bluuebunny/crossref_metadata_2025 huggingface dataset:
Experimental Model of Zygomatic and Mandibular Defects to Support the Development of Custom Three-Dimensional--Printed Bone Scaffolds
Authors: Mulloy Clairissa , Guidry Richard F. , Sharma Silpa , Prevot Adam , Wisecarver Ian R. , Takawira Catherine , Marrero Luis , Lopez Mandi J. , Mundinger Gerhard S.
Published: June 2020

Introduction:

Autologous reconstruction of segmental craniomaxillofacial bone defects is limited by insufficient graft material, donor site morbidity, and need for microsurgery. Reconstruction is challenging due to the complex three-dimensional (3D) structure of craniofacial skeleton. Customized 3D-printed patient-specific biologic scaffolds hold promise for reconstruction of the craniofacial skeleton without donor site morbidity. The authors report a porcine craniofacial defect model suitable for further evaluation of custom 3D-printed engineered bone scaffolds.

Methods:

The authors created a 6 cm critical load-bearing defect in the left mandibular angle and a 1.5 cm noncritical, nonload bearing defect in the contralateral right zygomatic arch in 4 Yucatan minipigs. Defects were plated with patient-specific titanium hardware based on preoperative CT scans. Serial CT imaging was done immediately postoperatively, and at 3 and 6 months. Animals were clinically assessed for masticatory function, ambulation, and growth. At the 6-month study endpoint, animals were euthanized, and bony regeneration was evaluated through histological staining and micro-CT scanning compared to contralateral controls.

Results:

All 4 animals reached study endpoint. Two mandibular plates fractured, but did not preclude study completion due to loss of masticatory function. One zygoma plate loosened while the site of another underwent heterotopic ossification. Gross examination of site defects revealed heterotopic ossification, confirmed by histological and micro-CT evaluation. Biomechanical testing was unavailable due to insufficient bony repair.

Conclusions:

The presented porcine zygoma and mandibular defect models are incapable of repair in the absence of bone scaffolds. Based on the authors’ results, this model is appropriate for further study of custom 3D-printed engineered bone scaffolds.
Outcomes After Tracheostomy in COVID-19 Patients
Authors: Chao Tiffany N. , Harbison Sean P. , Braslow Benjamin M. , Hutchinson Christoph T. , Rajasekaran Karthik , Go Beatrice C. , Paul Ellen A. , Lambe Leah D. , Kearney James J. , Chalian Ara A. , Cereda Maurizio F. , Martin Niels D. , Haas Andrew R. , Atkins Joshua H. , Rassekh Christopher H.
Published: June 2020

Objective:

To determine the outcomes of patients undergoing tracheostomy for COVID-19 and of healthcare workers performing these procedures.

Background:

Tracheostomy is often performed for prolonged endotracheal intubation in critically ill patients. However, in the context of COVID-19, tracheostomy placement pathways have been altered due to the poor prognosis of intubated patients and the risk of transmission to providers through this highly aerosolizing procedure.

Methods:

A prospective single-system multi-center observational cohort study was performed on patients who underwent tracheostomy after acute respiratory failure secondary to COVID-19.

Results:

Of the 53 patients who underwent tracheostomy, the average time from endotracheal intubation to tracheostomy was 19.7 days ± 6.9 days. The most common indication for tracheostomy was acute respiratory distress syndrome, followed by failure to wean ventilation and post-extracorporeal membrane oxygenation decannulation. Thirty patients (56.6%) were liberated from the ventilator, 16 (30.2%) have been discharged alive, 7 (13.2%) have been decannulated, and 6 (11.3%) died. The average time from tracheostomy to ventilator liberation was 11.8 days ± 6.9 days (range 2–32 days). Both open surgical and percutaneous dilational tracheostomy techniques were performed utilizing methods to mitigate aerosols. No healthcare worker transmissions resulted from performing the procedure.

Conclusions:

Alterations to tracheostomy practices and processes were successfully instituted. Following these steps, tracheostomy in COVID-19 intubated patients seems safe for both patients and healthcare workers performing the procedure.
Short-Term Outcomes of Vaginal Hysterectomy at the Time of Robotic Sacrocolpopexy
Authors: Jones Keisha , Thompson Nicole , Imamoglu Gizem , Solomon Ellen , Rastegar Vida , Harmanli Oz
Published: June 2020

Objective

With the introduction of robotic sacrocolpopexy (RSC) at our institution in 2008, we noted a reduction in residents’ vaginal hysterectomy (VH) experience. In 2012, we made a transition to perform VH on all robotic sacrocolpopexies. Our objective was to report our short-term outcomes and adverse events.

Methods

In this case series, we evaluated women who underwent VH with concomitant RSC for stages II to IV pelvic organ prolapse between 2012 and 2017. In these cases, the vesicovaginal and rectovaginal spaces were developed transvaginally. Descriptive analysis including demographics, short-term outcomes, and adverse events are reported.

Results

In this group of 209 women, median (interquartile interval) duration of follow-up was 49 (26–60) weeks. The majority of the women were white (84.7%) and postmenopausal (80.9%), with a mean (SD) age of 59 (9) years. At a median follow-up time of 49 weeks, pelvic organ prolapse quantification revealed 20 patients (12.4%) with Ba or Bp greater or equal to 0 and 1.4% of patients required repeat prolapse surgery. Among 9 women (4.3%) with postoperative fever, 4 (1.9%) were treated for pelvic collection/abscess. Of 5 women (2.4%) who had venous thromboembolism, 3 (1.4%) were diagnosed with pulmonary embolism. There were 18 patients (8.6%) treated for urinary tract infection within 6 postoperative weeks. Mesh exposure was noted in 16 (7.7%) of the patients, and 11 (6.2%) required reoperation.

Conclusions

Vaginal hysterectomy at the time of RSC may increase the risk of infection and mesh exposure compared with procedures without concomitant hysterectomy.
Live Birth Following Uterine Transplantation From a Nulliparous Deceased Donor
Authors: Fronek Jiri , Janousek Libor , Kristek Jakub , Chlupac Jaroslav , Pluta Marek , Novotny Robert , Maluskova Jana , Olausson Michael
Published: June 2020

Background.

Nulliparous uterine grafts have never been used in uterus transplantation (UTx), possibly due to presumed infertility. Our objective was to verify the feasibility of nulliparous uterine graft transplantation.

Methods.

The Czech Uterus Transplant Trial (registered under ClinicalTrials.gov, identifier NCT03277430) is a 2-arm trial comparing the efficacy of deceased donor (DD) versus live-donor uterus transplant (10 patients in both arms). A 25-year-old patient suffering from inborn absolute uterine factor infertility underwent a DD uterus transplant. The donor was a 20-year-old nulliparous brain-dead donor.

Results.

The transplant procedure was uneventful. The posttransplant period was complicated by (1) recurrent episodes of acute cellular rejection, (2) neutropenia necessitating the administration of granulocyte colony-stimulating factor, (3) vaginal anastomotic stenosis treated with the insertion of a self-expanding stent, (4) the concurrence of Clostridium difficile colitis and acute appendicitis, and (5) temporary renal function impairment of a combined cause. Two years after the UTx, after the fourth embryo transfer, the patient became pregnant. Apart from gestational diabetes mellitus, the pregnancy was uneventful. Due to preterm contractions, delivery was achieved via caesarean section at gestational age 34 + 6 years. The postoperative course was uneventful for both the mother and the newborn.

Conclusions.

Herein, we report the first live birth after a DD UTx in Europe. This report provides a proof of concept that nulliparous uteri may present a suitable source of uterine grafts for UTx. Stenting may serve as a feasible treatment method for vaginal anastomotic stenosis.
Grafting Islets to a Dissected Peritoneal Pouch to Improve Transplant Survival and Function
Authors: Kumano Kenjiro , Vasu Srividya , Liu Yang , Lo Su-Tang , Mulgaonkar Aditi , Pennington Jenelle , Darden Carly M. , Sun Xiankai , Lawrence Michael C. , Naziruddin Bashoo
Published: June 2020

Background.

Although the liver is the primary site for clinical islet transplantation, it poses several restrictions, especially limited tissue volume due to portal vein pressure. We evaluated the preperitoneal space as an extrahepatic islet transplant site to deliver high tissue volumes and sustain long-term graft function.

Methods.

A peritoneal pouch was formed by dissecting the parietal peritoneum from the transversalis fascia of mice. Syngeneic C57BL/6 donor islets were transplanted into the peritoneal pouch of diabetic mouse recipients. Blood glucose was monitored for islet function, and miR-375 was analyzed for islet damage. Islet graft morphology and vascularization were evaluated by immunohistochemistry. [18F] fluoro-d-glucose positron emission tomography/computed tomography was used to image islet grafts.

Results.

Transplantation of 300 syngeneic islets into the peritoneal pouch of recipients reversed hyperglycemia for >60 days. Serum miR-375 was significantly lower in the peritoneal pouch group than in the peritoneal cavity group. Peritoneal pouch islet grafts showed high neovascularization and sustained insulin and glucagon expression up to 80 days posttransplantation. A peritoneal pouch graft with high tissue volume (1000 islets) could be visualized by positron emission tomography/computed tomography imaging. Human islets transplanted into the peritoneal pouch of diabetic nude mice also reversed hyperglycemia successfully.

Conclusions.

Islets transplanted into a dissected peritoneal pouch show high efficiency to reverse diabetes and sustain islet graft function. The preperitoneal site has the advantages of capacity for high tissue volume, enriched revascularization and minimal inflammatory damage. It can also serve as an extrahepatic site for transplanting large volume of islets necessitated in islet autotransplantation.
Obese communities among the best predictors of COVID-19-related deaths
Authors: Fakhry AbdelMassih Antoine , Ghaly Ramy , Amin Abeer , Gaballah Amr , Kamel Aya , Heikal Bassant , Menshawey Esraa , Ismail Habiba-Allah , Hesham Hend , Attallah Josephine , Eshak Kirollos , Moursi Mai , Khaled-Ibn-ElWalid Mariam , Tawfik Marwa , Tarek Mario , Mohy-El-Din Mayan , Habib Menna , Hafez Nada , Bahnan Odette , Ismail Passant , Senoussy Sara , Ghaly Sherry , Farah Sousanna , Hozaien Rafeef , Adel Veronia , Khaled Mariam
Published: June 2020

Introduction

Coronavirus disease 2019 (COVID-19) is the largest outbreak to strike the world since the Spanish flu in 1918. Visual examination of the world map shows a wide variation of death tolls between countries. The main goal of our series is to determine the best predictors of such discrepancy.

Methods

This is a retrospective study in which the rate of COVID-19 deaths was correlated with each of the following independent variables: total tests per 1 million population, gross domestic product (GDP), average temperatures per country, ultraviolet index, median age, average BMI per country, food supply, Bacille Calmette-Guerin compulsory status, and passenger traffic.

Results

BMI per country proved to be the second best predictor of death rate with an R value of 0.43, and GDP being the best predictor with R = 0.65.

Conclusion

This article shows a tight correlation between average BMI, food supply per country, and COVID-19-related deaths. Such predisposing factors might operate by upregulating the inflammation pathway in heavily struck countries, leading to easier triggering of the infamous cytokine storm syndrome. Obesity also increases cardiovascular and respiratory morbidities, which are coupled to increased ICU demand and deaths among infected cases.

Video abstract: http://links.lww.com/CAEN/A25.
The importance of monitoring renal function and concomitant medication to avoid toxicity in patients taking lithium
Authors: Tobita Shuko , Sogawa Rintaro , Murakawa Toru , Kimura Sakiko , Tasaki Masanobu , Sakamoto Yuichiro , Monji Akira , Irie Hiroyuki
Published: June 2020

Lithium, which is used for bipolar disorder, can cause toxicity. There are two categories of lithium toxicity, namely, overdose-related and not overdose-related. However, the treatment and prognosis of each type of toxicity are not clearly understood. We, therefore, compared the clinical characteristics of patients with overdose-related and not overdose-related lithium toxicity. Relevant data were obtained from the medical records of 16 patients with lithium toxicity, and renal function and concomitant medications were retrospectively compared between the two groups. We also compared the treatment for, manifestations of, and duration of hospitalization between the two types of lithium toxicity. The not overdose-related group more frequently had a low creatinine clearance (<50 mL/min) than did the overdose-related group (P = 0.01). Multivariable regression analysis demonstrated that creatinine clearance <50 mL/min was a significant predictor of lithium toxicity in the not overdose-related group (P = 0.01). Tremor and dysarthria occurred only in the not overdose-related group, and duration of hospitalization was significantly longer in the not overdose-related than overdose-related group (P = 0.01). Clinicians must monitor the renal function of patients taking lithium, even when in compliance with the prescribed dosage, because they are at long-term risk of lithium toxicity.
Sunxiuqinia indica sp. nov., isolated from deep sea
Authors: Li Jianyang , Qi Mingming , Lai Qiliang , Wang Guangyi , Shao Zongze
Published: June 2020

A Gram-stain-negative, facultative anaerobic, red-pigmented, rod-shaped and non-motile strain (RC1_OXG_1FT) was isolated from deep sea water of the Indian Ocean. It was able to grow at pH 5–8 (optimum, pH 7), at 5–37 °C (optimum, 30 °C), and at salinity (% NaCl, w/v) of 0.5–5 % (optimum, 1–2 %). Catalase- and oxidase-positive. It had highest 16S rRNA gene similarity (96.7 %) to ‘

Sunxiuqinia dokdonensis

’ DH1T, followed by

Sunxiuqinia faeciviva

JAM-BA0302T (96.6 %),

Sunxiuqinia elliptica

CGMCC 1.9156T (96.2 %),

Sunxiuqinia rutila

HG677T (96.0 %) and species (less than 92.3 %) of other genera. It belongs to the genus

Sunxiuqinia

within the phylum

Bacteroidetes

, based on the phylogenetic analysis. The results of digital DNA–DNA hybridization and average nucleotide identity analyses indicated that the strain belonged to a novel species. Its genome size is 5,250, 885 bp, with DNA G+C content of 40.5 mol%. Genome analysis revealed that the strain possessed many genes involved in polysaccharide degradation, especially hemicellulose degradation, indicating that the strain could maintain its normal metabolism by using recalcitrant organic matter in the oligotrophic deep sea environment. Its principal fatty acids were anteiso-C15 : 0 and iso-C15 : 0 and the major polar lipids were phosphatidylethanolamine, two unidentified glycolipids, three unidentified phospholipids and two unidentified polar lipids. The isoprenoid quinone was MK-7. Based on the phenotypic, chemotaxonomic and genotypic data, the strain represents a novel species within the genus

Sunxiuqinia

, for which the name Sunxiuqinia indica sp. nov. is proposed. The type strain is RC1_OXG_1FT (=MCCC 1A13858T=KCTC 62805T).
Dynamics of the ACE2 - SARS-CoV/SARS-CoV-2 spike protein interface reveal unique mechanisms
Authors: Ali Amanat , Vijayan Ranjit
Published: June 2020

The coronavirus disease 2019 (COVID-19) pandemic, caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), is a major public health concern. A handful of static structures now provide molecular insights into how SARS-CoV-2 and SARS-CoV interact with its host target, which is the angiotensin converting enzyme 2 (ACE2). Molecular recognition, binding and function are dynamic processes. To evaluate this, multiple all atom molecular dynamics simulations of at least 500 ns each were performed to better understand the structural stability and interfacial interactions between the receptor binding domain of the spike protein of SARS-CoV-2 and SARS-CoV bound to ACE2. Several contacts were observed to form, break and reform in the interface during the simulations. Our results indicate that SARS-CoV and SARS-CoV-2 utilizes unique strategies to achieve stable binding to ACE2. Several differences were observed between the residues of SARS-CoV-2 and SARS-CoV that consistently interacted with ACE2. Notably, a stable salt bridge between Lys417 of SARS-CoV-2 spike protein and Asp30 of ACE2 as well as three stable hydrogen bonds between Tyr449, Gln493, and Gln498 of SARS-CoV-2 and Asp38, Glu35, and Lys353 of ACE2 were observed, which were absent in the SARS-CoV-ACE2 interface. Some previously reported residues, which were suggested to enhance the binding affinity of SARS-CoV-2, were not observed to form stable interactions in these simulations. Stable binding to the host receptor is crucial for virus entry. Therefore, special consideration should be given to these stable interactions while designing potential drugs and treatment modalities to target or disrupt this interface.
Diversity increases yield but reduces reproductive effort in crop mixtures
Authors: Chen Jianguo , Engbersen Nadine , Stefan Laura , Schmid Bernhard , Sun Hang , Schöb Christian
Published: June 2020

Resource allocation to reproduction is a critical trait for plant fitness1,2. This trait, called harvest index in the agricultural context3–5, determines how plant biomass is converted to seed yield and consequently financial revenue of numerous major staple crops. While plant diversity has been demonstrated to increase plant biomass6–8, plant diversity effects on seed yield of crops are ambiguous9. This discrepancy could be explained through changes in the proportion of resources invested into reproduction in response to changes in plant diversity, namely through changes of species interactions and microenvironmental conditions10–13. Here we show that increasing crop plant diversity from monoculture over 2- to 4-species mixtures increased annual primary productivity, resulting in overall higher plant biomass and, to a lesser extent, higher seed yield in mixtures compared with monocultures. The difference between the two responses to diversity was due to a reduced reproductive effort of the eight tested crop species in mixtures, possibly because their common cultivars have been bred for maximum performance in monoculture. While crop diversification provides a sustainable measure of agricultural intensification14, the use of currently available cultivars may compromise larger gains in seed yield. We therefore advocate regional breeding programs for crop varieties to be used in mixtures that should exploit facilitative interactions15among crop species.
Complete Chloroplast Genomes ofSaccharum giganteum,Saccharum longisetosum,Cleistachne sorghoides, Sarga timorense, Narenga porphyrocomaandTripsacum dactyloides. Comparisons with ITS phylogeny and Placement withinSaccharum
Authors: Evans Dyfed Lloyd , Hughes Ben
Published: June 2020

The first complete chloroplast and Internal Transcribed Sequence (ITS) cassette sequences for the species:Saccharum giganteum,Saccharum longisetosum,Cleistachne sorghoides, Saccharum narengaandTripsacum dactyloidesare presented. Corresponding sequences for a new isolate ofSarga timorensewere assembled. Phylogenetic analyses placeS. giganteum,S. longisetosumandS. narengawithin the Saccharinae but distinct from Saccharum, whilstC. sorghoidesemerges as a member of genusSargaandTripsacum datyloidesas a member of the Tripsacinae. Comparison of chloroplast and ITS phylogenies reveal complex reticulate evolution within the Saccharinae, withS. giganteum,S. longisetosumandS. narenga, despite having the same base chromosome count (15) having different evolutionary origins; making them members of different genera and not members of genusSaccharum. The importance of reticulate evolution in the origins of Andropogoneae, particularly the Saccharinae and the unique positions ofSaccharumandMiscanthusis discussed.
A circulating T-cell differentiation marker to predict response to immune checkpoint inhibitors
Authors: Yamauchi Takayoshi , Hoki Toshifumi , Oba Takaaki , Jain Vaibhav , Chen Hongbin , Attwood Kristopher , Battaglia Sebastiano , George Saby , Chatta Gurkamal , Puzanov Igor , Morrison Carl , Odunsi Kunle , Segal Brahm H. , Dy Grace K. , Ernstoff Marc S. , Ito Fumito
Published: June 2020

Immune checkpoint inhibitors (ICI) have revolutionized treatment for various cancers; however, durable response is limited to only a subset of patients. Discovery of blood-based biomarkers that reflect dynamic change of the tumor microenvironment, and predict response to ICI will markedly improve current treatment regimens. Here, we investigated a role of CX3C chemokine receptor 1 (CX3CR1), a marker of T-cell differentiation, in predicting response to ICI therapy. Successful treatment of tumor-bearing mice with ICI increased the frequency and T-cell receptor clonality of the peripheral CX3CR1+CD8+T-cell subset that included an enriched repertoire of tumor-specific and tumor-infiltrating CD8+T cells. Furthermore, an increase in the frequency of the CX3CR1+subset in circulating CD8+T cells early after initiation of anti-PD-1 therapy correlated with response and survival in patients with non-small cell lung cancer (NSCLC). Taken together, these data support T-cell CX3CR1 expression as a blood-based dynamic biomarker to predict response to ICI therapy.
Brain-predicted age associates with psychopathology dimensions in youth
Authors: Cropley Vanessa L. , Tian Ye , Fernando Kavisha , Sina Mansour L. , Pantelis Christos , Cocchi Luca , Zalesky Andrew
Published: June 2020

Background

This study aims to investigate whether dimensional constructs of psychopathology relate to advanced, attenuated or normal patterns of brain development, and to determine whether these constructs share common neurodevelopmental profiles.

Methods

Psychiatric symptom ratings from 9312 youths (8-21 years) were parsed into 7 independent dimensions of clinical psychopathology representing conduct, anxiety, obsessive-compulsive, attention, depression, bipolar, and psychosis symptoms. Using a subset of this cohort with structural MRI (n=1313), a normative model of brain morphology was established and the model was then applied to predict the age of youth with clinical symptoms. We investigated whether the deviation of brain-predicted age from true chronological age, called the brain age gap, explained individual variation in each psychopathology dimension.

Results

Individual variation in the brain age gap significantly associated with clinical dimensions representing psychosis (t=3.16,p=0.0016), obsessive-compulsive symptoms (t=2.5,p=0.01), and general psychopathology (t=4.08,p<0.0001). Greater symptom severity along these dimensions was associated with brain morphology that appeared older than expected for typically developing youth of the same age. Psychopathology dimensions clustered into two modules based on shared brain loci where putative accelerated neurodevelopment was most prominent. Patterns of morphological development were accelerated in frontal cortices for depression, psychosis and conduct symptoms (Module I), whereas acceleration was most evident in subcortex and insula for the remaining dimensions (Module II).

Conclusions

Our findings suggest that advanced brain development, particularly in frontal cortex and subcortical nuclei, underpins clinical psychosis and obsessive-compulsive symptoms in youth. Psychopathology dimensions share common neural substrates, despite representing clinically independent symptom profiles.
Single-cell screening of SARS-CoV-2 target cells in pets, livestock, poultry and wildlife
Authors: Chen Dongsheng , Sun Jian , Zhu Jiacheng , Ding Xiangning , Lan Tianming , Zhu Linnan , Xiang Rong , Ding Peiwen , Wang Haoyu , Wang Xiaoling , Wu Weiying , Qiu Jiaying , Wang Shiyou , Li Haimeng , An Fuyu , Bao Heng , Zhang Le , Han Lei , Zhu Yixin , Wang Xiran , Wang Feiyue , Yuan Yuting , Wu Wendi , Sun Chengcheng , Lu Haorong , Wu Jihong , Sun Xinghuai , Zhang Shenghai , Sahu Sunil Kumar , Chen Haixia , Fang Dongming , Luo Lihua , Zeng Yuying , Wu Yiquan , Cui ZeHua , He Qian , Jiang Sanjie , Ma Xiaoyan , Feng Weimin , Xu Yan , Li Fang , Liu Zhongmin , Chen Lei , Chen Fang , Jin Xin , Qiu Wei , Yang Huanming , Wang Jian , Hua Yan , Liu Yahong , Liu Huan , Xu Xun
Published: June 2020

A few animals have been suspected to be intermediate hosts of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). However, a large-scale single-cell screening of SARS-CoV-2 target cells on a wide variety of animals is missing. Here, we constructed the single-cell atlas for 11 representative species in pets, livestock, poultry, and wildlife. Notably, the proportion of SARS-CoV-2 target cells in cat was found considerably higher than other species we investigated and SARS-CoV-2 target cells were detected in multiple cell types of domestic pig, implying the necessity to carefully evaluate the risk of cats during the current COVID-19 pandemic and keep pigs under surveillance for the possibility of becoming intermediate hosts in future coronavirus outbreak. Furthermore, we screened the expression patterns of receptors for 144 viruses, resulting in a comprehensive atlas of virus target cells. Taken together, our work provides a novel and fundamental strategy to screen virus target cells and susceptible species, based on single-cell transcriptomes we generated for domesticated animals and wildlife, which could function as a valuable resource for controlling current pandemics and serve as an early warning system for coping with future infectious disease threats.
HYD3, a conidial hydrophobin of the fungal entomopathogenMetarhizium acriduminduces the immunity of its specialist host locust
Authors: Jiang Zeyuan , Ligoxygakis Petros , Xia Yuxian
Published: June 2020

Conidial hydrophobins in fungal pathogens of plants1,2, insects3,4, and humans5,6are required for fungal attachment and are associated with high virulence. They are believed to contribute to the pathogenesis of infection by preventing immune recognition5,6. Here, we refute this generalisation offering a more nuanced analysis. We show that MacHYD3, a hydrophobin located on the conidial surface of the specialist entomopathogenic fungusMetarhizium acridum, activates specifically the humoral and cellular immunity of its own host insect,Locusta migratoria manilensis(Meyen) but not that of other non-host insects. When topically applied to the cuticle, purified MacHYD3 improved the resistance of locusts to both specialist and generalist fungal pathogens but had no effect on the fungal resistance of other insects, includingSpodoptera frugiperdaandGalleria mellonella. Hydrophobins extracted from the generalist fungal pathogensM. anisopliaeandBeauveria bassianahad no effect on the resistance of locusts to fungal infection. Thus, the host locust has evolved to recognize the conidial hydrophobin of its specialist fungal pathogen, whereas conidial hydrophobins from generalist fungi are able to evade recognition. Our results distinguish the immunogenic potential of conidial hydrophobins between specialist and generalist fungi.
Divide and conquer – machine-learning integrates mammalian, viral, and network traits to predict unknown virus-mammal associations
Authors: Wardeh Maya , Blagrove Marcus S.C. , Sharkey Kieran J. , Baylis Matthew
Published: June 2020

Our knowledge of viral host ranges remains limited. Completing this picture by identifying unknown hosts of known viruses is an important research aim that can help identify zoonotic and animal-disease risks. Furthermore, such understanding can be used to mitigate against viral spill-over from animal reservoirs into human population. To address this knowledge-gap we apply a divide-and-conquer approach which separates viral, mammalian and network features into three unique perspectives, each predicting associations independently to enhance predictive power. Our approach predicts over 20,000 unknown associations between known viruses and mammalian hosts, suggesting that current knowledge underestimates the number of associations in wild and semi-domesticated mammals by a factor of 4.3, and the average mammalian host-range of viruses by a factor of 3.2. In particular, our results highlight a significant knowledge gap in the wild reservoirs of important zoonotic and domesticated mammals’ viruses: specifically, lyssaviruses, bornaviruses and rotaviruses.
Protein citrullination was introduced into animals by horizontal gene transfer from cyanobacteria
Authors: Cummings Thomas F. M. , Gori Kevin , Sanchez-Pulido Luis , Gavriilidis Gabriel , Moi David , Wilson Abigail R. , Murchison Elizabeth , Dessimoz Christophe , Ponting Chris P. , Christophorou Maria A.
Published: June 2020

Protein post-translational modifications (PTMs) add an enormous amount of sophistication to biological systems but their origins are largely unexplored. Citrullination, a key regulatory mechanism in human physiology and pathophysiology, is particularly enigmatic in an evolutionary context. The citrullinating enzymes peptidylarginine deiminases (PADIs) are ubiquitous across vertebrates but absent from yeast, worms and flies. Here, we map the surprising evolutionary trajectory of PADIs into the animal lineage. We present strong phylogenetic support for a clade encompassing animal and cyanobacterialPADIsthat excludes fungal and other bacterial homologues. The animal and cyanobacterial PADIs share unique, functionally relevant synapomorphies that are absent from all other homologues. Molecular clock calculations and sequence divergence analyses using the fossil record estimate the last common ancestor of the cyanobacterial and animal PADIs to be approximately 1 billion years old, far younger than the 3.35-4.52 billion years known to separate bacterial and eukaryotic lineages. Under an assumption of vertical descent, PADI sequence change is anachronistically slow during this evolutionary time frame, even when compared to mitochondrial proteins, products of likely endosymbiont gene transfer and some of the most highly conserved proteins in life. The consilience of evidence indicates thatPADIswere introduced from cyanobacteria into animals by horizontal gene transfer (HGT). The ancestral cyanobacterial protein is enzymatically active and can citrullinate eukaryotic proteins, suggesting that thePADIHGT event introduced a new catalytic capability into the regulatory repertoire of animals. This study reveals the unusual evolution of a pleiotropic protein modification with clear relevance in human physiology and disease.
Prediction of Individual Breast Cancer Evolution to Surgical Size
Authors: Axenie Cristian , Kurz Daria
Published: June 2020

Modelling surgical size is not inherently meant to replicate the tumor’s exact form and proportions, but instead to elucidate the degree of the tissue volume that may be surgically removed in terms of improving patient survival and minimize the risk that subsequent operations will be needed to eliminate all malignant cells entirely. Given the broad range of models of tumor growth, there is no specific rule of thumb about how to select the most suitable model for a particular breast cancer type and whether that would influence its subsequent application in surgery planning. Typically, these models require tumor biologydependent parametrization, which hardly generalizes to cope with tumor heterogeneity. In addition, the datasets are limited in size, owing to the restricted or expensive measurement methods. We address the shortcomings that incomplete biological specifications, the variety of tumor types, and the limited size of the data bring to existing mechanistic tumor growth models and introduce a Machine Learning model for the PRediction of INdividual breast Cancer Evolution to Surgical Size (PRINCESS). This is a data-driven model based on neural networks capable of unsupervised learning of cancer growth curves. PRINCESS learns the temporal evolution of the tumor along with the underlying distribution of the measurement space. We demonstrate the superior accuracy of PRINCESS, against four typically used tumor growth models, in learning tumor growth curves from a set of four clinical breast cancer datasets. Our experiments show that, without any modification, PRINCESS can accurately predict tumor sizes while being versatile between breast cancer types.
State-dependent cortical unit activity reflects dynamic brain state transitions in anesthesia
Authors: Lee Heonsoo , Wang Shiyong , Hudetz Anthony G.
Published: June 2020

How anesthesia affects cortical neuronal spiking and information transfer could help understand the neuronal basis of conscious state. Recent investigations suggest that global state of the anesthetized brain is not stationary but changes spontaneously at a fixed level of anesthetic concentration. How cortical unit activity changes with dynamically transitioning brain states under anesthesia is unclear. We hypothesized that distinct cortical states are characterized by distinct neuronal spike patterns. Extracellular unit activity was measured with sixty-four-channel silicon microelectrode arrays in cortical layers 5/6 of primary visual cortex of chronically instrumented, freely moving male rats (N = 7) during stepwise reduction of the anesthetic desflurane (6, 4, 2, and 0%). Unsupervised machine learning applied to multi-unit spike patterns revealed five distinct brain states of which four occurred at various anesthetic concentrations and shifted spontaneously. In deeper anesthesia states, the number of active units and overall spike rate decreased while the remaining active units showed increased bursting (excitatory neurons), spike timing variability, unit-to-population correlation and unit-to-unit transfer entropy, especially among putative excitatory units, despite the overall decrease in transfer entropy. A novel desynchronized brain state with increased spike timing variability, entropy and electromyographic activity that occurred mostly in deep anesthesia was discovered. These results provide evidence for distinct unit activity patterns associated with spontaneous changes in local cortical brain states at stationary anesthetic conditions. The appearance of a paradoxical, desynchronized brain state in deep anesthesia contends the prevailing view of monotonic dose-dependent anesthetic effects on the brain.

SIGNIFICANCE STATEMENT

Recent studies suggest that spontaneous changes in brain state occur under anesthesia. However, the spiking behavior of cortical neurons associated with such state changes has not been investigated. We found that local brain states defined by multi-unit activity had non-unitary relationship with the current anesthetic level. A paradoxical brain state displaying asynchronous firing pattern and high electromyographic activity was found unexpectedly at high-dose anesthesia. In contrast, the synchronous fragmentation of neuronal spiking appeared to be a robust signature of the state of anesthesia. The findings challenge the assumption of monotonic, anesthetic dose-dependent behavior of cortical neuron populations. They enhance the interpretation of neuroscientific data obtained under anesthesia and understanding of the neuronal basis of anesthetic-induced state of unconsciousness.
Requirement ofIrf6andEsrp1/2in frontonasal and palatal epithelium to regulate craniofacial and palate morphogenesis in mouse and zebrafish
Authors: Carroll Shannon H. , Macias Trevino Claudio , Li Edward B-H , Kawasaki Kenta , Alhazmi Nora , Hallett Shawn , Cotney Justin , Carstens Russ P. , Liao Eric C.
Published: June 2020

Orofacial clefts are among the most common human congenital malformations.Irf6andEsrp1are two key genes important for palate development, conserved across vertebrates. In the zebrafish, we found that irf6 regulates the expression ofesrp1. Using RNAscope, we detailed overlappingIrf6andEsrp1/2gene expression in the mouse frontonasal prominence ectoderm, lambda joint periderm, palate and lip epithelium. In the zebrafish,irf6andesrp1/2share expression in the pre-gastrulation periderm and the embryonic frontonasal ectoderm, oral epithelium ventral to the anterior neurocranium (ANC), and the developing stomodeum. Genetic disruption ofirf6andesrp1/2in the zebrafish resulted in cleft of the ANC. In theesrp1/2zebrafish mutant, cleft of the mouth opening formed and appeared to tether into the ANC cleft. Lineage tracing of the anterior cranial neural crest cells revealed that cleft of the ANC resulted not from migration defect, but from impaired chondrogenesis. Molecular analysis of the aberrant cells localized within the ANC cleft revealed that this cell population espressessox10, col1a1andirf6and is adjacent to cells expressing epithelialkrt4. Detailed morphogenetic analysis of mouseIrf6mutant revealed mesenchymal defects not observed in theEsrp1/2mutant. Analysis of breeding compoundIrf6;Esrp1;Esrp2mutant suggests that these genes interact where the triple mutant is not observed. Taken together, these studies highlight the complementary analysis ofIrf6andEsrp1/2in mouse and zebrafish models and captured an unique aberrant embryonic cell population that contributes to cleft pathogenesis. Future work characterizing this unqiuesox10+, col1a1+, irf6+ cell population will yield additional insight into cleft pathogenesis.
β-actin dependent chromatin remodeling mediates compartment level changes in 3D genome architecture
Authors: Mahmood Syed Raza , Xie Xin , El Said Nadine Hosny , Gunsalus Kristin C. , Percipalle Piergiorgio
Published: June 2020

β-actin is a crucial component of several chromatin remodeling complexes that control chromatin structure and accessibility. The mammalian Brahma-associated factor (BAF) is one such complex that plays essential roles in development and differentiation by regulating the chromatin state of critical genes and opposing the repressive activity of polycomb repressive complexes (PRCs). While previous work has shown that β-actin loss can lead to extensive changes in gene expression and heterochromatin organization, it is not known if changes in β-actin levels can directly influence chromatin remodeling activities of BAF and polycomb proteins. Here we conduct a comprehensive genomic analysis of β-actin knockout mouse embryonic fibroblasts (MEFs) using ATAC-Seq, HiC-seq, RNA-Seq and ChIP-Seq of various epigenetic marks. We demonstrate that β-actin levels can affect the complex interplay between chromatin remodelers such as BAF/BRG1 and EZH2 in a dosage-dependent manner. Our results show that changes in β-actin levels and associated chromatin remodeling activities can not only impact local chromatin accessibility but also induce reversible changes in 3D genome architecture. Our findings support a novel role for β-actin-dependent chromatin remodeling in shaping the chromatin landscape and regulating genes involved in development and differentiation.
The serotonin reuptake inhibitor Fluoxetine inhibits SARS-CoV-2
Authors: Zimniak Melissa , Kirschner Luisa , Hilpert Helen , Seibel Jürgen , Bodem Jochen
Published: June 2020

To circumvent time-consuming clinical trials, testing whether existing drugs are effective inhibitors of SARS-CoV-2, has led to the discovery of Remdesivir. We decided to follow this path and screened approved medications “off-label” against SARS-CoV-2. In these screenings, Fluoxetine inhibited SARS-CoV-2 at a concentration of 0.8µg/ml significantly, and the EC50 was determined with 387ng/ml. Fluoxetine is a racemate consisting of both stereoisomers, while the S-form is the dominant serotonin reuptake inhibitor. We found that both isomers show similar activity on the virus. Fluoxetine treatment resulted in a decrease in viral protein expression. Furthermore, Fluoxetine inhibited neither Rabies virus, human respiratory syncytial virus replication nor the Human Herpesvirus 8 or Herpes simplex virus type 1 gene expression, indicating that it acts virus-specific. We see the role of Fluoxetine in the early treatment of SARS-CoV-2 infected patients of risk groups.
A Network Polypharmacological Approach to Combinatorial Drug Repurposing for Diffuse Intrinsic Pontine Glioma
Authors: MacLean Finlay , Nazarian Javad , Przystal Justyna , Pantziarka Pan , Wilson Jabe
Published: June 2020

Despite five decades of clinical investigations, there is currently no effective treatment for children diagnosed with Diffuse Intrinsic Pontine Glioma (DIPG). We now understand that DIPGs share the same histone 3 mutation and fatal prognosis as other diffuse midline gliomas (DMGs), which led to the introduction of a new entity referred to as DMG, H3 K27M mutant. Indeed, therapeutics indicated for other brain neoplasms have proven ineffective for DIPGs. We posit that by using a polypharmacological approach to determine drug combinations that target distinct mechanistic pathways of DIPG, it is more likely that an efficacious treatment will be developed. We predict monodrug therapies using a link prediction model trained on various embeddings of a drug-disease regulatory network and physicochemical properties of small molecules and proteins. We validate thein silicopredictions by performing cell viability assays on patient-derived cell cultures for notable therapeutics. Using FDA-approved drugs as a proxy for viability of a drug pair for combinatorial use, we develop a model to predict the synergism of the relationship between drug pairs. Finally, we calculate the transitive probability that a drug pair contains drugs that individually regulate DIPG, are blood-brain barrier penetrant, and the drug pair are suitable for combined use. We find only moderate agreement between computational predictions and experimental results for both monodrug and multidrug therapies, we believe due to the heterogeneity of the disease, the difficulties of modelling brain permeability, and an inherent literature bias in the knowledge graph. Such challenges need to be overcome to develop an efficacious therapy for this disease.
Anopheles coluzziistearoyl-CoA desaturase is essential for adult female survival and reproduction upon blood feeding
Authors: Ferdous Zannatul , Fuchs Silke , Behrends Volker , Trasanidis Nikolaos , Vlachou Dina , Christophides George K.
Published: June 2020

Vitellogenesis and oocyte maturation require anautogenous femaleAnophelesmosquitoes to obtain a bloodmeal from a vertebrate host. The bloodmeal is rich in proteins that are readily broken down into amino acids in the midgut lumen and absorbed by the midgut epithelial cells where they are converted into lipids and then transported to other tissues including ovaries. The stearoyl-CoA desaturase (SCD) plays a pivotal role in this process by converting saturated (SFAs) to unsaturated (UFAs) fatty acids; the latter being essential for maintaining cell membrane fluidity amongst other housekeeping functions. Here, we report the functional and phenotypic characterization of SCD1 in the malaria vector mosquitoAnopheles coluzzii. We show that RNA interference (RNAi) silencing ofSCD1and administration of sterculic acid (SA), a small molecule inhibitor of SCD1, significantly impact on the survival and reproduction of female mosquitoes following blood feeding. Microscopic observations reveal that the mosquito thorax is quickly filled with blood, a phenomenon likely caused by the collapse of midgut epithelial cell membranes, and that epithelial cells are depleted of lipid droplets and oocytes fail to mature. Transcriptional profiling shows that genes involved in protein, lipid and carbohydrate metabolism and immunity-related genes are the most affected bySCD1knock down (KD) in blood-fed mosquitoes. Metabolic profiling reveals that these mosquitoes exhibit increased amounts of saturated fatty acids and TCA cycle intermediates, highlighting the biochemical framework by which theSCD1KD phenotype manifests as a result of a detrimental metabolic syndrome. Accumulation of SFAs is also the likely cause of the potent immune response observed in the absence of infection, which resembles an auto-inflammatory condition. These data provide insights into mosquito bloodmeal metabolism and lipid homeostasis and could inform efforts to develop novel interventions against mosquito-borne diseases.
Economic policy uncertainty and firms' labor investment decision
Authors: Chu Jian , Fang Junxiong
Published: June 2020

Purpose

The purpose of this paper is to empirically investigate the impact of economic policy uncertainty on firms' labor investment decision, which includes labor investment level and efficiency, especially human capital allocation.

Design/methodology/approach

This paper uses Economic Policy Uncertainty Index for China and Chinese A-share listed firms in the period 2002–2016 to constructs a sample of 20,779 firm-year observations and applies the methods of pooled OLS regressions to do an empirical study.

Findings

This paper finds that firms' labor investment is negatively correlated with economic policy uncertainty. And firms' labor investment efficiency (and overinvestment in labor) is positively (negatively) correlated with economic policy uncertainty, which is more significant for non-SOEs and firms with less government intervention. Further, the positive relation between economic policy uncertainty and labor investment efficiency is more significant for labor-intensive firms, firms in competitive industry, firms in developed labor market and firms under strong labor law protection. In addition, economic policy uncertainty induces firms to make adjustment on human capital structure and allocate more employees with high human capital, which eventually helps firms achieve higher total factor productivity.

Social implications

The study of this paper indicates that the government needs to consider economic policies' impact on firms when introducing and changing policies and guide firms to improve human capital allocation under different internal and external conditions to finally realize the optimal allocation of social resources.

Originality/value

This paper studies the influence of external economic policy environment on firms' labor investment decision, which lacks adequate attention in the literature and indicates that under economic policy uncertainty, firms actively decrease labor demand and increase labor investment efficiency by optimizing human capital allocation.
What national governance codes say about corporate culture
Authors: Lobrij Marie-Fleur , Kaptein Muel , Lückerath-Rovers Mijntje
Published: June 2020

Purpose

This study aims to provide insight into the current incorporation of corporate culture in national corporate governance codes. The authors identify three levels of incorporation for each of the following three dimensions: layers of corporate culture (the “what”), the alignment of corporate culture in the organization (the “for whom”) and the board’s roles regarding corporate culture (the “how”).

Design/methodology/approach

To assess the extent to which national codes have incorporated corporate culture, the authors used a sample of 88 national corporate governance codes. The authors performed a content analysis of these codes using a computer-aided text analysis program. The first step involved the identification of dimensions of corporate culture per national code. These dimensions were then assessed based on three levels of incorporation. Finally, the authors ranked national codes with similar levels of incorporation per dimension and aggregated the dimensions.

Findings

The data show that five of the 88 national corporate governance codes that the authors analysed scored the highest level in all three dimensions of corporate culture.

Originality/value

This is the first study to provide an overview of what national corporate governance codes say about corporate culture. The authors address two gaps in the existing literature. First, the authors develop and use a richer conceptualization of how corporate culture can be addressed in national corporate governance codes. Second, the authors analyse these corporate governance codes worldwide.