pancreatic ductal adenocarcinoma (PDAC) and Merkel cell carcinoma (MCC), both of which are associated with an immune-dampened TME. In this study, we applied mRNA lipid nanoparticles (LNP) to deliver a permanently active gain-of-function STINGR284S mutant into PDAC and MCC cells. Expression of STINGR284S induces cytokines and chemokines crucial for promoting intratumoral infiltration of CD8+ T cells and, importantly, also leads to robust cancer cell death while avoiding T cell entry and toxicity. Our studies demonstrated that mRNA-LNP delivery of STINGR284S could be explored as a novel therapeutic tool to reactivate antitumor response in an array of STING-deficient cancers while overcoming the toxicity and limitations of conventional STING agonists.
Real World Evidence of Neutralizing Monoclonal Antibodies for Preventing Hospitalization and Mortality in COVID-19 Outpatients
Authors: Wynia Matthew K. , Beaty Laurel E. , Bennett Tellen D. , Carlson Nichole E. , Davis Christopher B. , Kwan Bethany M. , Mayer David A. , Ong Toan C. , Russell Seth , Steele Jeffrey , Stocker Heather R. , Wogu Adane F. , Zane Richard D. , Sokol Ronald J. , Ginde Adit A.
Published: January 2022

Background

Neutralizing monoclonal antibodies (mAbs) are authorized for early symptomatic COVID-19 patients. Whether mAbs are effective against the SARS-CoV-2 Delta variant, among vaccinated patients, or for prevention of mortality remains unknown.

Objective

To evaluate the effectiveness of mAb treatment in preventing progression to severe disease during the Delta phase of the pandemic and based on key baseline risk factors.

Design, Setting, and Patients

Observational cohort study of non-hospitalized adult patients with SARS-CoV-2 infection from November 2020-October 2021, using electronic health records from a statewide health system plus state-level vaccine and mortality data. Using propensity matching, we selected approximately 2.5 patients not receiving mAbs for each patient who received mAbs.

Exposure

Neutralizing mAb treatment under emergency use authorization

Main Outcomes

The primary outcome was 28-day hospitalization; secondary outcomes included mortality and severity of hospitalization.

Results

Of 36,077 patients with SARS-CoV-2 infection, 2,675 receiving mAbs were matched to 6,677 not receiving mAbs. Compared to mAb-untreated patients, mAb-treated patients had lower all-cause hospitalization (4.0% vs 7.7%; adjusted OR 0.48, 95%CI 0.38-0.60) and all-cause mortality (0.1% vs. 0.9%; adjusted OR 0.11, 95%CI 0.03-0.29) to day 28; differences persisted to day 90. Among hospitalized patients, mAb-treated patients had shorter hospital length of stay (5.8 vs. 8.5 days) and lower risk of mechanical ventilation (4.6% vs. 16.6%). Relative effectiveness was similar in preventing hospitalizations during the Delta variant phase (adjusted OR 0.35, 95%CI 0.25-0.50) and across subgroups. Lower number-needed-to-treat (NNT) to prevent hospitalization were observed for subgroups with higher baseline risk of hospitalization (e.g., multiple comorbidities (NNT=17) and not fully vaccinated (NNT=24) vs. no comorbidities (NNT=88) and fully vaccinated (NNT=81).

Conclusion

Real-world evidence demonstrated mAb effectiveness in reducing hospitalization among COVID-19 outpatients, including during the Delta variant phase, and conferred an overall 89% reduction in 28-day mortality. Early outpatient treatment with mAbs should be prioritized, especially for individuals with highest risk for hospitalization.
Genetic Impairment of Succinate Metabolism Disrupts Bioenergetic Sensing in Adrenal Neuroendocrine Cancer
Authors: Gupta Priyanka , Strange Keehn , Telange Rahul , Guo Ailan , Hatch Heather , Sobh Amin , Elie Jonathan , Carter Angela M. , Totenhagen John , Tan Chunfeng , Sonawane Yogesh A. , Neuzil Jiri , Natarajan Amarnath , Ovens Ashley J. , Oakhill Jonathan S. , Wiederhold Thorsten , Pacak Karel , Ghayee Hans K. , Meijer Laurent , Reddy Sushanth , Bibb James A.
Published: January 2022

Metabolic dysfunction mutations can impair energy sensing and cause cancer. Loss of function of mitochondrial TCA cycle enzyme, succinate dehydrogenase B (SDHB) results in various forms of cancer typified by pheochromocytoma (PC). Here we delineate a signaling cascade where the loss ofSDHBinduces the Warburg effect in PC tumors, triggers dysregulation of Ca2+homeostasis, and aberrantly activates calpain and the protein kinase Cdk5, through conversion of its cofactor from p35 to p25. Consequently, aberrant Cdk5 initiates a cascade of phospho- signaling where GSK3 inhibition inactivates energy sensing by AMP-kinase through dephosphorylation of the AMP-kinase γ subunit, PRKAG2. Overexpression of p25-GFP in mouse adrenal chromaffin cells also elicits this phosphorylation signaling and causes PC tumor formation. A novel Cdk5 inhibitor, MRT3-007, reversed this phospho-cascade, invoking an anti- Warburg effect, cell cycle arrest, and senescence-like phenotype. This therapeutic approach halted tumor progressionin vivo. Thus, we reveal an important novel mechanistic feature of metabolic sensing and demonstrate that its dysregulation underlies tumor progression in PC and likely other cancers.

Highlights

Loss of SDHB function in pheochromocytoma causes Ca2+dysregulation, calpain activation, and aberrant activation of the protein kinase Cdk5.

Hyperactive Cdk5 deregulates a GSK3/PRKAG2/AMPKα signaling cascade.

p25 overexpression and consequent aberrant Cdk5 activity in chromaffin cells causes pheochromocytoma.

Inhibition of Cdk5 activates the PRKAG2/AMPK/p53 signaling to rescue cell senescence and block PC tumor progression.

Graphical Abstract
Oil Red O based method for Exosome Labelling and detection
Authors: Bharati Shikha , Anjaly Km , Thoidingjam Shivani , Tiku Ashu Bhan
Published: January 2022

With the realization of the role of exosomes in diseases especially cancer, exosome research is gaining popularity in biomedical sciences. To understand exosome biology, their labelling and tracking studies are important. New and improved methods of exosome labelling for detection and tracking of exosomes need to be developed to harness their therapeutic and diagnostic potential. In this paper, we report a novel, simple and effective method of labelling and detecting exosomes using Oil red O (ORO) which is a dye commonly used for lipid staining. Using ORO is a cost effective and easy approach with intense red colouration of stained exosomes. Further, the issues faced with commonly used lipophilic dyes for exosomes labelling such as long term persistence of dyes, aggregation and micelle formation of dyes, difficulty to distinguish dye particles from labelled exosomes and detection of large aggregates of dye or dye-exosome are not seen with ORO dye. This method shows good labelling efficiency of exosomes with very sensitive detection and real-time tracking of the cellular uptake of exosomes.

Abstract Figure
Robust and Brain-Like Working Memory through Short-Term Synaptic Plasticity
Authors: Kozachkov Leo , Tauber John , Lundqvist Mikael , Brincat Scott L. , Slotine Jean-Jacques , Miller Earl K.
Published: January 2022

Working memory has long been thought to arise from sustained spiking/attractor dynamics. However, recent work has suggested that short-term synaptic plasticity (STSP) may help maintain attractor states over gaps in time with little or no spiking. To determine if STSP endows additional functional advantages, we trained artificial recurrent neural networks (RNNs) with and without STSP to perform an object working memory task. We found that RNNs with and without STSP were able to maintain memories over distractors presented in the middle of the memory delay. However, RNNs with STSP showed activity that was similar to that seen in the cortex of a non-human primate (NHP) performing the same task. By contrast, RNNs without STSP showed activity that was less brain-like. Further, RNNs with STSP were more robust to noise and network degradation than RNNs without STSP. These results show that STSP can not only help maintain working memories, it also makes neural networks more robust and brain-like.
Membrane tension propagation couples axon growth and collateral branching
Authors: Shi Zheng , Innes-Gold Sarah , Cohen Adam E.
Published: January 2022

Neuronal axons must navigate a mechanically heterogeneous environment to reach their targets, but the biophysical mechanisms coupling mechanosensation, growth, and branching are not fully understood. Here, we show that local changes in membrane tension propagate along axons at approximately 20 µm/s, more than 1000-fold faster than in other non-motile cells. This rapid and long-range mechanical signaling mediates bidirectional competition between axonal branch initiation and growth cone extension. Our data suggest a mechanism by which mechanical cues at one part of a growing axon can affect growth dynamics remotely.
Cohort-specific serological recognition of SARS-CoV-2 variant RBD antigens
Authors: Fraser Douglas D. , Miller Michael R. , Martin Claudio M. , Slessarev Marat , Hahn Paul , Higgins Ian , Melo Christopher , Pest Michael A. , Rothery Nate , Wang Xiaoqin , Zeidler Johannes , Cruz-Aguado Jorge A.
Published: January 2022

Background

Estimating the response of different cohorts (e.g. vaccinated or critically ill) to new SARS-CoV-2 variants is important to customize measures of control. Thus, our goal was to evaluate binding of antibodies from sera of infected and vaccinated people to different antigens expressed by SARS-CoV-2 variants.

Methods

We compared sera from vaccinated donors with sera from four patient/donor cohorts: critically ill patients admitted to an intensive care unit (split in sera collected between 2 and 7 days after admission and more than ten days later), a NIBSC/WHO reference panel of SARS-CoV-2 positive individuals, and ambulatory or hospitalized (but not critically ill) positive donors. Samples were tested with an anti-SARS-CoV-2 IgG serological assay designed with microplates coated with a SARS-CoV-2 RBD recombinant antigen. The same sample sets were also tested with microplates coated with antigens harbouring RBD mutations present in eleven of the most widespread variants.

Results

Sera from vaccinated individuals exhibited higher antibody binding (P<0.001) than sera from infected (but not critically ill) individuals when tested against the WT and each of 11 variants’ RBD.

The optical density generated by sera from non-critically ill convalescence individuals upon binding to variant’s antigens was different (P<0.05) from that of the WT in some variants—noteworthy, Beta, Gamma, Delta, and Delta Plus variants.

Conclusions

Understanding differences in binding and neutralizing antibody titers against WT vs variant RBD antigens from different donor cohorts can help design variant-specific immunoassays and complement other diagnostic and clinical data to evaluate the epidemiology of new variants.
Genomic Machine Learning Meta-regression: Insights on Associations of Study Features with Reported Model Performance
Authors: Barnett Eric , Onete Daniel , Salekin Asif , Faraone Stephen V
Published: January 2022

Background

Many studies have been conducted with the goal of correctly predicting diagnostic status of a disorder using the combination of genetic data and machine learning. The methods of these studies often differ drastically. It is often hard to judge which components of a study led to better results and whether better reported results represent a true improvement or an uncorrected bias inflating performance.

Methods

In this systematic review, we extracted information about the methods used and other differentiating features in genomic machine learning models. We used the extracted features in mixed-effects linear regression models predicting model performance. We tested for univariate and multivariate associations as well as interactions between features.

Results

In univariate models the number of hyperparameter optimizations reported and data leakage due to feature selection were significantly associated with an increase in reported model performance. In our multivariate model, the number of hyperparameter optimizations, data leakage due to feature selection, and training size were significantly associated with an increase in reported model performance. The interaction between number of hyperparameter optimizations and training size as well as the interaction between data leakage due to optimization and training size were significantly associated reported model performance.

Conclusions

Our results suggest that methods susceptible to data leakage are prevalent among genomic machine learning research, which may result in inflated reported performance. The interactions of these features with training size suggest that if data leakage susceptible methods continue to be used, modelling efforts using larger data sets may result in unexpectedly lower results compared to smaller data sets. Best practice guidelines that promote the avoidance and recognition of data leakage may help the field advance and avoid biased results.
Changes in foot progression angle during gait reduce the knee adduction moment and do not increase hip moments in individuals with knee osteoarthritis
Authors: Seagers Kirsten , Uhlrich Scott D. , Kolesar Julie A. , Berkson Madeleine , Kaneda Janelle M. , Beaupre Gary S. , Delp Scott L.
Published: January 2022

People with knee osteoarthritis who adopt a modified foot progression angle (FPA) during gait often benefit from a reduction in the knee adduction moment. It is unknown, however, whether changes in the FPA increase hip moments, a surrogate measure of hip loading, which will increase the mechanical demand on the joint. This study examined how altering the FPA affects hip moments. Individuals with knee osteoarthritis walked on an instrumented treadmill with their baseline gait, 10° toe-in gait, and 10° toe-out gait. A musculoskeletal modeling package was used to compute joint moments from the experimental data. Fifty participants were selected from a larger study who reduced their peak knee adduction moment with a modified FPA. In this group, participants reduced the first peak of the knee adduction moment by 7.6% with 10° toe-in gait and reduced the second peak by 11.0% with 10° toe-out gait. Modifying the FPA reduced the early-stance hip abduction moment, at the time of peak hip contact force, by 4.3% ± 1.3% for 10° toe-in gait (p=0.005, d=0.49) and by 4.6% ± 1.1% for 10° toe-out gait (p<0.001, d=0.59) without increasing the flexion and internal rotation moments (p>0.15). Additionally, 74% of individuals reduced their total hip moment at time of peak hip contact force with a modified FPA. In summary, when adopting a FPA modification that reduced the knee adduction moment, participants, on average, did not increase surrogate measures of hip loading.
Covid-19 disease dynamics with vaccination: The effect of uncertainty
Authors: Majumder Abhijit , Bairagi Nandadulal
Published: January 2022

Rate parameters are critical in estimating the covid burden using mathematical models. In the Covid-19 mathematical models, these parameters are assumed to be constant. However, uncertainties in these rate parameters are almost inevitable. In this paper, we study a stochastic epidemic model of the SARS-CoV-2 virus infection in the presence of vaccination in which some parameters fluctuate around its average value. Our analysis shows that if the stochastic basic reproduction number (SBRN) of the system is greater than unity, then there is a stationary distribution, implying the long-time disease persistence. A sufficient condition for disease eradication is also prescribed for which the exposed class goes extinct, followed by the infected class. The disease eradication criterion may not hold if the rate of vaccine-induced immunity loss increases or/and the force of infection increases. Using the Indian Covid-19 data, we estimated the model parameters and showed the future disease progression in the presence of vaccination. The disease extinction time is estimated under various conditions. It is revealed that the mean extinction time is an increasing function of both the force of infection and immunity loss rate and shows the lognormal distribution. We point out that disease eradication might not be possible even at a higher vaccination rate if the vaccine-induced immunity loss rate is high. Our observation thus indicates the endemicity of the disease for the existing vaccine efficacy. The disease eradication is possible only with a higher vaccine efficacy or a reduced infection rate.
Environmental risk factors associated with the presence ofMycobacterium ulceransin Victoria, Australia
Authors: Blasdell Kim R. , McNamara Bridgette , O’Brien Daniel P. , Tachedjian Mary , Boyd Victoria , Dunn Michael , Mee Peter T. , Clayton Simone , Gaburro Julie , Smith Ina , Gibney Katherine B. , Tay Ee Laine , Hobbs Emma C , Waidyatillake Nilakshi , Lynch Stacey E. , Stinear Timothy P. , Athan Eugene
Published: January 2022

In recent years reported cases of Buruli ulcer (BU), caused byMycobacterium ulcerans(MU), have increased substantially in Victoria, Australia, with the epidemic also expanding geographically. To develop an understanding of how MU circulates in the environment and transmits to humans we analyzed environmental samples collected from 115 properties of recent BU cases and from 115 postcode-matched control properties, for the presence of MU. Environmental factors associated with increased odds of MU presence at a property included certain native plant species and native vegetation in general, more alkaline soil, lower altitude, the presence of common ringtail possums (Pseudocheirus peregrinus) and overhead powerlines. However, only powerlines and the absence of the native plantMelaleuca lanceolatawere associated with BU case properties. Samples positive for MU were more likely to be found at case properties and were associated with detections of MU in ringtail possum feces, supporting the hypothesis that MU is zoonotic, with ringtail possums the strongest reservoir host candidate. However, the disparity in environmental risk factors associated with MU positive properties versus case properties indicates a strong human behavioral component or the influence of other environmental factors in disease acquisition that requires further study.

Article Summary Line

Possums, powerlines, and native vegetation are associated with the presence ofMycobacterium ulceransin residential properties in Victoria, Australia.
Analytic sensitivity of the Abbott BinaxNOW™ lateral flow immunochromatographic assay for the SARS-CoV-2 Omicron variant
Authors: Kanjilal Sanjat , Chalise Sujata , Shah Adnan Shami , Cheng Chi-An , Senussi Yasmeen , Springer Michael , Walt David R.
Published: January 2022

The emergence of the SARS-CoV-2 Omicron variant has motivated a re-evaluation of the test characteristics for lateral flow immunochromatographic assays (LFIAs), commonly referred to as rapid antigen tests. To address this need, we evaluated the analytic sensitivity of one of the most widely used LFIAs in the US market, the Abbott BinaxNOW™ COVID-19 Ag At-Home Card using 32 samples of Omicron and 30 samples of the Delta variant. Samples were chosen to intentionally over-represent the range of viral loads where differences are most likely to appear. We found no changes in the analytic sensitivity of the BinaxNOW™ assay by variant even after controlling for variation in cycle threshold values in the two populations. Similar to prior studies, the sensitivity of the assay is highly dependent on the amount of virus present in the sample. While the analytic sensitivity of the BinaxNOW™ LFIA remains intact versus the Omicron variant, its clinical sensitivity is influenced by the interaction between viral replication, the dynamics of tissue tropism and the timing of sampling. Further research is necessary to optimally adapt current testing strategies to robustly detect early infection by the Omicron variant to prevent transmission.
Clinical outcomes associated with Omicron (B.1.1.529) variant and BA.1/BA.1.1 or BA.2 subvariant infection in southern California
Authors: Lewnard Joseph A. , Hong Vennis X. , Patel Manish M. , Kahn Rebecca , Lipsitch Marc , Tartof Sara Y.
Published: January 2022

The Omicron (B.1.1.529) variant of SARS-CoV-2 rapidly achieved global dissemination following its emergence in southern Africa in November, 2021.1,2 Epidemiologic surveillance has revealed changes in COVID-19 case-to-hospitalization and case-to-mortality ratios following Omicron variant emergence,3–6 although interpretation of these changes presents challenges due to differential protection against Omicron or Delta (B.1.617.2) variant SARS-CoV-2 infections associated with prior vaccine-derived and naturally-acquired immunity, as well as longer-term changes in testing and healthcare practices.7 Here we report clinical outcomes among 222,688 cases with Omicron variant infections and 23,305 time-matched cases with Delta variant infections within the Kaiser Permanente Southern California healthcare system, who were followed longitudinally following positive outpatient tests between 15 December, 2021 and 17 January, 2022, when Omicron cases were almost exclusively BA.1 or its sublineages. Adjusted hazard ratios of progression to any hospital admission, symptomatic hospital admission, intensive care unit admission, mechanical ventilation, and death were 0.59 (95% confidence interval: 0.51-0.69), 0.59 (0.51-0.68), 0.50 (0.29-0.87), 0.36 (0.18-0.72), and 0.21 (0.10-0.44) respectively, for cases with Omicron versus Delta variant infections. In contrast, among 14,661 Omicron cases ascertained by outpatient testing between 3 February and 17 March, 2022, infection with the BA.2 or BA.1/BA.1.1 subvariants did not show evidence of differential risk of severe outcomes. Lower risk of severe clinical outcomes among cases with Omicron variant infection merits consideration in planning of healthcare capacity needs amid establishment of the Omicron variant as the dominant circulating SARS-CoV-2 lineage globally, and should inform the interpretation of both case- and hospital-based surveillance data.
Channel integration affects usage intention in food delivery platform services: the mediating effect of perceived value
Authors: Yen Yung-Shen
Published: January 2022

Purpose

Structural equation modeling was conducted, and a sample with 577 consumers was investigated.

Design/methodology/approach

Based on the stimulus–organism–response (SOR) model, this study aims to explore how channel integration affects usage intention through perceived value in food delivery platform (FDP) services. Moreover, the author also examines the moderating effects of personal innovativeness and experience on the relationships in the model.

Findings

The study found that channel integration affects usage intention through perceived usefulness, perceived enjoyment and perceived price. Moreover, the moderating effects of personal innovativeness and experience are both significant in the model.

Research limitations/implications

This study found that perceived usefulness, perceived enjoyment and perceived price are three major values influencing the relationship between channel integration and usage intention in FDP services. Moreover, for consumers with high personal innovativeness, perceived usefulness, perceived enjoyment, social image and perceived risk affecting usage intention will be weaker than for consumers with low personal innovativeness. However, for highly experienced consumers, perceived usefulness, perceived enjoyment and perceived price affecting usage intention will be stronger than for less experienced consumers.

Practical implications

This study suggests that practitioners should develop value-driven innovative services and activities by integrating various channels for customers. Moreover, they should segment consumers on the basis of different levels of personal innovativeness and experience to provide different strategies for increasing the intention to use the service.

Originality/value

This study advances the extant knowledge of the SOR model in the context of online-to-offline commerce.