bluuebunny/crossref_metadata_2025 huggingface dataset:
Solving the mystery of HBV-related mixed cryoglobulinemia: potential biomarkers of disease progression
Authors: Pocino Krizia , Napodano Cecilia , Gragnani Laura , Ciasca Gabriele , Colantuono Stefania  , Marri Silvia , Vantaggio Lorenzo , Gulli Francesca , Lorini Serena , Barini Antonella , Stefanile Annunziata , Miele Luca , Casato Milvia , Zignego Anna Linda , Rapaccini Gian Ludovico , Marino Mariapaola , Visentini Marcella , Basile Umberto
Published: February 2021

Objectives

The biomarkers of an immunological dysregulation due to a chronic HBV infection are indeed understudied. If untreated, this condition may evolve into liver impairment co-occurring with extrahepatic involvements. Here, we aim to identify a new panel of biomarkers [including immunoglobulin G (IgG) subclasses, RF, and Free Light Chains (FLCs)] that may be useful and reliable for clinical evaluation of HBV-related cryoglobulinemia.

Methods

We retrospectively analysed clinical data from 44 HBV-positive patients. The patients were stratified (according to the presence/absence of mixed cryoglobulinemia) into two groups: 22 with cryoglobulins (CGs) and 22 without CGs. Samples from 20 healthy blood donors (HDs) were used as negative controls. Serum samples were tested for IgG subclasses, RF (-IgM, -IgG, and -IgA type), and FLCs.

Results

We detected a strikingly different distribution of serum IgG subclasses between HDs and HBV-positive patients, together with different RF isotypes; in addition, FLCs were significantly increased in HBV-positive patients compared with HDs, while no significant difference was shown between HBV-positive patients with/without mixed cryoglobulinemia.

Conclusion

The immune-inflammatory response triggered by HBV may be monitored by a peculiar profile of biomarkers. Our results open a new perspective in the precision medicine era; in these challenging times, they could also be employed to monitor the clinical course of those COVID-19 patients who are at high risk of HBV reactivation due to liver impairment and/or immunosuppressive therapies.
Thymus variants on imaging in patients with rheumatoid arthritis—clinical and immunological significance
Authors: Murata Okinori , Suzuki Katsuya , Sugiura Hiroaki , Kondo Yasushi , Takeshita Masaru , Koga Keiko , Takiguchi Maiko , Kurisu Rina , Kassai Yoshiaki , Yasuoka Hidekata , Yamaoka Kunihiro , Morita Rimpei , Yoshimura Akihiko , Takeuchi Tsutomu
Published: February 2021

Objectives

We sought to clarify the presence of radiographic thymus variants using a scoring system, and their association with clinical and immunological features in RA patients.

Methods

A total of 387 RA patients were randomly selected from all patients visiting our department who underwent chest CT scanning, with exclusion of patients with thymoma or thymic cyst, or age < 30 years. Thymus size and attenuation score in axial CT images were quantitatively interpreted and assessed. Associations between immunophenotype data and clinical and serological features were analysed in a subset of patients.

Results

Thymic enlargement was found in 76 (19.6%) patients, and a thymus attenuation score ≥ 2 was found in 50 (12.9%) patients. The score was significantly associated with antibodies to ACPA positivity. Thymic enlargement was significantly associated with the proportions of CD4+ effector memory T cells.

Conclusion

Radiographic thymus variants were frequently observed in RA patients and may reflect an abnormal immune response involved in the pathogenesis of RA.
IL11 is elevated in systemic sclerosis and IL11-dependent ERK signalling underlies TGFβ-mediated activation of dermal fibroblasts
Authors: Adami Eleonora , Viswanathan Sivakumar , Widjaja Anissa A , Ng Benjamin , Chothani Sonia , Zhihao Nevin , Tan Jessie , Lio Pei Min , George Benjamin L , Altunoglu Umut , Ghosh Kakaly , Paleja Bhairav S , Schafer Sebastian , Reversade Bruno , Albani Salvatore , Ling Andrea Low Hsiu , O'Reilly Steven , Cook Stuart A
Published: February 2021

Objectives

Interleukin 11 (IL11) is highly upregulated in skin and lung fibroblasts from patients with systemic sclerosis (SSc). Here we tested whether IL11 is mechanistically linked with activation of human dermal fibroblasts (HDFs) from patients with SSc or controls.

Methods

We measured serum IL11 levels in volunteers and patients with early diffuse SSc and manipulated IL11 signalling in HDFs using gain- and loss-of-function approaches that we combined with molecular and cellular phenotyping.

Results

In patients with SSc, serum IL11 levels are elevated as compared with healthy controls. All transforming growth factor beta (TGFβ) isoforms induced IL11 secretion from HDFs, which highly express IL11 receptor α-subunit and the glycoprotein 130 (gp130) co-receptor, suggestive of an autocrine loop of IL11 activity in HDFs. IL11 stimulated ERK activation in HDFs and resulted in HDF-to-myofibroblast transformation and extracellular matrix secretion. The pro-fibrotic action of IL11 in HDFs appeared unrelated to STAT3 activity, independent of TGFβ upregulation and was not associated with phosphorylation of SMAD2/3. Inhibition of IL11 signalling using either a neutralizing antibody against IL11 or siRNA against IL11RA reduced TGFβ-induced HDF proliferation, matrix production and cell migration, which was phenocopied by pharmacological inhibition of ERK.

Conclusions

These data reveal that autocrine IL11-dependent ERK activity alone or downstream of TGFβ stimulation promotes fibrosis phenotypes in dermal fibroblasts and suggest IL11 as a potential therapeutic target in SSc.
ESTABLISHING LOCAL DIAGNOSTIC REFERENCE LEVELS FOR ROUTINE COMPUTED TOMOGRAPHY EXAMINATIONS IN JIMMA UNIVERSITY MEDICAL CENTER SOUTH WEST ETHIOPIA
Authors: Zewdu Mesfin , Kadir Elias , Tesfaye Million , Berhane Melkamu
Published: February 2021

The main purpose of this study was to determine local diagnostic reference level (LDRL) for Routine Computed Tomography (CT) examination in, Jimma University Medical Center (JUMC) South West Ethiopia. Retrospective study was conducted to determine LDRL for routine CT examination in JUMC. We have considered CTDIvol and DLP as dosimetric quantity based on the recommended guidelines to determine LDRLs by different international legal Authorities. The 75th percentile values of the calculated CTDIvol and DLP were proposed as LDRL. LDRL was obtained as CTDIvol, 42.97mGy, 7.76mGy, 14.32mGy, and 10.86mGy for routine brain CT, routine chest CT, routine thoraco-lumbar CT and routine abdomen CT examination respectively. Similarly the determined LDRL from DLP was 1364.15mGycm, 368.96mGycm, 853.18mGycm, and 1568.96mGycm for brain, chest, thoraco-lumbar and abdomen examination respectively. The LDRL obtained for DLP was higher compared with international DRLs; it can be reduced by coordinating effort between radiologists, technologists and medical physicist.
Micropatterned Coculture With 3T3-J2 Fibroblasts Enhances Hepatic Functions and Drug Screening Utility of HepaRG Cells
Authors: Ware Brenton R , Liu Jennifer S , Monckton Chase P , Ballinger Kimberly R , Khetani Salman R
Published: February 2021

Human liver models are useful for assessing compound metabolism/toxicity; however, primary human hepatocyte (PHH) lots are limited and highly variable in quality/viability. In contrast, cell lines, such as HepaRG, are cheaper and more reproducible surrogates for initial compound screening; however, hepatic functions and sensitivity for drug outcomes need improvement. Here, we show that HepaRGs cocultured with murine embryonic 3T3-J2 fibroblasts, previously shown to induce PHH functions, could address such limitations. We either micropatterned HepaRGs or seeded them “randomly” onto collagen-coated plates before 3T3-J2 coculture. Micropatterned cocultures (HepaRG-MPCCs) secreted 2- to 4-fold more albumin and displayed more stable cytochrome P450 activities than HepaRG conventional confluent monocultures (HepaRG-CCs) and HepaRG micropatterned hepatocytes (HepaRG-MPHs) for 4 weeks, even when excluding dimethyl sulfoxide from the medium. Furthermore, HepaRG-MPCCs had the most albumin-only positive cells (hepatic), lowest cytokeratin 19 (CK19)-only positive cells (cholangiocytic), and highest mean albumin intensity per cell than HepaRG random cocultures and monocultures; however, 80%–84% of HepaRGs remained bipotential (albumin+/CK19+) across all models. The 3T3-J2s also induced higher albumin in HepaRG spheroids than HepaRG-only spheroids. Additionally, although rifampin induced CYP3A4 in HepaRG-MPCCs and HepaRG-CCs, only HepaRG-MPCCs showed the dual omeprazole-mediated CYP1A2/3A4 induction as with PHHs. Lastly, when treated for 6 days with 47 drugs and evaluated for albumin and ATP to make binary hepatotoxicity calls, HepaRG-MPCCs displayed a sensitivity of 54% and specificity of 100% (70%/100% in PHH-MPCCs), whereas HepaRG-CCs misclassified several hepatotoxins. Ultimately, HepaRG-MPCCs could be a more cost-effective and reproducible model than PHHs for executing a tier 1 compound screen.
Mycetoma spatial geographical distribution in the Eastern Sennar locality, Sennar State, Sudan
Authors: Ganawa El Taib S , Bushara Mesoud A , Musa Abdelrahman E A , Bakhiet Sahar M , Fahal Ahmed H
Published: February 2021

Background

Mycetoma is a unique neglected tropical disease caused by a substantial number of different fungi or bacteria. Many of the disease's epidemiological characteristics are an enigma. Hence, understanding the spatial geographic distribution of mycetoma may clarify the association between the local environmental indicators, the spatial geographical distribution of mycetoma and its epidemiology.

Methods

This study set out to determine the spatial geographical distribution of mycetoma in the Eastern Sennar locality, Sennar State, one of the highly endemic states in Sudan. It included 594 patients with confirmed mycetoma seen at the Mycetoma Research Centre, University of Khartoum, Khartoum, Sudan, from 1991 to 2020. The spatial geographical distribution of these mycetoma patients was studied. The study area geographic information system data, which included geological, soil, temperature and land cover details, were collected in different geographic information forms. Different geographical analytical techniques were used.

Results

The patients' demographic characteristics were similar to those of the general characteristics of mycetoma patients in Sudan. Eumycetoma was the predominant type of mycetoma encountered in the studied patients. The data studied showed that most patients were located in the southern part of the locality along the Blue Nile river. The study showed an association between patients' spatial geographical distribution and soil types. Most patients’ localities had light clay soil (475 patients [80%]), followed by sandy loam soil (79 [13%]) then loam soil (40 [6.71%]). Also, 85% of patients' localities had the same land cover and vegetation. There was no significant correlation between patients' localities with temperature or any other geological characteristic.

Conclusion

The present study showed certain associations between mycetoma spatial geographical distribution and certain environmental indicators. However, a further in-depth study to provide greater insight into the disease's epidemiological characteristics is needed.
Prevention, control and management of leptospirosis in India: an evidence gap map
Authors: Beri Deepti , Moola Sandeep , Jagnoor Jagnoor , Salam Abdul , Bhaumik Soumyadeep
Published: February 2021

Leptospirosis is an emerging public health problem in India. We developed an evidence gap map (EGM) on prevention, control and management of leptospirosis in India to inform research priorities. The EGM framework was developed in consultation with stakeholders and noted key parameters to influence state and national level research priorities. We searched six electronic databases and three relevant websites and included 27 studies (humans, 23; animals, 4; both, 0). Most studies (17/27 [63%]) were from three high-burden states. Controlled clinical trials (non-randomised, 6/27 [22%]; randomised, 2/27 [7%]) and pre–post studies (6/27 [22%]) suitable for evaluating interventions were sparse. Only 26% studies (6/23 human studies) included high-risk groups like animal caretakers, tribal people, relief/sanitation workers, pregnant women and people from slums. Nearly 56% of studies (15/27) evaluated pharmacological interventions at an individual level. Community-level interventions were limited (4/27 [15%]) with no studies on vaccination, personal protection, antibiotic policy or water, sanitation and hygiene interventions. Health systems and policy or multicomponent studies were rare (5/27 [19%]) with no reporting of key outcomes like healthcare coverage, quality of care and other relevant outcomes to evaluate interventions. There is a need for prioritising research to evaluate prevention and control interventions, including the One Health approach. Embedding national-level EGMs for research prioritisation exercises should be considered.
Thoracic actinomycetoma: a retrospective clinical-epidemiological study of 64 cases
Authors: Bonifaz Alexandro , Tirado-Sánchez Andrés , Araiza Javier , Fierro-Arias Leonel , Martínez-Gamboa Areli , Ponce-de-León Alfredo
Published: February 2021

Background

Actinomycetoma is a chronic granulomatous infection that follows traumatic implantation. Thoracic actinomycetoma (TA) is rare and may lead to severe complications.

Methods

A retrospective study of cases of TA diagnosed from 1985 to 2019 was carried out. Each case underwent direct examination, culture and biopsy.

Results

Sixty-four cases (12.8%) were included, with a male predominance (84.3%); the main occupation was peasant farmer (71.8%) and the main site was the back (76.5%). Vertebral involvement was observed in 21.8% and pulmonary involvement in 7.8%. Nocardia brasiliensis was the main aetiological agent (53 cases, 74.5%).

Conclusions

TA is a poorly studied disease that can cause neurological and lung complications.
Comparing various scoring systems in the treatment of hepatocellular carcinoma with ALPPS
Authors: Xu Yan , Hu Xiaoling , Li Jiangbin , Dong Rui
Published: February 2021

Introduction:

Associating liver partition and portal vein ligation for staged hepatectomy (ALPPS) results in a vast increase in the volume of the future liver remnant (FLR) in a short period of time. Although ALPPS has expanded the surgical scope of hepatectomy, its high mortality and complication rate are not to be ignored. Preoperative evaluation of the growth rate of FLR and liver function after ALPPS is necessary. In this article, we compared the predictive effects of various scoring systems on the growth rate of FLR and liver function after the stage-1 of ALPPS.

Methods:

A retrospective study of all patients undergoing ALPPS for hepatocellular carcinoma from January 2015 to August 2019 at Tang Du hospital was performed. The area under the receiver operating characteristic (ROC) curve was used to compare the predictive effects of various scoring systems on the growth rate of FLR and liver function after the stage-1 of ALPPS.

Results:

Platelet-albumin-bilirubin (PALBI) score has statistical significance for predicting the growth rate of FLR after stage-1 of ALPPS. The area under ROC curve is 0.917, P=0.033, <0.05. Albumin-bilirubin (ALBI) score has statistical significance for predicting posthepatectomy liver failure after stage-1 of ALPPS. The area under ROC curve is 0.917, P=0.033, <0.05.

Conclusions:

PALBI can predict the growth rate of FLR after the stage-1 of ALPPS, while ALBI can predict the liver function.
Descemet-Stripping Automated Endothelial Keratoplasty
Authors: Gorovoy Mark S.
Published: February 2021

Purpose:

To evaluate the speed of visual recovery in 16 consecutive patients with corneal endothelial dysfunction who received Descemetstripping automated endothelial keratoplasty (DSAEK).

Methods:

This is a retrospective study of a novel method for smallincision endothelial transplantation (DSAEK). Endothelial replacement was accomplished with Descemet stripping of the recipient and insertion of a posterior donor tissue that had been prepared with a microkeratome. Best spectacle-corrected visual acuity (BSCVA) by manifest refraction, endothelial counts, and dislocation rates were measured up to 12 months after DSAEK.

Results:

Sixteen consecutive patients underwent uncomplicated DSAEK. Three patients had known optic nerve or macular disease precluding vision better than 20/200. Of the remaining 14 patients, 11 had BSCVA of 20/40 by postoperative week 12 (7 by week 6). The remaining 2 were 20/50 by weeks 6 and 12. All 14 patients were 20/40 or better at 1 year. One patient had a primary graft failure, and surgery was repeated with 20/40 BSCVA at 1 year. The dislocation rate was 25%. The average cell count between 7 and 10 months was 1714. The average pachymetry was 682.

Conclusion:

DSAEK surgery allows rapid, excellent BSCVAvisual recovery. The rate of visual recovery is more rapid than usually found with penetrating keratoplasty.
COVID-19 Pandemic
Authors: Pate Kimberly , Shaffer Kathy , Belin Latasia , Brelewski Kiersten , Fuller Kayla , Gold Charles , Golden Leslie , Raynor Nora , Rutledge Sarah , Spangler Lacey , Weaver Kelley
Published: February 2021

Purpose/Objectives

The goal of this article is to describe how a high-functioning clinical nurse specialist (CNS) team rapidly responded to the needs of the patients, nursing staff, and organization as a whole to address the coronavirus disease 2019 (COVID-19) crisis.

Description of the Project

Using the advanced practice knowledge and skills, each CNS moved effortlessly between the 3 spheres of influence, patient, nursing, and organization, to address the unique needs of the COVID-positive patient, as well as the routinely ill who still needed care during a pandemic. In addition to observing and addressing opportunities at the bedside, the CNS team was essential in the development of plans of care, crisis care standards, and a structure for critical care cross-training.

Outcomes

Five themes essential to success were identified: a common motivation and goal, collaboration, the importance of communication in utilizing established groups to create rapid change, power of influence, and the availability of a vast number of resources including professional nursing roles.

Conclusion

Using the expertise of a specially trained team of CNSs, an effective plan was established to ensure safe, optimal care during the COVID-19 pandemic and effectively support frontline nurses.
Clinical Nurse Specialist Collaboration With a Community-Based Palliative Care Program
Authors: Fedel Patrice Renee , Pennington Gwen
Published: February 2021

Purpose/Objectives

The purpose of the project was to evaluate the impact of a clinical nurse specialist (CNS) collaborating with an established Midwestern community-based palliative care program on the following quality outcomes: care coordination, 30-day readmissions, and emergency department (ED) utilization.

Description of Project

Palliative care services are evolving from the inpatient setting to community-based models to meet the needs of patients in their homes. As community-based programs develop, healthcare systems are examining the various models of care. The evidence-based practice project evaluated a collaborative practice model between a CNS and a community-based palliative care team. Quantitative analysis included 30-day readmissions and ED utilization in a preimplementation and postimplementation design. Qualitative data were obtained from a focus group of the community-based palliative care team to discuss the role of the CNS on the team.

Outcomes

The addition of a CNS did not significantly impact 30-day readmissions or ED visits. An unexpected outcome was that the CNS intervention was associated with an increase in social work visits. Results of the focus groups suggested that the CNS improved care coordination, nursing support, education, and medical management.

Conclusion

Both quantitative and qualitative analyses suggest that the CNS enhanced coordination of care and quality outcomes. Examining the CNS contribution over a longer period will further clarify the CNS's impact to the team.
The ISGyP Endocervical Adenocarcinoma Project: Master Plan Summary, Acknowledgment of Participants, and Participant Responses to Final Recommendations of the Expert Panels
Authors: Singh Naveena , Rabban Joseph T.
Published: February 2021

The International Society of Gynecological Pathologists carried out a multifaceted project with the broad aim of improving the pathological reporting of endocervical adenocarcinoma (EAC). The intentions were to promote and align practices with the WHO 2020 classification, which endorses HPV status-based classification of EAC and the Silva pattern-based assessment of HPV-associated EAC, to promote uniformity in applying the recent FIGO staging revisions on cervical carcinoma, and to provide best practice guidelines on all aspects of EAC pathology reporting. To facilitate the use of the new WHO/IECC classification and the Silva system, two online educational portals were set up with training and test sets of scanned slides; these remain available to society members on the ISGyP educational website. In addition, a large international collaborative individual data collection project is ongoing, aiming to ascertain the prognostic value of EAC categories, and to provide a database with the potential to address unanswered questions. A single on-site meeting was held on February 29, 2020 in Los Angeles, in advance of the USCAP Annual Meeting; all other correspondence was by email and through electronic surveys. Project participants were invited to vote and comment on the recommendations contained within the practice guideline articles. The project received an enthusiastic response from pathologists across the world. This report includes an overview and summary of all aspects of the project, a list of participants and the results of polling on practice recommendations.
Donor-derived Cell-free DNA: Advancing a Novel Assay to New Heights in Renal Transplantation
Authors: Paul Rohan S. , Almokayad Ismail , Collins Ashte , Raj Dominic , Jagadeesan Muralidaran
Published: February 2021

Despite advances in transplant immunosuppression, long-term renal allograft outcomes remain suboptimal because of the occurrence of rejection, recurrent disease, and interstitial fibrosis with tubular atrophy. This is largely due to limitations in our understanding of allogeneic processes coupled with inadequate surveillance strategies. The concept of donor-derived cell-free DNA as a signal of allograft stress has therefore rapidly been adopted as a noninvasive monitoring tool. Refining it for effective clinical use, however, remains an ongoing effort. Furthermore, its potential to unravel new insights in alloimmunity through novel molecular techniques is yet to be realized. This review herein summarizes current knowledge and active endeavors to optimize cell-free DNA-based diagnostic techniques for clinical use in kidney transplantation. In addition, the integration of DNA methylation and microRNA may unveil new epigenetic signatures of allograft health and is also explored in this report. Directing research initiatives toward these aspirations will not only improve diagnostic precision but may foster new paradigms in transplant immunobiology.
Telehealth-delivered, Cardioprotective Diet and Exercise Program for Liver Transplant Recipients: A Randomized Feasibility Study
Authors: Hickman Ingrid J. , Hannigan Amy K. , Johnston Heidi E. , Elvin-Walsh Louise , Mayr Hannah L. , Staudacher Heidi M. , Barnett Amandine , Stoney Rachel , Salisbury Chloe , Jarrett Maree , Reeves Marina M. , Coombes Jeff S. , Campbell Katrina L. , Keating Shelley E. , Macdonald Graeme A.
Published: February 2021

Background.

Rapid excess weight gain and metabolic complications contribute to poor outcomes following liver transplant care. Providing specialist lifestyle intervention with equitable access is a challenge for posttransplant service delivery.

Methods.

This study investigated the feasibility of a 12-wk telehealth delivered lifestyle intervention for liver transplant recipients (randomized controlled trial with a delayed intervention control group). The intervention included 14 group sessions facilitated by nutrition and exercise specialists via video streaming telehealth and participants used their own devices. Feasibility was assessed across session attendance, the adequacy, acceptability, and confidence with the telehealth technology and adherence to diet (Mediterranean Diet Adherence Score). Secondary pooled analysis of effectiveness was determined from changes in quality of life and metabolic syndrome severity score.

Results.

Of the 35 participants randomized, dropout was 22.8% (n = 8) and overall session attendance rate was 60%. Confidence with and adequacy of home technology was rated high in 96% and 91% of sessions, respectively. Participants randomized to the intervention significantly improved Mediterranean Diet Adherence Score (2-point increase [95% confidence interval, 1.5-3.4] versus control 0 point change [95% confidence interval, –1.4 to 1.2]; P = 0.004). Intervention (within group) analysis found the intervention significantly decreased the metabolic syndrome severity score (–0.4 [95% confidence interval, –0.6 to –0.1] P = 0.01), and improved mental health-related quality of life (2.5 [95% confidence interval, 0.4-4.6] P = 0.03).

Conclusions.

A cardioprotective lifestyle intervention delivered via telehealth is feasible for liver transplant recipients and may improve access to specialist care to support metabolic health and wellness after transplant.
SARS-CoV-2 RBD-Tetanus toxoid conjugate vaccine induces a strong neutralizing immunity in preclinical studies
Authors: Valdes-Balbin Yury , Santana-Mederos Darielys , Quintero Lauren , Fernández Sonsire , Rodriguez Laura , Ramirez Belinda Sanchez , Perez Rocmira , Acosta Claudia , Méndez Yanira , Ricardo Manuel G. , Hernandez Tays , Bergado Gretchen , Pi Franciscary , Valdes Annet , Carmenate Tania , Ramirez Ubel , Oliva Reinaldo , Soubal Jean-Pierre , Garrido Raine , Cardoso Felix , Landys Mario , Gonzalez Humberto , Farinas Mildrey , Enriquez Juliet , Noa Enrique , Suarez Anamary , Fang Cheng , Espinosa Luis A. , Ramos Yassel , González Luis Javier , Climent Yanet , Rojas Gertrudis , Relova-Hernández Ernesto , Infante Yanelys Cabrera , Losada Sum Lai , Boggiano Tammy , Ojito Eduardo , Monzon Kalet Leon , Chiodo Fabrizio , Paquet Françoise , Chen Guang-Wu , Rivera Daniel G. , Garcia-Rivera Dagmar , Verez-Bencomo Vicente
Published: February 2021

Controlling the global COVID-19 pandemic depends, among other measures, on developing preventive vaccines at an unprecedented pace. Vaccines approved for use and those in development intend to use neutralizing antibodies to block viral sites binding to the host’s cellular receptors. Virus infection is mediated by the spike glycoprotein trimer on the virion surface via its receptor binding domain (RBD). Antibody response to this domain is an important outcome of the immunization and correlates well with viral neutralization. Here we show that macromolecular constructs with recombinant RBD conjugated to tetanus toxoid induce a potent immune response in laboratory animals. Some advantages of the immunization with the viral antigen coupled to tetanus toxoid have become evident such as predominant IgG immune response due to affinity maturation and long-term specific B-memory cells. This paper demonstrates that subunit conjugate vaccines can be an alternative for COVID-19, paving the way for other viral conjugate vaccines based on the use of small viral proteins involved in the infection process.
Arboreal aperitifs: Space use and activity of a major songbird nest predator in a tropical Thailand forest
Authors: D’souza Anji , Gale George , Marshall Benjamin Michael , Khamcha Daphawan , Waengsothorn Surachit , Strine Colin Thomas
Published: February 2021

Predator-prey interactions are fundamental drivers of population dynamics, yet rarely are both predator and prey species simultaneously studied. Despite being significant, widespread avian nest predators, research on the ecology of Southeast Asian snakes in relation to birds remains scarce. The green cat snake (Boiga cyanea) is a primary nest predator, responsible for ≈24% of forest songbird depredation in Northeast Thailand. We explored both diurnal and nocturnal movements of 14 (5 male, 9 female) adultB. cyaneawith radio-telemetry for an average of 68 ± 16 days per individual, between 21 October 2017 and 8 June 2019 in the dry evergreen forest of the Sakaerat Biosphere Reserve (SBR). We quantified area of space use (ha) and activity through motion variance (Ϭm2) during the study period using dynamic Brownian bridge movement models, and linked our findings to a simultaneously-run avian nest monitoring study, initiated in 2013 within the same forest fragment. On average, movements, space use and activity differed between males and females, and between the avian nesting and non-nesting seasons. Males moved 51.37 m/day farther than females. They used areas 15.09 ha larger than females, and their activity was 3.91 Ϭm2higher than that of females. In general, individuals moved 50.30 m/day farther during the nesting season than the non-nesting season. The snakes used areas 9.84 ha larger during the nesting season than the non-nesting season, and their activity during the nesting season was 3.24 Ϭm2higher than that during the non-nesting season. All individuals were exclusively nocturnal, moving throughout the night, and often descending from higher diurnal refugia (>2 m) to forage closer to the ground after sunset.Boiga cyaneaactivity followed a similar trend to that of the recorded nest depredations at SBR. Our study links snake activity to nest depredations in SBR. Our openly-available data may yield further insight when combined with other major avian nest predator species like the congeneric invasive brown tree snake (Boiga irregularis) on the island of Guam.
Relationships between biomechanical parameters, neurological recovery, and neuropathology following concussion in swine
Authors: Wofford Kathryn L. , Grovola Michael R. , Adewole Dayo O. , Browne Kevin D. , Putt Mary E. , O’Donnell John C. , Cullen D. Kacy
Published: February 2021

Mild traumatic brain injury (mTBI) affects millions of individuals annually primarily through falls, traffic collisions, or blunt trauma and can generate symptoms that persist for years. Closed-head rotational injury is the most common form of mTBI and is defined by a rapid change in acceleration within an intact skull. Injury kinematics – the mechanical descriptors of injury-inducing motion – explain movement of the head, energy transfer to the brain, and, therefore, determine injury severity. However, the relationship between closed-head rotational injury kinematics – such as angular velocity, angular acceleration, and injury duration – and outcome after mTBI is currently unknown. To address this gap in knowledge, we analyzed archived surgical records of 24 swine experiencing a diffuse closed-head rotational acceleration mTBI against 12 sham animals. Kinematics were contrasted against acute recovery outcomes, specifically apnea, extubation time, standing time, and recovery duration. Compared to controls, animals with mTBI were far more likely to have apnea (p<0.001) along with shorter time to extubation (p=0.023), and longer time from extubation to recovery (p=0.006). Using regression analyses with variable selection, we generated simplified linear models relating kinematics to apnea (R2=0.27), standing time (R2=0.39) and recovery duration (R2=0.42). Neuropathology was correlated with multiple kinematics, with maximum acceleration exhibiting the strongest correlation (R2=0.66). Together, these data suggest the interplay between multiple injury kinematics, including minimum velocity and middle to minimum acceleration time, best explain acute recovery parameters and neuropathology after mTBI in swine. Future experiments that independently manipulate individual kinematics could be instrumental in developing translational diagnostics for clinical mTBI.

HIGHLIGHTS

Acute recovery parameters including apnea, extubation time, and recovery duration were altered after a single closed-head mTBI in swine.

Lasso-based regressions utilized kinematic parameters, including minimum velocity and middle to minimum acceleration time, to relate kinematics to apnea time, standing time, and recovery duration.

Lasso regression equations were able to modestly predict apnea time (R2=0.27) and moderately predict standing time (R2=0.39) and recovery duration (R2=0.42).

Injury kinematic parameters, primarily maximum acceleration, were correlated with white matter pathology after mTBI.
Decrease of Functional Connectivity within the Default Mode Network by a Brief Training of Focused Attention on the Breath in Novices
Authors: Trova Sara , Tsuji Yuki , Horiuchi Haruka , Shimada Sotaro
Published: February 2021

Experienced meditators reduce the activity of the default mode network (DMN), a brain system preferentially active when people are not engaged in specific tasks. However, the neural modulation of the DMN in novices remain largely unexplored. By using electroencephalography, we investigated the DMN functional connectivity in two groups of novices: the meditation group practiced six consecutive days of focused attention on the breath; the control group practiced only on the first and last days. After the brief training, results showed a decrease in the DMN functional connectivity between the ventromedial prefrontal cortex and the posterior cingulate cortex in theta and alpha bands during the focused attention condition, in the meditation group compared to the control group. The change in DMN functional connectivity was significantly correlated with the increase in state-level mindfulness scores. These data elucidate DMN modifications already arising at the initial stages of mindfulness meditation training in novices.

Highlights

An effect of brief meditation training on brain activity in novices was examined by using EEG.

A six-day training of focused attention on the breath improved state-level mindfulness scores.

Brief meditation training also reduced the functional connectivity within anterior-posterior DMN.

The amount of change in DMN functional connectivity was significantly correlated with the subjective score.
tDCS modulates effective connectivity during motor command following; a potential therapeutic target for disorders of consciousness
Authors: Aloi Davide , Jalali Roya , Tilsley Penelope , Miall R. Chris , Fernández-Espejo Davinia
Published: February 2021

Transcranial direct current stimulation (tDCS) is attracting increasing interest as a potential therapeutic route for unresponsive patients with prolonged disorders of consciousness (PDOC). However, research to date has had mixed results. Here, we propose a new direction by directly addressing the mechanisms underlying lack of responsiveness in PDOC, and using these to define our targets and the success of our intervention in the healthy brain first. We report 2 experiments that assess whether tDCS to the primary motor cortex (M1-tDCS;Experiment 1) and the cerebellum (cb-tDCS;Experiment 2) administered at rest modulate thalamo-cortical coupling in a subsequent command following task typically used to clinically assess awareness. Both experiments use sham- and polarity-controlled, randomised, double-blind, crossover designs. InExperiment 1, 22 participants received anodal, cathodal, and sham M1-tDCS sessions while in the MRI scanner. A further 22 participants received the same protocol with cb-tDCS inExperiment 2. We use Dynamic Causal Modelling of fMRI to characterise the effects of tDCS on brain activity and dynamics during simple thumb movements in response to command. We found that M1-tDCS increased thalamic excitation and that Cathodal cb-tDCS increased excitatory coupling from thalamus to M1. All these changes were polarity specific. Combined, our experiments demonstrate that tDCS can successfully modulate long range thalamo-cortical dynamics during command following via targeting of cortical regions. This suggests that M1- and cb-tDCS may allow PDOC patients to overcome the motor deficits at the root of their reduced responsiveness, improving their rehabilitation options and quality of life as a result.
A Geometric Framework for Understanding Dynamic Information Integration in Context-Dependent Computation
Authors: Zhang Xiaohan , Liu Shenquan , Chen Zhe Sage
Published: February 2021

Prefrontal cortex plays a prominent role in performing flexible cognitive functions and working memory, yet the underlying computational principle remains poorly understood. Here we trained a rate-based recurrent neural network (RNN) to explore how the context rules are encoded, maintained across seconds-long mnemonic delay, and subsequently used in a context-dependent decision-making task. The trained networks emerged key experimentally observed features in the prefrontal cortex (PFC) of rodent and monkey experiments, such as mixed-selectivity, sparse representations, neuronal sequential activity and rotation dynamics. To uncover the high-dimensional neural dynamical system, we further proposed a geometric framework to quantify and visualize population coding and sensory integration in a temporally-defined manner. We employed dynamic epoch-wise principal component analysis (PCA) to define multiple task-specific subspaces and task-related axes, and computed the angles between task-related axes and these subspaces. In low-dimensional neural representations, the trained RNN first encoded the context cues in a cue-specific subspace, and then maintained the cue information with a stable low-activity state persisting during the delay epoch, and further formed line attractors for sensor integration through low-dimensional neural trajectories to guide decision making. We demonstrated via intensive computer simulations that the geometric manifolds encoding the context information were robust to varying degrees of weight perturbation in both space and time. Overall, our analysis framework provides clear geometric interpretations and quantification of information coding, maintenance and integration, yielding new insight into the computational mechanisms of context-dependent computation.
Beyond massive univariate tests: Covariance regression reveals complex patterns of functional connectivity related to attention-deficit/hyperactivity disorder, age, sex, and response control
Authors: Zhao Yi , Nebel Mary Beth , Caffo Brian S. , Mostofsky Stewart H. , Rosch Keri S.
Published: February 2021

We applied a novel Covariate Assisted Principal (CAP) whole-matrix regression approach to identify resting-state functional connectivity (FC) brain networks associated with attention-deficit/hyperactivity disorder (ADHD) and response control. Participants included 8-12 year-old children with ADHD (n=115, 29 girls) and typically developing controls (n=102, 35 girls) with a resting-state fMRI scan and go/no-go task behavioral data. We modeled three sets of covariates to identify resting-state networks associated with ADHD, age, sex, and response control. Four networks were identified across models revealing complex interactions between subregions of cognitive control, default mode, subcortical, visual, and somatomotor networks that relate to age, response control, and a diagnosis of ADHD among girls and boys. Unique networks were also identified in each of the three models suggesting some specificity to the covariates of interest. These findings demonstrate the utility of our novel covariance regression approach to studying functional brain networks relevant for development, behavior, and psychopathology.
Thresholded Partial Least Squares: Fast Construction of Interpretable Whole-brain Decoders
Authors: Lee Sangil , Bradlow Eric T. , Kable Joseph W.
Published: February 2021

Recent neuroimaging research has shown that it is possible to decode mental states and predict future consumer behavior from brain activity data (a time-series of images). However, the unique characteristics (and high dimensionality) of neuroimaging data, coupled with a need for neuroscientifically interpretable models, has largely discouraged the use of the entire brain’s data as predictors. Instead, most neuroscientific research uses “regionalized” (partial-brain) data to reduce the computational burden and to improve interpretability (i.e., localizability of signal), at the cost of losing potential information. Here we propose a novel approach that can build whole-brain neural decoders (using the entire data set and capitalizing on the full correlational structure) that are both interpretable and computationally efficient. We exploit analytical properties of the partial least squares algorithm to build a regularized regression model with variable selection that boasts (in contrast to most statistical methods) a unique ‘fit-once-tune-later’ approach where users need to fit the model only once and can choose the best tuning parameters post-hoc. We demonstrate its efficacy in a large neuroimaging dataset against off-the-shelf prediction methods and show that our new method scales exceptionally with increasing data size, yields more interpretable results, and uses less computational memory, while retaining high predictive power.
Elucidating Mechanisms of Antitumor Immunity Mediated by Live Oncolytic Vaccinia and Heat-Inactivated Vaccinia
Authors: Wang Weiyi , Dai Peihong , Liu Shuaitong , Yang Ning , Wang Yi , Giese Rachel A. , Merghoub Taha , Wolchok Jedd D. , Deng Liang
Published: February 2021

Background

Viral-based immunotherapy has the potential to overcome resistance to immune checkpoint blockade (ICB) and to fill the unmet needs of many cancer patients. Oncolytic viruses (OVs) are defined as engineered or naturally occurring viruses that selectively replicate in and kill cancer cells. OVs also induce antitumor immunity. The purpose of this study is to compare the antitumor effects of live OV-GM expressing murine granulocyte-macrophage colony-stimulating factor (mGM-CSF) versus inactivated OV-GM and elucidate the underlying immunological mechanisms.

Methods

In this study, we engineered a replication-competent, oncolytic vaccinia virus (OV-GM) by inserting a murine GM-CSF gene into the thymidine kinase (TK) locus of a mutant vaccinia E3LΔ83N, which lacks the Z-DNA-binding domain of vaccinia virulence factor E3. We compared the antitumor effects of intratumoral (IT) delivery of live OV-GM vs. heat-inactivated OV-GM (heat-iOV-GM) in a murine B16-F10 melanoma bilateral implantation model.

Results

Heat-iOV-GM infection of dendritic cells (DCs) and tumor cells in vitro induces type I IFN and pro inflammatory cytokines and chemokines, whereas live OV-GM does not. IT live OV-GM is less effective in generating systemic antitumor immunity compared with heat-iOV-GM. Similar to heat-iOV-GM, the antitumor effects of live OV-GM also require Batf3-dependent CD103+ dendritic cells. IT heat-iOV-GM induces higher numbers of infiltrating activated CD8+ and CD4+ T cells as well as higher levels of type I IFN, proinflammatory cytokines, and chemokines in the distant non-injected tumors, which is dependent on CD8+ T cells. When combined with systemic delivery of ICB, IT heat-iOV-GM is more effective in eradicating tumors compared with live OV-GM.

Conclusions

Tumor lysis induced by the replication of oncolytic DNA viruses has a limited effect on the generation of systemic antitumor immunity. The activation of Batf3-dependent CD103+ DCs is critical for antitumor effects induced by both live OV-GM and heat-iOV-GM. Heat-iOV-GM is more potent than live OV-GM in the induction of innate and adaptive immunity in both the injected and distant non-injected tumors. We propose that evaluations of both innate and adaptive immunity induced by IT oncolytic viral immunotherapy at injected and non-injected tumors should be included as potential biomarkers.
Lack of parent-of-origin effects in Nasonia jewel wasp: a replication and extension study
Authors: Olney Kimberly C. , Gibson Joshua D. , Natri Heini M. , Underwood Avery , Gadau Juergen , Wilson Melissa A.
Published: February 2021

In diploid cells, the paternal and maternal alleles are, on average, equally expressed. There are exceptions from this: a small number of genes express the maternal or paternal allele copy exclusively. This phenomenon, known as genomic imprinting, is common among eutherian mammals and some plant species; however, genomic imprinting in species with haplodiploid sex determination is not well characterized. Previous work reported no parent-of-origin effects in the hybrids of closely related haplodiploidNasonia vitripennisandNasonia giraultijewel wasps, suggesting a lack of epigenetic reprogramming during embryogenesis in these species. Here, we replicate the gene expression dataset and observations using different individuals and sequencing technology, as well as reproduce these findings using the previously published RNA sequence data following our data analysis strategy. The major difference from the previous dataset is that they used an introgression strain as one of the parents and we found several loci that resisted introgression in that strain. Our results from both datasets demonstrate a species-of-origin effect, rather than a parent-of-origin effect. We present a reproducible workflow that others may use for replicating the results. Overall, we reproduced the original report of no parent-of-origin effects in the haplodiploidNasoniausing the original data with our new processing and analysis pipeline and replicated these results with our newly generated data.
Postpartum corticosterone and fluoxetine shift the tryptophan-kynurenine pathway in dams
Authors: Qiu Wansu , Go Kimberly A. , Lamers Yvonne , Galea Liisa A. M.
Published: February 2021

Perinatal depression (PND) affects 15% of mothers. Selective serotonin reuptake inhibitors (SSRIs) are currently the first-line of treatment for PND but are not always efficacious. Previously, we found significant reductions in plasma tryptophan concentrations and higher hippocampal proinflammatory cytokine, IL-1b levels, due to maternal SSRI treatment. Both inflammation and tryptophan-kynurenine metabolic pathway (TKP) are associated with SSRI efficacy in individuals with major depressive disorder (MDD). TKP is divided into neuroprotective and neurotoxic pathways. Higher metabolite concentrations of the neurotoxic pathway are associated with depression onset and implicated in SSRI efficacy. Metabolites in TKP were investigated in a rodent model of de novo postpartum depression (PPD) given treatment with the SSRI, fluoxetine (FLX). Dams were administered corticosterone (CORT) (40mg/kg, s.c.), and treated with the SSRI, fluoxetine (FLX) (10mg/kg, s.c.), during the postpartum for 22 days after parturition. Plasma TKP metabolite concentrations were quantified on the last day of treatment. Maternal postpartum CORT increased neurotoxic metabolites and co-enzyme/cofactors in dams (3-hydroxykynurenine, 3-hydroxyanthranilic acid, vitamin B2, flavin adenine dinucleotide). The combination of both CORT and FLX shifted the neuroprotective-to-neurotoxic ratio towards neurotoxicity. Postpartum FLX decreased plasma xanthurenic acid concentrations. Together, our data indicate higher neurotoxic TKP expression due to maternal postpartum CORT treatment, similar to clinical presentation of MDD. Moreover, maternal FLX treatment showed limited efficacy to influence TKP metabolites, which may correspond to its limited efficacy to treat depressive-like endophenotypes. Overall suggesting changes in TKP may be used as a biomarker of de novo PPD and antidepressant efficacy and targeting this pathway may serve as a potential therapeutic target.

Highlights

Tryptophan-kynurenine pathway (TKP) is altered by postpartum corticosterone (CORT)

Postpartum CORT upregulated neurotoxic more metabolites (3HK, 3HAA)

Postpartum fluoxetine (FLX) increased xanthurenic acid concentrations

Postpartum CORT and FLX together shifted the TKP balance towards neurotoxicity