bluuebunny/crossref_metadata_2025 huggingface dataset:
The effect and mechanism of miR-607/CANT1 axis in lung squamous carcinoma
Authors: Qiao Gang , Wang Hai-Bo , Duan Xiu-Na , Yan Xiao-Fang
Published: March 2021

Lung squamous carcinoma (LUSC) is the second most frequent subtype of non-small cell lung cancer. Rarely gene alterations are identified in LUSC. Therefore, identifying LUSC-related genes to explain the relevant molecular mechanism is urgently needed. A potential biomarker, calcium-activated nucleotidase 1 (CANT1), was elevated in tissues of LUSC patients relative to normal cases based on the TCGA and/or GTEx database. CCK-8 and transwell tests were then implemented to measure the proliferative, invasive and migratory capacities, and showed that knockdown of CANT1 blocked LUSC cells proliferation. miR-607, predicted as an upstream factor for CANT1, was declined in LUSC using TargetScan analysis and luciferase activity test. Low miR-607 expression was related with unfavorable outcomes of LUSC patients. Moreover, miR-607 downregulation elevated cell viability, invasion and migration in LUSC cells, which was antagonized by si-CANT1. GEPIA website was accessed to estimate the relevance between CANT1 and epithelial-mesenchymal transition (EMT)-related positive factors. The protein levels of Fibronectin, Vimentin, Snail and β-catenin were altered due to the abnormal CANT1 and miR-607 expression. Together, these data unveiled that miR-607/CANT1 pair may exert a vital role in the progression of LUSC through mediating EMT process, which would furnish an available therapeutic therapy for LUSC.
Circular RNA circ_0021093 regulates miR-432/Annexin A2 pathway to promote hepatocellular carcinoma progression
Authors: Wang Yong , Xu Wei , Zu Maoheng , Xu Hao
Published: March 2021

Hepatocellular carcinoma (HCC) is a major histological subtype of liver cancer cases. Previous studies showed that circular RNA (circRNA) circ_0021093 was upregulated in HCC, but the regulatory mechanism of circ_0021093 is still rare. The expression levels of circ_0021093, miR-432 and Annexin A2 (ANXA2) were analyzed by real-time quantitative PCR. The relationship between the overall survival time of HCC patients and circ_0021093 level was analyzed with Kaplan–Meier analysis. Cell proliferation, migration and invasion were examined with cell counting kit-8 and transwell assays. Western blot was used to assess the protein expression of epithelial-mesenchymal transition markers and ANXA2. In addition, loss- or gain-of-function experiments and dual-luciferase reporter assay were performed to probe the relationship between miR-432 and circ_0021093 or ANXA2. The influences of circ_0021093 silencing in vivo were measured by using xenograft models. Circ_0021093 was highly expressed in HCC tissues and cells, and its level was associated with poor prognosis of HCC patients. Functional experiments showed that knockdown of circ_0021093 repressed proliferation, migration and invasion in vitro and tumor growth in vivo by regulating miR-432, while upregulation of circ_0021093 reversed these results. Moreover, miR-432 negatively regulated ANXA2 expression in HCC, and introduction of ANXA2 could abolish overexpression of miR-432-induced effects on HCC cells. Collectively, circ_0021093 boosted HCC progression via regulating proliferation, migration and invasion of HCC cells by acting as competing endogenous RNA to sponge miR-432.
Afatinib therapy in case of EGFR G724S emergence as resistance mechanism to osimertinib
Authors: Minari Roberta , Leonetti Alessandro , Gnetti Letizia , Zielli Teresa , Ventura Luigi , Bottarelli Lorena , Lagrasta Costanza , La Monica Silvia , Petronini Pier Giorgio , Alfieri Roberta , Tiseo Marcello
Published: March 2021

Osimertinib is a third-generation epidermal growth factor receptor-tyrosine kinase inhibitor (EGFR-TKI) used both as the first-line treatment of EGFR-mutated non–small cell lung cancer patients and in second-line after T790M-positive disease progression to first- or second-generation TKIs. Unfortunately, patients unavoidably experience disease progression to osimertinib and the current research is focused on resistance mechanisms and the relative therapeutic strategy. We report the case of a patient with advanced EGFR-mutated (exon 19 deletion and T790M-positive) non–small cell lung cancer who developed disease progression to osimertinib characterized by the loss of T790M concurrently with the emergence of G724S EGFR mutation, which was tackled by subsequent afatinib treatment. Next-generation sequencing molecular study of rebiopsy at time of progression to osimertinib revealed the persistence of EGFR exon 19 deletion, loss of T790M with a new G724S EGFR mutation; other concomitant mechanisms were excluded. Retrospective analysis of cell-free DNA revealed the emergence of G724S EGFR mutation four months before the radiologically-proven disease progression. The patient, after chemotherapy, was treated with afatinib with clinical and radiological benefit. Our case report contributes to increase the knowledge on acquired resistance mechanisms to osimertinib treatment, and it shows, for the first time, the efficacy of afatinib in the case of T790M loss and emergence of G724S EGFR mutation.
Climbing Mountains and Avoiding Slippery Slopes: Challenges in Constructing Measures of Children's Environments
Authors: Bradley Robert H.
Published: March 2021

Constructing valid, useful measures of children's environments is critical for advancing knowledge about relations between environmental conditions and child well-being. The approach to constructing useful measures of children's environments varies somewhat from the approach needed to construct valid, useful measures of children's personal characteristics. The commentary includes a review of literature on the distinction between reflective indicators and causal/formative indicators because it applies to the construction of measures of human environments. It also offers suggestions on how to select indicators for inclusion in measures of the environment and how to select assessments of child outcomes for validating measures of children's environments.
Effect of race and glucuronidation rates on the relationship between nicotine metabolite ratio and nicotine clearance
Authors: Liakoni Evangelia , Tyndale Rachel F. , Jacob Peyton , Dempsey Delia A. , Addo Newton , Benowitz Neal L.
Published: March 2021

Objectives

To investigate if the nicotine metabolite ratio (NMR, the ratio of nicotine metabolites 3′-hydroxycotinine/cotinine) is a reliable phenotypic biomarker for nicotine clearance across races, and as a function of differences in the rate of nicotine, cotinine and 3′-hydroxycotinine glucuronidation and UGT genotypes.

Methods

Participants [Caucasians (Whites), African Americans (Blacks) and Asian-Americans (Asians)] received an oral solution of deuterium-labeled nicotine and its metabolite cotinine. Plasma and saliva concentrations of nicotine and cotinine were used to determine oral clearances. Rates of glucuronidation were assessed from urine glucuronide/parent ratios, and UGT2B10 and UGT2B17 genotypes from DNA.

Results

Among the 227 participants, 96 (42%) were White, 67 (30%) Asian and 64 (28%) Black. Compared to the other two races, Whites had higher nicotine and cotinine total oral clearance, Blacks had lower nicotine and cotinine glucuronidation rates and Asians had lower 3′-hydroxycotinine glucuronidation rates. A strong positive correlation (correlations coefficients 0.77–0.84; P < 0.001) between NMR and nicotine oral clearance was found for all three races, and NMR remained a strong predictor for the nicotine oral clearance while adjusting for race, sex and age. Neither the metabolite glucuronidation ratios nor the UGT genotypes had significant effects on the ability of NMR to predict nicotine oral clearance.

Conclusion

NMR appears to be a reliable phenotypic biomarker for nicotine clearance across races, glucuronidation phenotypes and genotypes. Racial differences in the relationships between NMR, smoking behaviors and addiction are unlikely to be related to an inadequate estimation of nicotine clearance on the basis of NMR.
Influence of polymorphisms in anthracyclines metabolism genes in the standard induction chemotherapy of acute myeloid leukemia
Authors: Megías-Vericat Juan Eduardo , Martínez-Cuadrón David , Herrero María José , Rodríguez-Veiga Rebeca , Solana-Altabella Antonio , Boluda Blanca , Ballesta-López Octavio , Cano Isabel , Acuña-Cruz Evelyn , Cervera José , Poveda José Luis , Sanz Miguel Ángel , Aliño Salvador F. , Montesinos Pau
Published: March 2021

Objectives

Genetic variability in anthracycline metabolism could modify the response and safety of acute myeloid leukemia (AML) induction.

Methods

Polymorphisms in genes that encodes enzymes of anthracyclines metabolic pathway (CBR3: rs1056892, rs8133052, NQO1: rs1800566, NQO2: rs1143684, NOS3: rs1799983, rs2070744) were evaluated in 225 adult de novo AML patients.

Results

The variant CBR3 rs8133052 was associated with lower hepatotoxicity (P = 0.028). Wild-type genotype of NQO2 rs1143684 was related to higher complete remission (P = 0.014), and the variant allele with greater gastrointestinal toxicity (P = 0.024). However, the variant genotype of NQO1 rs1800566 was associated with mucositis (P = 0.018), but heterozygous genotype showed less gastrointestinal toxicity (P = 0.028) and thrombocytopenia (P = 0.009). Protective effects against nephrotoxicity and thrombocytopenia were reported with variant NOS3 rs1799983 (P = 0.006, P = 0.014), whereas carriers of NOS3 rs2070744 showed higher hepatotoxicity and thrombocytopenia (P = 0.017, P = 0.013).

Conclusions

This study supports the influence of genetic variability of idarubicin metabolizing could be critical in predicting anthracycline-induced toxicities.
An Evaluation Method for Meeting the Requirement of IEC 60825-1 Laser Safety Standard for Viewing Temporally-varied Radiant Power
Authors: Chen Chih-Hsiao , Hadi H.
Published: March 2021

There is no article discussing how to apply the International Electrotechnical Commission (EIC) 60825-1 standard to evaluate laser safety for irregular non-pulsed signal. Yet, as more and more laser applications are introduced, it is very possible that laser radiant power is irregular non-pulsed signal. Here, we present a method of laser safety evaluation for thermal damage under Requirement 3 of the IEC 60825-1 standard.
A Scoping Review of Process Indicators for Measuring Quality of Care in Glaucoma
Authors: Iorio-Aranha Flavio , Peleteiro Bárbara , Rocha-Sousa Amândio , Azevedo Ana , Barbosa-Breda João
Published: March 2021

Précis:

There are no standardized process quality indicators (QIs) in glaucoma care. Although they can be inferred from guidelines and trials, they should be designed and standardized to allow better assessment of the quality of care.

Purpose:

QIs are crucial for assessing the performance of any health care system. To allow efficiency, effectiveness, and patient-centeredness, there is a need for prompt acquisition of up-to-date information. Among the available QIs, process indicators have the highest sensitivity to frequent changes and could better reflect the implementation outcomes of novel ideas and technology. This study aimed to map the available information regarding process QIs in glaucoma care, identify the current development stage of these indicators, and systematically synthesize them.

Materials and Methods:

We performed a scoping review of 4 electronic bibliographic databases for studies reporting on process QIs in glaucoma. We retrieved 7502 references and created a domain list reflecting the core idea underlying each indicator.

Results:

We summarized information from 18 documents and listed 20 domains. The most mentioned domains were follow-up, optic nerve head assessment, visual field test, and intraocular pressure. Indicators regarding the quality of life assessment, patient assistance, or presence of written protocols were less frequently mentioned.

Conclusions:

There are notable variations among process QIs in glaucoma and significant heterogeneity in their descriptions in published studies. Although novel indicators can be inferred from guidelines and trials, they should be designed and standardized for better assessment of performance in health systems to improve their quality.
The Effect of Medical Lowering of Intraocular Pressure on Peripapillary and Macular Blood Flow as Measured by Optical Coherence Tomography Angiography in Treatment-naive Eyes
Authors: Liu Chang , Umapathi Ruthra M. , Atalay Eray , Schmetterer Leopold , Husain Rahat , Boey Pui Yi , Aung Tin , Nongpiur Monisha E.
Published: March 2021

Précis:

Reduction of intraocular pressure (IOP) by latanoprost in treatment-naive eyes is significantly correlated to an increase in vessel density (VD) at the optic nerve head (ONH).

Purpose:

To evaluate the effect of topical latanoprost on ocular microvasculature using optical coherence tomography angiography (OCTA).

Patients and Methods:

In this prospective case-control study, 26 eyes from 18 treatment-naive subjects in whom prostaglandin analogue (PGA) latanoprost 0.005% was initiated were included as cases. In 10 out of the 18 subjects, medication was initiated in only 1 eye; their contralateral untreated eyes were used as controls. OCTA (AngioVue, Optovue Inc., Fremont, CA) was performed at baseline and ≥3 weeks after commencing treatment. Main outcome measures were change in flow area and VD at the ONH, radial peripapillary capillaries (RPC), and macula. Comparison between the 2 visits was performed using a linear mixed model adjusted for intereye correlation and mean ocular perfusion pressure.

Results:

IOP decreased by 26.1%±11.3% (P<0.001) in the cases and 0.18%±12.2% (P=0.63) in controls. Significant correlations between change in IOP and change in ONH VD (correlation coefficient [r]=−0.42, P=0.04), and between change in IOP and change in RPC VD (r=−0.48, P=0.02) were observed in the cases, whereas none were observed in the controls. When multiple testing was considered, no significant changes in flow area and VD were observed in cases and controls.

Conclusions:

The reduction of IOP by a PGA in treatment-naive eyes was significantly correlated to the increase in ONH VD and RPC VD. This may indicate a mechanism by which IOP reduction modulates the risk of glaucoma progression by improving ocular microperfusion.
Capnocytophaga canimorsus Meningitis and Bacteremia Associated With Nivolumab Therapy
Authors: Mitra Subhashis , Kar Papia
Published: March 2021

Capnocytophaga canimorsus meningitis is rare, and only a few cases have been reported. We present a patient with metastatic lung cancer receiving nivolumab who developed C. canimorsus meningitis with concurrent bacteremia. Timely diagnosis and appropriate treatment were associated with a favorable outcome. To our knowledge, this is the first case of invasive C. canimorsus infection in the setting of nivolumab therapy.
Identification of Stenotrophomonas maltophilia in Blood Cultures by Fluorescence in Situ Hybridization
Authors: Asaadi Hanieh , Tajbakhsh Saeed , Naeimi Behrouz , Gharibi Omid
Published: March 2021

Background

Stenotrophomonas maltophilia is a serious causative agent for bacteremia. Rapid identification of S. maltophilia in blood cultures is important to enable a satisfactory pathogen-based antibiotic therapy at an early stage. The aim of this study was to evaluate fluorescence in situ hybridization (FISH) for the identification of S. maltophilia in blood culture specimens.

Methods

Three hundred positive blood culture specimens were examined by both FISH and conventional laboratory methods for the identification of S. maltophilia. The results of FISH were compared with the results of the conventional methods.

Results

By conventional cultural and biochemical methods, S. maltophilia was identified in 47 blood culture specimens. Fluorescence in situ hybridization identified S. maltophilia in 46 of these 47 S. maltophilia–positive blood cultures. Thus, the sensitivity and specificity of FISH were 97.9% and 100%, respectively.

Conclusions

Our findings suggest that FISH is a suitable method for the identification of S. maltophilia in blood cultures.
Consensus on the Diagnosis and Treatment of Vitiligo in China (2021 Revision)#
Authors: Lei Tie-Chi , Xu Ai-E , Gao Tian-Wen , He Li , Gu Hua , Li Ming , Li Tie-Nan , Li Chun-Ying , Lin Tong , Mu Kuan-Hou , Tu Chai-Xia , Wen Hai , Wu Ji-Yuan , Zhang Jun-Ling , Zhen Zhi-Zhong
Published: March 2021

Vitiligo is a common depigmented skin disease that negatively affects the physical and mental health of patients. The 2018 version of the Vitiligo Treatment Consensus has been updated based on the research progress on vitiligo in the past 3 years in combination with the clinical experiences of experts. The newly revised points include maintenance therapy, early glucocorticoid intervention, and oral mini-pulsed glucocorticoid administration protocols. The prospect of using JAK inhibitors in the treatment of vitiligo is also discussed.
Qualitative Study on the Acceptability of and Adherence to a Vaginal Ring for HIV Prophylaxis Among Adolescent Girls
Authors: Baker Zoë , Javanbakht Marjan , Moore Janell , Brosnan Hannah , Squires Kathleen , Bunge Katherine , Zimet Gregory , Mensch Barbara , Soto-Torres Lydia , Kapogiannis Bill , Levy Lisa , Hoesley Craig , Reirden Daniel , Gaur Aditya , Mayer Kenneth , Futterman Donna , Gorbach Pamina
Published: March 2021

Objective:

This study aims to assess the product-related, relationship-related, and sex-related factors that act as facilitators and barriers to the acceptability of a vaginal ring (VR) for HIV prevention among adolescent girls.

Design:

Qualitative study.

Methods:

Ninety-six girls aged 15–17 years from 6 urban US sites were enrolled in MTN-023/IPM 030, a 24-week randomized controlled trial, for assessing the safety and acceptability of a dapivirine VR for HIV prevention. At week 24, 21 girls were randomly selected to participate in in-depth interviews. Interviews were transcribed verbatim and data analyzed using a thematic analysis approach. Facilitators and barriers to VR acceptability related to participants' relationships, sexual activity, and characteristics of the VR product were identified.

Results:

Factors related to relationships rarely seemed to act as barriers to VR acceptability; most participants disclosed VR use to sexual partners, and positive reactions from sexual partners, which were common, seemed to facilitate VR acceptability. Emotional and/or physical discomfort surrounding VR use during sex was mentioned occasionally as a barrier to VR acceptability. Product characteristics were most frequently mentioned as barriers to VR acceptability. Many participants reported concerns about the large size of the VR on first impression. Although most found the VR comfortable, some reported pain with VR insertion. Several participants were concerned about VR cleanliness, particularly during menstruation.

Conclusion:

Product considerations, specifically size and use during menstruation, were the most commonly reported barriers to VR acceptability in this study. Adolescent girls may require additional counseling to assuage product concerns regarding a VR for HIV prevention.
State of Recovery 6 Months After Rectal Cancer Surgery
Authors: Jakobsson Jenny
Published: March 2021

Rectal cancer surgery has developed to be highly technological and precise. Nevertheless, postoperative symptoms can affect patients for a long time after surgery and might also be persistent. The purpose of this study was to describe the level of postoperative symptoms 6 months after rectal cancer surgery as well as differences in symptoms with regard to surgical procedure. Data from 117 patients recovering from rectal cancer surgery were collected 6 months after surgery using the Postoperative Recovery Profile (PRP) questionnaire measuring self-reported postoperative symptoms. Results showed that the majority of patients had no or mild problems with the 19 symptoms recorded in the questionnaire. There was a significant difference between surgical procedures: patients after anterior resection experienced mild problems in gastrointestinal function (physical domain) and interest in their surroundings (social domain), whereas most patients after abdominoperineal resection and abdominoperineal resection with myocutaneous flap showed no problems. In all groups, a considerably high proportion of patients reported severe problems in sexual activity (physical domain). Findings in this study emphasize that healthcare professionals should pay attention to patients recovering from anterior resection especially regarding problems in the gastrointestinal function. Moreover, there is a need to acknowledge eventual sexual dysfunctions in all rectal cancer patients.
Usefulness of Controlled Attenuation Parameter and Liver Stiffness Measurement for the Identification of Extended-criteria Donors and Risk-assessment in Liver Transplantation
Authors: Duarte-Rojo Andres , Heimbach Julie K. , Borja-Cacho Daniel , Barone Gary W. , Shaheen Mohammed F. , Lamps Laura W. , Graham Rondell P. , Tan Ek Khoon , Concepcion Waldo , Kim W. Ray
Published: March 2021

Background.

Controlled attenuation parameter (CAP) and liver stiffness measurement (LSM) are noninvasive surrogates for hepatic steatosis and fibrosis, respectively, and could help identify extended criteria donors in liver transplantation (LT). We aimed to determine the accuracy of CAP/LSM in deceased donors along with post-LT changes.

Methods.

Accuracy of preprocurement CAP/LSM to grade/stage steatosis/fibrosis was determined using liver biopsy as reference. Transplant outcomes, including primary nonfunction (PNF) and early allograft dysfunction, were recorded. Recipients underwent CAP/LSM as outpatients. Areas under the receiver operating characteristic curve and regression models were constructed to analyze data.

Results.

We prospectively evaluated 160 allografts (138 transplanted). Same-probe paired baseline/post-LT CAP was 231 dB/m (181–277)/225 (187–261) (P = 0.61), and LSM 7.6 kPa (6.3–10.8)/5.9 (4.6–8.7) (P = 0.002), respectively. CAP reading was affected by BMI and LSM by ALT, race and bilirubin. Although CAP did not correlate with steatosis from frozen sections (ρ = 0.08, P = 0.47), it correlated with steatosis from permanent sections (ρ = 0.32, P < 0.001) and with oil red O histomorphometry (ρ = 0.35, P = 0.001). CAP identified moderate-to-severe steatosis with an areas under the receiver operating characteristic curve curve of 0.79 (0.66–0.91), for a negative predictive value of 100% at a cutoff value of 230 dB/m. LSM correlated with fibrosis staging (ρ = 0.22, P = 0.007) and it identified discarded allografts with advanced fibrosis/cirrhosis. Patients with no to minimal fibrosis had an LSM of 7.6 (6–10.1) kPa.

Conclusions.

Our results are proof-of-concept of the utility of CAP/LSM during organ procurement. Establishing the precise role of these noninvasive tools in the organ allocation process mandates confirmatory studies.
Psychosocial Evaluation of Candidates for Solid Organ Transplantation
Authors: Bailey Pippa , Vergis Nikhil , Allison Michael , Riddell Amy , Massey Emma
Published: March 2021

Transplant candidates should undergo an assessment of their mental health, social support, lifestyle, and behaviors. The primary aims of this “psychosocial evaluation” are to ensure that transplantation is of benefit to life expectancy and quality of life, and to allow optimization of the candidate and transplant outcomes. The content of psychosocial evaluations is informed by evidence regarding pretransplant psychosocial predictors of transplant outcomes. This review summarizes the current literature on pretransplant psychosocial predictors of transplant outcomes across differing solid organ transplants and discusses the limitations of existing research. Pretransplant depression, substance misuse, and nonadherence are associated with poorer posttransplant outcomes. Depression, smoking, and high levels of prescription opioid use are associated with reduced posttransplant survival. Pretransplant nonadherence is associated with posttransplant rejection, and nonadherence may mediate the effects of other psychosocial variables such as substance misuse. There is evidence to suggest that social support is associated with likelihood of substance misuse relapse after transplantation, but there is a lack of consistent evidence for an association between social support and posttransplant adherence, rejection, or survival across all organ transplant types.

Psychosocial evaluations should be undertaken by a trained individual and should comprise multiple consultations with the transplant candidate, family members, and healthcare professionals. Tools exist that can be useful for guiding and standardizing assessment, but research is needed to determine how well scores predict posttransplant outcomes. Few studies have evaluated interventions designed to improve psychosocial functioning specifically pretransplant. We highlight the challenges of carrying out such research and make recommendations regarding future work.
Secondary Endothelial Keratoplasty—A Narrative Review of the Outcomes of Secondary Corneal Endothelial Allografts
Authors: Moura-Coelho Nuno , Cunha João Paulo , Morral Merce , Gris Oscar , Manero Felicidad , Güell José Luis
Published: March 2021

Background.

We review the literature on the efficacy and safety outcomes of secondary Descemet stripping endothelial keratoplasty (DSEK) and Descemet membrane endothelial keratoplasty (DMEK).

Methods.

Literature search of English-written publications up to September 27, 2020 in PubMed database, using the terms “endothelial keratoplasty” in combination with keywords “secondary” or “repeat.” In addition, we manually searched the references of the primary articles.

Results.

Twenty-seven studies (n = 651 eyes) were retained and reviewed, including 10 studies on repeat DSEK, 8 studies on repeat DMEK, 6 studies of DMEK following DSEK, and 3 studies of DSEK after failed DMEK. All studies reported significant improvement in visual acuity after secondary endothelial keratoplasty (EK). Twelve studies compared visual outcomes between primary and secondary EK, reporting conflicting findings. Sixteen studies reported endothelial cell loss rates after secondary EK, and only 1 study reported significantly increased endothelial cell loss rates compared with primary EK. Allograft rejection episodes occurred in 1.8% of eyes (range, 0%–50%). Six studies compared complication rates between primary and secondary EK eyes, and only 1 study found a higher median number of complications. However, 2 studies reported higher regraft failure rates compared with primary EK eyes.

Conclusions.

Secondary EK is surgically feasible and renders significant visual improvement after failed primary EK, although it is not clear whether visual outcomes and allograft survival are comparable with primary EK, raising the question of whether secondary EK eyes are “low risk” as primary EK eyes. Further larger, prospective studies are encouraged to obtain additional quality data on secondary corneal endothelial allotransplantation.
Analysis of SARS-CoV-2 Mutations Over Time Reveals Increasing Prevalence of Variants in the Spike Protein and RNA-Dependent RNA Polymerase
Authors: Showers William M. , Leach Sonia M. , Kechris Katerina , Strong Michael
Published: March 2021

Amid the ongoing COVID-19 pandemic, it has become increasingly important to monitor the mutations that arise in the SARS-CoV-2 virus, to prepare public health strategies and guide the further development of vaccines and therapeutics. The spike (S) protein and the proteins comprising the RNA-Dependent RNA Polymerase (RdRP) are key vaccine and drug targets, respectively, making mutation surveillance of these proteins of great importance.

Full protein sequences for the spike proteins and RNA-dependent RNA polymerase proteins were downloaded from the GISAID database, aligned, and the variants identified. Polymorphisms in the protein sequence were investigated at the protein structural level and examined longitudinally in order to identify sequence and strain variants that are emerging over time. Our analysis revealed a group of variants in the spike protein and the polymerase complex that appeared in August, and account for around five percent of the genomes analyzed up to the last week of October. A structural analysis also facilitated investigation of several unique variants in the receptor binding domain and the N-terminal domain of the spike protein, with high-frequency mutations occurring more commonly in these regions. The identification of new variants emphasizes the need for further study on the effects of these mutations and the implications of their increased prevalence, particularly as these mutations may impact vaccine or therapeutic efficacy.
Monitoring deep-tissue oxygenation with a millimeter-scale ultrasonic implant
Authors: Sonmezoglu Soner , Fineman Jeffrey R. , Maltepe Emin , Maharbiz Michel M.
Published: March 2021

Deep tissue oxygenation monitoring has many potential applications. Vascular complications after solid organ transplantation, for example, frequently lead to graft ischemia, dysfunction or loss, and can occur months after transplantation. While imaging approaches can provide intermittent assessments of graft perfusion, they require highly skilled practitioners, and fail to directly assess graft oxygenation. Existing tissue oxygen monitoring systems have many drawbacks, including the need for wired connections, the inability to provide real-time data, and, crucially, an operation that is limited to surface tissues. Here, we present the first wireless, minimally-invasive deep tissue oxygen monitoring system that provides continuous real-time data from centimeter-scale depths in a clinically-relevant large animal (sheep) model and demonstrates operation at great depths (up to 10 cm) throughex vivoporcine tissue. The system relies on a millimeter-sized, wireless, battery-free, implantable luminescence oxygen sensor that is powered by ultrasound and capable of bi-directional data transfer with an external transceiver. We present various aspects of system and sensor performance and demonstrate the operation of the systemin vitroin distilled water, phosphate-buffered saline (PBS) and undiluted human serum,ex vivothrough porcine tissue, andin vivoin a sheep model. We believe this technology represents a new class of diagnostic system particularly suitable for organ monitoring, as well as other surgical or critical care indications.
The ketogenic diet preserves skeletal muscle with aging in mice
Authors: Wallace Marita A. , Aguirre Nicholas W. , Marcotte George R. , Marshall Andrea G. , Baehr Leslie M. , Hughes David C. , Hamilton Karyn L. , Roberts Megan N. , Lopez‐Dominguez Jose Alberto , Miller Benjamin F. , Ramsey Jon J. , Baar Keith
Published: March 2021

The causes of the decline in skeletal muscle mass and function with age, known as sarcopenia, are poorly understood. Nutrition (calorie restriction) interventions impact many cellular processes and increase lifespan and preserve muscle mass and function with age. As we previously observed an increase in life span and muscle function in aging mice on a ketogenic diet (KD), we aimed to investigate the effect of a KD on the maintenance of skeletal muscle mass with age and the potential molecular mechanisms of this action. Twelve‐month‐old mice were assigned to an isocaloric control or KD until 16 or 26 months of age, at which time skeletal muscle was collected for evaluating mass, morphology, and biochemical properties. Skeletal muscle mass was significantly greater at 26 months in the gastrocnemius of mice on the KD. This result in KD mice was associated with a shift in fiber type from type IIb to IIa fibers and a range of molecular parameters including increased markers of NMJ remodeling, mitochondrial biogenesis, oxidative metabolism, and antioxidant capacity, while decreasing endoplasmic reticulum (ER) stress, protein synthesis, and proteasome activity. Overall, this study shows the effectiveness of a long‐term KD in mitigating sarcopenia. The diet preferentially preserved oxidative muscle fibers and improved mitochondrial and antioxidant capacity. These adaptations may result in a healthier cellular environment, decreasing oxidative and ER stress resulting in less protein turnover. These shifts allow mice to better maintain muscle mass and function with age.
Biological significance of KRAS mutant allele expression in ovarian endometriosis
Authors: Yachida Nozomi , Yoshihara Kosuke , Suda Kazuaki , Nakaoka Hirofumi , Ueda Haruka , Sugino Kentaro , Yamaguchi Manako , Mori Yutaro , Yamawaki Kaoru , Tamura Ryo , Ishiguro Tatsuya , Kase Hiroaki , Motoyama Teiichi , Enomoto Takayuki
Published: March 2021

KRAS is the most frequently mutated in ovarian endometriosis. However, it is unclear whether the KRAS mutant allele's mRNA is expressed and plays a biological role in ovarian endometriosis. Here, we performed mutation‐specific RNA in situ hybridization to evaluate mutant allele expression of KRAS p.G12V, the most frequently detected mutation in ovarian endometriosis in our previous study, in formalin‐fixed paraffin‐embedded tissue (FFPE) samples of ovarian endometriosis, cancer cell lines, and ovarian cancers. First, we verified that mutant or wild‐type allele of KRAS were expressed in all 5 cancer cell lines and 9 ovarian cancer cases corresponding to the mutation status. Next, we applied this assay to 26 ovarian endometriosis cases, and observed mutant allele expression of KRAS p.G12V in 10 cases. Mutant or wild‐type allele of KRAS were expressed in line with mutation status in 12 available endometriosis cases for which KRAS gene sequence was determined. Comparison of clinical features between ovarian endometriosis with KRAS p.G12V mutant allele expression and with KRAS wild‐type showed that KRAS p.G12V mutant allele expression was significantly associated with inflammation in ovarian endometriosis. Finally, we assessed the spatial distribution of KRAS mutant allele expression in 5 endometriosis cases by performing multiregional sampling. Intratumor heterogeneity of KRAS mutant allele expression was observed in two endometriosis cases, whereas the spatial distribution of KRAS p.G12V mutation signals were diffuse and homogenous in ovarian cancer. In conclusion, evaluation of oncogene mutant expression will be useful for clarifying the biological significance of oncogene mutations in benign tumors.
Reciprocal microbiome transplants differentially rescue fitness in two syntopic dung beetle sister species (Scarabaeidae: Onthophagus)
Authors: Parker Erik S. , Moczek Armin P. , Macagno Anna L. M.
Published: March 2021

1. Microbial symbionts play a crucial role in the development, health, and homeostasis of their hosts. However, the eco‐evolutionary conditions shaping these relationships and the evolutionary scale at which host–microbiome interactions may diverge warrant further investigation, especially in non‐model systems. This study examines the impact of reciprocal gut microbiome transplants between two ecologically very similar, sympatric, and syntopic dung beetle sister species.

2. Onthophagus vacca and Onthophagus medius were specifically used to compare the growth, development, and fitness outcomes of individuals that were either (i) reared in the presence of a microbiome provided by a mother of the same species (“self‐inoculated”), (ii) forced to develop with a microbiome derived from a heterospecific mother (“cross‐inoculated”), or (iii) reared without a maternally transmitted microbiome.

3. This study found that individuals reared in the absence of a maternally derived gut microbiome incur detrimental changes in survival, as well as in several metrics signalling normative development. Furthermore, such negative effects are only partly rescued through inoculation with a heterologous microbiome.

4. Collectively, this study's results suggest that inoculation with a species‐specific, maternally transmitted microbiome is critical for normative development, that the significance of maternally derived microbiota for host survival differs across species, and that the phenotypic outcomes resulting from host–microbiome interactions may diverge even between closely related, ecologically similar host species.
Characterization of acute pain‐induced behavioral passivity in mice: Insights from statistical modeling
Authors: Yeung Sung Ching , Ganesan Kumar , Wong Stanley Sau Ching , Chung Sookja K. , Cheung Chi Wai
Published: March 2021

Affective‐motivational disturbances are highly inconsistent in animal pain models. The reproducibility of the open‐field test in assessing anxiety, malaise or disability remains controversial despite its popularity. While traumatic, persistent or multiregional pain models are commonly considered more effective in inducing negative affect or functional impairment, the early psychobehavioral changes before pain chronification are often underexplored. Here, we aimed to clarify the fundamental relationship between hypernociception and passive distress‐like behavior using a model of transient inflammatory pain. To minimize latent confounders and increase data consistency, male C57BL/6N mice were habituated to the open‐field arena 6 times before receiving the unilateral intraplantar injection of prostaglandin E2 (PGE2) or vehicle. Open‐field (40‐min exploration) and nociceptive behavior were evaluated repeatedly along the course of hypernociception in both wild‐type and transgenic mice with a known pronociceptive phenotype. To reduce subjectivity, multivariate open‐field behavioral outcomes were analyzed by statistical modeling based on exploratory factor analyses, which yielded a 2‐factor solution. Within 3 hr after PGE2 injection, mice developed significantly reduced center exploration (factor 1) and a marginally significant increase in their habituation tendency (factor 2), which were not apparent in vehicle‐injected mice. The behavioral passivity generally improved as hypernociception subsided. Therefore, transient inflammatory irritation is sufficient to suppress mouse open‐field exploratory activity. The apparent absence of late affective‐motivational changes in some rodents with prolonged hypernociception may not imply a lack of preceding or underlying neuropsychological alterations. Procedural pain after invasive animal experiments, however small, should be assessed and adequately controlled as a potential research confounder.
Speech auditory‐motor adaptation to formant‐shifted feedback lacks an explicit component: Reduced adaptation in adults who stutter reflects limitations in implicit sensorimotor learning
Authors: Kim Kwang S. , Max Ludo
Published: March 2021

The neural mechanisms underlying stuttering remain poorly understood. A large body of work has focused on sensorimotor integration difficulties in individuals who stutter, including recently the capacity for sensorimotorlearning. Typically, sensorimotor learning is assessed with adaptation paradigms in which one or more sensory feedback modalities are experimentally perturbed in real time. Our own previous work on speech with perturbed auditory feedback revealed substantial auditory‐motor learning limitations in both children and adults who stutter (AWS). It remains unknown, however, which subprocesses of sensorimotor learning are impaired. Indeed, new insights from research on upper limb motor control indicate that sensorimotor learning involves at least two distinct components: (a) an explicit component that includes intentional strategy use and presumably is driven by target error and (b) an implicit component that updates an internal model without awareness of the learner and presumably is driven by sensory prediction error. Here, we attempted to dissociate these components for speech auditory‐motor learning in AWS versus adults who do not stutter (AWNS). Our formant‐shift auditory‐motor adaptation results replicated previous findings that such sensorimotor learning is limited in AWS. Novel findings are that neither control nor stuttering participants reported any awareness of changing their productions in response to the auditory perturbation and that neither group showed systematic drift in auditory target judgments made throughout the adaptation task. These results indicate that speech auditory‐motor adaptation to formant‐shifted feedback relies exclusively on implicit learning processes. Thus, limited adaptation in AWS reflects poor implicit sensorimotor learning. Speech auditory‐motor adaptation to formant‐shifted feedback lacks an explicit component: Reduced adaptation in adults who stutter reflects limitations in implicit sensorimotor learning.
Plantar flexor muscle stretching depresses the soleus late response but not tendon tap reflexes
Authors: Pulverenti Timothy S. , Trajano Gabriel S. , Kirk Benjamin J. C. , Bochkezanian Vanesa , Blazevich Anthony J.
Published: March 2021

The purpose of this study was to investigate changes in muscle spindle sensitivity with early and late soleus reflex responses via tendon taps and transcranial magnetic stimulation, respectively, after an acute bout of prolonged static plantar flexor muscle stretching. Seventeen healthy males were tested before and after 5 min (5 × 60‐s stretches) of passive static stretching of the plantar flexor muscles. Maximal voluntary isometric torque and M wave‐normalized triceps surae muscle surface electromyographic activity were recorded. Both soleus tendon reflexes, evoked by percussion of the Achilles tendon during rest and transcranial magnetic stimulation‐evoked soleus late responses during submaximal isometric dorsiflexion were also quantified. Significant decreases in maximal voluntary isometric plantar flexion torque (−19.2 ± 13.6%, p = .002) and soleus electromyographic activity (−20.1 ± 11.4%, p < .001) were observed immediately after stretching, and these changes were highly correlated (r = 0.76, p < .001). No changes were observed in tendon reflex amplitude or latency or peak muscle twitch torque (p > .05). Significant reductions in soleus late response amplitudes (−46.9 ± 36.0%, p = .002) were detected, although these changes were not correlated with changes in maximal electromyographic activity, torque or tendon reflex amplitudes. No changes in soleus late response latency were detected. In conclusion, impaired neural drive was implicated in the stretch‐induced force loss; however, no evidence was found that this loss was related to changes in muscle spindle sensitivity. We hypothesize that the decrease in soleus late response indicates a stretch‐induced reduction in a polysynaptic postural reflex rather than spindle reflex sensitivity.
The evolutionary dynamics of biological invasions: A multi‐approach perspective
Authors: Sherpa Stéphanie , Després Laurence
Published: March 2021

Biological invasions, the establishment and spread of non‐native species in new regions, can have extensive economic and environmental consequences. Increased global connectivity accelerates introduction rates, while climate and land‐cover changes may decrease the barriers to invasive populations spread. A detailed knowledge of the invasion history, including assessing source populations, routes of spread, number of independent introductions, and the effects of genetic bottlenecks and admixture on the establishment success, adaptive potential, and further spread, is crucial from an applied perspective to mitigate socioeconomic impacts of invasive species, as well as for addressing fundamental questions on the evolutionary dynamics of the invasion process. Recent advances in genomics together with the development of geographic information systems provide unprecedented large genetic and environmental datasets at global and local scales to link population genomics, landscape ecology, and species distribution modeling into a common framework to study the invasion process. Although the factors underlying population invasiveness have been extensively reviewed, analytical methods currently available to optimally combine molecular and environmental data for inferring invasive population demographic parameters and predicting further spreading are still under development. In this review, we focus on the few recent insect invasion studies that combine different datasets and approaches to show how integrating genetic, observational, ecological, and environmental data pave the way to a more integrative biological invasion science. We provide guidelines to study the evolutionary dynamics of invasions at each step of the invasion process, and conclude on the benefits of including all types of information and up‐to‐date analytical tools from different research areas into a single framework.
Changes in body composition and low blood urea nitrogen level related to an increase in the prevalence of fatty liver over 20 years: A cross‐sectional study
Authors: Imamura Yasushi , Mawatari Seiichi , Oda Kohei , Kumagai Kotaro , Hiramine Yasunari , Saishoji Akiko , Kakihara Atsuko , Nakahara Mai , Oku Manei , Hosoyamada Kaori , Kanmura Shuji , Moriuchi Akihiro , Miyahara Hironori , Akio ido
Published: March 2021

Aim

Qualitative body composition (BC) change, characterized by the combination of visceral fat gain and muscle loss, is drawing attention as a risk factor for fatty liver (FL). The present study aimed to describe trends in BC change and its association with FL in the Japanese population.

Methods

Data from medical checkups carried out on 56 639 Japanese participants every 5 years from 1997 to 2017 were analyzed. Fat mass index (FMI) and fat‐free mass index (FFMI) were calculated using body mass index and body fat percentage. Subjects were divided into two groups according to deviations from the correlation line of FMI and FFMI as the reference: FMI‐predominant BC and FFM‐dominant BC. Fatty liver was determined using abdominal ultrasonography.

Results

The prevalence of FL significantly increased from 27.3% to 42.7% in men and from 18.0% to 25.5% in women. The prevalence of FMI predominance significantly increased from 33.6% to 43.9% in men and from 29.1% to 47.0% in women. Fat mass index predominance was independently associated with FL in men and women (odds ratio: 1.96 and 1.94, respectively). Serum blood urea nitrogen level was inversely associated with FL in men and women (0.958 and 0.961, respectively) and significantly decreased from 15.8 to 14.9 mg/dl in men and from 15.1 to 14.0 mg/dl in women.

Conclusions

Increasing FMI‐predominant BC and decreasing serum blood urea nitrogen level could account for the increase in the prevalence of FL over 20 years. We believe that these factors stem from current lifestyle habits in Japan.