bluuebunny/crossref_metadata_2025 huggingface dataset:
FDG PET/CT in Disseminated Intracranial and Intramedullary Spinal Cord Tuberculomas
Authors: Liu Mingyuan , Lu Lingdan , Liu Qianyun , Bai Yushu , Dong Aisheng
Published: January 2021

A 54-year-old woman was referred because of dizziness with fatigue for 2 months. MRI of the head and spinal cord revealed multiple ring or homogeneous enhancing nodules in the brain and spinal cord, concerning for metastases. FDG PET/CT showed multiple hypermetabolic nodules in the brain and spinal cord corresponding to the gadolinium-enhanced nodules and diffuse FDG uptake in the bilateral lower lobes of the lungs. Chest high-resolution CT showed diffuse, bilateral miliary opacities, most predominant in the lower lobes. The imaging findings and results of cerebrospinal fluid analysis were consistent with disseminated central nervous system tuberculomas with miliary pulmonary tuberculosis.
Pulmonary Embolism in an Asymptomatic COVID-19 Patient Detected on Ventilation/Perfusion SPECT/CT
Authors: Mahaletchumy Thanuja , Muhamad Maimanah , Mohammad Kazmin Nur Ezzaty , Kori Najma , Periyasamy Petrick
Published: January 2021

Severe COVID-19 infection is associated with significant coagulopathy. We would like share a case of an asymptomatic 26-year-old man who tested positive for COVID-19 and had elevated d-dimer levels. Because of inconclusive CTPA findings, V/Q (ventilation/perfusion) SPECT/CT was performed, which confirmed the presence of pulmonary embolism. This case highlights the fact that pulmonary embolism should not be overlooked in a COVID-19 patient who has raised d-dimer levels, even in the absence of symptoms. It also highlights the importance of performing a V/Q study when CTPA results are inconclusive or when there are contraindications for iodinated contrast media.
Quality of Life Structural Equation Model for Patients With Amyotrophic Lateral Sclerosis
Authors: Oh Juyeon , Kim Jung A.
Published: January 2021

Purpose

The aim of the study was to propose and test a quality of life model among Korean patients with amyotrophic lateral sclerosis (ALS) using structural equation modeling.

Design

A cross-sectional study was performed.

Methods

Data from 184 patients with ALS were collected from two university hospitals in Seoul and Busan, South Korea, between June and December 2018.

Findings

The modified model indices indicated adequate data fit. Quality of life predictors were social support, physical functional status, depression, and general health perception.

Conclusion

This study improved the understanding of quality of life for Korean patients with ALS, including complex direct and indirect relationships among quality of life factors.

Clinical Relevance

Depression was identified as the most influential factor in this population; hence, early assessment and timely intervention for depression are essential for better quality of life in patients with ALS.
Prefabricated Expanded Flap Combined With Expanded Scalp Flap for Total Face Resurfacing
Authors: Sun Haiyang , Liu Yachen , Yao Ping , Shi Yanyan , Char Sydney , Wang Xuelian , Yao Jianmin , Yang Chuan , Tan Xiaoyan
Published: January 2021

Reconstruction of total facial deformities and defects has been a major challenge of reconstructive surgery. Allotransplantation is limited by the number of donors and the need for life-long immunosuppression. Autotransplantation, where multiple autogenous tissue grafts from various donor sites are used to repair facial defects, inevitably leaves conspicuous patchwork scars. A prefabricated monoblock flap, although the preferred treatment modality, is limited by insufficient blood supply and the large size of the flap. In the Journal of Craniofacial Surgery (2014;25:21–25), Li et al applied the technique of flap prefabrication and stem cell–assisted tissue expansion to reconstruct total facial injuries, but the operations were complicated and the final expanded flap area was also uncertain. This article introduces an approach to reconstruct total facial injuries with a prefabricated expanded thoracic flap combined with an expanded scalp flap (called combined flaps), which not only solves the limitations of blood supply and expanded volume but also reduces patchwork scars. The approach is a simple, feasible, and effective surgical method for total face resurfacing.
Beneficial Effects of Astragaloside IV‐Treated and 3-Dimensional‐Cultured Endothelial Progenitor Cells on Angiogenesis and Wound Healing
Authors: Huang Nan-Chieh , Dai Lien-Guo , Kang Lan-Ya , Huang Nien-Chi , Fu Keng-Yen , Hsieh Pai-Shan , Dai Niann-Tzyy
Published: January 2021

Introduction

Astragaloside IV (AS-IV) is a natural herb extract and a popular compound used in traditional Chinese medicine because of its effect on multiple biological processes, such as promotion of cell proliferation, improvement in cardiopulmonary and vascular function, and promotion of angiogenesis around wounds, leading to accelerated wound healing. Vascular regeneration primarily results from the differentiation of endothelial progenitor cells (EPCs). Biomedical acceleration of angiogenesis and differentiation of EPCs around the wound remain challenging.

Materials and Methods

In this study, we treated human umbilical cord blood–derived EPCs with AS-IV and cultured them on 2-dimensional (tissue culture polystyrene) and 3-dimensional culture plates (3DPs). These cultured cells were then combined with human blood plasma gel and applied on the skin of nude mice in an attempt to repair full-thickness skin defects.

Results

The results show that using 3DP culture could increase vascular-related gene expression in EPCs. Furthermore, 12.5 μg/mL AS-IV–treaded EPCs were combined with plasma gels (P-3DP-EPC12.5) and showed enhanced vascular-related protein expression levels after 3 days of culture. Finally, P-3DP-EPC12.5s were used to repair full-thickness skin defects in nude mice, and we could register a wound healing rate greater than 90% by day 14.

Conclusions

Based on these results, we concluded that we have developed a potential therapeutic approach for wound healing using plasma gel containing 3-dimensional surface–cultured AS-IV–treated EPCs.
Impact of the Different Types of Le Fort I Maxillary Surgical Movement on Nasal Width Changes
Authors: Lin Yi-Yu , Denadai Rafael , Chou Pang-Yun , Yao Chuan-Fong , Chen Ying-An , Wang Po-Fang , Lin Clement Cheng-Hui , Chen Yu-Ray
Published: January 2021

Background

Le Fort I maxillary movements affect nasal width, but nasal width changes with specific movement types have not been formally addressed to date.

Objectives

The purpose of this study was to analyze and compare the changes in nasal width with different maxillary movements.

Methods

A retrospective study was performed among consecutive patients who underwent bimaxillary orthognathic surgery (n = 138) and who were grouped based on the type of maxillary movement (ie, maxillary advancement with intrusion [MAI], maxillary advancement with extrusion [MAE], and maxillary setback with intrusion [MSI]). Preoperative and 12-month postoperative nasal widths were analyzed photogrammetrically by 2 blinded evaluators.

Results

Maxillary advancement with intrusion and MAE presented a significantly (P < 0.05) higher alar base widening than MSI did, with no significant (P > 0.05) differences between MAI and MAE. Maxillary advancement movements (MAI and MAE) showed significantly (P < 0.05) higher alar base widening than maxillary setback movement (MSI). However, no significant (P > 0.05) difference was observed between maxillary intrusion (MAI and MSI) and maxillary extrusion (MAE) movements.

Conclusions

This study shows that the nasal width varies distinctly depending on the type of Le Fort I maxillary surgical movement.
Clinical Performance of Hydrogel-based Dressing in Facial Burn Wounds
Authors: Ou Kuang-Ling , Tzeng Yuan-sheng , Chiao Hao-Yu , Chiu Han-ting , Chen Chun-Yu , Chu Tzi-Shiang , Huang Dun-Wei , Hsu Kuo-Feng , Chang Chun-Kai , Wang Chih-Hsin , Dai Niann-Tzyy , Wu Chien-Ju
Published: January 2021

Preserving both esthetic and functional outcome remains challenging in facial burn injuries. The major issue is the initial treatment of injury. In this study, we focused on patients with partial-thickness facial burns admitted to the burn unit of Tri-Service General Hospital, Taipei, from November 2016 to November 2018. In 21 included patients, customized mask-style, transparent hydrogel-based dressing was applied to the burns. The mean age of included patients was 37.4 years. The mean area of burn injury was 11.9% of total body surface area, and the mean area of second-degree facial burns was 162.3 cm2. Full reepithelialization took, on average, 10.86 days. Scarring was acceptable in terms of texture and color, and no hypertrophic or keloidal scarring was noted. The mean Vancouver Scar Scale score was 2.07. Use of the hydrogel-based dressing masks seems to be a promising means of reducing pain, providing uninterrupted wound healing, facilitating observation, and positively affecting scarring in patients with second-degree facial burns.
Dynamic Traction Splint as an Alternative Surgical Treatment for Comminuted Intraarticular Fracture of Metacarpophalangeal Joint
Authors: Hung Kuo-Shu , Hsu Hsiu-Yun , Kuo Li-Chieh , Chang Jer-Hao , Lee Yao-Chou , Ho Chien-Liang , Pan Shin-Chen , Shieh Shyh-Jou
Published: January 2021

Background

Comminuted intraarticular fractures of the metacarpophalangeal joint (MPJ) are difficult to treat. We evaluated the clinical outcomes of using a dynamic traction splint to treat comminuted intraarticular fracture of MPJ.

Patients and Methods

We conducted a retrospective chart review on patients with comminuted intraarticular fracture of the MPJ treated with a dynamic traction splint at National Cheng Kung University Hospital between March 2014 and February 2018. The surgical procedures consisted of a transverse Kirschner wire insertion and treatment for concomitant injuries. The patients then received staged regular rehabilitation programs under a hand therapists' supervision for 14 weeks. Active range of motion (ROM) of injured digits, Visual Analog Scale score for pain, and return-to-work status were recorded to evaluate functional outcomes.

Results

A total of 10 patients were included. All were male patients and aged 8 to 66 years. The most common injury mechanism was motor vehicle accident (70%). The locations of fractures were 1 at the metacarpal head and 9 at the proximal phalangeal bases. Half of the fractures were open. Concomitant injuries were 1 digital nerve severance, 1 extensor tendon rupture, and 3 dorsal skin avulsions. There were no postoperative complications. The active ROM of the MPJ ranged from 40° to 90° with a median ROM of 80°. The Visual Analog Scale score for pain was 0 in 8 patients and 1 in the other 2 patients. All patients returned to their original workplace after rehabilitation.

Conclusions

Dynamic traction splints and postoperative rehabilitation programs could be an alternative treatment for comminuted intraarticular fracture of the MPJ.
Does the Presence of a Preexisting Open Wound Increase Complication Risk for Implant Procedures?
Authors: Nie James , Torabi Sina , Hsia Henry C.
Published: January 2021

Despite limited evidence, a common belief in surgical practice is that patients should not undergo elective surgery until any open wounds heal because of the risk of seeding infection to the new surgical site. To our knowledge, this is the first study to analyze postoperative complication rates for implants placed in the context of open wounds using the American College of Surgeons National Surgical Quality Improvement Program database. We examined 30-day postoperative infections for breast, hip, knee, and spine implants using the 2012–2016 American College of Surgeons National Surgical Quality Improvement Program database. Patients were excluded for missing data and propensity matched 1:10 for demographics and comorbidities to minimize confounders. Complication rates were assessed using Pearson χ2 tests. Of 475,101 patients who received breast, hip, knee, or spine implants, 1491 did so with an open wound. After propensity score matching, the overall complication rate remained higher with the open wound cohort (6.7% vs 3.8%, P < 0.001). Although the presence of an open wound was associated with an increased risk of superficial surgical site infection, it was not associated with an increased risk of organ space surgical site infection, the site best correlated with infection at the implant. Nor was the presence of an open wound associated with a statistically significantly increased risk of deep incisional surgical site infection or wound dehiscence. After controlling for demographics, preoperative comorbidities, and surgical factors, the presence of an open wound before implant surgery is associated with an increased risk of complications, readmission, and reoperation, but not necessarily infection at the surgical site.
Sonoelastography in the Diagnosis of Carpal Tunnel Syndrome
Authors: Lee Che-Hsiung , Lin Yu-Te , Wu Chen-Te , Lin Cheng-Hung , Chen Shih-Heng , Hsu Chung-Chen
Published: January 2021

Background

Sonoelastography (SEL) is widely used for assessing tissue stiffness and pathophysiology. It has also been used to diagnose carpal tunnel syndrome (CTS). However, the current criteria to diagnose CTS in SEL are diverse. The aim of this study was to systematically review the literature and assess the diagnostic value of SEL for CTS.

Methods

A literature review was performed using MEDLINE (PubMed), EMBASE, and the Cochrane Collaboration Library for primary research articles using the keywords sonoelastography and carpal tunnel syndrome. Data related to diagnostic and cutoff value were extracted. Bias assessment was performed.

Results

A total of 121 publications were reviewed. Nineteen primary case series met the inclusion criteria and were selected for full analysis. Different diagnostic approaches were identified, with units/expressions including kilopascals, conduct velocity, and strain ratio. The kilopascals and conduct velocity were measured using shear wave elastography, whereas strain ratio was calculated by relative compression quantification. A mean shear modulus cutoff value from 38.25 to 86 kPa and an acoustic radiation force impulse cutoff value of 3.0 to 3.23 m/s were used to diagnose CTS. Eight articles reported strain ratio between the median nerve and nearby tissues with diverse results due to different reference points. The other 3 additional diagnostic values were reported.

Conclusions

Sonoelastography is a useful noninvasive and promising modality to diagnose CTS. It may reflect both the condition of soft tissue scarring and quantitative values for CTS and median nerve stiffness. A diversity of examination values was found in different modalities. A high level of evidence was absent.
Automatic Assessment of 3-Dimensional Facial Soft Tissue Symmetry Before and After Orthognathic Surgery Using a Machine Learning Model
Authors: Lo Lun-Jou , Yang Chao-Tung , Ho Cheng-Ting , Liao Chun-Hao , Lin Hsiu-Hsia
Published: January 2021

Purpose

An objective and quantitative assessment of facial symmetry is essential for the surgical planning and evaluation of treatment outcomes in orthognathic surgery (OGS). This study applied the transfer learning model with a convolutional neural network based on 3-dimensional (3D) contour line features to evaluate the facial symmetry before and after OGS.

Methods

A total of 158 patients were recruited in a retrospective cohort study for the assessment and comparison of facial symmetry before and after OGS from January 2018 to March 2020. Three-dimensional facial photographs were captured by the 3dMD face system in a natural head position, with eyes looking forward, relaxed facial muscles, and habitual dental occlusion before and at least 6 months after surgery. Three-dimensional contour images were extracted from 3D facial images for the subsequent Web-based automatic assessment of facial symmetry by using the transfer learning with a convolutional neural network model.

Results

The mean score of postoperative facial symmetry showed significant improvements from 2.74 to 3.52, and the improvement degree of facial symmetry (in percentage) after surgery was 21% using the constructed machine learning model. A Web-based system provided a user-friendly interface and quick assessment results for clinicians and was an effective doctor-patient communication tool.

Conclusions

This work was the first attempt to automatically assess the facial symmetry before and after surgery in an objective and quantitative value by using a machine learning model based on the 3D contour feature map.
Advanced Technical Pearls for Successful Supermicrosurgical Lymphaticovenular Anastomosis
Authors: Chen Wei F. , Tuncer Fatma Betul , Zeng Weifeng
Published: January 2021

Lymphaticovenular anastomosis (LVA) is now accepted as one of the mainstays of surgical treatment of lymphedema. The unique advantages of LVA that set it apart from other procedures such as vascularized lymph node transfer are its safety and its minimally invasive nature. To date, there has been no report of worsening of disease as a result of LVA, even when performed unsuccessfully. Despite these notable advantages, the procedure is much less frequently performed compared with vascularized lymph node transfer because of inconsistent procedural outcome. In our experience, LVA is highly effective when performed with proper patient selection and meticulous technical execution. In this article, we share the senior author's LVA “tips and tricks” to help readers achieve greater success when performing this extraordinary supermicrosurgical procedure.
Prelamination of Vascularized Tensor Fascia Lata for Complex Abdominal Wall Reconstruction
Authors: Norwich-Cavanaugh Amanda , Kim Samuel , Panse Gauri , Saberski Ean , Hsia Henry C. , Narayan Deepak
Published: January 2021

There are 2 to 5 million laparotomies performed in the United States annually. Of these, 250,000 to 350,000 will undergo a ventral hernia repair. Repairs are often complicated by recurrence and infection. These risks are significantly increased in previously infected repairs, with reported recurrence rates varying from 17% to 28% after repair of infected ventral hernias, double the rates reported for first-time uninfected repairs. We describe here a novel treatment strategy involving the creation then use of bilateral prelaminated permanent mesh-reinforced tensor fascia latae flaps for abdominal wall reconstruction in patients who have recurrent ventral hernias and had undergone previous repairs complicated by infection. Previous repairs included anterior components separation, thereby making subsequent fascial release techniques and achievement of a reinforced repair extremely unlikely. Three patients were treated by a single surgeon using this 2-stage technique. There have been no incidences of recurrence and no infections after 2 to 10 years. In these patients, the only conventional option would have been a bridged repair with absorbable mesh. Combining the advantages of permanent mesh and well-vascularized autologous tissue optimizes the repair's tensile strength while mitigating the chance of recurrent infection associated with the use of permanent mesh. We propose that this strategy may be an appropriate treatment option for patients with recurrent ventral hernias that have not responded to other conventional modalities of treatment.
Severe Vascular Complications Caused by Facial Autologous Fat Grafting
Authors: Wang Kai , Rong Xiangke , Dang Juanli , Yang Jizhong , Zheng Hui , Hou Mengmeng , Li Huichen , Jiang Conghang , Xiong Shaoheng , Qiu Lihong , Yu Zhou , Yi Chenggang
Published: January 2021

Background

Vascular embolism is the most severe complication after autologous fat grafting. With a worldwide increase in fat grafting, there has been a rise in severe vascular complications, such as ophthalmic artery embolism, cerebral artery embolism, and even death. This article aims to review the role of fat in causing severe vascular complications and the association between fat grafting and severe vascular complications.

Methods

A critical review was conducted by appraising the cases of severe vascular complications associated with facial fat grafting reported globally. Repeated cases that were reported in multiple publications were further screened.

Results

The final search yielded 50 publications in English that met the inclusion criteria for review. A total of 113 cases of fat-induced severe vascular complications in the literature were identified. The number of cases reported yearly has increased over time, with even more significant increases since 2010. The glabella and temple are the most common sites of severe vascular complications described in the literature. In addition, only one case of ophthalmic artery embolism and one case of cerebral artery embolism have been treated successfully.

Conclusions

Given the increase in reported cases of severe vascular complications, both doctors and patients should pay careful attention to the risks of facial fat grafting. Because of the unclear mechanism of vascular embolism and the lack of guidelines for prevention and treatment, the effective cure rate is unsatisfactory. We propose that preventing vascular embolism is a priority in fat grafting and that timely, multidisciplinary treatment should be performed when severe vascular complications occur. It is necessary in future studies to explore the mechanisms of vascular embolism and effective treatment strategies to promote the development of fat grafting.
Conflicts of Interest in Studies Related to Mesh Use in Ventral Hernia Repair and Abdominal Wall Reconstruction
Authors: Sekigami Yurie , Tian Tina , Char Sydney , Radparvar Jacob , Aalberg Jeffrey , Chen Lilian , Chatterjee Abhishek
Published: January 2021

Objective:

To examine the accuracy of the reporting of conflicts of interest (COI) among studies related to mesh use in ventral hernia repair and abdominal wall reconstruction.

Summary Background Data:

Accurate declaration of COI is integral to ensuring transparency of study results. Multiple studies have demonstrated undeclared COI are prevalent in surgical literature.

Methods:

Studies with at least 1 American author accepted between 2014 and 2018 in 12 major, peer-reviewed general surgery and plastic surgery journals were included. Declared COI were compared with payments listed in the “Open Payments” database [maintained by the Centers for Medicare & Medicaid Services (CMS)] during the year of acceptance and 1 year prior. Studies and authors were considered to have a COI if they received payments from any of 8 major mesh companies totaling >$100.00 from each company. Risk factors for undeclared COI were determined at the study and author levels.

Results:

One hundred twenty-six studies (553 authors) were included. One hundred two studies (81.0%) had one or more authors who received payments from industry and inaccurately declared their COI. Two hundred forty-eight authors (44.8%) did not declare their COI accurately. On multivariate analysis, last authors were found to be at highest risk for undeclared payments (OR 3.59, 95%CI 2.02–6.20), whereas middle authors were at significantly higher risk for undeclared payments than first authors (OR 1.64, 95%CI 1.04-2.56).

Conclusions:

The majority of studies investigating the use of mesh in ventral hernia repairs and abdominal wall reconstructions did not accurately declare COI. Last authors are at highest risk of undisclosed payments. Current policies on disclosing COI seem to be insufficient to ensure transparency of publications.
Psychometric Properties of the ICECAP-O Quality of Life Measurement Tool When Self-reported by Community-dwelling Older People With Mild and Moderate Dementia
Authors: Nyman Samuel R. , Casey Chloe , Polman Remco
Published: January 2021

To evaluate interventions designed to improve the quality of life of people with dementia (PWD), there is a need for psychometrically validated instruments. We tested the psychometric properties of the ICEpop CAPability measure for Older people (ICECAP-O) as a self-report measure of quality of life with PWD. We used data from a randomized controlled trial of Tai Chi with 83 community-dwelling older people with mild and moderate dementia. The ICECAP-O was found to be valid with correlations in the expected directions for fear of falls (r=−0.36, P=0.001) and age (r=0.12, P=0.29), sensitive to change (mean difference=0.051, P=0.04, d=0.51), and have an adequate factorial structure. The ICECAP-O is a valid, generic measure of quality of life for use with PWD without a proxy.
A Unique Radiologic Case of Optic Nerve Infarction in a Patient With Mucormycosis
Authors: Chaulk Alexandria L. , Do Thai H. , Supsupin Emilio P. , Bhattacharjee Meenakshi B. , Richani Karina , Adesina Ore-Ofe O.
Published: January 2021

This is a rare presentation of a unilateral optic nerve infarction of the left eye caused by mucormycosis in a 51-year-old man with poorly controlled Type 2 diabetes. Diffusion-weighted MRI of the orbit demonstrated extensive infarction of the left optic nerve with ipsilateral cavernous sinus thrombosis and periorbital adnexal inflammation. Left orbital exenteration and sinus debridement were performed, and mucormycosis involving the optic nerve sheath was confirmed on histopathology.
Mediator of DNA damage checkpoint 1 (MDC1) is a novel estrogen receptor co-regulator in invasive lobular carcinoma of the breast
Authors: Bordeaux Evelyn K. , Sottnik Joseph L. , Mehrotra Sanjana , Ferrara Sarah E. , Goodspeed Andrew E. , Costello James C. , Sikora Matthew J.
Published: January 2021

Invasive lobular carcinoma (ILC) is the most common histological subtype of breast cancer, and nearly all ILC tumors express estrogen receptor alpha (ER). However, clinical and laboratory data suggest ILC are strongly estrogen-driven but not equally sensitive to anti-estrogen therapies. We hypothesized that ILC-specific ER transcriptional co-regulators mediate ER functions in ILC and anti-estrogen resistance, and profiled ER-associated proteins by mass spectrometry. Three ER+ ILC cell lines, MDA MB 134VI, SUM44PE, and BCK4, were compared to published data from ER+ invasive ductal carcinoma (IDC) cell lines, and we examined whether siRNA knockdown of identified proteins suppressed ER-driven proliferation in ILC cells. This approach found mediator of DNA damage checkpoint 1 (MDC1), a key tumor suppressor in DNA damage response (DDR), as a putative novel ER co-regulator in ILC. We confirmed ER:MDC1 interaction was specific to ILC cell lines versus IDC cells, and found MDC1 knockdown suppressed ILC cell proliferation and suppressed tamoxifen resistance in MDA MB 134VI. Using RNA-sequencing, we found that in ILC cells, MDC1 knockdown broadly dysregulates the estrogen-driven ER transcriptome, with ER:MDC1 target genes enriched for hormone-response-elements in their promoter regions. Importantly, our data are inconsistent with MDC1 regulating ER via MDC1 DDR and tumor suppressor functions, but instead suggest a novel oncogenic role for MDC1 in mediating ER transcriptional activity as a co-regulator. Supporting this, in breast tumor tissue microarrays MDC1 protein was frequently low or absent in IDC or ER-ILC, but MDC1 loss is rare in ER+ ILC. ER:MDC1 interaction and MDC1 co-regulator functions may underlie cell type-specific ER functions in ILC, and serve as important biomarkers and therapeutic targets to overcome anti-estrogen resistance in ILC.
Antibody-induced glomerulonephritis is amplified by RTEC-intrinsic IL-17 signaling and restrained by IL-17-mediated induction of the endoribonuclease Regnase-1 (Zc3h12a)
Authors: Li De-Dong , Bechara Rami , Ramani Kritika , Jawale Chetan V. , Li Yang , Kolls Jay K. , Gaffen Sarah L. , Biswas Partha S.
Published: January 2021

Antibody-mediated glomerulonephritis (AGN) is a clinical manifestation of many autoimmune kidney diseases for which few effective treatments exist. Chronic inflammatory circuits in renal glomerular and tubular cells lead to tissue damage in AGN. These cells are targeted by the cytokine IL-17, which has recently been shown to be a central driver of the pathogenesis of AGN. However, surprisingly little is known about the regulation of pathogenic IL-17 signaling in the kidney. Here, using a well characterized mouse model of AGN, we show that IL-17 signaling in renal tubular epithelial cells (RTECs) is necessary for AGN development. We also show that Regnase-1, an RNA binding protein with endoribonuclease activity, is a negative regulator of IL-17 signaling in RTECs. Accordingly, mice with a selective Regnase-1 deficiency in RTECs exhibited exacerbated kidney dysfunction in AGN. Mechanistically, Regnase-1 inhibits IL-17-driven expression of the transcription factor IκBξ and consequently its downstream gene targets includingIl6andLcn2. Moreover, deletion of Regnase-1 in human RTECs reduced inflammatory gene expression in an IκBξ-dependent manner. Overall, these data identify an IL-17-driven inflammatory circuit in RTECs during AGN that is constrained by Regnase-1.
Maternal Biological Age Assessed in Early Pregnancy is Associated with Gestational Age at Birth
Authors: Lancaster Eva E. , Lapato Dana M. , Jackson-Cook Colleen , Strauss Jerome F. , Roberson-Nay Roxann , York Timothy P.
Published: January 2021

Abstract

Maternal age is an established predictor of preterm birth independent of other recognized risk factors. The use of chronological age makes the assumption that individuals age at a similar rate. Therefore, it does not capture interindividual differences that may exist due to genetic background and environmental exposures. As a result, there is a need to identify biomarkers that more closely index the rate of cellular aging. One potential candidate is biological age (BA) estimated by the DNA methylome. This study investigated whether maternal BA, estimated in either early and/or late pregnancy, predicts gestational age at birth. BA was estimated from a genome-wide DNA methylation platform using the Horvath algorithm. Linear regression methods assessed the relationship between BA and pregnancy outcomes, including gestational age at birth and perceived stress during pregnancy, in a primary and replication cohort. Prenatal BA estimates from early pregnancy explained variance in gestational age at birth above and beyond the influence of other recognized preterm birth risk factors. Sensitivity analyses indicated that this signal was driven primarily by self-identified African American participants. This predictive relationship was sensitive to small variations in the BA estimation algorithm. Benefits and limitations of using BA in translational research and clinical applications for preterm birth are considered.
Tinnitus-like “hallucinations” elicited by sensory deprivation in an entropy maximization recurrent neural network
Authors: Dotan Aviv , Shriki Oren
Published: January 2021

Sensory deprivation has long been known to cause hallucinations or “phantom” sensations, the most common of which is tinnitus induced by hearing loss, affecting 10–20% of the population. An observable hearing loss, causing auditory sensory deprivation over a band of frequencies, is present in over 90% of people with tinnitus. Existing plasticity-based computational models for tinnitus are usually driven by homeostasis mechanisms, modeled to fit phenomenological findings. Here, we use an objective-driven learning algorithm to model an early auditory processing neuronal network, e.g., in the dorsal cochlear nucleus. The learning algorithm maximizes the network’s output entropy by learning the feed-forward and recurrent interactions in the model. We show that the connectivity patterns and responses learned by the model display several hallmarks of early auditory neuronal networks. We further demonstrate that attenuation of peripheral inputs drives the recurrent network towards its critical point and transition into a tinnitus-like state. In this state, the network activity resembles responses to genuine inputs even in the absence of external stimulation, namely, it “hallucinates” auditory responses. These findings demonstrate how objective-driven plasticity mechanisms that normally act to optimize the network’s input representation can also elicit pathologies such as tinnitus as a result of sensory deprivation.

Author summary

Tinnitus or “ringing in the ears” is a common pathology. It may result from mechanical damage in the inner ear, as well as from certain drugs such as salicylate (aspirin). A common approach toward a computational model for tinnitus is to use a neural network model with inherent plasticity applied to early auditory processing, where the input layer models the auditory nerve and the output layer models a nucleus in the brain stem. However, most of the existing computational models are phenomenological in nature, driven by a homeostatic principle. Here, we use an objective-driven learning algorithm based on information theory to learn the feed-forward interactions between the layers, as well as the recurrent interactions within the output layer. Through numerical simulations of the learning process, we show that attenuation of peripheral inputs drives the network into a tinnitus-like state, where the network activity resembles responses to genuine inputs even in the absence of external stimulation; namely, it “hallucinates” auditory responses. These findings demonstrate how plasticity mechanisms that normally act to optimize network performance can also lead to undesired outcomes, such as tinnitus, as a result of reduced peripheral hearing.
The Mimivirus L375 Nudix enzyme hydrolyzes the 5’ mRNA cap
Authors: Kago Grace , Parrish Susan
Published: January 2021

The giant Mimivirus is a member of the nucleocytoplasmic large DNA viruses (NCLDV), a group of diverse viruses that contain double-stranded DNA (dsDNA) genomes that replicate primarily in eukaryotic hosts. Two members of the NCLDV, Vaccinia Virus (VACV) and African Swine Fever Virus (ASFV), both synthesize Nudix enzymes that have been shown to decap mRNA, a process thought to accelerate viral and host mRNA turnover and promote the shutoff of host protein synthesis. Mimivirus encodes two Nudix enzymes in its genome, denoted as L375 and L534. Importantly, L375 exhibits sequence similarity to ASFV-DP and eukaryotic Dcp2, two Nudix enzymes shown to possess mRNA decapping activity. In this work, we demonstrate that recombinant Mimivirus L375 cleaves the 5’ m7GpppN mRNA cap, releasing m7GDP as a product. L375 did not significantly cleave mRNAs containing an unmethylated 5’GpppN cap, indicating that this enzyme specifically hydrolyzes methylated-capped transcripts. A point mutation in the L375 Nudix motif completely eliminated cap hydrolysis, showing that decapping activity is dependent on this motif. Addition of methylated cap derivatives or uncapped RNA inhibited L375 decapping activity, suggesting that L375 recognizes its substrate through interaction with both the mRNA cap and RNA body.
Sequence and structure comparison of ATP synthase F0 subunits 6 and 8 in notothenioid fish.
Authors: Katyal Gunjan , Ebanks Brad , Lucassen Magnus , Papetti Chiara , Chakrabarti Lisa
Published: January 2021

The Channichthyidae family (icefish) are the only known vertebrate species to be devoid of haemoglobin. Mitochondrial changes such as tight coupling of the mitochondria have facilitated sustained oxygen and respiratory activity in the fish. This makes it important to appreciate features in the sequence and structure of the proteins directly involved in proton transport, which could have physiological implications. ATP synthase subunit a (ATP6) and subunit 8 (ATP8) are proteins that function as part of the F0component (proton pump) of the F0F1complex. Both are encoded by the mitochondrial genome and involved in oxidative phosphorylation. To explore mitochondrial sequence variation for ATP6 and ATP8 we have gathered sequences and predicted structures of these two proteins of fish from the Notothenioidei sub-order, a sub-Antarctic species. We compared these with seven other vertebrate species in order to reveal whether there might be physiologically important differences that can help us to understand the unique biology of the icefish.
Chronic SSRI treatment reverses HIV-1 protein-mediated synaptodendritic damage
Authors: Denton Adam R. , Mactutus Charles F. , Lateef Almeera U. , Harrod Steven B. , Booze Rosemarie M.
Published: January 2021

HIV-1 infection affects approximately 37 million individuals and approximately 50% of seropositive individuals will develop symptoms of clinical depression and apathy. Dysfunctions of both serotonergic and dopaminergic neurotransmission have been implicated in the pathogenesis of motivational alterations. The present study evaluated the efficacy of a SSRI (escitalopram) in the HIV-1 transgenic (Tg) rat. Behavioral, neurochemical, and neuroanatomical outcomes with respect to HIV-1 and sex were evaluated to determine the efficacy of chronic escitalopram treatment. Escitalopram treatment restored function in each of the behavioral tasks that were sensitive to HIV-1 induced impairments. Further, escitalopram treatment restored HIV-1-mediated synaptodendritic damage in the nucleus accumbens; treatment with escitalopram significantly increased dendritic proliferation in HIV-1 Tg rats. However, restoration did not consistently occur with the neurochemical analysis in the HIV-1 rat. Taken together, these results suggest a role for SSRI therapies in repairing long-term HIV-1 protein-mediated neuronal damage and restoring function.
Modular basis for potent SARS-CoV-2 neutralization by a prevalent VH1-2-derived antibody class
Authors: Rapp Micah , Guo Yicheng , Reddem Eswar R. , Liu Lihong , Wang Pengfei , Yu Jian , Cerutti Gabriele , Bimela Jude , Bahna Fabiana , Mannepalli Seetha , Zhang Baoshan , Kwong Peter D. , Ho David D. , Shapiro Lawrence , Sheng Zizhang
Published: January 2021

Antibodies with heavy chains that derive from the VH1-2 gene constitute some of the most potent SARS-CoV-2-neutralizing antibodies yet identified. To provide insight into whether these genetic similarities inform common modes of recognition, we determined structures of the SARS-CoV-2 spike in complex with three VH1-2-derived antibodies: 2-15, 2-43, and H4. All three utilized VH1-2-encoded motifs to recognize the receptor-binding domain (RBD), with heavy chain N53I enhancing binding and light chain tyrosines recognizing F486RBD. Despite these similarities, class members bound both RBD-up and -down conformations of the spike, with a subset of antibodies utilizing elongated CDRH3s to recognize glycanN343 on a neighboring RBD – a quaternary interaction accommodated by an increase in RBD separation of up to 12 Å. The VH1-2-antibody class thus utilizes modular recognition encoded by modular genetic elements to effect potent neutralization, with VH-gene component specifying recognition of RBD and CDRH3 component specifying quaternary interactions.

Highlights

Determine structures of VH1-2-derived antibodies 2-43, 2-15, and H4 in complex with SARS-CoV-2 spike

Define a multi-donor VH1-2-antibody class with modular components for RBD and quaternary recognition

Reveal structural basis of RBD-up and RBD-down recognition within the class

Show somatic hypermutations and avidity to be critical for potency

Delineate changes in spike conformation induced by CDRH3-mediated quaternary recognition
Phospho-dependent Signaling during the General Stress Response by the Atypical Response Regulator and ClpXP Adaptor RssB
Authors: Schwartz Jacob , Son Jonghyeon , Brugger Christiane , Deaconescu Alexandra M.
Published: January 2021

In the model organismEscherichia coliand related species, the general stress response relies on tight regulation of the intracellular levels of the promoter specificity subunit RpoS. RpoS turnover is exclusively dependent on RssB, a two-domain response regulator that functions as an adaptor that delivers RpoS to ClpXP for proteolysis. Here we report crystal structures of the receiver domain of RssB both in its unphosphorylated form and bound to the phosphomimic BeF3−. Surprisingly, we find only modest differences between these two structures, suggesting that truncating RssB may partially activate the receiver domain to a “meta-active” state. Our structural and sequence analysis points to RssB proteins not conforming to either the Y-T coupling scheme for signaling seen in prototypical response regulators, such as CheY, or to the signaling model of the less understood FATGUY proteins.
Microsecond simulations and CD spectroscopy reveals the intrinsically disordered nature of SARS-CoV-2 Spike-C-terminal cytoplasmic tail (residues 1242-1273) in isolation
Authors: Kumar Prateek , Bhardwaj Taniya , Garg Neha , Giri Rajanish
Published: January 2021

All available SARS-CoV-2 spike protein crystal and cryo-EM structures have shown missing electron densities for cytosolic C-terminal regions. Generally, the missing electron densities point towards the intrinsically disordered nature of the protein region. This curiosity has led us to investigate the C terminal cytosolic region of the spike glycoprotein of SARS-CoV-2 in isolation. The cytosolic regions is supposed to be from 1235-1273 residues or 1242-1273 residues depending on what prediction tool we use. Therefore, we have demonstrated the structural conformation of cytosolic region and its dynamics through computer simulations up to microsecond timescale using OPLS and CHARMM forcefields. The simulations have revealed the unstructured conformation of cytosolic region. Also, in temperature dependent replica-exchange molecular dynamics simulations it has shown its conformational dynamics. Further, we have validated our computational observations with circular dichroism (CD) spectroscopy-based experiments and found its signature spectra at 198 nm which is also adding the analysis as its intrinsically disordered nature. We believe that our findings will surely help us understand the structure-function relationship of the spike protein’s cytosolic region.

Graphical Abstract
The oligomannose N-glycans 3D architecture and its response to the FcγRIIIa structural landscape
Authors: Fogarty Carl A , Fadda Elisa
Published: January 2021

Oligomannoses are evolutionarily the oldest class of N-glycans, where the arms of the common pentasaccharide unit, i.e. Man α1-6)-[Manα(1-3)]-Manβ(1-4)-GlcNAcβ(1-4)-GlcNAcβ1-Asn, are functionalized exclusively with branched arrangements of mannose (Man) monosaccharide units. In mammalian species oligomannose N-glycans can have up to 9 Man, meanwhile structures can grow to over 200 units in yeast mannan. The highly dynamic nature, branching complexity and 3D structure of oligomannoses have been recently highlighted for their roles in immune escape and infectivity of enveloped viruses, such as HIV-1 and SARS-CoV2. The architectural features that allow these N-glycans to perform their functions is yet unclear, due to their intrinsically disordered nature that hinders their structural characterization. In this work we will discuss the results of over 54 µs of cumulative sampling by molecular dynamics (MD) simulations of differently processed, free (not protein-linked) oligomannose N-glycans common in vertebrates. We then discuss the effects of a protein surface on their structural equilibria based on over 4 µs cumulative MD sampling of the fully glycosylated CD16a Fc gamma receptor (FcγRIIIa), where the type of glycosylation is known to modulate its binding affinity for IgG1s, regulating the antibody-dependent cellular cytotoxicity (ADCC). Our results show that the protein’s structural constraints shift the oligomannoses conformational ensemble to promote conformers that satisfy the steric requirements and hydrogen bonding networks demanded by the protein’s surface landscape. More importantly, we find that the protein does not actively distort the N-glycans into structures not populated in the unlinked forms in solution. Ultimately, the highly populated conformations of the Man5 linked glycans support experimental evidence of high levels of hybrid complex forms at N45 and show a specific presentation of the arms at N162, which may be involved in mediating binding affinity to the IgG1 Fc.
Pharmacological Inhibition of BTK reduces neuroinflammation and stress induced anxietyin vivo
Authors: Ghosh Simantini , Mohammed Zaidan , Singh Itender
Published: January 2021

Stress related disorders lead to serious psychiatric disabilities and are comorbid with anxiety and depression. Current therapies targeting several neurotransmitter systems are only able to mitigate symptoms partially. It is well recognized that stress and trauma related disorders lead to a prominent inflammatory response in humans, and in several animal models a robust neuroinflammatory response has been observed. However, the therapeutic potential of targeting specific components of the inflammatory response has not been adequately studied in this context. The current study investigated the NLRP3 - Caspase1-IL-1β pathway, which recent research has identified as a major contributor to exacerbated inflammatory response in several peripheral and central nervous system pathological conditions. Using two different models of stress, first - single prolonged restraint stress followed by brief underwater submersion and second - predator odor exposure in mice, we demonstrate heightened anxious behavior in mice one-week after stress. Females in both models display an exacerbated anxiety response than males within the stressed group. Consistent with this data stressed animals demonstrate upregulation of IL-1β, IL-6, Caspase1 activity and NLRP3 inflammasome activation in brain, with female animals showing a stronger neuroinflammatory phenotype. Pharmacological inhibition of NLRP3 inflammasome activation led to a rescue in terms of anxious behavior as well as attenuated neuroinflammatory response, both of which were significantly more prominent in female animals. Further, we observed induction of activated Bruton’s Tyrosine Kinase (BTK), an upstream positive regulator of NLRP3 inflammasome activation, in hippocampus and amygdala of stressed mice. Next, we conducted proof-of-concept pharmacological BTK inhibitor studies with Ibrutinib, a drug that is already FDA approved for use in certain types of lymphomas and leukemias, as well as a second inhibitor of BTK, LFM-A13. In both sets of experiments, we found inhibition of BTK significantly reduced the anxious behavior in stressed mice and attenuated the induction of NLRP3 inflammasome, Caspase 1 and IL1β. Our results suggest that BTK inhibition can be further investigated in context of human stress and trauma related disorders as a therapeutic strategy.