bluuebunny/crossref_metadata_2025 huggingface dataset:
MR-guided Cryoablation for the Treatment of Symptomatic Pedal Vascular Malformations
Authors: Knavel Koepsel Erica M. , Thompson Scott , Bendel Emily C. , Augustine Matthew , Tollefson Megha M. , Gorny Krzysztof R. , Lu Aiming , Favazza Christopher P. , Woodrum David A.
Published: December 2021

Objective:

Vascular malformations are benign vascular anomalies characterized by abnormally developed arterial, venous, and lymphatic structures, which are often symptomatic. Historical and current treatment techniques include intravascular embolization/sclerosis and surgical resection. While these techniques have proven to be successful at managing and treating these types of lesions, these techniques are not without risk, especially in the small spaces of the hands and feet. Cryoablation for the treatment of low-flow vascular malformations is a new and evolving technique. We present five cases of symptomatic pedal vascular malformations treated with MR guided cryoablation, which provides encouraging safety and feasibility results for these difficult to treat lesions.

Methods:

A retrospective review of patients who had undergone MR-guided cryoablation of their pedal vascular malformations between January 2016 and January 2020 was performed.

Results:

Five cryoablations were completed without immediate complication. All patients reported markedly decreased pain corresponding to the treated area and improvement in their ability to return to a more active lifestyle. Two patients experienced mild transient numbness which resolved by 2–3 months and one patient experienced a transient motor and sensory neuropathy which resolved by 6 months.

Conclusion:

We present five cases of successful MR-guided cryoablation of symptomatic pedal venous malformations. Many of the patients included in this review failed conservative and other interventional/surgical treatments. The treatment options for this patient cohort can be limited given small space within the plantar aspect of the foot. Cryoablation of these lesions can be performed safely especially under continuous MRI monitoring.

Level of Evidence: Case series (Level 4)
SARC-F and other screening tests for sarcopenia
Authors: Bahat Gülistan , Erdoğan Tuğba , İlhan Birkan
Published: December 2021

Purpose of review

Sarcopenia screening tools can enable clinicians to select individuals for more demanding evaluations, and hence, may facilitate its timely diagnosis and management. The most common recommended screening test is SARC-F, whereas many others are proposed. We aimed to summarize the recent studies and evidence performed on SARC-F and other sarcopenia screening tools.

Recent findings

Meta-analysis studies reported that despite having moderate-high specificity, SARC-F has low-moderate sensitivity to detect sarcopenia, which would cause a significant number of individuals having sarcopenia to be unrecognized. Several recent studies aimed to increase sensitivity and utility of SARC-F as a screening tool by i.e., application of lower cut-offs, adding extra-items, and combining with other screening tests. Some of these approaches increased its screening efficacy significantly. In line with its previous studies, SARC-F showed success to predict adverse outcomes in the latest studies as well. Recently, it has also been suggested as a reasonable screening test for frailty. In addition to the long-standing screening tests i.e., anthropometric measures, Ishii Test and Mini Sarcopenia Risk Assessment (MSRA) Questionnaire; new tests, i.e., Taiwan Risk Score for Sarcopenia, Sarcopenia Scoring Assessment Model (SarSA-Mod) and re-purposed tests, i.e., SARQoL questionnaire and fracture risk assessment tool have been investigated as potential screening tests for sarcopenia. Some of these tests performed as well as or superior to standard SARC-F.

Screening of sarcopenia is critical for public health given its significant prevalence and adverse outcomes. SARC-F is the most recommended tool for screening but has low-moderate sensitivity. Studies performed recently indicate that its sensitivity can be increased by some attempts and it may be used as a reasonable test to screen frailty as well. Some other tests have also been developed/re-purposed for an efficient screening, needing to be tested for their performance and usability with future studies in different populations and settings.
Successful treatment using immunotherapy in combination with chemotherapy for metastatic squamous cell carcinoma of unknown primary origin with bulky abdominal mass
Authors: Zhang Min , Zhao Meng , Jin Li-fang , Shen Wei-zhang
Published: December 2021

Rationale:

Cancer of unknown primary (CUP) means that the primary focus cannot be found after preliminary clinical evaluation. It accounts for 2.3% to 5% of newly diagnosed cancer cases. Due to the lack of standard treatment, CUP is usually associated with poor prognosis and is the third to fourth most common cause of cancer-related deaths.

Patient concerns:

We report the case of a 42-year-old female patient who was admitted to the hospital for intermittent right abdominal pain and abdominal distension. Abdominal computed tomography (CT) showed a large abdominal mass of unknown origin, which was difficult to resect due to its close relationship with surrounding tissues. Twenty days later, the patient had enlarged left supraclavicular lymph nodes, and percutaneous biopsy revealed squamous cell carcinoma. In addition, next-generation sequencing (NGS) of tissue and blood samples showed immune-related mutations and PD-L1 expression.

Diagnoses:

The patient was diagnosed with metastatic squamous cell carcinoma of unknown primary origin, with a bulky abdominal mass.

Interventions:

The patient was treated with carboplatin, albumin-binding paclitaxel, and immune checkpoint inhibitor (carilizumab). After 6 cycles, the patient was switched to maintenance treatment with carilizumab.

Outcomes:

The general condition of the patient improved, and the lesion was significantly reduced. The treatment efficacy was assessed as partial remission according to Response Evaluation Criteria in Solid Tumors. The patient benefited from immunotherapy combined with chemotherapy.

Lessons:

There is no recommended standard treatment for most CUPs, which leads to their poor prognoses. By performing NGS for patients and targeting immune-related positive predictors, immunotherapy combined with chemotherapy may prolong the overall survival of patients. This case report suggests that immunotherapy combined with chemotherapy is feasible and effective in patients with CUP.
Assessing aCCess to Investigations in Inflammatory Bowel Disease (ACCID): results from an international survey
Authors: Ding Nik S. , Lee Tanya , Bettenworth Dominik , Cleynen Isabelle , Yassin Nuha A. , Burisch Johan , Armuzzi Alessandro , Ferrante Marc , Zagorowicz Edyta , Mansfield John , Gesce Krisztina , Gisbert Javier P. , Raine Timothy
Published: December 2021

Background

Multiple investigations are available to aid the diagnosis and monitoring of disease activity in inflammatory bowel disease (IBD). Fecal calprotectin (FC) is an established surrogate for intestinal inflammatory activity. Therapeutic drug monitoring (TDM) including thiopurine metabolites, anti-tumor necrosis factor (TNF) levels and antidrug antibody measurements are a step toward personalized medicine in IBD, but face access barriers. We aimed to assess test availability and barriers for these investigations in European practice.

Methods

Five-hundred questionnaires were distributed to workshop participants at the 11th Congress of the European Crohn’s and Colitis Organisation (ECCO). Access to FC, TDM for thiopurines and anti-tumor necrosis factor agents, as well as factors associated with usage and barriers to access were recorded.

Results

Responses were obtained from 195 attendees from 38 countries across a range of practices, healthcare settings and levels of experience. FC was available to 92.3% while access to anti-TNF (78.9%, P = 0.02 vs.  thiopurine TDM, P = 0.0002 vs.  FC) and thiopurine TDM (67.7%, P = 0.0001) were less widespread. Cost was a frequently cited barrier to test access or usage, with access having a significant West–East and North–South divide across all three investigations. The strongest independent predictor of access to all tests was healthcare spending per capita (P = 0.005 for FC; P < 0.0001 for both TDM).

Conclusion

FC, anti-TNF and thiopurine TDM are increasingly incorporated as part of routine practice in IBD care across Europe and have the potential to impact positively on patient care. However, access barriers remain of which we found test cost the most significant with the investment required to reduce these barriers.
Effects of naringenin supplementation on cardiovascular risk factors in overweight/obese patients with nonalcoholic fatty liver disease: a pilot double-blind, placebo-controlled, randomized clinical trial
Authors: Naeini Fatemeh , Namkhah Zahra , Tutunchi Helda , Rezayat Seyed Mahdi , Mansouri Siavash , Yaseri Mehdi , Hosseinzadeh-Attar Mohammad Javad
Published: December 2021

Objective

Although several experimental models have suggested promising pharmacological effects of naringenin in the management of obesity and its related disorders, the effects of naringenin supplementation on cardiovascular disorders as one of the main complications of nonalcoholic fatty liver disease (NAFLD) are yet to be examined in humans.

Methods

In this double-blind, placebo-controlled, randomized clinical trial, 44 overweight/obese patients with NAFLD were equally allocated into either naringenin or placebo group for 4 weeks. Cardiovascular risk factors including atherogenic factors, hematological indices, obesity-related parameters, blood pressure, and heart rate were assessed pre- and postintervention.

Results

The atherogenic index of plasma value, serum non-HDL-C levels as well as total cholesterol/high-density lipoprotein cholesterol (HDL-C), triglyceride/HDL-C, low-density lipoprotein cholesterol/HDL-C, and non-HDL-C/HDL-C ratios were significantly reduced in the intervention group, compared to the placebo group post intervention (P < 0.05). Moreover, there was a significant reduction in BMI and visceral fat level in the intervention group when compared with the placebo group (P = 0.001 and P = 0.039, respectively). Furthermore, naringenin supplementation could marginally reduce systolic blood pressure (P = 0.055). Mean corpuscular hemoglobin increased significantly in the naringenin group compared to the placebo group at the endpoint (P = 0.023). Supplementation with naringenin also resulted in a marginally significant increase in the mean corpuscular hemoglobin concentration when compared with the placebo group (P = 0.050). There were no significant between-group differences for other study outcomes post intervention.

Conclusion

In conclusion, these data indicate that naringenin supplementation may be a promising treatment strategy for cardiovascular complications among NAFLD patients. However, further trials are warranted.
Safety of Irreversible Electroporation Ablation of the Pancreas
Authors: Lee Edward Wolfgang , Shahrouki Puja , Peterson Stephanie , Tafti Bashir A. , Ding Peng-Xu , Kee Stephen T.
Published: December 2021

Objectives

To evaluate the safety of irreversible electroporation (IRE) on swine pancreatic tissue including its effects on peripancreatic vessels, bile ducts, and bowel.

Methods

Eighteen Yorkshire pigs underwent IRE ablation of the pancreas successfully and without clinical complications. Contrast-enhanced computed tomography angiography and laboratory studies before the IRE ablation with follow-up computed tomography angiography, laboratory testing, and pathological examination up to 4 weeks postablation were performed.

Results

In a subset of cases, anatomic peripancreatic vessel narrowing was seen by 1 week postablation, persisting at 4 weeks postablation, without apparent functional impairment of blood flow. Laboratory studies revealed elevated amylase and lipase at 24 hours post-IRE, suggestive of acute pancreatitis, which normalized by 4 weeks post-IRE. There was extensive pancreatic tissue damage 24 hours after IRE with infiltration of immune cells, which was gradually replaced by fibrotic tissue. Ductal regeneration without loss of pancreatic acinar tissue and glandular function was observed at 1 and 4 weeks postablation.

Conclusions

In our study, we demonstrated and confirmed the safety and minimal complications of IRE ablation in the pancreas and its surrounding vital structures. These results show the potential of IRE as an alternative treatment modality in patients with pancreatic cancer, especially those with locally advanced disease.
Reduced Free Fatty Acid Receptor 4 Gene Expression is Associated With Extreme Obesity and Insulin Resistance in Children
Authors: Codoñer‐Alejos Alan , Carrasco‐Luna Joaquín , Carrasco‐García Álvaro , Codoñer‐Franch Pilar
Published: December 2021

Objectives:

Free fatty acid receptor 4 (FFAR4) is a G‐protein‐coupled membrane receptor highly expressed in macrophages that triggers anti‐inflammatory effects and promotes insulin sensitization. We have previously found significant associations between the FFAR4 rs11187533 single nucleotide polymorphism (SNP) and various obesity comorbidity parameters. We aimed to verify the FFAR4 expression levels in children with obesity and the associated comorbidities.

Methods:

Thirty‐eight children with obesity were studied. Clinical and anthropometric evaluation was performed. A venous sample under fasting conditions was obtained. Biochemical study included parameters of metabolic risk. DNA was extracted and genotyped for the rs11187533 FFAR4 SNP. Real‐time PCR technique was performed to investigate the gene expression. Relative FFAR4 mRNA levels were determined according to the 2−ΔΔCt method.

Results:

Significant differences in FFAR4 expression levels between the CC and CT‐TT genotypes of the rs11187533 FFAR4 SNP were observed (P = 0.034). The minor allele T presented higher levels of FFAR4 expression. We found that a loss of FFAR4 expression was associated with extreme obesity (P = 0.032). The lowest FFAR4 expression levels were observed in children who had higher insulin (P = 0.008) and homeostasis model assessment insulin resistance values (P = 0.012) and lower quantitative insulin‐sensitivity check index (P = 0.033).

Conclusions:

The underexpression of FFAR4 was associated with extreme obesity and parameters indicative of obesity comorbidities in children. This under expression could be partially influenced by the presence of the C allele rs11187533 FFAR4 SNP.
Clinical Implications for Children Developing Direct Hyperbilirubinemia on Extracorporeal Membrane Oxygenation
Authors: Alexander Erin , O'Sullivan Donnchadh , Aganga Devon , Hassan Sara , Ibrahim Samar H. , Absah Imad
Published: December 2021

Objective:

Extracorporeal membrane oxygenation (ECMO)‐associated direct hyperbilirubinemia (DHB) is likely multifactorial. The objective of this study is to assess the frequency and risk factors for developing direct hyperbilirubinemia while on ECMO, and its implication on the mortality of children.

Methods:

We performed a retrospective study between January 2010 and January 2020. Using Mayo Clinic electronic health record, we identified children (<18 years) who required veno‐arterial (VA) ECMO support. Demographics, ECMO indication, laboratory findings, and outcomes were abstracted. Illness acuity scores, including vasoactive‐ionotropic score (VIS), were used to assess disease severity at time of admission. Study cohort was divided into two groups: children who developed direct hyperbilirubinemia (DHB) on ECMO and children who did not (control). DHB was defined as direct bilirubin (DB) of >1.0 mg/dL. Disease acuity and mortality rates were compared between the two groups. Logistic regression was used to analyze the risk of mortality independent of potential confounding variables.

Results:

We identified 106 children who required ECMO support during the study period. Of those, 36 (34%) children developed DHB on ECMO. Illness acuity scores were significantly higher in the DHB group on ECMO day 2 (P = 0.046) and day 7 (P = 0.01). Mortality rate was higher in the DHB group 72%, versus 29% in the control group (P < 0.001).

Conclusion:

DHB was associated with a higher mortality rate than the control group.
Long‐Term Outcomes With Adalimumab Therapy in Pediatric Crohn Disease
Authors: Rinawi Firas , Popalis Cynthia , Tersigni Claudia , Frost Karen , Muise Aleixo , Church Peter C. , Walters Thomas D. , Ricciuto Amanda , Griffiths Anne M.
Published: December 2021

Background/Aims:

Pediatric Crohn disease (CD) treatment goals have evolved. Among children receiving adalimumab (ADA) we examined long‐term durability of clinical remission, linear growth, and associations of trough concentration (TC) with biomarker, endoscopic and imaging outcomes.

Methods:

Single‐center retrospective study. Pediatric CD activity index, C‐reactive protein, fecal calprotectin, and height measured longitudinally. Discontinuation due to secondary loss of response (LOR) was assessed using Cox proportional hazards model. Associations between TC and clinical and biomarker remission, endoscopic and magnetic resonance imaging (MRI) improvements were assessed using Cox regression with time‐dependent covariates.

Results:

Between January 2007 and June 2018, 213 children (median age 14.1 years (interquartile range [IQR] 12.5–15.7) 65% males) initiated ADA. One hundred and seventy‐four (82%) achieved clinical remission (PCDAI < 10). During 24.8 (IQR 15.6–38.4) months follow‐up, 26 (15%) discontinued ADA due to LOR, and 10 (6%) due to adverse events. Being anti‐tumor necrosis factor (TNF) naïve and inflammatory behavior associated with increased likelihood of clinical remission (odds ratio [OR] 2.39, P = 0.033, and 3.13, P = 0.013, respectively) and with decreased LOR (hazard ratio [HR] 0.3, P = 0.002, and HR 0.35, P = 0.01, respectively). Cumulative LOR among 135 anti‐TNF naïve patients: 0%, 8%, 15% within 1, 2, 3 years, similarly durable with mono‐ and immunomodulator combination therapy. Among pre‐/early pubertal children mean height (−0.82) normalized to −0.07. TC consistently >7.5 ug/mL was associated with durable clinical remission (HR = 17.24, P < 0.001); TC >10 ug/mL with durable biomarker remission (HR = 6.56, P < 0.001) and endoscopic (OR 10.4, P = 0.002) and MRI (OR 7.6, P = 0.001) improvements.

Conclusion:

ADA monotherapy maintains durable clinical remission. Biomarker remission, mucosal and transmural improvements were associated with greater ADA exposure.
Growth patterns of uninfected children born to women living with perinatally versus nonperinatally acquired HIV
Authors: Yu Wendy , Jacobson Denise L. , Williams Paige L. , Patel Kunjal , Geffner Mitchell E. , Van Dyke Russell B. , Kacanek Deborah , DiMeglio Linda A. , Jao Jennifer
Published: December 2021

Objective:

The aim of this study was to compare long-term growth between HIV-exposed uninfected children (CHEU) born to women with perinatally acquired HIV (CHEU-PHIV) and CHEU born to women with nonperinatally acquired HIV (CHEU-NPHIV).

Design:

A longitudinal analysis of anthropometric measurements from a U.S.-based multisite prospective cohort study enrolling CHEU and their mothers since April 2007.

Methods:

CHEU were evaluated for growth annually from birth through age 5 and again at age 7 years. Z-scores were calculated using U.S. growth references for weight (WTZ), height (HTZ), and weight-for-length or BMI-for-age (WLZ/BMIZ). Mid-upper arm circumference (MUACZ) and triceps skinfold thickness (TSFZ) Z-scores were obtained from ages 1 and 2, respectively, through age 7 years. Piecewise mixed-effects models, overall and stratified by race and sex, were fit to assess differential growth patterns across age by maternal PHIV status.

Results:

One thousand four hundred fifty-four singleton infants (286 CHEU-PHIV and 1168 CHEU-NPHIV) were included. CHEU-PHIV had slower growth rates than CHEU-NPHIV for WTZ and WLZ/BMIZ at earlier ages and continued to have lower mean WTZ [−0.27, 95% confidence interval (95% CI): −0.50, −0.04] and WLZ/BMIZ (−0.39, 95% CI: −0.67, −0.11) through age 7. Among non-Black boys, CHEU-PHIV had slightly lower WTZ and WLZ/BMIZ at birth than CHEU-NPHIV and these growth deficits persisted through age 7 years.

Conclusion:

Compared with CHEU-NPHIV, CHEU-PHIV had diminished growth in early childhood with differences most pronounced among non-Black male children. Further longitudinal follow-up of CHEU-PHIV into young adulthood is needed to understand whether these early effects of maternal PHIV status on growth persist and have other health consequences.
Quantitative Analysis of Radial Peripapillary Capillary Network in Patients With Papilledema Compared with Healthy Subjects Using Optical Coherence Tomography Angiography
Authors: Chonsui Moerani , Le Goff Mélanie , Korobelnik Jean-François , Rougier Marie-Bénédicte
Published: December 2021

Background:

To quantitatively compare the peripapillary microvascular network between patients with papilledema and healthy subjects using swept source optical coherence tomography angiography.

Methods:

In this retrospective observational study, patients with papilledema secondary to idiopathic intracranial hypertension and healthy controls were imaged with swept source optical coherence tomography angiography (PLEX Elite 9000; Carl Zeiss Meditec, Dublin, CA) using a 6 × 6 mm scan pattern centered on the optic disc. The capillary perfusion density (CPD) and capillary flux index (CFI) of the radial peripapillary capillaries in the retinal nerve fiber layer (RNFL) were calculated using Zeiss algorithm.

Results:

Thirty-nine eyes of 20 patients with papilledema and 66 eyes of 33 healthy subjects were imaged. The mean (P < 0.01), superior (P < 0.01), inferior (P < 0.01), and temporal (P = 0.02) CPD significantly differed between both groups. No significant difference was found between both groups for the CFI. The mean (P < 0.01), superior (P < 0.01), inferior (P = 0.01), temporal (P < 0.01), and nasal (P < 0.01) quadrants of the RNFL were positively associated with the CFI. The mean (P < 0.01), superior (P = 0.01), inferior (P = 0.01), temporal (P < 0.01), and nasal (P = 0.01) quadrants of the RNFL were negatively associated with the CPD.

Conclusion:

Our study showed a decreased peripapillary capillary density without changes in flux intensity in eyes with papilledema. There were a positive association between the CFI and the RNFL and a negative association between the CPD and the RNFL. It confirmed the discriminatory ability of OCTA in differentiating a papilledema secondary to IIH from a normal optic disc, while providing complementary information for understanding papilledema pathophysiology.
Machine learning, artificial intelligence and the prediction of dementia
Authors: Merkin Alexander , Krishnamurthi Rita , Medvedev Oleg N.
Published: December 2021

Purpose of review

Artificial intelligence and its division machine learning are emerging technologies that are increasingly applied in medicine. Artificial intelligence facilitates automatization of analytical modelling and contributes to prediction, diagnostics and treatment of diseases. This article presents an overview of the application of artificial intelligence in dementia research.

Recent findings

Machine learning and its branch Deep Learning are widely used in research to support in diagnosis and prediction of dementia. Deep Learning models in certain tasks often result in better accuracy of detection and prediction of dementia than traditional machine learning methods, but they are more costly in terms of run times and hardware requirements. Both machine learning and Deep Learning models have their own strengths and limitations. Currently, there are few datasets with limited data available to train machine learning models. There are very few commercial applications of machine learning in medical practice to date, mostly represented by mobile applications, which include questionnaires and psychometric assessments with limited machine learning data processing.

Application of machine learning technologies in detection and prediction of dementia may provide an advantage to psychiatry and neurology by promoting a better understanding of the nature of the disease and more accurate evidence-based processes that are reproducible and standardized.
CHRONOSIG: Digital Triage for Secondary Mental Healthcare using Natural Language Processing - rationale and protocol
Authors: Joyce Dan W , Kormilitzin Andrey , Hamer-Hunt Julia , James Anthony , Nevado-Holgado Alejo , Cipriani Andrea
Published: December 2021

Background

Accessing specialist secondary mental health care in the NHS in England requires a referral, usually from primary or acute care. Community mental health teams triage these referrals deciding on the most appropriate team to meet patients’ needs. Referrals require resource-intensive review by clinicians and often, collation and review of the patient’s history with services captured in their electronic health records (EHR). Triage processes are, however, opaque and often result in patients not receiving appropriate and timely access to care that is a particular concern for some minority and under-represented groups. Our project, funded by the National Institute of Health Research (NIHR) will develop a clinical decision support tool (CDST) to deliver accurate, explainable and justified triage recommendations to assist clinicians and expedite access to secondary mental health care.

Methods

Our proposed CDST will be trained on narrative free-text data combining referral documentation and historical EHR records for patients in the UK-CRIS database. This high-volume data set will enable training of end-to-end neural network natural language processing (NLP) to extract ‘signatures’ of patients who were (historically) triaged to different treatment teams. The resulting algorithm will be externally validated using data from different NHS trusts (Nottinghamshire Healthcare, Southern Health, West London and Oxford Health). We will use an explicit algorithmic fairness framework to mitigate risk of unintended harm evident in some artificial intelligence (AI) healthcare applications. Consequently, the performance of the CDST will be explicitly evaluated in simulated triage team scenarios where the tool augments clinician’s decision making, in contrast to traditional “human versus AI” performance metrics.

Discussion

The proposed CDST represents an important test-case for AI applied to real-world process improvement in mental health. The project leverages recent advances in NLP while emphasizing the risks and benefits for patients of AI-augmented clinical decision making. The project’s ambition is to deliver a CDST that is scalable and can be deployed to any mental health trust in England to assist with digital triage.
Systemic lipid peroxidation and skeletal tissues metabolism in animals with simulated posttraumatic osteoarthrosis
Authors: Belova Svetlana V. , Zubavlenko Roman A. , Ulyanov Vladimir Yu.
Published: December 2021

The role of individual factors in the progressing of degenerative and dystrophic changes of articular cartilage as the focus of pathologic changes in posttraumatic osteoarthrosis (PTOA) has been studied comprehensively. However, no single concept of pathogenetic mechanisms leading to the formation of permanent changes in the affected joint has been represented yet. Therefore, the investigation of lipid peroxidation and skeletal tissues metabolism in animals with simulated PTOA is a challenging and important issue.

In 28 non-linear male rats (12 intact control animals and 16 experimental animals with simulated knee OA) we studied the lipid peroxidation rate by the level of lipid hydroperoxides, antioxidant system activity by the indicants of total antioxidant, and thiol statuses. The destruction processes in skeletal tissues were evaluated by the level of hyaluronan, a cartilaginous tissue marker, and subchondral bone turnover makers (fibroblast growth factor-23, osteoprotegerin, sclerostin, osteocalcin).

In rats with simulated PTOA, we observed the activation of lipid peroxidation with the accumulation of lipid hydroperoxides in systemic blood flow along with the insignificant decrease of thiol status indicant while the normal antioxidant activity is maintained. We also revealed the significant increase of biopolymer hyaluronan (p<0.05) in a negative change of turnover regulation marker (the significant increase in fibroblast growth factor-23 (p<0.05) with the emerging trend for osteoprotegerin and sclerostin decrease) and bone formation marker (high osteocalcin) as compared to the intact controls.

Our findings confirmed that animals with simulated PTOA featured rearranging of skeletal tissues as compared to intact animals. This process involved degenerative destruction of both chondral and osseous tissues along with profound prooxidant activity and relative incompetence of the thiol system while the indicants of general antioxidant activity remain normal. This suggests the importance of the analyzed markers in PTOA pathogenesis and determined the prospects of their use for the evaluation of therapy efficacy.
The Politics of Vaccine Hesitancy in the United States
Authors: Cao Jian , Ramirez Christina , Alvarez R. Michael
Published: December 2021

Objective

Why are Americans COVID-19 vaccine hesitant? We test social science hypotheses for vaccine hesitancy, focusing on partisanship, trust in institutions, and social-demographic characteristics of registered voters.

Methods

We use survey data from a representative sample of American registered voters collected in November 2020 to study vaccine hesitancy, and the reasons for vaccine hesitancy, at a point in time before the vaccine was available and hence show underlying responses based on beliefs and not on clinical trial data. We use multivariate logistic regression models to test hypotheses on vaccine hesitancy.

Results

We find that consistently similar groups of people tend to be vaccine hesitant. Specifically, Black voters, those between the ages of 45 and 64, female voters, voters without college degrees, voters not worried about the spread of COVID-19, and voters who are concerned about government and the CDC’s handling of the COVID-19 pandemic, were vaccine hesitant. We also provide intriguing results showing the nuanced reasons that the vaccine hesitant provide.

Conclusions

Our analysis allows us to establish important baseline information from a social science perspective on vaccine hesitancy at a crucial time, right before COVID-19 vaccines were beginning to be made available to adult Americans. What emerges from our analysis is a nuanced perspective on vaccine hesitancy in the United States, from this important point in the history of the COVID-19 pandemic.
Imaging analysis to quantitate the Interplay of membrane and cytoplasm protein dynamics
Authors: Kislev N , Egozi M , Benayahu D
Published: December 2021

Plasma membrane proteins are extremely important in cell signaling and cellular functions. Protein expression and localization alter in response to various signals in a way that is dependent on cell type and niche. Compartmental quantification of the expression of particular proteins is a very useful means of understanding their role in cellular processes. Immunofluorescence staining is frequently used to investigate the distribution of proteins of interest. Here, we present an imaging method for quantifying the membrane to cytoplasm ratio (MCR) of proteins analyzed at single-cell resolution. This technique provides a robust quantification of membrane proteins and contributes new insights into membrane expression dynamics. We have developed a protocol that uses immunostaining to assess protein expression according to the fluorescent cellular distribution and to compute the MCR. The method was applied to measure the MCR of glucose transporter 4 (GLUT4) in response to insulin in 3T3-L1 cells, an in-vitro model for adipocyte function and adipogenesis. The results revealed informative changes in the subcellular localization of GLUT4 following insulin induction. MCR analysis is a powerful imaging tool that can be generally applied to membrane proteins to provide a rapid and efficient quantitative analysis of protein distribution and sub-cellular processes in cells.
Application of Parallel Reaction Monitoring in 15N labeled Samples for Quantification
Authors: Reyes Andres V. , Shrestha Ruben , Baker Peter R. , Chalkley Robert J. , Xu Shou-Ling
Published: December 2021

Accurate relative quantification is critical in proteomic studies. The incorporation of stable isotope 15N to plant-expressed proteins in vivo is a powerful tool for accurate quantification with a major advantage of reducing preparative and analytical variabilities. However, 15N labeling quantification has several challenges. Less identifications are often observed in the heavy labeled samples because of incomplete labeling, resulting in missing values in reciprocal labeling experiments. Inaccurate quantification can happen when there is contamination from co-eluting peptides or chemical noise in the MS1 survey scan. These drawbacks in quantification can be more pronounced in less abundant but biologically interesting proteins, which often have very few identified peptides. Here we demonstrate the application of parallel reaction monitoring (PRM) to 15N labeled samples on a high resolution, high mass accuracy Orbitrap mass spectrometer to achieve reliable quantification even of low abundance proteins in samples.
The ENDS of assumptions; an online tool for the Epistemic Nonparametric Drug-response Scoring
Authors: Amiryousefi Ali , Williams Bernardo , Jafari Mohieddin , Tang Jing
Published: December 2021

Motivation

The drugs sensitivity analysis is often elucidated from drug dose-response curves. These curves capture the degree of cell viability (or inhibition) over a range of induced drugs, often with parametric assumptions that are rarely validated.

Results

We present a class of nonparametric models for the curve fitting and scoring of drug dose-responses. To allow a more objective representation of the drug sensitivity, these epistemic models devoid of any parametric assumptions attached to the linear fit, allow the parallel indexing such as IC50 and AUC. Specifically, three nonparametric models including Spline, Monotonic, and Bayesian (npS, npM, npB) and the parametric Logistic (pL) are implemented. Other indices including Maximum Effective Dose (MED) and Drug-response Span Gradient (DSG) pertinent to the npS are also provided to facilitate the interpretation of the fit. The collection of these models are implemented in an online app, standing as useful resource for drug dose-response curve fitting and analysis.

Availability

The ENDS is freely available online at https://irscope.shinyapps.io/ENDS/ and source codes can be obtained from https://github.com/AmiryousefiLab/ENDS.

Supplementary information

Supplementary data are available at Bioinformatics and https://irscope.shinyapps.io/ENDS/

Contact

ali.amiryousefi@helisnki.fi; jing.tang@helisnki.fi.

Contributions

AA conceived the study and developed the models, AA and BW adopted and implemented the methods, JT provided the funding, AA, BW, MJ, and JT wrote the paper.
CaveCrawler: An interactive analysis suite for cavefish bioinformatics
Authors: Perry Annabel , McGaugh Suzanne E. , Keene Alex C. , Blackmon Heath
Published: December 2021

The growing use of genomics data in diverse animal models provides the basis for identifying genomic and transcriptional differences across species and contexts. Databases containing genomic and functional data have played critical roles in the development of numerous genetic models but are lacking for most emerging models of evolution. There is a rapidly expanding use of genomic, transcriptional, and functional genetic approaches to study diverse traits of the Mexican tetra, Astyanax mexicanus. This species exists as two morphs, eyed surface populations and at least 30 blind cave populations, providing a system to study convergent evolution. We have generated a web-based analysis suite that integrates datasets from different studies to identify how gene transcription and genetic markers of selection differ between populations and across experimental contexts. Results can be processed with other analysis platforms including Gene Ontology (GO) to enable biological inference from cross-study patterns and identify future avenues of research. Furthermore, the framework that we have built A. mexicanus can readily applied to other emerging model systems.
Neoisoptera repetitively colonised Madagascar after the Middle Miocene climatic optimum
Authors: Wang Menglin , Hellemans Simon , Buček Aleš , Kanao Taisuke , Arora Jigyasa , Clitheroe Crystal , Rafanomezantsoa Jean-Jacques , Fisher Brian L. , Scheffrahn Rudolf , Sillam-Dussès David , Roisin Yves , Šobotník Jan , Bourguignon Thomas
Published: December 2021

Madagascar is home to many endemic plant and animal species owing to its ancient isolation from other landmasses. This unique fauna includes several lineages of termites, a group of insects known for their key role in organic matter decomposition in many terrestrial ecosystems. How and when termites colonised Madagascar remains unknown. In this study, we used 601 mitochondrial genomes, 93 of which were generated from Madagascan samples, to infer the global historical biogeography of Neoisoptera, a lineage containing upwards of 80% of described termite species. Our results indicate that Neoisoptera colonised Madagascar between seven to ten times independently during the Miocene, between 8.4-16.6 Ma (95% HPD: 6.1-19.9 Ma). This timing matches that of the colonization of Australia by Neoisoptera. Furthermore, the taxonomic composition of the Neoisopteran fauna of Madagascar and Australia are strikingly similar, with Madagascar harbouring an additional two lineages absent from Australia. Therefore, akin to Australia, Neoisoptera colonised Madagascar during the global expansion of grasslands, possibly helped by the ecological opportunities arising from the spread of this new biome.
NRF2-dependent epigenetic regulation can promote the hybrid epithelial/mesenchymal phenotype
Authors: Jia Wen , Jolly Mohit Kumar , Levine Herbert
Published: December 2021

The epithelial-mesenchymal transition (EMT) is a cellular process critical for wound healing, cancer metastasis and embryonic development. Recent efforts have identified the role of hybrid epithelial/mesenchymal states, having both epithelial and mesehncymal traits, in enabling cancer metastasis and resistance to various therapies. Also, previous work has suggested that NRF2 can act as phenotypic stability factor to help stablize such hybrid states. Here, we incorporate a phenomenological epigenetic feedback effect into our previous computational model for EMT signaling. We show that this type of feedback can stabilize the hybrid state as compared to the fully mesenchymal phenotype if NRF2 can influence SNAIL at an epigenetic level, as this link makes transitions out of hybrid state more difficult. However, epigenetic regulation on other NRF2-related links do not significantly change the EMT dynamics. Finally, we considered possible cell division effects in our epigenetic regulation model, and our results indicate that the degree of epigenetic inheritance does not appear to be a critical factor for the hybrid E/M state stabilizing behavior of NRF2.
Coupling adipose tissue architecture and metabolism via cytoophidia
Authors: Liu Jingnan , Zhang Yuanbing , Zhou Youfang , Wang Qiao-Qi , Ding Kang , Zhao Suwen , Lu Pengfei , Liu Ji-Long
Published: December 2021

Tissue architecture determines its unique physiology and function. How these properties are intertwined has remained unclear. Here, we show that the metabolic enzyme CTP synthase (CTPS) form filamentous structures termed cytoophidia along the adipocyte cortex in Drosophila adipose tissue. Interestingly, loss of cytoophidia, whether due to reduced CTPS expression or a point mutation that specifically abrogates its polymerization ability, leads to downregulated Collagen-Integrin signaling, weakened adipocyte adhesion, and defective adipose architecture. Strikingly, CTPS specifically binds with Integrin subunit α2, which influences Integrin function and Collagen IV deposition. cytoophidia promote Collagen IV mRNA expression and thus its extracellular deposition to strengthen adipocyte adhesion. Remarkably, Collagen IV-Integrin signaling reciprocally regulates cytoophidium formation at a post-translational level. Together, we demonstrate that a positive feedback signaling loop containing both cytoophidia and Integrin adhesion complex couples tissue architecture and metabolism in the fly adipose.
A novelPhytophthora sojaeeffector PsFYVE1 modulates transcription and alternative splicing of immunity related genes by targeting host RZ-1A protein
Authors: Lu Xinyu , Yang Zitong , Song Wen , Si Jierui , Yin Zhiyuan , Jing Maofeng , Shen Danyu , Dou Daolong
Published: December 2021

Oomycete pathogens secrete many effectors to manipulate plant immunity and promote infection. However, relatively few effector types have been well characterized. In this study, members of a FYVE domain-containing protein family that is highly expanded in oomycetes were systematically identified, and one secreted protein, PsFYVE1, was selected for further study. PsFYVE1 enhancedPhytophthorainfection inNicotiana benthamianaand was necessary forP. sojaevirulence. The FYVE domain of PsFYVE1 had PI3P-binding activity that depended on four conservative amino acid residues. Furthermore, PsFYVE1 targeted RNA-binding proteins RZ-1A/1B/1C inN. benthamianaand soybean, and silencing ofNbRZ-1A/1B/1Cgenes attenuates plant immunity. NbRZ-1A was associated with spliceosome that included three important components, NbGRP7, NbGRP8, and NbU1-70K. Notably, PsFYVE1 could disrupt NbRZ-1A–NbGRP7 interaction. RNA-seq and subsequent experimental analysis demonstrated that PsFYVE1 and NbRZ-1A not only co-regulated transcription ofNbHCT,NbEIN2, andNbSUS4genes but also modulated pre-mRNA alternative splicing (AS) of theNbNSL1gene, which participated in plant immunity. Collectively, these findings indicate that the FYVE domain-containing protein family includes potential new effector types and also highlight that plant pathogen effectors can regulate plant immunity related genes at both transcription and AS levels to promote disease.

Author summary

Many plant pathogenic oomycetes secrete effector proteins into plants to facilitate infection. Discovering potential repertoire of novel effectors and corresponding molecular mechanisms are major themes in the study of oomycete–plant interactions. Here, we characterized a FYVE domain-containing protein (PsFYVE1) inP. sojae. PsFYVE1 carries a functional secretory signal peptide and is a virulence-essential effector forP. sojaeinfection. We demonstrated that PsFYVE1 interacted with a class of plant RNA-binding proteins, including soybean GmRZ-1A/1B/1C andN. benthamianaNbRZ-1A/1B/1C. Silencing ofNbRZ-1A/1B/1Cproteins increasedPhytophthorainfection and suppressed plant defense. Furthermore, NbRZ-1A interacted with the spliceosome components, and PsFYVE1 disrupted association between NbRZ-1A and spliceosome component NbGRP7. We examined the global transcription and alternative splicing (AS) changes regulated by PsFYVE1 and NbRZ-1A, which indicated that PsFYVE1 and NbRZ-1A co-regulated transcription and pre-mRNA AS of immunity-related genes. Thus, this study identifies a novel virulence-related effector fromP. sojaeand a class of positive regulators of plant immunity, and reveals a detailed mechanism of effector-medicated transcription and AS regulation during pathogen–plant interactions.
Accurate sequence-dependent coarse-grained model for conformational and elastic properties of double-stranded DNA
Authors: Assenza Salvatore , Pérez Rubén
Published: December 2021

We introduce MADna, a sequence-dependent coarse-grained model of double-stranded DNA (dsDNA), where each nucleotide is described by three beads localized at the sugar and base moieties, and at the phosphate group. The sequence dependence is included by considering a step-dependent parameterization of the bonded interactions, which are tuned in order to reproduce the values of key observables obtained from exhaustive atomistic simulations from literature. The predictions of the model are benchmarked against an independent set of all-atom simulations, showing that it captures with high fidelity the sequence dependence of conformational and elastic features beyond the single step considered in its formulation. A remarkably good agreement with experiments is found for both sequence-averaged and sequence-dependent conformational and elastic features, including the stretching and torsion moduli, the twist-stretch and twist-bend couplings, the persistence length and the helical pitch. Overall, for the inspected quantities, the model has a precision comparable to atomistic simulations, hence providing a reliable coarse-grained description for the rationalization of singlemolecule experiments and the study of cellular processes involving dsDNA. Owing to the simplicity of its formulation, MADna can be straightforwardly included in common simulation engines.
Structural Basis for an Unprecedented Enzymatic Alkylation in Cylindrocyclophane Biosynthesis
Authors: Braffman Nathaniel R. , Ruskoski Terry B. , Davis Katherine M. , Glasser Nate , Johnson Cassidy , Denise Okafor C. , Boal Amie K. , Balskus Emily P.
Published: December 2021

The cyanobacterial enzyme CylK assembles the cylindrocyclophane natural products by performing two unusual alkylation reactions, forming new carbon-carbon bonds between aromatic rings and secondary alkyl halide substrates. This transformation is unprecedented in biology and the structure and mechanism of CylK are unknown. Here, we report x-ray crystal structures of CylK, revealing a distinctive fusion of a Ca2+ binding domain and a β-propeller fold. We use a mutagenic screening approach to locate CylK’s active site at its domain interface, identifying two residues, Arg105 and Tyr473, that are required for catalysis. Anomalous diffraction datasets collected with bound bromide ions, a product analog, suggest these residues interact with the alkyl halide electrophile. Additional mutagenesis and molecular dynamics simulations implicates Asp440 and Glu374 in activating the nucleophilic aromatic ring. Bioinformatic analysis of CylK homologs from other cyanobacteria establishes that they conserve these key catalytic amino acids but they are likely associated with divergent reactivity and altered secondary metabolism. By gaining a molecular understanding of this unusual biosynthetic transformation, this work fills a gap in our understanding of how alkyl halides are activated and used by enzymes as biosynthetic intermediates, informing enzyme engineering, catalyst design, and natural product discovery.