bluuebunny/crossref_metadata_2025 huggingface dataset:
The role of beta-cell dysfunction in early type 1 diabetes
Authors: Sims Emily K. , Mirmira Raghavendra G. , Evans-Molina Carmella
Published: June 2020

Purpose of review

Emerging data have suggested that β-cell dysfunction may exacerbate the development and progression of type 1 diabetes (T1D). In this review, we highlight clinical and preclinical studies suggesting a role for β-cell dysfunction during the evolution of T1D and suggest agents that may promote β-cell health in T1D.

Recent findings

Metabolic abnormalities exist years before development of hyperglycemia and exhibit a reproducible pattern reflecting progressive deterioration of β-cell function and increases in β-cell stress and death. Preclinical studies indicate that T1D may be prevented by modification of pathways impacting intrinsic β-cell stress and antigen presentation. Recent findings suggest that differences in metabolic phenotypes and β-cell stress may reflect differing endotypes of T1D. Multiple pathways representing potential drug targets have been identified, but most remain to be tested in human populations with preclinical disease.

This cumulative body of work shows clear evidence that β-cell stress, dysfunction, and death are harbingers of impending T1D and likely contribute to progression of disease and insulin deficiency. Treatment with agents targeting β-cell health could augment interventions with immunomodulatory therapies but will need to be tested in intervention studies with endpoints carefully designed to capture changes in β-cell function and health.
Lipid management for cardiovascular risk reduction in type 1 diabetes
Authors: Tell Shoshana , Nadeau Kristen J. , Eckel Robert H.
Published: June 2020

Purpose of review

To review the recent evidence for lipid management in type 1 diabetes (T1D) for cardiovascular risk reduction.

Recent findings

Individuals with T1D are at increased risk for cardiovascular morbidity and mortality, with atherosclerosis beginning as early as adolescence. Elevated low-density lipoprotein cholesterol (LDL-C), triglycerides, and lipoprotein (a) are associated with increased cardiovascular risk in T1D. Although high-density lipoprotein cholesterol (HDL-C) in T1D is often normal or higher than in nondiabetic controls, HDL in T1D has structural alterations, which make it proatherogenic rather than cardioprotective. Similarly, although LDL-C is not particularly elevated in T1D, LDL still contributes to cardiovascular risk. Studies in individuals with diabetes have primarily included T2D participants, with a much smaller number of T1D participants; such studies have shown that lipid-lowering therapies, such as statins, ezetimibe, and proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitors reduce LDL-C levels and cardiovascular events in both those with and without diabetes. Individuals with T1D have increased cholesterol absorption, suggesting that ezetimibe may be particularly effective in T1D. Results of the REDUCE-IT trial show cardiovascular risk reduction from high-dose omega-3 fatty acid (Icosapent Ethyl) therapy in patients with diabetes (primarily type 2 diabetes), independent of triglyceride lowering, but similar data in T1D are currently lacking.

Individuals with T1D are at high risk of cardiovascular disease, necessitating close lipid monitoring and management from adolescence through adulthood.
Recent advances in orthognathic surgery
Authors: Jandali Danny , Barrera Jose E.
Published: June 2020

Purpose of review

The aim of this article is to review the recent literature on orthognathic surgery for treatment of malocclusion and obstructive sleep apnea (OSA). The discussion outlines the refinements of the procedure and advances in technology.

Recent findings

Maxillomandibular advancement (MMA) may be performed for complex malocclusion and OSA. Although orthodontic management followed by MMA has been the gold standard in managing complex cases, the surgery first approach for treatment of malocclusion has increased in popularity because of decreased treatment time and improved patient quality of life. MMA continues to be the gold-standard for treatment of refractory sleep apnea. Technological advancements, including 3D printing and virtual surgical planning, have enhanced the patient experience and provided more efficiency to this surgery.

First introduced in the 19th century, orthognathic surgery has continuously been refined. Over the last few decades, there has been increasing support for a surgery first approach in the treatment of malocclusion. MMA has revolutionized the surgical treatment of OSA and provides the best opportunity for success or cure in patients with complex obstructive patterns. Technology has enhanced the surgical process and created more efficiency for the surgeon and patient.

Video abstract

http://links.lww.com/COOH/A40.
Molecular Profiles of Mixed Endometrial Carcinoma
Authors: Matrai Cathleen , Motanagh Samaneh , Mirabelli Susanna , Ma Lucy , He Bing , Chapman-Davis Eloise , Kurtis Boaz , Elemento Olivier , Mosquera Juan Miguel , Ellenson Lora H.
Published: June 2020

Mixed endometrial carcinomas are defined as a combination of 2 or more distinct histologic subtypes, one of which must be a type II tumor comprising at least 5% of the tumor volume. The oncogenesis of these tumors remains unclear, particularly in light of the increasingly appreciated morphologic overlap among subtypes, as well as evolving molecular data. We evaluated 8 cases of mixed endometrial carcinoma, including 4 endometrioid (EC)/serous (SC), 1 SC/clear cell (CC), and 3 EC/CC cases, to study the underlying molecular features and oncogenic mechanisms at play. Each component was analyzed by a targeted next-generation sequencing assay. All tumors shared mutations in both components. In 6 cases, one component showed additional mutations. Two EC/SC cases showed shared mutations and mutations unique to each component. When present, unique mutations were typically seen in the SC component, including variants in POLE and TP53, as well as potentially targetable genes DDR2, MAP2K1, and CCNE1. In EC/SC tumors, ERBB2 abnormalities were seen in 2 cases. EC/CC cases showed FGFR2 activating mutations in the EC component only. No fusion drivers were identified. Our data suggest that the majority of these tumors begin as a single clone and diverge along 2 pathways: (1) tumor progression, with one component showing additional mutations, and (2) tumor divergence, in which tumor components have both shared mutations and mutations unique to each component. In addition, the findings suggest a component of morphologic mimicry in these tumors. Our findings are clinically relevant since targetable mutations may be present in only one component of mixed tumors.
A Molecular Reappraisal of Glomus Tumors and Related Pericytic Neoplasms With Emphasis on NOTCH-gene Fusions
Authors: Agaram Narasimhan P. , Zhang Lei , Jungbluth Achim A. , Dickson Brendan C. , Antonescu Cristina R.
Published: June 2020

Glomus tumors (GTs), together with myofibroma (MF), myopericytoma (MP), and angioleiomyoma (AL) are classified as members of the perivascular myoid family of tumors. The reported genetic abnormalities across these neoplasms is dissimilar, arguing against a pathogenetically unified family; half of the GT showing NOTCH-gene fusions and a smaller subset BRAF
V600E mutations, while PDGFRB mutations are noted in a subset of MF and MP. This study aimed to investigate the prevalence and specificity of NOTCH-gene fusions in a large group of GT and correlate with clinical features. BRAF-VE1 and PDGFRB immunoexpression was also investigated in this cohort. A total of 93 GT and 43 other pericytic lesions (11 MP, 13 MF, and 19 AL) were selected. All cases were tested by fluorescence in situ hybridization for NOTCH1-4 and MIR143 gene abnormalities and 6 cases were investigated by targeted RNA-sequencing. Fluorescence in situ hybridization revealed NOTCH-gene rearrangements in 50 (54%) GT, 2 MP (18%), and 2 AL (11%). NOTCH-rearrangements were present in 34 (68%) benign and 16 (32%) malignant GT. Fusion-positive benign GT were overwhelmingly seen in males with a predilection for extremities, while the malignant GT occurred mostly in viscera. Among the fusion-negative GT, 88% were benign, 9% uncertain malignant potential, and 2% malignant. Half of the fusion-negative GTs occurred in the finger/subungual region. In summary, rearrangements of NOTCH genes are seen in over half of GT, with NOTCH2-MIR143 being the most common fusion (73%), while only a small subset of AL and MP share these abnormalities. The common subungual GT subset lack NOTCH-gene fusions suggesting an alternative pathogenesis. BRAF-VE1 was negative in all 37 cases studied, while strong PDGFRB staining was seen in 14 (21%) cases. Additional studies are needed to investigate the genetic alterations in the fusion-negative cases.
Prevalence and Seriousness of Analgesic-Induced Adverse Events in Korea: A 10-Year Nationwide Surveillance
Authors: Choi Yeo Jin , Kim Myoung-Hee , Chung Eun Kyoung , Lee Jun Kyu , Yoon Jimin , Yug Ji Seob , Jang Dong Kee
Published: June 2020

Objectives

The objectives of this study were to describe the prevalence and seriousness of analgesic-induced adverse events (AEs) and to identify factors associated with serious analgesic-related AEs in Korea.

Methods

Voluntarily reported analgesic-induced AEs to the Korea Adverse Event Reporting System from 2007 to 2016 were retrospectively reviewed. Analgesic medications were classified into nonopioids and opioids based on the Anatomical Therapeutic Chemical classification system. All AEs were grouped using System Organ Classes according to the World Health Organization-Adverse Reaction Terminology. Logistic regression was performed to identify factors associated with serious AEs.

Results

Overall, 194,566 AEs (32.2% for nonopioids, 67.8% for opioids) were included in this analysis. The most common causative nonopioid and opioid analgesics was ketorolac (n = 10,789) and tramadol (n = 53,727), respectively. The most frequent AEs were skin and appendage disorders for nonopioids (31.8%) and gastrointestinal disorders (59.5%) for opioids. Serious AEs occurred in 6102 (9.7%) and 3326 (2.5%) cases of the nonopioid and opioid groups, respectively. The most common serious AEs were skin and appendage disorders (33.2%) for nonopioids and neurologic disorders (19.3%) for opioids. Serious AEs were significantly associated with male (odds ratio [OR] = 1.423), advanced age (OR = 1.570), certain causality (OR = 2.304), nonopioid analgesics (OR = 4.182), and polypharmacy (OR = 1.009; P <0.001 for all).

Conclusions

In Korea, analgesic-induced AEs are prevalent with opioids more commonly implicated. Tramadol is the most common etiologic medication. Serious AEs are more frequently caused by nonopioids with skin and appendage disorders most common.
HIV-Exposed, Uninfected Infants in Uganda Experience Poorer Growth and Body Composition Trajectories than HIV-Unexposed Infants
Authors: Lane Charlotte E. , Widen Elizabeth M. , Collins Shalean M. , Young Sera L.
Published: June 2020

Background:

HIV-uninfected infants of HIV-positive women may experience worse growth and health outcomes than infants of HIV-negative women, but this has not been thoroughly investigated under the World Health Organization's most recent recommendations to reduce vertical transmission.

Objective:

To determine whether HIV-exposed and -uninfected (HEU) infants whose mothers received Option B+ have higher odds of experiencing suboptimal growth trajectories than HIV-unexposed, -uninfected infants, and if this relationship is affected by food insecurity.

Design:

Repeated anthropometric measures were taken on 238 infants (HEU = 86) at 1 week and 1, 3, 6, 9, and 12 months after delivery in Gulu, Uganda. Latent class growth mixture modeling was used to develop trajectories for length-for-age z-scores, weight-for-length z-scores, mid-upper arm circumference, sum of skinfolds, and arm fat area. Multinomial logistic models were also built to predict odds of trajectory class membership, controlling for socioeconomic factors.

Results:

HEU infants had greater odds of being in the shortest 2 length-for-age z-scores trajectory classes [odds ratio (OR) = 3.80 (1.22–11.82), OR = 8.72 (1.80–42.09)] and higher odds of being in smallest sum of skinfolds trajectory class [OR = 3.85 (1.39–10.59)] vs. unexposed infants. Among HEU infants, increasing food insecurity was associated with lower odds of being in the lowest sum of skinfolds class [OR = 0.86 (0.76–0.98)].

Conclusions:

There continues to be differences in growth patterns by HIV-exposure under the new set of World Health Organization guidelines for the prevention of mother-to-child transmission of HIV and the feeding of HEU infants in low-resource settings that are not readily identified through traditional mixed‐effects modeling. Food insecurity was not associated with class membership, but differentially affected adiposity by HIV-exposure status.
Susceptibility-Based Characterization of Cerebral Arteriovenous Malformations
Authors: Schneider Till M. , Möhlenbruch Markus , Denoix Michael , Ladd Mark E. , Bendszus Martin , Heiland Sabine , Straub Sina
Published: June 2020

Objectives

The aim of this study was to explore blood deoxygenation across cerebral arteriovenous malformations (AVMs) for functional characterization of AVM vasculature.

Materials and Methods

Fifteen patients with cerebral arteriovenous vascular malformation were prospectively studied by digital subtraction angiography and using a 3 T magnetic resonance imaging system, with which three-dimensional (3D) gradient echo data for the calculation of quantitative susceptibility maps, velocity-encoded 3D gradient echo data for 3D flow assessment, and contrast-enhanced 3D time-of-flight data were acquired.

The nidus, major supplying artery, and major draining veins were identified on digital subtraction angiography, and volumes of interest of the AVM nidus, AVM-related inflow and outflow vessels, and non–AVM-related normal veins were drawn on coregistered contrast-enhanced 3D time-of-flight data. The resulting volumes of interest were applied to quantitative susceptibility mapping and flow data.

Results

All patients showed a significant stepwise increase in susceptibility between feeding artery and nidus as well as between nidus and draining vein (P
adjusted = 0.035, P
adjusted
= 0.007, respectively). Results revealed between 9.3% and 50.9% of the normal transcapillary blood deoxygenation-related susceptibility change between the feeding artery and the draining vein of the AVMs. When normalized by nidal blood flow velocity, this change was correlated with the presence of perinidal blood products. The mean susceptibility change across cerebral AVMs normalized with nidal volume inversely correlated with mean nidal flow velocity.

Conclusions

Susceptibility changes indicating blood deoxygenation across cerebral AVMs were shown for the first time in this study and were associated with the presence of perinidal blood products. Deoxygenation measures may serve as functional characterization of AVM vasculature and may offer the potential for individual treatment assessment and possible risk stratification.
Cost-Effectiveness Analysis, Psychosocial, and Utility Outcomes of Early Mandibular Distraction in Craniofacial Microsomia
Authors: Almadani Yasser H. , Gilardino Mirko S.
Published: June 2020

Background:

The cost-effectiveness, utility outcomes, and most optimal timing of mandibular distraction osteogenesis (MDO) in craniofacial microsomia (CFM) continue to be a topic of debate, especially in the population of patients with mild or nonsignificant functional issues. The objective of this study was to quantitatively assess the burden of mandibular asymmetry in CFM, and to accurately evaluate the impact of early MDO on patients’ perceived quality of life and social acceptance, in addition to examining the cost-effectiveness of early MDO in CFM.

Methods:

A validated crowdsourcing platform was utilized to recruit participants. Psychosocial acceptance and utility outcomes were assessed for patients with CFM. Participants were presented with health-state scenarios supplemented with pre- and postoperative images. Quality-adjusted life years (QALYs) were subsequently calculated and costs were estimated based on Medicare fee schedules using the Current Procedural Terminology codes. Incremental cost-effectiveness ratios for early MDO were calculated and plotted against a $100,000/QALY threshold.

Results: :

A total of 463 participants were included in the study. The mean visual analog scale score for untreated mandibular hypoplasia in CFM was 0.48 ± 0.24, which improved significantly (P < 0.0001) to 0.63 ± 0.20 following early MDO. Time trade-off scores for an imaginary surgery leading to perfect health with no complications were not statistically different from undergoing early MDO (P = 0.113). Early mandibular distraction decreased social distance in all 8 social situations assessed. Incremental cost-effectiveness ratios varied by the duration of time between early MDO and a potential second intervention, ranging from $148,142.09 per QALY gained at an interval of 1 year to $9876.14 per QALY gained after 15 years. Using a willingness-to-pay threshold of $100,000/QALY, early MDO in CFM becomes cost-effective when patients enjoy an improved health-state post-MDO for more than 1.48 years before a potential second intervention, if deemed necessary.

Conclusion:

Early mandibular distraction may lead to tangible positive gains in CFM patients based on utility outcome scores, psychosocial acceptance, and social distance. Therefore, although further interventions may be needed at skeletal maturity, early MDO can improve the psychological well-being of CFM patients during their crucial developmental years in a cost-effective manner. The incremental cost per QALY gained post-early MDO correlates negatively with time until a second potential surgical intervention.
Trends in Utilization of Virtual Surgical Planning in Pediatric Craniofacial Surgery
Authors: Kalmar Christopher L. , Xu Wen , Zimmerman Carrie E. , Vu Giap H. , Humphries Laura S. , Swanson Jordan W. , Bartlett Scott P. , Taylor Jesse A.
Published: June 2020

Introduction:

While the use of virtual surgical planning (VSP) has been well described in the adult craniofacial literature, there has been little written about pediatric uses or trends. The purpose of this study is to evaluate the evolving utilization of VSP for pediatric craniofacial procedures.

Methods:

The authors’ prospective institutional review board-approved craniofacial registry was queried for index craniofacial procedures from January 2011 through December 2018. Data was collected regarding utilization of traditional surgical planning versus VSP, as well as the extent of VSP's influence on the operative procedure. These data were analyzed for trends over time and compared using appropriate statistics.

Results:

During the study period, a total of 1131 index craniofacial cases were performed, of which 160 cases (14.1%) utilized VSP. Utilization of VSP collectively increased over time, from 2.0% in 2011 to 18.6% in 2018 (P < 0.001). Utilization rates of VSP varied across procedures from 0% of craniosynostosis cases and fronto-orbital advancement cases to 67% of osteocutaneous free tissue transfers (P < 0.001). The most profound contributor to increase in VSP utilization was orthognathic surgery, utilized in 0% of orthognathic procedures in 2011 to 68.3% of orthognathic procedures in 2018 (P < 0.001).

Conclusions:

Utilization of virtual surgical planning for pediatric craniofacial procedures is increasing, especially for complex orthognathic procedures and osteocutaneous free tissue transfers. Utilization patterns of individual components of the VSP system demonstrate unique footprints across the spectrum of craniofacial procedures, which reinforces the specific and variable benefits of this workflow for treating pediatric craniofacial disorders.
Use of Thermoplastic Splint for the Treatment of Auricular Hematoma
Authors: Yerlikaya Huseyin Serdar , Akyildiz Ilker , Ugurlu Burak Numan , Gulel Onur , Arslan Necmi
Published: June 2020

Auricular hematoma is commonly seen in ear nose and throat clinical practice and mostly caused by blunt trauma as a result of traffic accident, wrestling, boxing etc. If hematoma does not discharge, blood supply of the cartilage fails and this results with the necrosis of the auricular cartilage. Incision and drainage of the hematoma is the cornerstone of the surgical treatment and simple compression methods are limited in terms of their ability to eliminate the empty space. Various techniques have been described for the elimination of the death space such as; dental rolls, cotton bolsters, buttons, silastic sheets, etc but compression materials may be insufficient to apply this pressure because of irregular shape of auricle. Resolving these problems, the authors have used thermoplastic splint as a compressive material at 7 patients for elimination of the death space in auricular hematoma treatment.
The Impact of Middle Eastern Crisis on Cleft Care: Evaluation of Demographic and Perioperative Data in Syrian Refugees With Cleft Lip and Palate
Authors: Boynuyogun Etkin , Calis Mert , Kara Murat , Çinar Sevil , Ozgur Figen
Published: June 2020

The cleft lip and palate (CL/P) define a heterogeneous group of congenital deformities, which are morphologically highly diverse, with a complex and multifactorial etiology. Affected children may experience social problems due to negative effects on speech, hearing, facial appearance, as well as negative psychological effects on the parents. In 2011, after the civil war began in Syria, a great wave of immigration began to Turkey and other neighboring countries. Refugees may not be able to receive optimal health care because of cultural differences, socioeconomic status, language problems, and psychosocial problems. To increase awareness about this issue, the authors investigated the demographic, perioperative, and post-operative data of Syrian refugee patients with CL/P who were admitted to our cleft center between January 2016 and May 2019. Sixty-eight refugees with CL/P were detected as the result of the screening. Unlike the protocol the authors follow in our center, cleft lip repair was performed at an average of 7.6 months and cleft palate repair was performed at an average of 28.7 months of age. The rate of fistula was found 26.2%.

The civil war in Syria has caused the repair of the patients with cleft lip and palate at a later age, hampered the follow-up and treatment, and caused more complications. Considering the demographic, social, economic and cultural characteristics of the patients, it was demonstrated that the necessary health precautions and infrastructure should be provided on the pillar of plastic surgery.
The Effect of Zigzag Palatoplasty on the Repair of Cleft Palate and its Comparative Study With Sommerlad Palatoplasty and the Double Opposing Z Palatoplasty
Authors: Wang Kun , Wang Qian , He Wei , Wang Fang , Chen Shang , Zhang Nini , Song Qinggao
Published: June 2020

Purpose:

At present, there are a variety of surgical methods for cleft palate repair, the authors first created the zigzag plasty of nasal mucosa musculature. The method is characteristic of better repair effect for anatomy and function of palatopharyngeal compared with the traditional method.

Methods:

Fifty patients with cleft palate were involved in this study, and treated with 3 different operative methods, respectively: zigzag palatoplasty for the repair of nasal mucosa myometrium (n = 17), Sommerlad palatoplasty (n = 18) and the double opposing Z palatoplasty (n = 15), respectively. The length of soft palate (the distance from incisor to the tip of uvula) and the distance from uvula to posterior pharynx before and after operation were selected as outcome index. The post-operative speech intelligibility, nasal resonance, and nasal leaking were also evaluated.

Results:

The results showed that the lengths of soft palate were increased by 14.50%, 13.23%, 10.10% with the zigzag palatoplasty, the double opposing Z palatoplasty and Sommerlad palatoplasty, respectively; the distances from the vertical tip to the posterior pharyngeal wall of 3 kinds of operation were reduced by 49.03%, 47.78%, 49.03%, respectively. The comparison of speech intelligibility, nasal resonance and nasal resonance assessment between/among groups were not significant.

Conclusion:

The authors’ research showed that the effect of zigzag palatoplasty works well in the repair of nasal mucosa myometrium and can be used as an optional method for functional repair of cleft palate.
The Effectiveness of a New Dispatcher-Assisted Basic Life Support Training Program on Quality in Cardiopulmonary Resuscitation Performance During Training and Willingness to Perform Bystander Cardiopulmonary Resuscitation
Authors: Park Gwan Jin , Kong So Yeon Joyce , Song Kyoung Jun , Shin Sang Do , Kim Tae Han , Ro Young Sun , Myklebust Helge , Birkenes Tonje Soraas
Published: June 2020

Introduction

A new dispatcher-assisted basic life support training program, called “Home Education and Resuscitation Outcome Study (HEROS)” was developed with a goal to provide high-quality dispatcher-assisted cardiopulmonary resuscitation (CPR) training, with a focus on untrained home bystanders. This study aimed to determine whether the HEROS program is associated with improved quality in CPR performance during training and willingness to provide bystander CPR compared with other basic life support programs without dispatcher-assisted CPR (non-HEROS).

Methods

This clustered randomized trial was conducted in 3 district health centers in Seoul. Intervention group was trained with the HEROS program and control group was trained with non-HEROS program. The primary outcome was overall CPR quality, measured as total CPR score. Secondary outcomes were other CPR quality parameters including average compression depth and rate, percentages of adequate depth, and acceptable release. Tertiary outcomes were posttraining survey results. Difference in difference analysis was performed to analyze the outcomes.

Results

Among total 1929 trainees, 907 (47.0%) were trained with HEROS program. Compared with the non-HEROS group, the HEROS group showed higher-quality CPR performances and better maintenance of their CPR quality throughout the course (total scores of 84% vs. 80% for first session and 72% vs. 67% for last session; difference in difference of 12.2 vs. 13.2). Other individual CPR parameters also showed significantly higher quality in the HEROS group. The posttraining survey showed that both groups were highly willing to perform bystander CPR (91.4% in the HEROS vs. 92.3% in the non-HEROS) with only 3.4% of respondents in the HEROS group were not willing to volunteer compared with 6.2% in the non-HEROS group (P < 0.01).

Conclusions

The HEROS training program helped trainees perform high-quality CPR throughout the course and enhanced their willingness to provide bystander CPR.
Enhanced wall shear stress prevents obstruction by astrocytes in ventricular catheters
Authors: Lee S. , Kwok N. , Holsapple J. , Heldt T. , Bourouiba L.
Published: June 2020

The treatment of hydrocephalus often involves the placement of a shunt catheter into the cerebrospinal ventricular space, though such ventricular catheters often fail by tissue obstruction. While diverse cell types contribute to the obstruction, astrocytes are believed to contribute to late catheter failure that can occur months after shunt insertion. Using
in vitro
microfluidic cultures of astrocytes, we show that applied fluid shear stress leads to a decrease of cell confluency and the loss of their typical stellate cell morphology. Furthermore, we show that astrocytes exposed to moderate shear stress for an extended period of time are detached more easily upon suddenly imposed high fluid shear stress. In light of these findings and examining the range of values of wall shear stress in a typical ventricular catheter through computational fluid dynamics (CFD) simulation, we find that the typical geometry of ventricular catheters has low wall shear stress zones that can favour the growth and adhesion of astrocytes, thus promoting obstruction. Using high-precision direct flow visualization and CFD simulations, we discover that the catheter flow can be formulated as a network of Poiseuille flows. Based on this observation, we leverage a Poiseuille network model to optimize ventricular catheter design such that the distribution of wall shear stress is above a critical threshold to minimize astrocyte adhesion and growth. Using this approach, we also suggest a novel design principle that not only optimizes the wall shear stress distribution but also eliminates a stagnation zone with low wall shear stress, which is common to current ventricular catheters.
The pVHL neglected functions, a tale of hypoxia-dependent and -independent regulations in cancer
Authors: Minervini Giovanni , Pennuto Maria , Tosatto Silvio C. E.
Published: June 2020

The von Hippel–Lindau protein (pVHL) is a tumour suppressor mainly known for its role as master regulator of hypoxia-inducible factor (HIF) activity. Functional inactivation of pVHL is causative of the von Hippel–Lindau disease, an inherited predisposition to develop different cancers. Due to its impact on human health, pVHL has been widely studied in the last few decades. However, investigations mostly focus on its role in degrading HIFs, whereas alternative pVHL protein–protein interactions and functions are insistently surfacing in the literature. In this review, we analyse these almost neglected functions by dissecting specific conditions in which pVHL is proposed to have differential roles in promoting cancer. We reviewed its role in regulating phosphorylation as a number of works suggest pVHL to act as an inhibitor by either degrading or promoting downregulation of specific kinases. Further, we summarize hypoxia-dependent and -independent pVHL interactions with multiple protein partners and discuss their implications in tumorigenesis.
Computational analysis of hygromorphic self-shaping wood gridshell structures
Authors: Grönquist Philippe , Panchadcharam Prijanthy , Wood Dylan , Menges Achim , Rüggeberg Markus , Wittel Falk K.
Published: June 2020

Bi-layered composites capable of self-shaping are of increasing relevance to science and engineering. They can be made out of anisotropic materials that are responsive to changes in a state variable, e.g. wood, which swells and shrinks by changes in moisture. When extensive bending is desired, such bilayers are usually designed as cross-ply structures. However, the nature of cross-ply laminates tends to prevent changes of the Gaussian curvature so that a plate-like geometry of the composite will be partly restricted from shaping. Therefore, an effective approach for maximizing bending is to keep the composite in a narrow strip configuration so that Gaussian curvature can remain constant during shaping. This represents a fundamental limitation for many applications where self-shaped double-curved structures could be beneficial, e.g. in timber architecture. In this study, we propose to achieve double-curvature by gridshell configurations of narrow self-shaping wood bilayer strips. Using numerical mechanical simulations, we investigate a parametric phase-space of shaping. Our results show that double curvature can be achieved and that the change in Gaussian curvature is dependent on the system’s geometry. Furthermore, we discuss a novel architectural application potential in the form of self-erecting timber gridshells.
Vigorous convection in porous media
Authors: Hewitt D. R.
Published: June 2020

The problem of convection in a fluid-saturated porous medium is reviewed with a focus on ‘vigorous’ convective flow, when the driving buoyancy forces are large relative to any dissipative forces in the system. This limit of strong convection is applicable in numerous settings in geophysics and beyond, including geothermal circulation, thermohaline mixing in the subsurface and heat transport through the lithosphere. Its manifestations range from ‘black smoker’ chimneys at mid-ocean ridges to salt-desert patterns to astrological plumes, and it has received a great deal of recent attention because of its important role in the long-term stability of geologically sequestered CO
2
. In this review, the basic mathematical framework for convection in porous media governed by Darcy’s Law is outlined, and its validity and limitations discussed. The main focus of the review is split between ‘two-sided’ and ‘one-sided’ systems: the former mimics the classical Rayleigh–Bénard set-up of a cell heated from below and cooled from above, allowing for detailed examination of convective dynamics and fluxes; the latter involves convection from one boundary only, which evolves in time through a series of regimes. Both set-ups are reviewed, accounting for theoretical, numerical and experimental studies in each case, and studies that incorporate additional physical effects are discussed. Future research in this area and various associated modelling challenges are also discussed.
Bi-Lipschitz Mané projectors and finite-dimensional reduction for complex Ginzburg–Landau equation
Authors: Kostianko Anna
Published: June 2020

We present a new method of establishing the finite-dimensionality of limit dynamics (in terms of bi-Lipschitz Mané projectors) for semilinear parabolic systems with cross diffusion terms and illustrate it on the model example of three-dimensional complex Ginzburg-Landau equation with periodic boundary conditions. The method combines the so-called spatial-averaging principle invented by Sell and Mallet–Paret with temporal averaging of rapid oscillations which come from cross-diffusion terms.
SARS-CoV-2 Simulations Go Exascale to Capture Spike Opening and Reveal Cryptic Pockets Across the Proteome
Authors: Zimmerman Maxwell I. , Porter Justin R. , Ward Michael D. , Singh Sukrit , Vithani Neha , Meller Artur , Mallimadugula Upasana L. , Kuhn Catherine E. , Borowsky Jonathan H. , Wiewiora Rafal P. , Hurley Matthew F. D. , Harbison Aoife M , Fogarty Carl A , Coffland Joseph E. , Fadda Elisa , Voelz Vincent A. , Chodera John D. , Bowman Gregory R.
Published: June 2020

SARS-CoV-2 has intricate mechanisms for initiating infection, immune evasion/suppression, and replication, which depend on the structure and dynamics of its constituent proteins. Many protein structures have been solved, but far less is known about their relevant conformational changes. To address this challenge, over a million citizen scientists banded together through the Folding@home distributed computing project to create the first exascale computer and simulate an unprecedented 0.1 seconds of the viral proteome. Our simulations capture dramatic opening of the apo Spike complex, far beyond that seen experimentally, which explains and successfully predicts the existence of ‘cryptic’ epitopes. Different Spike homologues modulate the probabilities of open versus closed structures, balancing receptor binding and immune evasion. We also observe dramatic conformational changes across the proteome, which reveal over 50 ‘cryptic’ pockets that expand targeting options for the design of antivirals. All data and models are freely available online, providing a quantitative structural atlas.
Global profiling of the crotonylome in Small Cell Lung Cancer
Authors: Guo Zongpei , Gu Meng , Huang Jiaqiang , Zhou Ping-kun , Ma Teng
Published: June 2020

Small cell lung cancer is a deadly neuroendocrine lung cancer subtype, which harbors the driver mutations ofRB1andTP53as well asEP300/CREBBP. Since CREBBP/p300 are two prominent crotonyl-CoA transferases responsible for the global crotonylation in cells, here we investigated the crotonylome in SCLC tissues compared with normal lung tissues through TMT labeling coupled with LC-MS/MS and found unique patterns of protein crotonylation in SCLC related pathways.
Linear and nonlinear chromatic integration in the mouse retina
Authors: Khani Mohammad Hossein , Gollisch Tim
Published: June 2020

The computation performed by a neural circuit depends on how it integrates its input signals into an output of its own. In the retina, ganglion cells integrate visual information over time, space, and chromatic channels. Unlike the former two, chromatic integration in the retina is largely unexplored. Analogous to classical studies of spatial integration, we here studied chromatic integration in mouse retina by identifying chromatic stimuli for which activation from one cone type is maximally balanced by deactivation in the other cone type. This revealed nonlinear chromatic integration in subsets of On, Off, and On-Off ganglion cells. Nonlinear On cells differed from the other two classes by displaying response suppression rather than activation under balanced chromatic stimulation. Furthermore, nonlinear chromatic integration occurs independently of nonlinear spatial integration, depends on inhibitory signals from the receptive field surround, and may provide information about chromatic boundaries, such as the skyline in natural scenes.
Dissociation of tic generation from tic expression during the sleep-wake cycle
Authors: Harduf Esther Vinner , Matzner Ayala , Belelovsky Katya , Bar-Gad Izhar
Published: June 2020

Motor tics, the hallmark of Tourette syndrome, are modulated by different behavioral and environmental factors. A major modulating factor is the sleep-wake cycle in which tics are attenuated to a large extent during sleep. This study demonstrates a similar reduction in tic expression during sleep in an animal model of chronic tic disorders and investigates the underlying neural mechanism. We recorded the neuronal activity during spontaneous sleep-wake cycles throughout continuous GABAAantagonist infusion into the striatum. Analysis of video streams and concurrent kinematic assessments indicated tic reduction during sleep in both frequency and intensity. Extracellular recordings in the striatum revealed a state dependent dissociation between motor tic expression and their macro-level neural correlates (“LFP spikes”) during the sleep-wake cycle. LFP spikes, which are highly correlated with tic expression during wakefulness, persisted during tic-free sleep and did not change their properties despite the reduced behavioral expression. Local, micro-level, activity near the infusion site was time-locked to the LFP spikes during wakefulness but this locking decreased significantly during sleep. These results suggest that while LFP spikes encode motor tic generation and feasibility, the behavioral expression of tics requires local striatal neural activity entrained to the LFP spikes, leading to the propagation of the activity to downstream targets and consequently their motor expression. These findings point to a possible mechanism for the modulation of tic expression in TS patients during sleep and potentially during other behavioral states.

The expression of motor tics, the defining symptom of Tourette syndrome, is modulated by environmental and behavioral factors. In this study, we explored tic modulation during the sleep-wake cycle and its underlying neurophysiological mechanism, using the rat model of chronic motor tic expression. Behaviorally, during sleep, tic frequency and intensity declined considerably. Physiologically, however, the macro-level neural correlates (termed “LFP spikes”) of tics persisted throughout the sleep-wake cycle, whereas the micro-level correlates were reduced during sleep. This dissociation between neuronal activity and its behavioral expression leads not only to a better understanding of tic modulation during sleep but may also suggest potential ways of affecting tic expression during natural behavior and when exposed to external modulating factors.

Highlights

The wake-sleep cycle modulates tic expression in chronically tic-expressing rats

Sleep attenuates tics in the rats reminiscent of the phenomenon in TS Patients

During tic-less sleep tic generation persists via LFP spikes

During sleep tic expression is blocked via striatal activity desynchronization
The Arabidopsis bZIP19 and bZIP23 transcription factors act as zinc-sensors to control plant zinc status
Authors: Lilay Grmay H. , Persson Daniel P. , Castro Pedro Humberto , Liao Feixue , Alexander Ross D. , Aarts Mark G.M. , Assunção Ana G.L.
Published: June 2020

Zinc (Zn) is an essential micronutrient for plants and animals because of its structural and catalytic roles in many proteins. Zn deficiency affectsca. two billion people, mainly those living on plant-based diets that rely on crops from Zn deficient soils. Plants maintain adequate Zn levels through tightly regulated Zn homeostasis mechanisms, involving Zn uptake, distribution and storage, but it was not known how they sense Zn status. We usein vitroandin plantaapproaches to show that theArabidopsis thalianaF-group bZIP transcription factors bZIP19 and bZIP23, which are the central regulators of the Zn deficiency response, act as Zn sensors by binding Zn2+ions to a Zn sensor motif (ZSM). Deletions or modifications of this ZSM disrupts Zn binding, leading to a constitutive transcriptional Zn deficiency response, which causes a significant increase in plant and seed Zn accumulation. Since the ZSM is highly conserved in F-bZIPs across land plants, the identification of the first plant Zn-sensor will promote new strategies to improve the Zn nutritional quality of plant-derived food and feed, and contribute to tackle the global Zn deficiency health problem.
Geometric deep learning on brain shape predicts sex and age
Authors: Besson Pierre , Parrish Todd , Katsaggelos Aggelos K. , Bandt S. Kathleen
Published: June 2020

The complex relationship between the shape and function of the human brain remains elusive despite extensive studies of cortical folding over many decades. The analysis of cortical gyrification presents an opportunity to advance our knowledge about this relationship, and better understand the etiology of a variety of pathologies involving diverse degrees of cortical folding abnormalities. Surface-based approaches have been shown to be particularly efficient in their ability to accurately describe the folded sheet topology of the cortical ribbon. However, the utility of these approaches has been blunted by their reliance on manually defined features in order to capture all relevant geometric properties of cortical folding. In this paper, we propose a deep-learning based method to analyze cortical folding patterns in a data-driven way that alleviates this reliance on manual feature definition. This method builds on the emerging field of geometric deep-learning and uses convolutional neural network architecture adapted to the surface representation of the cortical ribbon. MRI data from 6,410 healthy subjects obtained from 11 publicly available data repositories were used to predict age and sex via brain shape analysis. Ages ranged from 6-89 years. Both inner and outer cortical surfaces were extracted using Freesurfer and then registered into MNI space. Two gCNNs were trained, the first of which to predict subject’s self-identified sex, the second of which to predict subject’s age. Class Activation Maps (CAM) and Regression Activation Maps (RAM) were constructed to map the topographic distribution of the most influential brain regions involved in the decision process for each gCNN. Using this approach, the gCNN was able to predict a subject’s sex with an average accuracy of 87.99% and achieved a Person’s coefficient of correlation of 0.93 with an average absolute error 4.58 years when predicting a subject’s age.
Functional characterization of human Heschl’s gyrus in response to natural speech
Authors: Khalighinejad Bahar , Herrero Jose L. , Bickel Stephan , Mehta Ashesh D. , Mesgarani Nima
Published: June 2020

Heschl’s gyrus (HG) is a brain area that includes the primary auditory cortex in humans. Due to the limitations in obtaining direct neural measurements from this region during naturalistic speech listening, the functional organization and the role of HG in speech perception remains uncertain. Here, we used intracranial EEG to directly record the neural activity in HG in eight neurosurgical patients as they listened to continuous speech stories. We studied the spatial distribution of acoustic tuning and the organization of linguistic feature encoding. We found a main gradient of change from posteromedial to anterolateral parts of HG. Along this direction, we observed a decrease in frequency and temporal modulation tuning, and an increase in phonemic representation, speaker normalization, speech-sensitivity, and response latency. We did not observe a difference between the two brain hemispheres. These findings reveal a functional role for HG in processing and transforming simple to complex acoustic features and informs neurophysiological models of speech processing in the human auditory cortex.
Enhanced hippocampal theta rhythmicity and emergence of eta oscillation in virtual reality
Authors: Safaryan Karen , Mehta Mayank R.
Published: June 2020

Hippocampal theta oscillations in rodents profoundly impact neural activity, spatial coding, and synaptic plasticity and learning. What are the sensory mechanisms governing slow oscillations? We hypothesized that the nature of multisensory inputs is a crucial factor in hippocampal rhythmogenesis. We compared the rat hippocampal slow oscillations in the multisensory-rich real world (RW) and in a body-fixed, visual virtual reality (VR). The amplitude and rhythmicity of the hippocampal ~8 Hz theta were enhanced in VR compared to RW. This was accompanied by the emergence of a ~4 Hz oscillation, termed the eta rhythm, evident in the local field potential (LFP) in VR, but not in RW. Similar to theta, eta band amplitude increased with running speed in VR, but not in RW. However, contrary to theta, eta amplitude was highest in the CA1 cell layer, implicating intra-CA1 mechanisms. Consistently, putative CA1 interneurons, but not pyramidal neurons, showed substantially more eta modulation in VR than in RW. These results elucidate the multisensory mechanisms of hippocampal rhythms and the surprising effects of VR on enhancing these rhythms, which has not been achieved pharmacologically and has significant broader implications for VR use in humans.

One Sentence Summary

Navigation in virtual reality greatly enhances hippocampal 8Hz theta rhythmicity, and generates a novel, ~4Hz eta rhythm that is localized in the CA1 cell layer and influences interneurons more than pyramidal neurons.
Consensus Finder web tool to predict stabilizing substitutions in proteins
Authors: Jones Bryan J. , Kan Chi Nok Enoch , Luo Christine , Kazlauskas Romas J.
Published: June 2020

The consensus sequence approach to predicting stabilizing substitutions in proteins rests on the notion that conserved amino acids are more likely to contribute to the stability of a protein fold than non-conserved amino acids. To implement a prediction for a target protein sequence, one finds homologous sequences and aligns them in a multiple sequence alignment. The sequence of the most frequently occurring amino acid at each position is the consensus sequence. Replacement of a rarely occurring amino acid in the target with a frequently occurring amino acid is predicted to be stabilizing. Consensus Finder is an open-source web tool that automates this prediction. This chapter reviews the rationale for the consensus sequence approach and explains the options for fine-tuning this approach usingStaphylococcusnuclease A as an example.