bluuebunny/crossref_metadata_2025 huggingface dataset:
Changes in Measures of Vestibular and Balance Function and Hippocampus Volume in Alzheimer’s Disease and Mild Cognitive Impairment
Authors: Cohen Helen S. , Lincoln Christie M. , Pavlik Valory N. , Sangi-Haghpeykar Haleh
Published: June 2022

Objective

To test the hypotheses that people with Alzheimer’s disease and mild cognitive impairment have increased frequency of vestibular impairments and decreased hippocampal volume compared with healthy age-matched controls.

Study Design

Retrospective, with some historical controls.

Setting

Out-patient, tertiary care center.

Subjects

People with mild to moderate dementia diagnosed with Alzheimer’s disease and with mild cognitive impairment. Main Outcome Measures: A standard clinical battery of objective tests of the vestibular system, and screening for balance; available clinical diagnostic magnetic resonance imaging (MRIs) were reviewed and postprocessed to quantify the left and right hippocampal volumes utilizing both manual segmentation and computer automated segmentation.

Results

Study subjects (N = 26) had significantly more vestibular impairments, especially on Dix-Hallpike maneuvers and cervical vestibular evoked myogenic potentials (cVEMP), than historical controls. No differences were found between mild and moderate dementia subjects. Independence on instrumental activities of daily living in subjects with age-normal balance approached statistical differences from subjects with age-abnormal balance. MRI data were available for 11 subjects. Subjects with abnormal cVEMP had significantly reduced left hippocampal MRIs using manual segmentation compared with subjects with normal cVEMP.

Conclusion

The data from this small sample support and extend previous evidence for vestibular impairments in this population. The small MRI sample set should be considered preliminary evidence, and suggests the need for further research, with a more robust sample and high-resolution MRIs performed for the purpose of hippocampal analysis.
Impact of gastroesophageal reflux disease on idiopathic pulmonary fibrosis and lung transplant recipients
Authors: Reddy Chanakyaram A. , Wakwaya Yosafe T.
Published: June 2022

Purpose of review

Idiopathic pulmonary fibrosis (IPF) is a prevalent subset of interstitial lung disease (ILD) that often progresses to require lung transplantation. Gastroesophageal reflux disease (GERD) is common in the IPF population, and GER-related micro-aspiration appears to be an important risk factor for IPF pathogenesis and for the deterioration of transplanted lung function.

Recent findings

Many patients with IPF have elevated esophageal acid exposure on reflux testing despite having no or minimal symptoms. Studies on the effects of medical GERD therapy on IPF-related outcomes have had mixed results. Antireflux surgery is safe in appropriately selected IPF patients, and appears to have potential for slowing the decline of lung function. GERD can persist, improve or develop after lung transplantation, and the presence of GERD is associated with allograft injury and pulmonary function decline in lung transplant recipients.

Clinicians should have a low threshold to assess for objective evidence of GERD in IPF patients. Antireflux surgery in IPF patients with GERD appears to improve lung function, but further studies are needed before surgical treatment can be recommended routinely in this setting. In lung transplant recipients, reflux testing after transplant is the most accurate way to guide GERD treatment decisions.
Refractory eosinophilic esophagitis: what to do when the patient has not responded to proton pump inhibitors, steroids and diet
Authors: Strauss Alexandra L. , Falk Gary W.
Published: June 2022

Purpose of review

Management for patients with refractory eosinophilic esophagitis (EoE) remains a clinical challenge. This review aims to define refractory EoE, explore rates and reasons for nonresponse, and discuss the evidence that informs the approach to these patients.

Recent findings

Many patients will fail first-line therapies for EoE. Longer duration of therapy can increase response rates, and initial nonresponders may respond to alternative first-line therapies. There are ongoing clinical trials evaluating novel therapeutics that hold promise for the future of EoE management. Increasingly, there is recognition of the contribution of oesophageal hypervigilance, symptom-specific anxiety, abnormal motility and oesophageal remodelling to ongoing clinical symptoms in patients with EoE.

For refractory EoE, clinicians should first assess for adherence to treatment, adequate dosing and correct administration. Extending initial trials of therapy or switching to an alternative first-line therapy can increase rates of remission. Patients who are refractory to first-line therapy can consider elemental diets, combination therapy or clinical trials of new therapeutic agents. Patients with histologic remission but ongoing symptoms should be evaluated for fibrostenotic disease with EGD, barium esophagram or the functional luminal imaging probe (FLIP) and should be assessed for the possibility of oesophageal hypervigilance.
Functional luminal imaging probe in the evaluation of esophago-gastric junction outflow obstruction
Authors: Ellison Ashton , Nguyen Anh D.
Published: June 2022

Purpose of review

Esophagogastric junction outflow obstruction (EGJOO) comprises a heterogeneous group of conditions that demonstrate impaired deglutitive relaxation of the esophagogastric junction (EGJ) with intact esophageal peristalsis on high-resolution manometry. Functional luminal imaging probe (FLIP) panometry is a powerful tool that can help to clarify the etiology of this manometric diagnosis. The aim of this review is to summarize the use of FLIP for the evaluation and management of EGJOO.

Recent findings

FLIP panometry provides measures of esophageal compliance at the EGJ and information on esophageal body contractile responses to balloon distention that have important implications for the management of patients with EGJOO. After excluding anatomic causes of impaired EGJ distensibility, FLIP panometry is useful in differentiating true lower esophageal sphincter dysfunction from manometric artifact. FLIP panometry has been shown to be useful in determining the need for invasive treatment in patients with EGJOO, and in intraoperative tailoring of myotomy procedures.

FLIP panometry is easy to perform during endoscopy and provides useful information for characterizing the EGJOO population. FLIP panometry can be used to guide treatment and improve outcomes in the management of patients with EGJOO.
The future of telemedicine and wearable technology in IBD
Authors: Rowan Catherine , Hirten Robert
Published: June 2022

Purpose of review

Telemedicine has quickly become an essential part of modern healthcare, particularly in the management of chronic conditions like inflammatory bowel disease. The purpose of this review is to describe the current use of telehealth, mobile applications and wearable devices in inflammatory bowel disease and potential future applications.

Recent findings

Telemedicine was increasingly used during the Coronavirus Disease 2019 pandemic. Virtual consultations allowed clinical care to continue despite pandemic-related restrictions without compromising the quality of care for patients with inflammatory bowel disease (IBD). It also benefits patients who would not have access to care due to financial or geographical barriers. Mobile applications allow patients with IBD to record disease activity among other metrics, allowing for earlier healthcare provider intervention. Wearable devices are increasingly being explored to monitor physiological indicators of disease activity and flare.

Telehealth and remote patient monitoring has been successfully integrated into the care of IBD patients. The advantages of these modalities include better access to specialist care and remote noninvasive disease monitoring. Careful consideration must be given to patient privacy, data protection and equitable access. These modalities have enormous potential to improve patient care through accurate consistent data collection and even the prediction of disease activity.
Precision medicine: how multiomics will shape the future of inflammatory bowel disease?
Authors: Borren Nienke Z. , Ananthakrishnan Ashwin N.
Published: June 2022

Purpose of review

In this article, we provide an overview of studies examining multiomic profiling in various clinical scenarios in the management of inflammatory bowel diseases (IBDs).

Recent findings

IBD arises as a result of an interplay between genetic, environmental, microbial and immunologic perturbations. The access to high throughput technology as well as the decrease in costs associated with such studies has led to a growing wealth of literature examining the utility of single or multiomic profiles in the management of IBD. Such studies have commonly examined the genome (and less frequently the epigenome), transcriptome, metabolome, proteome and the gut microbial metagenome in the context of overall IBD status or specific clinical scenarios, including the disease progression or response to treatment. The findings have provided important insight into how each of these compartments reflect underlying disease pathophysiologic processes and, in turn, can influence stratification of patients for clinical management.

Multiomic profiling in IBD has the potential to advance the field of personalized precision medicine in the management of IBDs.
Management of refractory inflammatory bowel disease
Authors: Gergely Maté , Prado Eric , Deepak Parakkal
Published: June 2022

Purpose of review

Nearly one-third of patients with inflammatory bowel disease (IBD) do not achieve remission despite our best therapies. When this happens, it is critical to understand the reason for treatment failure. Once nonresponse is confirmed, these patients should be referred to an IBD centre for multidisciplinary care. This review will discuss the remaining treatment options, including escalation of biologics to unlicensed doses, combination biologics, nonvalidated therapies and surgical options. It will additionally provide updates in the management of acute severe ulcerative colitis (ASUC).

Recent findings

There is an increasing interest in combination biologics to treat refractory IBD, although data supporting its safety and effectiveness are limited. The use of hyperbaric oxygen, mesenchymal stem cell therapy and dietary interventions also show early promise in this area. Studies have additionally focused on personalized therapy to identify aggressive phenotypes and predict treatment response in these challenging patients. In ASUC, infliximab and cyclosporine remain mainstays of treatment, and tofacitinib shows promise as a salvage therapy.

Refractory IBD is common, yet large knowledge gaps remain. Recent and ongoing studies have focused on medical, surgical and dietary approaches with mixed success. Larger prospective studies are desperately needed to address this complex issue.
Inflammatory bowel disease in underserved populations: lessons for practice
Authors: Odufalu Florence-Damilola , Aboubakr Aiya , Anyane-Yeboa Adjoa
Published: June 2022

Purpose of review

The incidence of inflammatory bowel disease (IBD) is increasing in minority groups across the USA. There are racial and ethnic disparities in IBD care and outcomes that are rooted in historical injustice and inequities in the social determinants of health.

Recent findings

Current literature has identified racial, ethnic and sociodemographic disparities in therapeutics and outcomes for IBD, including disease severity, morbidity and mortality.

Strategies to achieve equity in IBD include tackling structural racism as a driver of health disparities and making actionable changes against multilevel barriers to care.
Clinical decision support systems to guide healthcare providers on HIV testing
Authors: Smit Mikaela , Jordans Carlijn C.E. , Reinhard Jitte M. , Bramer Wichor M. , Verbon Annelies , Rokx Casper , Calmy Alexandra
Published: June 2022

Objective:

To understand the impact of clinical decision support systems (CDSSs) on improving HIV testing and diagnosis.

Design:

An original global systematic review (PROSPERO Number: CRD42020175576) of peer-reviewed articles reporting on electronic CDSSs that generate triggers encouraging healthcare providers to perform an HIV test.

Methods:

Medline, Embase, Cochrane CENTRAL and CINAHL EBSCOhost were searched up to 17 November 2020 and reference lists of included articles were checked. Qualitative and quantitative syntheses (using meta-analyses) of identified studies were performed.

Results:

The search identified 1424 records. Twenty-two articles met inclusion criteria (19 of 22 non-HIV endemic settings); 18 clinical and four laboratory-driven reminders. Reminders promoted ‘universal’ HIV testing for all patients without a known HIV infection and no recent documented HIV test, or ‘targeted’ HIV testing in patients with clinical risk-factors or specific diagnostic tests. CDSSs increased HIV testing in hospital and nonhospital setting, with the pooled risk-ratio amongst studies reporting comparable outcome measures in hospital settings (n = 3) of 2.57 [95% confidence interval (CI) 1.53–4.33, random-effect model] and in nonhospital settings (n = 4) of 2.13 (95% CI 1.78–4.14, random effect model). Results of the clinical impact of CDSSs on HIV diagnosis were mixed.

Conclusion:

CDSSs improve HIV testing and may, potentially, improve diagnosis. The data support the broader study of CDSSs in low- and high prevalent HIV settings to determine their precise impact on UNAIDS goals to reach universal HIV testing and treatment coverage.
Effectiveness of an Interactive, Highly Tailored “Video Doctor” Intervention to Suppress Viral Load and Retain Patients With HIV in Clinical Care: A Randomized Clinical Trial
Authors: Lewis Megan A. , Harshbarger Camilla , Bann Carla , Marconi Vincent C. , Somboonwit Charurut , Piazza Michelle Dalla , Swaminathan Shobha , Burrus Olivia , Galindo Carla , Borkowf Craig B. , Marks Gary , Karns Shawn , Zulkiewicz Brittany , Ortiz Alexa , Abdallah Iddrisu , Garner Bryan R. , Courtenay-Quirk Cari ,   for the Positive Health Check Study Team
Published: June 2022

Background:

To determine whether Positive Health Check, a highly tailored video doctor intervention, can improve viral suppression and retention in care.

Setting:

Four clinics that deliver HIV primary care.

Methods:

A hybrid type 1 effectiveness-implementation randomized trial design was used to test study hypotheses. Participants (N = 799) who were not virally suppressed, were new to care, or had fallen out of care were randomly assigned to receive Positive Health Check or the standard of care alone. The primary endpoint was viral load suppression, and the secondary endpoint was retention in care, both assessed at 12 months, using an intention-to-treat approach. A priori subgroup analyses based on sex assigned at birth and race were examined as well.

Results:

There were no statistically significant differences between Positive Health Check (N = 397) and standard of care (N = 402) for either endpoint. However, statistically significant group differences were identified from a priori subgroup analyses. Male participants receiving Positive Health Check were more likely to achieve suppression at 12 months than male participants receiving standard of care adjusted risk ratio [aRR] [95% confidence interval (CI)] = 1.14 (1.00 to 1.29), P = 0.046}. For retention in care, there was a statistically significant lower risk for a 6-month visit gap in the Positive Health Check arm for the youngest participants, 18–29 years old [aRR (95% CI) = 0.55 (0.33 to 0.92), P = 0.024] and the oldest participants, 60–81 years old [aRR (95% CI) = 0.49 (0.30 to 0.81), P = 0.006].

Conclusions:

Positive Health Check may help male participants with HIV achieve viral suppression, and younger and older patients consistently attend HIV care.

Registry Name:

Positive Health Check Evaluation Trial. Trial ID: 1U18PS004967-01. URL: https://clinicaltrials.gov/ct2/show/NCT03292913.
Pediatric Cases of Recurrent Skull Giant Osteoma Misdiagnosed as Fibrous Dysplasia
Authors: Kim Yumin , Kim Byungjun
Published: June 2022

Osteomas are benign mature bone tumors that typically arise in the skull. Osteomas larger than 3 cm in diameter are considered giant osteomas. Giant osteomas of the skull vault are very rare, especially in children; therefore, only a few cases have been reported in the literature. Although osteomas are usually asymptomatic, a large skull mass can cause headache, as well as esthetic disfigurement of the forehead. it can be misdiagnosed as other conditions, such as fibrous dysplasia, ossifying cephalhematoma, or other malignant bone tumors. Herein, the authors report 2 rare pediatric cases of giant osteomas mimicking fibrous dysplasia and their successful surgical excision. These cases showed good results without recurrence or complications on long-term follow-up after complete excision.
Prognosis of Continuous Positive Airway Pressure Treatment to Velopharyngeal Insufficiency: Preliminary Study
Authors: Kim Jong Seong , Lee Seung Eun , Ryu Jeong Yeop , Lee Joon Seok , Yang Jung Dug , Chung Ho Yun , Cho Byung Chae , Choi Kang Young
Published: June 2022

Background:

Cleft palate is a congenital malformation that causes hypernasality and decreases the intelligibility of pronunciation and leads to velopharyngeal insufficiency. It causes difficulty in language development. Many studies and treatments have been conducted to reduce this problem, but there are limitations. In this study, the effect obtained through continuous positive airway pressure (CPAP) treatment was analyzed by statistical methods.

Methods:

From May 2012 to December 2018, using patient demographics, computed tomography (CT) scan, and nasalance test was performed on 25 patient groups treated with CPAP devices for 8 weeks to confirm the effect after 6 months.

Results:

After CPAP treatment in a total of 25 patients, 13 patients had a therapeutic effect. The average age of the patient group with treatment effect (effective group [EG]) was 51.2months, and the patient group with no treatment effect (ineffective group [iG]) was 73.6 months. (P < 0.05). In CT data analysis, the highest palatal arch point was 6.31 mm in EG and 7.36 mm in IG, which was lower in EG (P < 0.01), and the distance from incisive foramen to posterior pharyngeal wall was 41.39 mm in EG and 49.07 mm in IG (P < 0.05).

Conclusions:

Through the statistical analysis, the group of patients who were effective in treatment had a low age at the beginning of treatment, the height of highest palatal arch point was low on CT data, and the length of distance from incisive foramen to posterior pharyngeal wall was short. It will be helpful to set the CPAP treatment patient group with respect to the results and age and CT data when treating VPI patients.
Two Pre-Expanded Free Flaps Used for Auricular Reconstruction and Ipsilateral Facial Scar Release
Authors: Pei Jiaomiao , Zhang Juan , Song Baoqiang , Li Yang , Guo Shuzhong
Published: June 2022

Objectives:

Auricular reconstruction is a great challenge for surgeons to achieve good aesthetic outcomes when adjacent tissues were burned. Compared with pedicle flap therapies, there are some advantages of pre-expanded free flaps for ear rebuilding, such as thinner layer tissues for aesthetic requirements of delicate auricular structures and less donor site deformity. In this study, the authors introduced 6 sequential surgical procedures for total auricular reconstruction with severe ipsilateral facial scar.

Methods:

Pre-expanded deltopectoral flap was used to release periauricular contracture and repair facial scar. The injured ear was restored by expanded forearm flap including autologous cartilage framework. The surgical procedures were lasted more than 2 years. An 8 and half year's follow-up was performed from November 2012 to April 2021. The clinical data and surgical techniques were recorded and analyzed.

Results:

The patient was satisfied with the aesthetic outcomes of the new ear. The skin texture and color of the grafts were approximately matched to the recipient sites. Facial expression was not affected severely. Sensations of the transferred flap and new ear had partially recovered. The donor sites were recovered without severe complication.

Conclusions:

The pre-expanded free forearm flap is a feasible method for total ear reconstruction when local flap therapies could not be applied. Repair of ipsilateral facial scar is beneficial for auricular procedures.
Efficacy and Safety of Cryotherapy for Residual Tarsus and Free Tarsal Graft Implantation After Excision of Malignant Eyelid Tumor
Authors: Yunoki Tatsuya , Hayashi Atsushi , Oiwake Toshihiko , Yamazaki Hitoshi
Published: June 2022

Purpose:

To examine the usefulness and safety of cryotherapy for residual tarsus and free tarsal graft implantation for eyelid reconstruction after excision of malignant eyelid tumor.

Methods:

Fifteen patients with 17 eyelid malignancies (10 sebaceous gland carcinomas and 7 basal cell carcinomas) who underwent eyelid reconstruction between June 2017 and February 2021 were included in the study. In these patients, the tumors were resected in the entire eyelid layer including the safety margin. Only sebaceous gland carcinomas patients underwent cryotherapy at the residual tarsus margin. Then, a free tarsal graft taken from the ipsilateral or contralateral upper eyelid was transplanted into the eyelid plate defect, and anterior lamella reconstruction was performed with an orbicularis oculi myocutaneous advance flap.

Results:

In both the non-cryotherapy and cryotherapy groups, there were no serious complications such as dropout or necrosis of the free tarsal graft. There were no differences in the occurrence of complications such as eyelid retraction or trichiasis between the 2 groups, but 1 patient who underwent cryotherapy required revision surgery to correct eyelid retraction. In addition, there were no complications on the donor side associated with free tarsal graft collection.

Conclusions:

The use of a free tarsal graft in the reconstruction of eyelid malignancies is relatively effective and safe, and if vascular support of the anterior lamella is obtained, cryotherapy is less likely to affect the viability of the free tarsal graft and may contribute to a decrease in local recurrence.
Analysis of Pediatric Facial Fracture Repair Rates and Complications Using California’s Office of Statewide Health Planning and Development Database
Authors: Chopra Christina Shree , Neubauer Daniel C. , Hornacek Michael , Calvo Richard , Segal Rachel , Martin Matthew , Reid Christopher M. , Gosman Amanda A.
Published: June 2022

Background:

There exists a paucity of data on which pediatric facial fractures should be surgically repaired and when. In this study, the authors used a California state-wide database to determine the prevalence of facial fractures in the pediatric population and examine, which fractures are repaired. in addition to the timing of the repair, complications and resource utilization of the healthcare system were analyzed.

Methods:

Pediatric patients under the age of 18 were identified using the California Office of Statewide Health Planning and Development patient discharge database for admissions occurring between January 2015 and December 2018. International Classification of Diseases, Version 10 diagnosis codes were used to classify facial fractures. The associated diagnoses, complications, and number of subsequent repairs patients underwent were analyzed to determine the typical course of pediatric facial fractures.

Results:

Of the 3058 patients diagnosed with facial fracture, 32% underwent surgical repair (N = 982). The 4 most repaired fractures were mandible (40%), nasal (16.2%), and orbital (15.1%). Surgical intervention steadily increased with age, with a peak in the 12 to 15-year-old cohort.

Conclusions:

Our analysis found that most fractures were managed nonoperatively, but those that did receive an operation did so during their index admission. In addition, the most repaired fractures were mandibular, nasal, and orbital fractures. The present study represents 1 of the largest pediatric samples to have assessed facial fractures, repair rates, and their sequelae.
Clinico-Pathological Characteristics, Management, and Outcome of Benign Intraosseous Maxillary Tumors in Adolescents: A Prospective Study
Authors: Hassanein Ahmed Gaber , Kukreja Pankaj , Hassanein Kamal A.M. , Mansour Omar Mohammed , Amer Islam A. , Ftohy Tarek Elsayed
Published: June 2022

Introduction:

Benign intraosseous maxillary tumors, although uncommon among the adolescents, represent a major challenge to the maxillofacial surgeons. Treatment ranges from conservative surgery to radical resection and reconstruction. Maxillary defect reconstruction in adolescents is uncommon. it can be achieved by prosthetic obturators, local and regional flaps, and free-tissue transfer.

Aim of the work:

To investigate the clinical and pathological patterns, treatment, and outcome of benign intraosseous maxillary tumors in adolescents.

Patients and methods:

A 10-years prospective study included patients between 12–18 years who presented with benign intraosseous maxillary tumors and surgically treated (conservative surgery or radical resection) with immediate reconstruction. Cases were followed up to assess functional and aesthetic outcomes and detect complications.

Results:

Study included 38 patients; 63.2% had non-odontogenic tumors and 36.8% had odontogenic tumors. The most common non-odontogenic tumor was central giant cell granuloma (31.6%). The most common odontogenic tumors were adenomatoid odontogenic tumor and ameloblastoma (10.5% each). Treatment included Conservative surgery (55.3%) and radical resection (44.7%). Reconstruction was performed in 17 cases by temporalis muscle flap (9.83%), obturator (2.46%), and free fibula flap (1.64%). All cases gained accepted functional and esthetic results.

Conclusions:

Non-odontogenic tumors were more common than odontogenic tumors. Central giant cell granulomas and ossifying fibromas were the most common non-odontogenic tumors. Ade-nomatoid odontogenic tumor and ameloblastoma were the most common odontogenic tumors. Maxillary reconstructions with tem-poralis muscle flap and obturator were simple and satisfactory. Microsurgical reconstruction had high success rates. Aesthetic, and functional results were satisfactory when appropriate reconstruction was performed.
Single-cell Transcriptomics Reveals Dynamic Role of Smooth Muscle Cells and Enrichment of Immune Cell Subsets in Human Abdominal Aortic Aneurysms
Authors: Davis Frank M. , Tsoi Lam C. , Ma Feiyang , Wasikowski Rachael , Moore Bethany B. , Kunkel Steven L. , Gudjonsson Johann E. , Gallagher Katherine A.
Published: June 2022

Objective:

To determine cell-specific gene expression profiles that contribute to development of abdominal aortic aneurysms (AAAs).

Background:

AAAs represent the most common pathological aortic dilation leading to the fatal consequence of aortic rupture. Both immune and structural cells contribute to aortic degeneration, however, gene specific alterations in these cellular subsets are poorly understood.

Methods:

We performed single-cell RNA sequencing (scRNA-seq) analysis of AAAs and control tissues. AAA-related changes were examined by comparing gene expression profiles as well as detailed receptor-ligand interactions. An integrative analysis of scRNA-seq data with large genome-wide association study data was conducted to identify genes critical for AAA development.

Results:

Using scRNA-seq we provide the first comprehensive characterization of the cellular landscape in human AAA tissues. Unbiased clustering analysis of transcriptional profiles identified seventeen clusters representing 8 cell lineages. For immune cells, clustering analysis identified 4 T-cell and 5 monocyte/macrophage subpopulations, with distinct transcriptional profiles in AAAs compared to controls. Gene enrichment analysis on immune subsets identified multiple pathways only expressed in AAA tissue, including those involved in mitochondrial dysfunction, proliferation, and cytokine secretion. Moreover, receptor-ligand analysis defined robust interactions between vascular smooth muscle cells and myeloid populations in AAA tissues. Lastly, integrated analysis of scRNA-seq data with genome-wide association study studies determined that vascular smooth muscle cell expression of SORT1 is critical for maintaining normal aortic wall function.

Conclusions:

Here we provide the first comprehensive evaluation of single-cell composition of the abdominal aortic wall and reveal how the gene expression landscape is altered in human AAAs.
Enhanced conformational exploration of protein loops using a global parameterization of the backbone geometry
Authors: O’Donnell Timothée , Cazals Frédéric
Published: June 2022

Flexible loops are paramount to protein functions, with action modes ranging from localized dynamics contributing to the free energy of the system, to large amplitude conformational changes accounting for the repositioning whole secondary structure elements or protein domains. However, generating diverse and low energy loops remains a difficult problem.

This work introduces a novel paradigm to sample loop conformations, in the spirit of the Hit-and- Run (HAR) Markov chain Monte Carlo technique. The algorithm uses a decomposition of the loop into tripeptides, and a novel characterization of necessary conditions for Tripeptide Loop Closure to admit solutions. Denotingmthe number of tripeptides, the algorithm works in an angular space of dimension 12m. In this space, the hyper-surfaces associated with the aforementioned necessary conditions are used to run a HAR-like sampling technique.

On classical loop cases up to 15 amino acids, our parameter free method compares favorably to previous work, generating more diverse conformational ensembles. We also report experiments on a 30 amino acids long loop, a size not processed in any previous work.
Functional regulation of an intrinsically disordered protein via a conformationally excited state
Authors: Madhurima Kulkarni , Nandi Bodhisatwa , Munshi Sneha , Naganathan Athi N. , Sekhar Ashok
Published: June 2022

A longstanding goal in the field of intrinsically disordered proteins (IDP) is to characterize their structural heterogeneity and pinpoint the role of this heterogeneity in IDP function. Here, we use multinuclear chemical exchange saturation (CEST) NMR to determine the structure of a thermally accessible globally folded excited state in equilibrium with the intrinsically disordered native ensemble of a bacterial transcriptional regulator CytR. We further provide evidence from double resonance CEST experiments that the excited state, which structurally resembles the DNA-bound form of CytR, recognizes DNA by means of a ‘folding-before-binding’ conformational selection pathway. The disorder-to-order regulatory switch in DNA recognition by natively disordered CytR therefore operates through a dynamical variant of the lock-and-key mechanism where the structurally complementary conformation is transiently accessed via thermal fluctuations.

One-Sentence Summary

The intrinsically disordered cytidine repressor binds DNA via a folding-before-binding conformational selection mechanism
Penetratin inhibits α-synuclein fibrillation and improves locomotor functions in mice model of Parkinson’s disease
Authors: Gupta Arpit , Singh Priyanka , Mehrotra Arpit , Gautam Ankur , Srividya K. , Panigrahi Rajlaxmi , Vashishtha Shubham , Singh Jasdeep , Jaiswal Gagandeep , Upadhayay Krishna , Frank Signe Andrea , Nielsen Janni , Nath Samir Kumar , Khatri Neeraj , Otzen Daniel E. , Raghava G.P.S. , Koul Anil , Kundu Bishwajit , Kumar Ashutosh , Nazir Aamir , Sharma Deepak
Published: June 2022

Parkinson’s disease (PD) is the second most common neurodegenerative disease. The presence of lewy bodies, primarily consisting of α-synuclein (α-syn) aggregates is one of the common features seen in the substantia nigra region of the brain in PD patients. The disease remains incurable and only symptomatic relief is available. We screened various cell-penetrating peptides and reveal that penetratin is a potent inhibitor of α-syn aggregationin-vitro, and significantly improved locomotor coordination in mice models of PDin-vivo. The peptide inhibits α-syn aggregation in vitro as well as in yeast, andC.elegansmodels. We further made a cyclic derivative of penetratin by disulfide coupling of N- and C-terminal cysteine residues. Both penetratin and its cyclized derivative interact with α-syn. NMR studies show that both linear as well as cyclic derivative interact at the acidic C-terminal tail of the protein. Similar to penetratin, its cyclic derivative inhibited α-syn aggregation in theC.elegansmodel of Parkinson’s disease, and also improved worm motility. Molecular Dynamics studies show that penetratin interacts with α-synuclein and prevents its conformational transition from disordered into β-sheet rich structure. The therapeutic efficacy of penetratin was further confirmed in a transgenic mice model of the disease, wherein penetratin treatment over a period of 90 days improved locomotor coordination, and halted disease progression. Overall, the present work provides a potent therapeutic agent that could be further explored in the management of PD.
Control Limited Perceptual Decision Making
Authors: Castiñeiras Juan R. , Renart Alfonso
Published: June 2022

Periods of disengagement are generally observed during perceptual decision-making tasks, but a normative understanding of engagement is lacking. Here, we develop a theory that frames disengagement as a problem in cognitive control. Good performance through task engagement requires control, but control is costly, and this establishes a performance-control tradeoff. We derive decision policies that optimize this tradeoff as a function of the capacity of an agent for cognitive control. When their control ability is sufficiently low, agents lapse. For intermediate control limitations, a new decision-making regime appears where agents don’t lapse, but their behavior is nevertheless shaped by control. We identify hidden signatures of control-limited behavior at the level of accuracy, reaction time and decision confidence which are often observed experimentally, but had not been normatively explained. Our findings provide a path to the study of normative decision strategies in real biological agents.
Using a substitute species to inform translocation of an endangered territorial mammal
Authors: Morandini Marina , Koprowski John L.
Published: June 2022

Substitute species can inform management strategies without exposing endangered species unnecessarily. Further, experimental approaches may help to identify the causes of translocation failures, leading to improve the chances of success. We used a surrogate subspecies,Tamiasciurus fremonti fremontito test different translocation techniques to inform potential management actions on the endangered Mt. Graham red squirrel (Tamiasciurus fremonti grahamensis). We fitted VHF radio collars to 54 animals, and we monitored their survival and movements until individuals settled on a new territory. We considered the effect of season, translocation technique (soft or hard release), and body mass on survival, distance moved after release, and time to settlement of translocated animals. Survival probability averaged 0.48 after 60 days from the translocation event and was not affected by season or translocation technique. 54% of the mortality was caused by predation. Distance moved and number of days to settlement varied with season, where winter was characterized by shorter distances (average of 364 m in winter versus 1752 m in fall) and a smaller number of days (6 in winter versus 23 in fall). These data emphasize the potential of substitute species to provide valuable information on possible outcomes of management strategies for closely related endangered species.
Proteome-wide antigenic profiling in Ugandan cohorts identifies associations between age, exposure intensity, and responses to repeat-containing antigens in Plasmodium falciparum
Authors: Raghavan Madhura , Kalantar Katrina L. , Duarte Elias , Teyssier Noam , Takahashi Saki , Kung Andrew F. , Rajan Jayant V , Rek John , Tetteh Kevin K.A. , Drakeley Chris , Ssewanyana Isaac , Rodriguez-Barraquer Isabel , Greenhouse Bryan , DeRisi Joseph L.
Published: June 2022

Protection against Plasmodium falciparum, which is primarily antibody-mediated, requires recurrent exposure to develop. The study of both naturally acquired limited immunity and vaccine induced protection against malaria remains critical for ongoing eradication efforts. Towards this goal, we deployed a customized P. falciparum PhIP-seq T7 phage display library containing 238,068 tiled 62-amino acid peptides, covering all known coding regions, including antigenic variants, to systematically profile antibody targets in 198 Ugandan children and adults from high and moderate transmission settings. Repeat elements – short amino acid sequences repeated within a protein – were significantly enriched in antibody targets. While breadth of responses to repeat-containing peptides was twofold higher in children living in the high versus moderate exposure setting, no such differences were observed for peptides without repeats, suggesting that antibody responses to repeat-containing regions may be more exposure dependent and/or less durable in children than responses to regions without repeats. Additionally, short motifs associated with seroreactivity were extensively shared among hundreds of antigens, potentially representing cross- reactive epitopes. PfEMP1 shared motifs with the greatest number of other antigens, partly driven by the diversity of PfEMP1 sequences. These data suggest that the large number of repeat elements and potential cross-reactive epitopes found within antigenic regions of P. falciparum could contribute to the inefficient nature of malaria immunity.
ANTHRACNOSE RESISTANCE GENE2confers fungal resistance in sorghum
Authors: Mewa Demeke B. , Lee Sanghun , Liao Chao-Jan , Souza Augusto M. , Adeyanju Adedayo , Helm Matthew , Lisch Damon , Mengiste Tesfaye
Published: June 2022

Sorghum is an important food and feed crop globally; its production is hampered by anthracnose disease caused by the fungal pathogenColletotrichum sublineola(Cs). Here, we report identification and characterization ofANTHRACNOSE RESISTANCE GENE 2(ARG2) encoding a nucleotide-binding leucine-rich repeat (NLR) protein that confers race-specific resistance toCsstrains.ARG2is one of a cluster of severalNLRgenes in the sorghum differential line SC328C that is resistant to someCsstrains. This cluster shows structural and copy number variations in different sorghum genotypes. Different sorghum variants carrying independentARG2alleles provided the genetic validation for the identity of theARG2gene.ARG2expression is induced byCs, and chitin induceARG2expression in resistant but not in susceptible lines. ARG2-mediated resistance is accompanied by higher expression of defense and secondary metabolite genes at early stages of infection, and anthocyanin and zeatin metabolisms are upregulated in resistant plants. Interestingly, ARG2 localizes to the plasma membrane when transiently expressed inNicotiana benthamiana. Importantly,ARG2plants produced higher shoot dry matter than near-isogenic lines carrying the susceptible allele suggesting absence of anARG2associated growth trade-off. Further, ARG2-mediated resistance is stable at a wide range of temperatures. Our observations open avenues for resistance breeding and for dissecting mechanisms of resistance.
Coupling cell communication and optogenetics: Implementation of a light-inducible intercellular system in yeast
Authors: Rojas Vicente , Larrondo Luis F.
Published: June 2022

Cell communication is a widespread mechanism in biology, allowing the transmission of information about environmental conditions. In order to understand how cell communication modulates relevant biological processes such as survival, division, differentiation or apoptosis, different synthetic systems based on chemical induction have been successfully developed. In this work, we coupled cell communication and optogenetics in the budding yeast Saccharomyces cerevisiae. Our approach is based on two strains connected by the light-dependent production of α-factor pheromone in one cell type, which induces gene expression in the other type. After the individual characterization of the different variants of both strains, the optogenetic intercellular system was evaluated by combining the cells under contrasting illumination conditions. Using luciferase as a reporter gene, specific co-cultures at 1:1 ratio displayed activation of the response upon constant blue-light, which was not observed for the same cell mixtures grown in darkness. Then, the system was assessed at several dark/blue-light transitions, where the response level varies depending on the moment in which illumination was delivered. Furthermore, we observed that the amplitude of response can be tuned by modifying the initial ratio between both strains. Finally, the two-population system showed higher fold-inductions in comparison with autonomous strains. Altogether, these results demonstrated that external light information is propagated through a diffusible signaling molecule to modulate gene expression in a synthetic system, which will pave the road for studies allowing optogenetic control of population-level dynamics.

Graphical Abstract
Hearing Loss and Tinnitus: Uncover the Mechanism of Tinnitus using Resting-State Functional Magnetic Resonance Imaging (rs-fMRI) Technologies
Authors: Du Haoliang , Feng Xu , Qian Xiaoyun , Zhang Jian , Liu Bing , Huang Zhichun , Gao Xia
Published: June 2022

Purpose

This project aimed to investigate the differences in the intra-regional brain activity and inter-regional functional connectivity in subjects with tinnitus only and subjects with hearing loss and tinnitus, using resting-state functional magnetic resonance imaging (rs-fMRI) technologies, including the Amplitude of Low-Frequency Fluctuations (ALFF), regional homogeneity (ReHo), and Voxel-Wise Functional Connectivity (FC).

Method

We acquired rs-fMRI scans from 82 subjects (21 tinnitus subjects without hearing loss, 32 subjects with tinnitus and hearing loss, and 29 subjects as healthy control). Age, gender, and year of education were matched across all three groups. We consecutively performed ALFF, ReHo, and Voxel-Wise Functional Connectivity (FC) for all subjects.

Result

Compared with the control group (CN), subjects with tinnitus only (T group) and with tinnitus and hearing loss (T+H group) manifested significantly reduced ALFF and ReHo activity within the left and right dorsolateral superior frontal gyrus (SFG). Additional Voxel-Wise Functional Connectivity (FC) revealed decreased connectivity between the dorsolateral SFG (left and right) and right Superior Parietal Gyrus (SPG), right Middle Frontal Gyrus (MFG), and left medial Superior Frontal Gyrus (mSFG) within these two groups. No significant differences were observed between the T and T+H groups.

Conclusion

Upon analyzing our data, we suggested disruptions in brain regions responsible for attention and stimuli monitoring and orientations contribute to tinnitus generation. Thus, hearing loss might not be the primary cause of tinnitus.
Machine learning-based noise reduction for craniofacial bone segmentation in CT images
Authors: Nishimoto Soh , Saito Takuya , Ishise Hisako , Fujiwara Toshihiro , Kawai Kenichiro , Kakibuchi Maso
Published: June 2022

Objective

When high X-ray absorption rate materials such as metal prosthetics are in the field of CT scan, noise called metal artifacts might appear. In reconstructing a three-dimensional bone model from X-ray CT images, the metal artifacts remain. Often, the image of the scanning bed also remains. A machine learning-based system to reduce noises in the craniofacial CT images was constructed.

Methods

DICOM images of CT archives of patients with head and neck tumors were used. The metal artifacts and beds were removed from the threshold segmented images to obtain the target bony images. U-nets, respectively with the function loss of mean squared error, Dice and Jaccard, were trained by the datasets consisting of 5671 DICOM images and corresponding target images. DICOM images of 2000 validation datasets were given to the trained models and predicted images were obtained.

Results

The use of mean squared errors presented superiority to Dice or Jaccard loss. The mean prediction error pixels were 14.43, 778.57, and 757.60 respectively per 512 × 512 pixeled image.

Discussion

Dedicated to the delineation of craniofacial bones, the presented study showed high prediction accuracy. The simplification of the target images may have contributed. The “correctness” of the predictions made by this system may not be guaranteed, but the predictions made in this system were generally satisfactory.
Long-term intrinsic cycling in human life-course antibody responses to influenza A(H3N2)
Authors: Yang Bingyi , Garcia-Carreras Bernardo , Lessler Justin , Read Jonathan M. , Zhu Huachen , Metcalf C. Jessica E. , Hay James A. , Kwok Kin On , Shen Ruiyin , Jiang Chao Qiang , Guan Yi , Riley Steven , Cummings Derek A.T.
Published: June 2022

Over a life-course, human adaptive immunity to antigenically mutable pathogens exhibits competitive and facilitative interactions. We hypothesize that such interactions may lead to cyclic dynamics in immune responses over a lifetime. Here, we demonstrated a long-term periodicity (about 24 years) in individual antibody responses, by analyzing hemagglutination inhibition titers against 21 historical influenza A(H3N2) strains spanning 47 years from a cohort in Guangzhou, China. The reported cycles were robust to analytic and sampling approaches. Simulations suggested that individual-level cross-reaction between antigenically similar strains likely explain the reported cycle. We showed that the reported cycles are predictable at both individual and birth-cohort level and that cohorts show a diversity of phases of these cycles. Phase of cycle was associated with the risk of response to circulating strains, after accounting for age and pre-existing titers of the circulating strains. Our findings reveal the existence of long-term periodicities in individual antibody responses to A(H3N2). We hypothesize that these cycles are driven by pre-existing antibody responses blunting responses to antigenically similar pathogens (by preventing infection and/or robust antibody responses upon infection), leading to reductions in antigen specific responses over time until individual’s increasing risk leads to an infection with an antigenically distant enough virus to generate a robust immune response. These findings could help disentangle cohort-effects from individual-level exposure histories, improve our understanding of observed heterogeneous antibody responses to immunizations, and inform targeted vaccine strategy.