bluuebunny/crossref_metadata_2025 huggingface dataset:
Hit-hard and early versus step-up treatment in severe sarcoidosis
Authors: Vorselaars Adriane D.M. , Culver Daniel A.
Published: July 2022

Purpose of review

The treatment of sarcoidosis remains uncertain, despite 70 years of study. The conventional approach is to initiate corticosteroids in individuals who require treatment. The position of more aggressive regimes is unknown.

Recent findings

Recent recognition that many patients will require prolonged therapy, and the observation that corticosteroids lead to overt and insidious toxicities, have led to suggestions that steroid-sparing medications be used earlier in the management of sarcoidosis. Individuals with poor prognostic features, designated as ‘high-risk’ sarcoidosis may, especially benefit from a broader palette of therapeutic options in the initial treatment regimen. An even more aggressive approach, known as ‘top-down’ or ‘hit-hard and early’ therapy has emerged in the fields of gastroenterology and rheumatology in the past 15 years, on the premise that highly effective early control of inflammation leads to better outcomes. These regimens typically involve early initiation of biologic therapies.

For certain subpopulations of sarcoidosis patients, ‘top-down’ therapy could be helpful. Severe pulmonary sarcoidosis, neurosarcoidosis, cardiac sarcoidosis and multiorgan sarcoidosis are phenotypes that may be most relevant for revised therapeutic algorithms. Precision medicine approaches and randomized trials will be necessary to confirm a role for top-down therapy in the routine management of sarcoidosis.
Can low-carbohydrate diets be recommended for reducing cardiovascular risk?
Authors: Berger Amy , Thorn Eric
Published: July 2022

Purpose of review

This review provides a rationale for implementing carbohydrate restriction as a dietary therapy to improve biomarkers of cardiovascular health and suggests that this will require a paradigm shift away from what is currently promulgated as a ‘heart-healthy’ diet.

Recent findings

Type 2 diabetes mellitus (T2DM), metabolic syndrome, and related co-morbidities are major risk factors for cardiovascular disease (CVD). Ideally, then, a diet intended to support cardiovascular health should be one that improves or reverses these underlying risk factors. Carbohydrate restriction is effective for this purpose as well as for favorably impacting atherogenic dyslipidemia. Recent consensus reports from select national organizations have endorsed low-carbohydrate diets for improving glycemia and cardiovascular risk. Reluctance among public health organizations and some clinicians to more widely promote this therapeutic nutritional approach is driven primarily by the increase in serum low-density lipoprotein cholesterol (LDL-C) observed in a proportion of individuals who adopt a low-carbohydrate diet. Here we explore the rationale for using carbohydrate restriction to improve cardiovascular health by way of favorably impacting T2DM and insulin resistance, and why this salutary effect outweighs the potential adverse effects of an increase in serum LDL-C.

Carbohydrate restriction is a logical foundation for a dietary intervention intended to reduce CVD risk, particularly among individuals with T2DM or metabolic syndrome.
The Influence of Practice Structure on Urologists’ Treatment of Men With Low-Risk Prostate Cancer
Authors: Mitchell Jean M. , Gresenz Carole Roan
Published: July 2022

Background:

Vertical and horizontal integration among health care providers has transformed the practice arrangements under which many physicians work.

Objective:

To examine the influence of type of practice structure, and by implication the financial incentives associated with each structure, on treatment received among men newly diagnosed with low-risk prostate cancer.

Research Design:

We compiled a unique database from cancer registry records from 4 large states, Medicare enrollment and claims for the years 2005−2014 and SK & A physician surveys corroborated by extensive internet searches. We estimated a multinomial logit model to examine the influence of urologist practice structure on type of initial treatment received.

Results:

The probability of being monitored with active surveillance was 7.4% and 4.2% points higher for men treated by health system and nonhealth system employed urologists (P<0.01), respectively, in comparison to men treated by single specialty urology practices. Among multispecialty practices, the rate of active surveillance use was 3% points higher compared with single specialty urology practices(P<0.01). Use of intensity modulated radiation therapy among urologists with ownership in intensity modulated radiation therapy was 17.4% points higher compared with urologists working in small single specialty practices.

Conclusions:

Physician practice structure attributes are significantly associated with type of treatment received but few studies control for such factors. Our findings—coupled with the observation that urologist practice structure shifted substantially over this time period due to mergers of small urology groups—provide one explanation for the limited uptake of active surveillance among men with low-risk disease in the US.
The Role of Social Risk Factors in Dialysis Quality and Patient Outcomes Under a Medicare Quality Incentive Program
Authors: Breck Andrew , Marr Jeffrey , Turenne Marc , Esposito Dominick
Published: July 2022

Background:

There have been critical improvements in dialysis care and mortality in the last decade. These improvements track with the implementation of the end-stage renal disease (ESRD) Quality Incentive Program (QIP) beginning in 2012, which aligns Medicare payments to dialysis facilities with performance on quality measures. This study explores whether the improvements in dialysis care and patient outcomes under the ESRD QIP have been shared equally among patient groups.

Methods:

Our analyses focus on 4 social risk factors: Black race, Hispanic ethnicity, dual eligibility for Medicare and Medicaid, and rurality. We estimated multivariable regressions using longitudinal Medicare and Consolidated Renal Operations in a Web-Enabled Network data.

Results:

ESRD QIP payment reductions were more common at dialysis facilities with higher proportions of Black and dual-eligible ESRD patients. Patients with dual eligibility and Black race had persistently worse relative outcomes as the ESRD QIP was implemented. This finding was true for differences in outcomes when comparing patients within and across facilities and was not affected by the addition of specific quality measures to the ESRD QIP measure set. Hispanic patients and patients at rural facilities have generally not had worse outcomes since the start of the ESRD QIP.

Conclusions:

There is no evidence of widening disparities in dialysis care or patient outcomes across patient groups under the ESRD QIP, which is a longstanding and well-publicized concern with value-based purchasing programs. Relative changes between patient groups since the start of ESRD QIP have not favored any patient group. Many disparities in dialysis quality measures and assessment of dialysis facility payment reductions persist.
Active surveillance for non-muscle-invasive bladder cancer: fallacy or opportunity?
Authors: von Deimling Markus , Pallauf Maximilian , Bianchi Alberto , Laukhtina Ekaterina , Karakiewicz Pierre I. , Rink Michael , Shariat Shahrokh F. , Pradere Benjamin
Published: July 2022

Purpose of review

This review aims to analyze the current place of active surveillance (AS) in non-muscle-invasive bladder cancer (NMIBC).

Recent findings

A growing body of evidence suggests that AS protocols for pTa low-grade (TaLG) NMIBC are safe and feasible. However, current guidelines have not implemented AS due to a lack of high-quality data. Available studies included pTa tumors, with only one study excluding pT1-NMIBC. Inclusion/exclusion criteria were heterogeneously defined based on tumor volume, number of tumors, carcinoma in situ (CIS), or high-grade (HG) NMIBC. Tumor volume <10 mm and <5 lesions were used as cut-offs. Positive urinary cytology (UC) or cancer-related symptoms precluded inclusion. Surveillance within the first year consisted of quarterly cystoscopy. AS stopped upon the presence of cancer-related symptoms, change in tumor morphology, positive UC, or patient's request. With a median time on AS of 16 months, two-thirds of the patients failed AS. Progression to muscle-invasive bladder cancer (MIBC) was rare and occurred only in patients with pT1-NIMBC at inclusion.

AS in NMIBC is an attractive concept in the era of personalized medicine, but strong evidence is still awaited. A more precise definition of patient inclusion, follow-up, and failure criteria is required to improve its implementation in daily clinical practice.
Pediatric Medical Traumatic Stress in Inflammatory Bowel Disease, Pancreatitis, and Cystic Fibrosis
Authors: Cuneo Addison A. , Abu-El-Haija Maisam , Marsac Meghan L. , Verstraete Sofia , Heyman Melvin B. , Ly Ngoc , Perito Emily R.
Published: July 2022

Objectives:

Known as pediatric medical traumatic stress (PMTS), posttraumatic stress symptoms from medical experiences have not been explored in children with chronic gastrointestinal diseases. This cross-sectional study of children and adolescents with inflammatory bowel disease, chronic pancreatitis and cystic fibrosis, aimed to (1) estimate the prevalence of medical potentially traumatic events (PTEs) and PMTS, (2) explore potential risk factors for PMTS, and (3) explore potential consequences of PMTS.

Methods:

This cross-sectional study used validated, self-report measures to evaluate PTEs and PMTS. Descriptive statistics and regression analyses were used to achieve study objectives.

Results:

Over two-thirds of children reported a medical potentially traumatic event (91 of 132, 69%). Forty-eight had PMTS symptoms (36%). PMTS was associated with medication burden, emergency and intensive care visits, and parent posttraumatic stress disorder in multivariate analysis. Potential consequences associated with PMTS included school absenteeism, home opioid use, poor quality of life, and parent missed work.

Conclusions:

A substantial portion of our cohort reported medical PTEs and PMTS. The exploratory analysis identified potential associations between PMTS and illness factors, parent posttraumatic stress disorder, and functional impairments. Further studies of PMTS detection, prevention and treatment are integral to optimizing these children’s health and quality of life.
Understanding Cultural Beliefs of a Good Death by Older People in South Korea: An Integrative Review of the Literature
Authors: Yun Kyoungsun , Jo Minjeong , Lee Yunji
Published: July 2022

With the enforcement of the Hospice and Palliative Care and Decisions on Life-Sustaining Treatment for Patients at the End-of-Life Act in 2018, interest in the quality of death in South Korea is increasing. However, few studies have provided an updated perspective on a good death. This integrative review describes the attributes of a good death from the perspective of South Korean older adults. Among the 32 studies included in this review, 16 main themes representing good death were identified. Themes of maintaining dignity, not burdening others, living a meaningful life, being pain-free, and being prepared to die were commonly reported attributes of a good death in other cultures; themes further reflected in Korean culture were filial piety and parenting. In contrast, older adult characteristics such as low income and education level, bereavement experience, disease uncertainty, and depressive symptoms were associated with high levels of fear of death or negative attitudes, such as trying to avoid suffering through death. This review provides insights into the health care provider's approach to older people at the end of their life in South Korea. Consequently, this can help determine potential unmet needs that can be improved.
Acute Decompensated Heart Failure
Authors: Joseph Josmi , Choudhury Aeman , Kane Sean P.
Published: July 2022

Chronic heart failure (CHF) is a growing disease in the United States. Exacerbations of CHF can lead to acute decompensated heart failure (ADHF) and hospitalizations. Nurses play a key role in the treatment of ADHF as they administer medications, monitor patients' response to therapy, and can prompt providers to alter therapy if therapeutic outcomes are not being achieved. Nurses also play a vital role in discharge education for patients who are hospitalized for ADHF, as they can counsel patients on ways to reduce further hospitalizations. It is important for nurses to understand and recognize symptoms of ADHF, pharmacologic treatments for ADHF, and common etiologies of ADHF to help improve patient outcomes.
Acute Popliteal Artery Thrombosis Resulting From a Closed Comminuted Tibia Fracture
Authors: Zhang Shuliang , Xu Bin
Published: July 2022

Acute popliteal artery thrombosis is a rare and limb-threatening traumatic event. It can lead to soft-tissue necrosis or even amputation of the lower limb. In patients suffering from trauma around the knee joint, the clinician should be highly vigilant to risk of popliteal artery acute thrombosis. It is essential to detect and treat acute popliteal artery thrombosis timely for limb salvaging. We present a case of acute popliteal artery thrombosis resulting from a closed comminuted tibia fracture and discuss its injury mechanism, diagnostic methods, and treatment measures.
Perspectives on Specific Carbohydrate Diet Education from Inflammatory Bowel Disease Patients and Caregivers: A Needs Assessment
Authors: Rivera Nancy , Nguyen Kaylie , Kalami Venus , Blankenburg Rebecca , Ming Yeh Ann
Published: July 2022

The specific carbohydrate diet (SCD) has potential health benefits for inflammatory bowel disease (IBD); however, adherence is challenging. Through an online needs assessment survey, this study explored the perspectives of patients and caregivers using the SCD to manage IBD to determine barriers, knowledge gaps, and desired areas for further learning about the SCD. Inclusion criteria included patients with IBD or their caregivers who had experience with the SCD. Of the 208 participants, 87% of participants were female with a mean age of 46 years. Fifty-seven percent had never received SCD training before starting the diet. Participants favored more education on several topics within the SCD and identified one-on-one sessions as the preferred learning modality. Barriers identified were initial steep learning curve, time commitment, and a desire for more support from healthcare professionals. This needs assessment survey highlights the gaps in educational priorities for patients on the SCD.
Fat Malabsorption and Ursodeoxycholic Acid Treatment in Children With Reduced Organic Solute Transporter-α (SLC51A) Expression
Authors: Tronstad Rune Rose , Berland Siren , Tjora Erling , El Jellas Khadija , Aukrust Ingvild , Kristensen Kurt , Tveitnes Dag , Molven Anders , Marschall Hanns-Ulrich , Rao Anuradha , Dawson Paul A.
Published: July 2022

Objectives:

A bile acid homeostasis disorder was suspected in 2 siblings and their second cousin who presented in infancy with fat malabsorption, severe fat-soluble vitamin deficiency, rickets, and mild liver involvement. Our aims were to identify the genetic cause, describe the disease, and evaluate the response to ursodeoxycholic acid (UDCA) treatment.

Methods:

Whole exome sequencing, immunohistochemistry of duodenal biopsies and candidate variant testing in a cell-based model was performed. Fecal fat excretion, serum bile acids, 7α-hydroxy-4-cholesten-3-one (C4), and fibroblast growth factor 19 (FGF19) were quantified in both siblings on and off UDCA treatment.

Results:

A novel homozygous variant of SLC51A, which encodes the bile acid carrier organic solute transporter (OST)-α, was identified in all affected children. OSTα protein expression was readily detected by immunohistochemistry in duodenum of pediatric control subjects but not in the affected siblings. The siblings had low serum levels of bile acids and C4 and high serum levels of FGF19 consistent with repression of hepatic bile acid synthesis. On treatment with UDCA, fecal fat excretion was reduced and serum levels of C4, FGF19, and liver enzymes normalized.

Conclusions:

We report an apparent deficiency of OSTα associated with early onset fat malabsorption and mild liver involvement. The clinical presentation partially overlaps previous reports for 3 patients with OSTα or OSTβ deficiency and extends the clinical spectrum associated with loss of SLC51A expression. Our data suggest that repression of hepatic bile acid synthesis contributes to fat malabsorption in OSTα-OSTβ deficiency but can be partly reversed with UDCA treatment.
Comparison of Current Free Flap Options for Intraoral Lining and Tongue Reconstruction
Authors: Gur Ersin , Tiftikcioglu Yigit Ozer , Ozturk Kerem , Yegin Mehmet Emre , Kuybulu Turgut Furkan , Durukan Kutay
Published: July 2022

Free flaps have become the main alternative for intraoral reconstruction in current practice. However, controversy exists on pros and cons of different free flap options for this challenging area. Although there are various studies focusing on different free flap options, comparative studies are very few and there is not a single study comparing all 4 thin free flap options for intraoral reconstruction. Between 2018 and 2021, 30 patients underwent intraoral reconstruction. Four pliable and thin flaps, medial sural artery perforator flap, superficial circumflex iliac artery perforator flap, radial forearm free flap, and superthin anterolateral thigh flap were used for reconstructions and compared per functionality and patients’ quality of life. One medial sural artery perforator flap and 1 superficial circumflex iliac artery perforator flap failed because of perfusion problems, and the remaining flaps survived. Harvest time and donor site closure were with significant difference (P<0.05) between groups. Quality of life results were similar except one of the disease-specific questions. In authors’ opinion, anterolateral thigh flap is the best option in normal-weight individuals because of its reliability, pliability, and constant reliable vascular structure. Although other options may be considered in overweighted patients, thinly elevated anterolateral thigh flap still seems to be the most reliable option.
Minimally Invasive Surgery for Early-Stage Nasopharyngeal Carcinoma
Authors: Liu Jinping , Zeng Zesheng , Wang Dingting , Qin Gang
Published: July 2022

According to the National Comprehensive Cancer Network guidelines, the preferred treatment for early-stage nasopharyngeal carcinoma (NPC) is radiotherapy, however, the toxic effects associated with radiotherapy have been a nuisance for patients. Minimally invasive surgery for recurrent NPC has been widely recognized as an effective way to completely remove the tumor and free the patient from or mitigate the toxicity of radiotherapy. Therefore, some researchers hope that minimally invasive surgery can be used to treat early-stage NPC. It is a bold and controversial attempt, and the researchers’ efforts have achieved initial results. This article reviews the preliminary results of minimally invasive surgery for NPC, especially the feasibility and challenges of minimally invasive surgery for early-stage NPC.
Does Gastric Expansibility Affect Weight Loss Success After Laparoscopic Sleeve Gastrectomy?
Authors: Uprak Tevfik Kivilcim , Erdim Aylin , Karatas Sabri Alper , Gunal Omer
Published: July 2022

Reduced excess weight loss (EWL) or regain is a worrying problem after metabolic surgery. Factors attainable from the resected specimen that can predict this outcome are investigated. We retrospectively analyzed 64 patients who had undergone laparoscopic sleeve gastrectomy. We collected demographic data, preoperative gastric emptying measurements, volume, expansion capacity, and 6-dimensional measurements of sleeve gastrectomy specimens. Correlations between EWL, body mass index levels, and gastric specimen measurements related to gastric remnant dimensions were also scrutinized. We found a significant correlation between the gastric specimen and remnant gastric volume, the resection line length in the gastric specimen, and 12th-month EWL%. Antrum expansibility was significantly increased in patients with weight regain. There was also a negative correlation between weight loss and age at postoperative first and third years. Sleeve resection line measurement and resected antrum diameter measurements can be used to predict weight loss, especially in the first year postoperatively.
Reasons Affecting the Choice of Patient-Identified Goals Set by Occupational Therapists in Low Vision Rehabilitation
Authors: Smith Theresa M.
Published: July 2022

Background:

Goal setting is done in collaboration with the patient, but patient-identified (PID) goals are not always addressed. The purpose of this study was to determine reasons PID goals are not set in low-vision rehabilitation and for which tasks.

Methods:

Occupational therapists completed an individualized survey to determine from 15 probable reasons why they did not set a PID for specific tasks.

Results and Conclusion:

PID goals were not set for 3 activities of daily living, 13 instrumental activities of daily living, 4 social participation, and 10 leisure tasks. Further research is needed to understand how prioritization of PID goals differs between therapists and patients.
Social Determinants of Health for Older Adults With Low Vision
Authors: Bryant Kimberly D. , Wengerd Lauren , Smith Cristina R.
Published: July 2022

Objective:

To analyze the literature to increase understanding and awareness of how the social determinants of health can impact visual impairment in the elderly population.

Methods:

The authors used secondary and tertiary data sources on the subject area.

Results:

Although there has been minimal data collected on the effect of social determinants of health on visual impairment for older adults, more evidence is needed to show the influence of the social inequalities involved in the onset of low vision for the elderly population and to increase education on the resources available to improve function impacted by visual impairment.
Acquired Monocular Vision
Authors: Hsu Yu-Pin , Babaeva Inna
Published: July 2022

The purpose of this study is to describe the etiology and effects of acquired monocular vision in older adults and how it can affect clients' daily activities and functional mobility. This study will describe how occupational therapy interventions facilitate functional visual skills, in order to support occupational performance of a client with acquired monocular vision. This case illustrates the potential benefit of providing occupational therapy through low vision evaluation, occupational therapy and intervention specific to this condition, and to incorporate compensatory strategies to facilitate client's occupational performances. It was found that after occupational therapy services, the client had benefitted intervention to address acquired monocular vision condition.
SMAP design: A multiplex PCR amplicon and gRNA design tool to screen for natural and CRISPR-induced genetic variation
Authors: Develtere Ward , Waegneer Evelien , Debray Kevin , Van Glabeke Sabine , Maere Steven , Ruttink Tom , Jacobs Thomas B.
Published: July 2022

Multiplex amplicon sequencing is a versatile method to identify genetic variation in natural or mutagenized populations through eco-tilling or multiplex CRISPR screens. Such genotyping screens require reliable and specific primer designs, combined with simultaneous gRNA design for CRISPR screens. Unfortunately, current tools are unable to combine multiplex gRNA and primer design into a high-throughput and easy-to-use manner with high design flexibility. Here, we report the development of a bioinformatics tool called SMAP design to overcome these limitations. We tested SMAP design on several plant and non-plant genomes and obtained designs for more than 80-90% of the target genes, depending on the genome and gene family. We validated the primer designs with Illumina multiplex amplicon sequencing and Sanger sequencing in Arabidopsis and soybean. We also used SMAP design to perform eco-tilling by tilling PCR amplicons across nine candidate genes putatively associated with haploid induction in Cichorium intybus. We screened 60 accessions of chicory and witloof and identified thirteen knockout haplotypes and their carriers. SMAP design is an easy-to-use command-line tool that generates highly specific gRNA and/or primer designs for any number of loci for CRISPR or natural variation screens and is compatible with other SMAP modules for seamless downstream analysis.
Reconstructing protein interactions across time using phylogeny-aware graph neural networks
Authors: Moi David , Dessimoz Christophe
Published: July 2022

Motivation

Genes which are involved in the same biological processes tend to co-evolve. Thus, metabolic pathways, protein complexes, and other kinds of protein-protein interactions can be inferred by looking for correlated patterns of gene retention and loss across the tree of life—a technique called phylogenetic profiling. Recent methodological developments on phylogenetic profiling have focused on scalability improvements to take advantage of the rapidly accumulating genomic data. However, state-of-the-art methods assume that the correlation resulting from co-evolving proteins is uniform across all species considered. This is reasonable for interactions already present at the root of the species considered, but less so for ones that emerge in more recent lineages. To address this challenge and take advantage of recent developments in deep learning methods, we introduce a phylogenetic profiling method which processes large gene co-phylogenies using neural networks.

Results

We show that post-processing conventional phylogenetic profiles using deep neural networks can improve predictions, but requires onerous training on specific phylogenies. Overcoming this limitation by taking the topology of the species tree as an input, Graph Neural Networks are shown to outperform all other methods when interaction detection is not centered on just one species of interest, while also predicting when interactions appeared and in which taxa they are present.

Conclusion

Graph Neural Networks constitute a promising new approach for phylogenetic profiling. Our work is a first foray into “dynamic phylogenetic profiling”—the reconstruction of pairwise protein interaction across time.

Availability

All of the code is available on the project Git at https://github.com/DessimozLab/HogProf/tree/master/pyprofiler/notebooks/Graphnet. Datasets used are hosted at http://humap2.proteincomplexes.org/download and https://string-db.org/cgi/download.

Contact

dmoi@unil.ch
Mapping the unicellular transcriptome of the ascending thoracic aorta to changes in mechanosensing and mechanoadaptation during aging
Authors: Farra Yasmeen M. , Rivera Cristobal , Silvestro Michele , Matz Jacqueline , Pratama Yogi , Kumari Puja , Vlahos John , Ramkhelawon Bhama , Bellini Chiara
Published: July 2022

Aortic stiffening is an inevitable manifestation of chronological aging, yet the mechano-molecular programs that orchestrate region- and layer-specific adaptations along the length and through the wall of the aorta are incompletely defined. Here, we show that the decline in passive cyclic distensibility is more pronounced in the ascending thoracic (ATA) compared to distal segments of the aorta and that tissues in both the medial and adventitial compartments of the ATA stiffen during aging. Single-cell RNA sequencing of aged ATA tissues reveals altered cellular senescence, remodeling, and inflammatory responses accompanied by enrichment of T-lymphocytes and rarefaction of vascular smooth muscle cells, compared to young samples. T-lymphocytes accumulate in the adventitia and likely promote fibrosis, while activation of mechanosensitive piezo-1 enhances medial vasoconstriction. These results portray the immuno-mechanical aging of the ATA as a process that culminates in a stiffer conduit permissive to the accrual of multi-gerogenic signals priming to disease development.
Simulation study of Cell Transmembrane Potential and Electroporation Induced by Time-Varying Magnetic Fields
Authors: Guo Fei , Qian Kun , Li Xin , Deng Hao
Published: July 2022

In this work, an improved simulation model was proposed to assess the transmembrane potential (TMP) evolution on the cellular membrane exposed to time-varying magnetic fields (TMFs). Comparatively, we extended the research on TMP induced by TMF to the electroporation phenomenon by introducing the Smoluchowski function, thereby predicting the occurrence of electroporation. The simulation results based on our numerical model showed that with exposure to the sub-microsecond trapezoidal pulsed magnetic field (PMF), the pore density did not reach the conventional electroporation criterion (1014m−2) even if the TMP exceeded the electroporation threshold (∼1V); however, with the same energy import, it was easier for the nanosecond pulse to electroporate the membrane evidenced by higher pore density. Further, the capability of predicting the occurrence of electroporation was verified by extending our simulation model to compare experimental results. The comparative analysis showed that our simulation model has predictive and guiding significance for experimental studies and practical applications.
Hybrid Rank Aggregation (HRA): A novel rank aggregation method for ensemble-based feature selection
Authors: Jain Rahi , Xu Wei
Published: July 2022

Background

Feature selection (FS) reduces the dimensions of high dimensional data. Among many FS approaches, ensemble-based feature selection (EFS) is one of the commonly used approaches. The rank aggregation (RA) step influences the feature selection of EFS. Currently, the EFS approach relies on using a single RA algorithm to pool feature performance and select features. However, a single RA algorithm may not always give optimal performance across all datasets.

Method and Results

This study proposes a novel hybrid rank aggregation (HRA) method to perform the RA step in EFS which allows the selection of features based on their importance across different RA techniques. The approach allows creation of a RA matrix which contains feature performance or importance in each RA technique followed by an unsupervised learning-based selection of features based on their performance/importance in RA matrix. The algorithm is tested under different simulation scenarios for continuous outcomes and several real data studies for continuous, binary and time to event outcomes and compared with existing RA methods. The study found that HRA provided a better or at par robust performance as compared to existing RA methods in terms of feature selection and predictive performance of the model.

Conclusion

HRA is an improvement to current single RA based EFS approaches with better and robust performance. The consistent performance in continuous, categorical and time to event outcomes suggest the wide applicability of this method. While the current study limits the testing of HRA on cross-sectional data with input features of a continuous distribution, it could be applied to longitudinal and categorical data.
A Data-Driven Biopsychosocial Framework Determining the Spreading of Chronic Pain
Authors: Tanguay-Sabourin Christophe , Fillingim Matt , Parisien Marc , Guglietti Gianluca V , Zare Azin , Norman Jax , Da-ano Ronrick , Perez Jordi , Thompson Scott J , Martel Marc O , Roy Mathieu , Diatchenko Luda , Vachon-Presseau Etienne
Published: July 2022

Chronic pain conditions are complex syndromes characterized by a mosaic of biological, psychological, and social factors. We derived predictive models for the number of co- existing pain sites in the UK Biobank and identified a common risk score that classified different chronic pain conditions in cross-sectional data, predicted the development of chronic pain in pain-free individuals, and determined the spreading of chronic pain to multiple sites or its recovery nine years later. The features with the strongest prognosis included sleeplessness, feeling ‘fed-up’, tiredness, stressful life events, and a BMI > 30. The risk score for pain was associated with an inflammatory blood marker, a polygenic risk score for pain, and a neuroimaging-based marker for sustained pain. The demonstration of a common biopsychosocial risk factor for different clinical pain conditions may help better characterize a general chronic pain syndrome, tailor research protocols, optimize patient randomization in clinical trials, and improve pain management.
Novel kinome profiling technology reveals drug treatment is patient and 2D/3D model dependent in GBM
Authors: Fabro Federica , Kannegieter Nynke M. , de Graaf Erik L. , Queiroz Karla , Lamfers Martine L.M. , Ressa Anna , Leenstra Sieger
Published: July 2022

Glioblastoma is the deadliest brain cancer. One of the main reasons for poor outcome resides in therapy resistance, which adds additional challenges in finding an effective treatment. Small protein kinase inhibitors are molecules that have become widely studied for cancer treatments, including glioblastoma. However, none of these drugs have demonstrated a therapeutic activity or brought more benefit compared to the current standard procedure in clinical trials. Hence, understanding the reasons of the limited efficacy and drug resistance is valuable to develop more effective strategies toward the future. To gain novel insights into the method of action and drug resistance in glioblastoma, we established in parallel two patient-derived glioblastoma 2D and 3D organotypic multicellular spheroids models, and exposed them to a prolonged treatment of three weeks with temozolomide or either the two small protein kinase inhibitors enzastaurin and imatinib. We coupled the phenotypic evidence of cytotoxicity, proliferation, and migration to a novel kinase activity profiling platform (QuantaKinome™) that measured the activities of the intracellular network of kinases affected by the drug treatments. The results revealed a heterogeneous inter-patient phenotypic and molecular response to the different drugs. In general, small differences in kinase activation were observed, suggesting an intrinsic low influence of the drugs to the fundamental cellular processes like proliferation and migration. The pathway analysis indicated that many of the endogenously detected kinases were associated with the ErbB signaling pathway. We showed the intertumoral variability in drug responses, both in terms of efficacy and resistance, indicating the importance of pursuing a more personalized approach. In addition, we observed the influence derived from the application of 2D or 3D models in in vitro studies of kinases involved in the ErbB signaling pathway. We identified in one 3D sample a new resistance mechanism derived from imatinib treatment that results in a more invasive behavior. The present study applied a new approach to detect unique and specific drug effects associated with pathways in in vitro screening of compounds, to foster future drug development strategies for clinical research in glioblastoma.
Multimodal electrocorticogram active electrode array based on zinc oxide-thin film transistors
Authors: Zhang Fan , Zhang Luxi , Xia Jie , Zhao Wanpeng , Dong Shurong , Ye Zhi , Pan Gang , Luo Jikui , Zhang Shaomin
Published: July 2022

Active electrocorticogram (ECoG) electrodes can amplify the weak electrophysiological signals and improve the anti-interference ability, but the traditional active electrodes are so opaque that cannot realize photoelectric collaborative observation. Here an active and fully-transparent ECoG array based on zinc oxide-thin film transistors (ZnO-TFTs) was developed as the local neural signal amplifier for electrophysiological monitoring. The transparency of the proposed ECoG array was up to 85% which is superior to previous reported active electrode array. Various electrical characterizations demonstrated its ability of electrophysiological signal recording, with a higher signal-to-noise ratio of 19.9 dB compared to the Au grid one (13.2 dB). The high transparency of ZnO-TFT electrode array allowed the collecting electrophysiological signals under direct light stimulation on optogenetic mice brain concurrently. The ECoG array could also work under 7-Tesla magnetic resonance imaging to record local brain signal without affecting brain tissue imaging. As the most transparent active ECoG array to date, it provides a powerful multimodal tool for brain observation, including recording brain activity under synchronized optical modulation and 7-Tesla magnetic resonance imaging.
Self-organized anteroposterior regionalization of early midbrain and hindbrain using micropatterned human embryonic stem cells
Authors: Xie Tianfa , Brown Lauren E. , Pak ChangHui , Sun Yubing
Published: July 2022

To develop into the central nervous system, neuroepithelial cells must first form a neural tube consisting of a series of patterned neural progenitor cells along the anterior-posterior (AP) axis. Based on studies using model organisms, it has been revealed that AP spatial regionalization is dominated by gradients of morphogens that regulate retinoic acid (RA), sonic hedgehog (SHH), bone morphogenetic proteins (BMPs), and Wingless/int1 (WNT) signaling pathways. Recently, human pluripotent stem cells (hPSCs) were successfully induced into a patterned neural tissue with differential AP gene expression levels by a gradient of WNT activity controlled by a microfluidic device. However, the midbrain and hindbrain boundaries were not as sharp as observed in vivo, likely due to the lack of additional important morphogenic factors, such as RA and SHH. Here, we induced micropatterned hPSCs into AP patterned neural tissue by activating not only WNT but also RA and SHH signals under fully defined culture conditions. We found that hPSCs self-organized into spatially patterned midbrain (FOXG1-OTX2+) and hindbrain (HOXB4+) progenitors with a sharp boundary after 6 days of induction. Following the initial induction, the cells with midbrain identities near the pattern boundary folded inwardly to form a 3D structure, maintaining a distinct boundary between OTX2+ and HOXB4+ zones. To investigate the mechanism of cell fates patterning, we found that the reaction-diffusion of BMP/Noggin played a role in AP regionalization, while differential mechanical stress and cell sorting were unlikely to be involved. Then, we validated our model by investigating the effects of exposure to two known teratogens including valproic acid and isotretinoin. Drug treatment results successfully predicted that valproic acid inhibited the development of both midbrain and hindbrain development while isotretinoin disrupts the normal AP patterning of the midbrain and hindbrain. In conclusion, by integrating engineering approaches and chemically defined culture conditions, we have developed an in vitro AP patterned model of early human midbrain and hindbrain development, and we have revealed its potential to be employed as a high throughput drug discovery system.
DrosOmics: a comparative genomics browser to explore omics data in natural populations ofD. melanogaster
Authors: Coronado-Zamora Marta , Salces-Ortiz Judit , González Josefa
Published: July 2022

The advent of long-read sequencing technologies has allowed the generation of multiple high-quality de novo genome assemblies for multiple species, including well-known model species such asDrosophila melanogaster. Genome assemblies for multiple individuals of the same species are key to discover the genetic diversity present in natural populations, especially the one generated by transposable elements, the most common type of structural variant. Despite the availability of multiple genomic datasets forD. melanogasterpopulations, we lack an efficient visual tool to display different genomes assemblies simultaneously. In this work, we present DrosOmics, a comparative genomics-oriented browser for 52 high-quality reference genomes ofD. melanogaster, including annotations from a highly reliable set of transposable elements, and functional transcriptomics and epigenomics data for half the populations. DrosOmics is based on JBrowse 2, which allows the visualization of multiple assemblies at once, key to unraveling structural and functional features ofD. melanogasternatural populations.
Grain filling leads to backflow of surplus water in maize grain via the xylem to the cob and plant
Authors: Zhang Gui-Ping , Marasini Mukti , Li Wei-Wei , Zhang Feng-Lu
Published: July 2022

The rapid dehydration rate of maize grain is one of the main characteristics of cultivar selection of mechanical grain harvest, but the dominant driving force and mechanism of grain dehydration before physiological maturity remains disputable and obscure, respectively. This study found that, from grain formation to 5-10 days before physiological maturity of early and middle maturity maize cultivars, the main driving force of grain dehydration is filling and then converts to surface evaporation, by comparing the grain moisture content and dehydration rate between grain coated treatment and control. In the dye movement experiment, xylem-mobile dye movement into grain through pedicel xylem was observed during grain formation period, and declined and gradually not observed after grain formation. Xylem-mobile dye movement out of ear via cob, ear-pedicel and stem xylem was observed after grain formation. In addition, from grain formation to physiological maturity, there was a very significant positive correlation between grain filling rate and dehydration rate. According to these results, it is proposed here that in the grain dehydration phase driven by filling, the surplus water in grain flows back to cob via pedicel xylem, and some of it flows back to plant via cob and ear-pedicel xylem.

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The surplus water in grain driven by grain filling flows back to the cob and plant for recyclingvia the xylem during the development of maize grain.
PD-L1ATTAC mice reveal the potential of targeting PD-L1 expressing cells in cancer therapy
Authors: Fueyo-Marcos Elena , Fustero-Torre Coral , Lopez Gema , Antón Marta Elena , Al-Shahrour Fátima , Fernández-Capetillo Oscar , Murga Matilde
Published: July 2022

Antibodies targeting the PD-1 receptor and its ligand PD-L1 have shown impressive responses in some tumors of bad prognosis. We hypothesized that the selective elimination of PD-L1 expressing cells could similarly have antitumoral effects. To address this question, we developed an inducible suicidal knock-in mouse allele of Pd-l1 (PD-L1ATTAC) which allows for the tracking and specific elimination of PD-L1-expressing cells in adult tissues. Elimination of PD-L1 expressing cells from the mouse peritoneum increased the septic response to lipopolysaccharide (LPS), due to an exacerbated inflammatory response to the endotoxin. In addition, mice depleted of PD-L1+ cells were resistant to colon cancer peritoneal allografts, which was associated with a loss of immunosuppresive B cells and macrophages, concomitant with an increase in activated cytotoxic CD8 T cells. Collectively, these results illustrate the usefulness of PD-L1ATTAC mice and provide genetic support to the concept of targeting PD-L1 expressing cells in cancer therapy.
Dynamicin vivomapping of the methylproteome using a chemoenzymatic approach
Authors: Farhi Jonathan , Emenike Benjamin , Lee Richard S. , Beusch Christian M. , Jones Robert B. , Verma Ashish K. , Jones Celina Y. , Foroozani Maryam , Reeves Monica , Sad Kirti , Parwani Kiran K. , Bagchi Pritha , Deal Roger B. , Katz David J. , Corbett Anita H. , Gordon David E. , Raj Monika , Spangle Jennifer M.
Published: July 2022

Dynamic protein post-translation methylation is essential for cellular function, highlighted by the essential role of methylation in transcriptional regulation and its aberrant dysregulation in diseases including cancer. This underscores the importance of cataloging the cellular methylproteome. However, comprehensive analysis of the methylproteome remains elusive due to limitations in current enrichment and analysis pipelines. Here, we employ an L-Methionine analogue, ProSeMet, that is chemoenzymatically converted to the SAM analogue ProSeAM in cells andin vivoto tag proteins with a biorthogonal alkyne that can be directly detected via LC-MS/MS, or functionalized for subsequent selective enrichment and LC-MS/MS identification. Without enrichment, we identify lysine mono-, di-, and trimethylation, histidine methylation, and arginine methylation with site specific resolution on proteins including heat shock protein HSPA8, for which methylation is implicated in human disease. With enrichment, we identify 486 proteins known to be methylated and 221 proteins with novel methylation sites encompassing diverse cellular functions. Systemic ProSeMet delivery in mice pseudomethylates proteins across organ systems with blood-brain barrier penetrance and identifies site-specific pseudomethylationin vivowith LC-MS/MS. Leveraging these pipelines to define the cellular methylproteome may have broad applications for understanding the methylproteome in the context of disease.
Tauopathy and alcohol consumption interact to alter locus coeruleus excitatory transmission and excitability in male and female mice
Authors: Downs Anthony M. , Catavero Christina M , Kasten Michael R. , McElligott Zoé A.
Published: July 2022

Alcohol use disorder is a major public health concern in the United States. Recent work has suggested a link between chronic alcohol consumption and the development of tauopathy disorders, such as Alzheimer’s Disease and Frontal-Temporal Dementia. However, relatively little work has investigated changes in neural circuitry involved in both tauopathy disorders and alcohol use disorder. The locus coeruleus (LC) is the major noradrenergic nuclei in the brain and is one of the earliest sites to be affected by tau lesions. The LC is also implicated in the rewarding effects of ethanol and alcohol withdrawal. In this study we assessed effects of long-term ethanol consumption and tauopathy on the physiology of LC neurons. Male and female P301S mice, a humanized transgenic mouse model of tauopathy, underwent 16 weeks of intermittent access to 20% ethanol from 3 to 7 months of age. We observed higher total alcohol consumption in female mice regardless of genotype. Male P301S mice consumed more ethanol and had a greater preference for ethanol than WT males. At the end of the drinking study, LC function was assessed usingex vivowhole cell electrophysiology. We found significant changes in excitatory inputs to the LC due to both ethanol and genotype., We found significantly increased excitability of the LC due to ethanol with greater effects in female P301S mice than WT. Our study identifies significant changes in the LC due to interactions between tauopathy and long-term ethanol use. These findings could have important implications regarding LC activity and changes in behavior due to both ethanol and tauopathy related dementia.