bluuebunny/crossref_metadata_2025 huggingface dataset:
The Medial Femoral Condyle Free Flap for Reconstruction of Recalcitrant Defects in the Head and Neck
Authors: Singh Kuldeep , Huang Tony C.T. , Meaike Jesse D. , Mills Andrew M. , Nathan John M. , Lettieri Salvatore C. , Arce Kevin , Moran Steven L.
Published: February 2021

Background

Small recalcitrant defects of the mandible and maxilla may be secondary to tumor, trauma, infection, and congenital origin. Vascularized bone grafting has been shown to effectively manage these defects; however, donor sites are limited. The vascularized medial femoral condyle (MFC) provides adequate cortical cancellous bone with the option of a skin island, consistent anatomy, and minimal donor site morbidity. This article outlines the use of the MFC flap for maxillomandibular reconstruction.

Methods

A retrospective chart review of patients who required segmental maxillomandibular reconstruction with the MFC flap was conducted. A total of 9 patients (5 men and 5 women) with an average age of 45.3 years were identified. The etiology of the defects, flap sizes, and postoperative outcomes were recorded.

Results

Three patients had osteoradionecrosis of the neomandible after irradiation of the free fibula reconstruction, 3 patients had defects after cancer extirpation (1 mandible, 2 maxillary), 1 patient had a maxillary defect from trauma, and 2 patients had a residual cleft palate defect. All defects failed initial treatment with nonvascularized bone grafts. The average dimensions of the MFC flaps were 1.2 × 2.5 × 4 cm. Two of 9 flaps included a skin island. Eight flaps survived completely, but 1 patient suffered from flap failure requiring debridement and resulted in an oroantral fistula. Four patients received endosseous dental implants. Average time to union was 6.7 months, and average time to implant was 6.75 months. The average follow-up time was 24.9 months.

Conclusions

The MFC flap is useful in the reconstruction of small segmental maxillomandibular defects and for the salvage of a neomandible after osteoradionecrosis. The MFC flap provides a reliable platform for endosseous dental implants and serves as an alternative source of vascularized bone reconstruction in the head and neck.
Perforator Detection by Thermographic Imaging Augmented With Tourniquet-Reperfusion
Authors: Pan Jia-Dong , Xu Heng , Xiao Dong-chao , Hacquebord Jacques Henri , Chang Shi-Min , Wang Xin
Published: February 2021

Background

Dynamic infrared thermography provides a new imaging method of perforator detection. This study introduces an augmented technique to improve its accuracy by tourniquet-reperfusion and reports its preliminary use in the distal lower leg reconstruction.

Methods

A tourniquet (450 mm Hg) was applied for 3 minutes on proximal thighs. After the tourniquet release, the rewarming rate and pattern of hotspots were observed by thermography to delineate the location and quality of perforators. The results were compared with those detected by computed tomographic angiography. Clinically, the local transferred posterior tibial artery or peroneal artery propeller perforator flap was performed in 9 patients for the distal lower leg reconstruction.

Results

There was a 20- to 140-second “perforator observing window” after the tourniquet release. Tourniquet-reperfusion augmented thermal imaging method (TRATIM) had a sensitivity of 90.3% and a positive predictive value of 93.3%. The TRATIM and computed tomographic angiography had an excellent concordance with a kappa index value of 0.839 (P < 0.001). Based on the TRATIM, 9 propeller perforator flaps were successfully designed and raised for the distal lower leg resurfacing. All flaps survived entirely, except one with size of 1.0 cm × 2.0 cm that had terminal necrosis.

Conclusions

The TRATIM is a quick, easy, cheap, and reliable approach for perforator detection in the lower leg. With the aid of TRATIM, a customized propeller perforator flap could be raised efficiently for the distal lower leg reconstruction.
Variations in Orofacial Clefts
Authors: Jahanbin Arezoo , Jamalinasab Abdollah , Niazi Ahmad Ehsan
Published: February 2021

Objectives:

The main objective of this study was to report the prevalence and other relative risk factors of oral clefts among newborn infants.

Methods:

In this study, we reviewed the data regarding 234 infants with cleft anomalies as collected in questionnaires from 2004 to 2019 and demographic parameters were assessed.

Results:

Cleft lip and palate was the most common anomaly (66.7%), followed by isolated cleft palate (28.2%), isolated cleft lip (3.8%), and cleft lip and alveolus (1.3%). The study also showed that 54.3% of all cleft patients were boys and 45.7% were girls (with a rate of 1.18) and the difference between both sexes was significant (P-value = 0.010). In addition, cleft lip and palate was more common in males and isolated cleft palate was seen more in girls (P-value = 0.002, P-value = 0.001, respectively). The parents (56.4%) had consanguinity and 20% of them had a history of cleft in their family.

Conclusion:

Cleft lip and palate in boys and cleft palate in girls was more common. Parents’ consanguinity and history of cleft in their family are also important factors to consider. Further studies on cleft anomalies along with or without genetic factors are required.
Morphometric Analysis of Cleft Lip Palate and Prognathic Mandibles in Relation to Mandibular Canal Course
Authors: Sancar Bahadir , Dedeoğlu Numan
Published: February 2021

Introduction:

This study aimed to evaluate the mandibular canal course in individuals with cleft lip palate (CLP) and mandibular prognathism in terms of the sagittal split-ramus osteotomy using cone-beam computed tomography.

Materials and Methods:

Individuals with CLP older than 16 years of age and planned to undergo Le fort I + SSR osteotomies and those with class III occlusion planned to undergo Le fort I + SSR osteotomies were included. The measurements on the cleft side of CLP patients were compared with both their noncleft sides and those with class III occlusion. The course of the inferior alveolar nerve and its position in the mandible were evaluated starting from the mandibular foramen, the first entrance to the mandible, to the mental foramen, the exit from the mandible.

Results:

The distance between the mandibular canal and the buccal surface of the mandible (B3) on the plane tangent to the distal of the mandibular first molar and perpendicular to the occlusal plane was found to be greater in individuals with CLP (P = 0.011). Buccal cortex thickness (C4) at the level of the mandibular canal on the plane tangent to the distal of the mandibular second molar and perpendicular to the occlusal plane was found to be lower in individuals with CLP (P = 0.021).

Conclusions:

The buccal cortex thickness of the mandible corpus and the distance of the mandibular canal to the buccal surface is different in patients with CLP compared to class III individuals’ posterior to the mandible. Surgeons should take these differences into consideration during mandibular osteotomy.
The Effect of Smoking on the Postoperative Course After Head and Neck Reconstruction With a Vascularized Free Flap: A Retrospective Study
Authors: Garip Melisa , Croonenborghs Tomas-Marijn , Bila Michel , Vranckx Jan Jeroen , Politis Constantinus
Published: February 2021

Objectives:

The objective of the present study is to determine the impact of smoking on hospital and intensive care unit stay, need for surgical reintervention, Portsmouth Physiological and Operative Severity Score for the enumeration of Mortality and morbidity, and surgical complications after head and neck reconstructions.

Methods:

All 153 patients who underwent head and neck reconstructions with free tissue transfer at the department of oral and maxillofacial surgery at the University Hospitals of Leuven between January 1, 2015 and December 31, 2018 were enrolled in this retrospective cohort study. Data from medical charts were extracted. Univariate and multiple regression analyses were performed. A level of significance of P < 0.05 (α = 0.05) was used.

Results:

Smoking was not associated with Portsmouth Physiological and Operative Severity Score for the enumeration of Mortality and morbidity, hospital or ICU stay, the incidence of postoperative complications in both flap and donor site, or surgical reintervention.

Conclusions:

Regarding the outcomes included in this study, smoking status should not be considered as a critical factor in patient selection for head and neck reconstructions with a vascularized free flap.
A Giant Diving Ranula Extending to the Skull Base in Pediatric Age
Authors: Kumbul Yusuf Çağdaş , Okur Nazan , Çiriş Ibrahim Metin , Okur Erdoğan , Sivrice Mehmet Emre , Akin Vural
Published: February 2021

Ranula is a retention cyst that develops from the salivary glands. It has 2 subtypes, oral and diving. There are differences in the clinical features of ranula subtypes. In particular, diving ranula is more prone to extend in the neck spaces than oral ranula. The enlargement of the diving ranula is generally downward in the neck. If the opposite occurs, we may encounter very interesting and difficult cases. Diving ranula should be kept in mind in the differential diagnosis of cystic neck masses in the pediatric age group and its treatment should be done surgically.

A 15-year-old girl admitted to our clinic with the complaint of swelling in the floor of the mouth and neck. In physical examination of the patient, a mass with cystic content was observed adjacent to the left Wharton canal. In addition, a 4 × 3 cm, soft, fluctuant, nonfixed, painless mass was palpated in the left submandibular area. Magnetic resonance imaging revealed that the neck mass was a diving ranula extending from the parapharyngeal space to the skull base. In the surgery, submandibular and sublingual salivary glands were removed together with the diving ranula. We observed no complications in the postoperative period.

Magnetic resonance imaging should be used to confirm the diagnosis of diving ranula. In the treatment of diving ranula, excision of the ranula alone is not enough surgically. We also recommend excision of the submandibular and/or sublingual salivary glands associated with ranula to reduce the recurrence rate.
Association of Plasma Levels of Fas Ligand with Severity and Outcome of Sepsis
Authors: Yoo Hongseok , Lee Jin Young , Park Junseon , Suh Gee Young , Jeon Kyeongman
Published: February 2021

Introduction:

Levels of the apoptosis regulator Fas ligand (FasL) are associated with severity of sepsis, but its association with the mortality of sepsis and necroptosis, a regulated cell death mechanism, is not yet clear. We aimed to assess the association of FasL level with outcomes of sepsis and receptor interacting protein kinase-3 (RIPK3), an essential necroptosis mediator, for determining the relationship between FasL and necroptosis.

Methods:

Plasma FasL and RIPK3 levels were measured by ELISA from prospectively enrolled critically ill adult patients. The best cut-off level of FasL for 28-day mortality prediction was determined by Youden's index. The association between plasma levels of FasL and RIPK3 was assessed by a linear regression method.

Results:

Among 188 patients, 58 (30.9%) were diagnosed with sepsis and 84 (44.7%) with septic shock, respectively. Plasma levels of FasL increased in the group order of control, sepsis, and septic shock groups (P for trend < 0.001). For 142 patients with sepsis, organ dysfunction and septic shock were more prevalent in the group with plasma FasL levels that were higher than the best cut-off level. A significant difference in mortality between high and low FasL patients was observed up to 90 days (Log-rank P = 0.013). FasL levels did not significantly change over day 3 and day 7. FasL levels were not correlated with those of RIPK3.

Conclusions:

The plasma level of FasL was associated with severity of sepsis and was predictive of mortality. However, it was not correlated with RIPK3 level.
Center-level Utilization of Hepatitis C Virus–positive Donors for Orthotopic Heart Transplantation
Authors: Huckaby Lauren V. , Seese Laura M. , Handzel Robert , Wang Yisi , Hickey Gavin , Kilic Arman
Published: February 2021

Background.

The use of hepatitis C virus–positive (HCV+) donors has expanded the donor pool for orthotopic heart transplantation (OHT). This study evaluated center-level trends and utilization of HCV+ donors for OHT.

Methods.

Data were extracted from the Scientific Registry of Transplant Recipients on adults (≥18 y) undergoing OHT between January 1, 2016 and December 31, 2019. Centers performing <10 OHTs during the study period were excluded. Donor utilization rates were evaluated at the center level. Center-level characteristics were compared between centers performing HCV+ donor hepatitis C virus–negative (HCV−) recipient OHTs and those not utilizing HCV+ donors for HCV− recipients.

Results.

A total of 10 134 patients underwent OHT, including 613 (6.05%) HCV+ donors transplanted into HCV− recipients. The number of HCV+ OHTs increased from 15 of 2512 (0.60%) in 2016 to 285 of 2490 (11.45%) in 2019 (P < 0.001). In 2016, among 105 centers performing OHTs, 7 (6.67%) utilized HCV+ donors compared to 2019 during which 55 (52.89%) of 104 centers utilized HCV+ donors (P < 0.001). In total, 57 of 107 (53.27%) centers utilized HCV+ donors during the study period. Centers utilizing HCV+ donors had higher overall donor utilization rates (7376/24 378 [30.26%] versus 3463/15 335 [22.58%], P < 0.001) and were higher volume as compared to nonutilizing centers (mean annual OHT volume 30.72 ± 1.21 versus 16.2 ± 1.40, P < 0.001).

Conclusions.

Although the use of HCV+ donors for OHT is rapidly expanding in the United States, almost half of transplant centers remain nonutilizers. Broader education and implementation of HCV+ donor protocols may be important in expanding OHT to more patients with end-stage heart failure.
Primary Nonfunction of the Liver Allograft
Authors: Hartog Hermien , Hann Angus , Perera M. Thamara P.R.
Published: February 2021

Severe allograft dysfunction, as opposed to the expected immediate function, following liver transplantation is a major complication, and the clinical manifestations of such that lead to either immediate retransplant or death are the catastrophic end of the spectrum. Primary nonfunction (PNF) has declined in incidence over the years, yet the impact on patient and healthcare teams, and the burden on the organ pool in case of the need for retransplant should not be underestimated. There is no universal test to define the diagnosis of PNF, and current criteria are based on various biochemical parameters surrogate of liver function; moreover, a disparity remains within different healthcare systems on selecting candidates eligible for urgent retransplantation. The impact on PNF from traditionally accepted risk factors has changed somewhat, mainly driven by the rising demand for organs, combined with the concerted approach by clinicians on the in-depth understanding of PNF, optimal graft recipient selection, mitigation of the clinical environment in which a marginal graft is reperfused, and postoperative management. Regardless of the mode, available data suggest machine perfusion strategies help reduce the incidence further but do not completely avert the risk of PNF. The mainstay of management relies on identifying severe allograft dysfunction at a very early stage and aggressive management, while excluding other identifiable causes that mimic severe organ dysfunction. This approach may help salvage some grafts by preventing total graft failure and also maintaining a patient in an optimal physiological state if retransplantation is considered the ultimate patient salvage strategy.
Excessive Masturbation Successfully Treated With Methylphenidate in a 6-Year-Old Child With Autism Spectrum Disorder Accompanied by Attention Deficit Hyperactivity Disorder
Authors: Ferahkaya Hurşit , Bilgiç Ayhan
Published: February 2021

Children with autism spectrum disorder frequently exhibit inappropriate sexual behaviors, such as excessive masturbation. However, research on the control and management of excessive masturbation in these children is very limited. In this presentation, excessive masturbation that responded to treatment with methylphenidate is described in a young boy diagnosed with autism spectrum disorder and comorbid attention deficit hyperactivity disorder.
Qingshengfaniella alkalisoli gen. nov., sp. nov., a p-hydroxybenzoate-degrading strain isolated from saline soil
Authors: Wang Shuai , Yang Rui , Xu Lian , Xing Ya-Ting , Sun Ji-Quan
Published: February 2021

p-Hydroxybenzoate is an allelopathic compound commonly found in soil from long-term monoculture cropping systems. During the bacterial diversity analysis of saline soil, a Gram-negative, non-spore forming, non-motile, aerobic p-hydroxybenzoate-degrading bacterial strain, designated LN3S51T, was isolated from saline soil which was sampled from Tumd Right Banner, Inner Mongolia, northern China. Strain LN3S51T grew at 4–40 °C (optimum, 30 °C), pH 5.0–10.0 (optimum, pH 7.0) and 0–15 % NaCl (optimum 3.0 %). Though strain LN3S51T has the highest 16S rRNA gene similarities to

Litoreibacter ponti

GJSW-31T (96.0 %), the phylogenetic tree based on the 16S rRNA gene sequences showed that it clustered with

Fluviibacterium aquatile

SM1902T (95.8 %),

Meridianimarinicoccus roseus

TG-679T (93.9 %), and

Phycocomes zhengii

LMIT002T (93.9 %). Strain LN3S51T contained Q-10 as the major ubiquinone. Phosphatidylethanolamine (PE), phosphatidylglycerol (PG), phosphatidylcholine (PC), diphosphatidylglycerol (DPG), an unidentified aminolipid (AL), and two unidentified lipids (L) were the major polar lipids. The major fatty acids were sum feature 8 (C18 : 1
 ω7c and/or C18 : 1
 ω6c), C16 : 0, C18 : 0, and C18 : 1
 ω7c 11-methyl. The genome of strain LN3S51T consisted of a 2 257 066 bp chromosome and four plasmids with a 59.1 mol% of genomic DNA G+C content. The average nucleotide identity (ANI) and digital DNA–DNA hybridization score (dDDH) values of strain LN3S51T to

F. aquatile

SM1902T,

M. roseus

TG-679T,

P. zhengii

LMIT002T, and

L. ponti

GJSW-31T were 69.6, 70.9, 70.6, and 69.5 %, and 20.0, 19.5, 19.0, and 20.0 %, respectively. Based on the results of phylogenetic, chemtaxonomic and phenotypic characterization, strain LN3S51T is considered to represent a novel species in a new genus within the family

Rhodobacteraceae

, for which Qingshengfaniella alkalisoli gen. nov., sp. nov. is proposed. The type strain is LN3S51T (=CGMCC 1.17099T=KCTC 72457T).
Genomic relatedness and clinical significance of Streptococcus mitis strains isolated from the urogenital tract of sexual partners
Authors: Mores Carine R. , Price Travis K. , Wolff Birte , Halverson Thomas , Limeira Roberto , Brubaker Linda , Mueller Elizabeth R. , Putonti Catherine , Wolfe Alan J.
Published: February 2021

Research into the lower urinary tract (LUT) microbiota has primarily focused on its relationship to LUT symptoms (LUTS), taking snapshots of these communities in individuals with and without LUTS. While certain bacterial taxa have been associated with LUTS, or the lack thereof, the temporal dynamics of this community were largely unknown. Recently, we conducted a longitudinal study and found that vaginal intercourse resulted in a shift in species richness and diversity within the LUT microbiota. This is particularly relevant as frequent vaginal intercourse is a major risk factor for urinary tract infection (UTI) in premenopausal women (Aydin et al. Int Urogynecol J 2015;26:795–804). To further investigate the relationship between vaginal intercourse and LUT microbiota, here we present the results of a 3 week study in which daily urogenital specimens were collected from a female participant and her male sexual partner. Consistent with our previous findings, the LUT microbiota changed after vaginal intercourse, most notably a high abundance of

Streptococcus mitis

was observed post-coitus. We isolated and sequenced

S. mitis

from both sexual partners finding that: (i) the

S. mitis

isolates from the female partner’s urogenital tract were genomically similar throughout the duration of the study, and (ii) they were related to one isolate from the male partner’s oral cavity collected at the end of the study, suggesting transmission between the two individuals. We hypothesize that blooms in

S. mitis

after vaginal intercourse may play a role in coitus-related UTI. We found that a

S. mitis

isolate, in contrast to a

Lactobacillus jensenii

isolate displaced after vaginal intercourse, cannot inhibit the growth of uropathogenic

Escherichia coli

. Thus, this bloom in

S. mitis

may provide a window of opportunity for a uropathogen to colonize the LUT.
Roles for phthiocerol dimycocerosate lipids in Mycobacterium tuberculosis pathogenesis
Authors: Rens Céline , Chao Joseph D. , Sexton Danielle L. , Tocheva Elitza I. , Av-Gay Yossef
Published: February 2021

The success of

Mycobacterium tuberculosis

as a pathogen is well established: tuberculosis is the leading cause of death by a single infectious agent worldwide. The threat of multi- and extensively drug-resistant bacteria has renewed global concerns about this pathogen and understanding its virulence strategies will be essential in the fight against tuberculosis. The current review will focus on phthiocerol dimycocerosates (PDIMs), a long-known and well-studied group of complex lipids found in the

M. tuberculosis

cell envelope. Numerous studies show a role for PDIMs in several key steps of

M. tuberculosis

pathogenesis, with recent studies highlighting its involvement in bacterial virulence, in association with the ESX-1 secretion system. Yet, the mechanisms by which PDIMs help

M. tuberculosis

to control macrophage phagocytosis, inhibit phagosome acidification and modulate host innate immunity, remain to be fully elucidated.
SARS-CoV-2 detection and genomic sequencing from hospital surface samples collected at UC Davis
Authors: Coil David A. , Albertson Timothy , Banerjee Shefali , Brennan Greg , Campbell A.J. , Cohen Stuart H. , Dandekar Satya , Díaz-Muñoz Samuel L. , Eisen Jonathan A. , Goldstein Tracey , Jose Ivy R. , Juarez Maya , Robinson Brandt A , Rothenburg Stefan , Sandrock Christian , Stoian Ana M. M. , Tompkins Daniel G , Tremeau-Bravard Alexandre , Haczku Angela
Published: February 2021

Rationale

There is little doubt that aerosols play a major role in the transmission of SARS-CoV-2. The significance of the presence and infectivity of this virus on environmental surfaces, especially in a hospital setting, remains less clear.

Objectives

We aimed to analyze surface swabs for SARS-CoV-2 RNA and infectivity, and to determine their suitability for sequence analysis.

Methods

Samples were collected during two waves of COVID-19 at the University of California, Davis Medical Center, in COVID-19 patient serving and staff congregation areas. qRT-PCR positive samples were investigated in Vero cell cultures for cytopathic effects and phylogenetically assessed by whole genome sequencing.

Measurements and Main Results

Improved cleaning and patient management practices between April and August 2020 were associated with a substantial reduction of SARS-CoV-2 qRT-PCR positivity (from 11% to 2%) in hospital surface samples. Even though we recovered near-complete genome sequences in some, none of the positive samples (11 of 224 total) caused cytopathic effects in cultured cells suggesting this nucleic acid was either not associated with intact virions, or they were present in insufficient numbers for infectivity. Phylogenetic analysis suggested that the SARS-CoV-2 genomes of the positive samples were derived from hospitalized patients. Genomic sequences isolated from qRT-PCR negative samples indicate a superior sensitivity of viral detection by sequencing.

Conclusions

This study confirms the low likelihood that SARS-CoV-2 contamination on hospital surfaces contains infectious virus, disputing the importance of fomites in COVID-19 transmission. Ours is the first report on recovering near-complete SARS-CoV-2 genome sequences directly from environmental surface swabs.
A scoping review exploring the impact of digital systems on processes and outcomes in the care management of acute kidney injury and progress towards establishing learning healthcare systems
Authors: Chew Clair , Hogan Helen , Jani Yogini
Published: February 2021

Background

Digital systems have long been used to improve the quality and safety of care when managing Acute Kidney Injury (AKI). The availability of digitised clinical data can also turn organisations and their networks into Learning Healthcare Systems (LHSs) if used across all levels of health and care. This review explores the impact of digital systems on AKI patient care to gauge progress towards establishing LHSs and to identify existing gaps in the research.

Method

Embase, PubMed, Medline, Cochrane, Scopus and Web of Science databases were searched. Studies of real-time or near real-time digital AKI management systems which reported process and outcome measures were included.

Results

Thematic analysis of 43 studies showed that most interventions used real-time serum creatinine (SCr) levels to trigger responses to enable risk prediction, early recognition of AKI or harm prevention by individual clinicians (micro level) or specialist teams (meso level). Interventions at system (macro level) were rare. There was limited evidence of change in outcomes.

Conclusion

Whilst the benefits of real time digital clinical data at micro level for AKI management have been evident for some time, their application at meso and macro levels is emergent therefore limiting progress towards establishing LHSs. Lack of progress is due to digital maturity, system design, human factors and policy levers. Future approaches need to harness the potential of interoperability and data analytic advances and include multiple stakeholder perspectives to overcome these factors.
Emergence and Expansion of the SARS-CoV-2 Variant B.1.526 Identified in New York
Authors: Annavajhala Medini K. , Mohri Hiroshi , Wang Pengfei , Nair Manoj , Zucker Jason E. , Sheng Zizhang , Gomez-Simmonds Angela , Kelley Anne L. , Tagliavia Maya , Huang Yaoxing , Bedford Trevor , Ho David D. , Uhlemann Anne-Catrin
Published: February 2021

Recent months have seen surges of SARS-CoV-2 infection across the globe with considerable viral evolution1-3. Extensive mutations in the spike protein may threaten efficacy of vaccines and therapeutic monoclonal antibodies4. Two signature mutations of concern are E484K, which plays a crucial role in the loss of neutralizing activity of antibodies, and N501Y, a driver of rapid worldwide transmission of the B.1.1.7 lineage. Here, we report the emergence of variant lineage B.1.526 that contains E484K and its alarming rise to dominance in New York City in early 2021. This variant is partially or completely resistant to two therapeutic monoclonal antibodies in clinical use and less susceptible to neutralization by convalescent plasma or vaccinee sera, posing a modest antigenic challenge. The B.1.526 lineage has now been reported from all 50 states in the US and numerous other countries. B.1.526 rapidly replaced earlier lineages in New York upon its emergence, with an estimated transmission advantage of 35%. Such transmission dynamics, together with the relative antibody resistance of its E484K sub-lineage, likely contributed to the sharp rise and rapid spread of B.1.526. Although SARS-CoV-2 B.1.526 initially outpaced B.1.1.7 in the region, its growth subsequently slowed concurrent with the rise of B.1.1.7 and ensuing variants.
Cortical Tension Initiates the Positive Feedback Loop Between E-cadherin and F-actin
Authors: Yu Qilin , Holmes William R. , Thiery Jean P. , Luwor Rodney B. , Rajagopal Vijay
Published: February 2021

Adherens junctions (AJs) physically link two cells at their contact interface via extracellular homophilic interactions between cadherin molecules and intracellular connections between cadherins and the actomyosin cortex. Both cadherin and actomyosin cytoskeletal dynamics are reciprocally regulated by mechanical and chemical signals, which subsequently determine the strength of cell-cell adhesions and the emergent organization and stiffness of the tissues they form. However, an understanding of the integrated system is lacking. We present a new mechanistic computational model of intercellular junction maturation in a cell doublet to investigate the mechano-chemical crosstalk that regulates AJ formation and homeostasis. The model couples a 2D lattice-based model of cadherin dynamics with a continuum, reaction-diffusion model of the reorganizing actomyosin network through its regulation by Rho signaling at the intercellular junction. We demonstrate that local immobilization of cadherin induces cluster formation in a cis less dependent manner. We further investigate how cadherin and actin regulate and cooperate. By considering the force balance during AJ maturation and the force-sensitive property of the cadherin/F-actin linking molecules, we show that cortical tension applied on the contact rim can explain the ring distribution of cadherin and F-actin on the cell-cell contact of the cell-doublet. Meanwhile, the positive feedback loop between cadherin and F-actin is necessary for maintenance of the ring. Different patterns of cadherin distribution can be observed as an emergent property of disturbances of this feedback loop. We discuss these findings in light of available experimental observations on underlying mechanisms related to cadherin/F-actin binding and the mechanical environment.

Significance Statement

The formation, maintenance and disassembly of adherens junctions (AJs) is fundamental to organ development, tissue integrity as well as tissue function. E-cadherins and F-actin are two major players of the adherens junctions (AJs). Although it is well known that cadherins and F-actin affect each other, how these two players work together to maintain the intercellular contact is unclear. Using a novel mechano-chemical model of E-cadherin and F-actin remodeling, we demonstrate that a positive feedback loop between cadherins and F-actin allows them to stabilize each other locally. Mechanical and chemical stimuli applied to the cell adhesion change E-cadherin and F-actin distribution by consolidating or interrupting the feedback loop locally. Our study mechanistically links mechanical force to E-cadherin patterning at cell-cell junctions.
BMSS2: a unified database-driven modelling tool for systematic model selection and identifiability analysis
Authors: Jie Ngo Russell Kai , Wui Yeoh Jing , Wei Fan Gerald Horng , Siang Loh Wilbert Keat , Loo Poh Chueh
Published: February 2021

Modelling in Synthetic Biology constitutes a powerful tool in our continuous search for improved performance with rational Design-Build-Test-Learn approach. In particular, kinetic models unravel system dynamics, enabling system analysis for guiding experimental designs. However, a systematic yet modular pipeline that allows one to identify the “right” model and guide the experimental designs while tracing the entire model development and analysis is still lacking. Here, we introduce a unified python package, BMSS2, which offers the principal tools in model development and analysis—simulation, Bayesian parameter inference, global sensitivity analysis, with an emphasis on model selection, and a priori and a posteriori identifiability analysis. The whole package is database-driven to support interactive retrieving and storing of models for reusability. This allows ease of manipulation and deposition of models for the model selection and analysis process, thus enabling better utilization of models in guiding experimental designs.

Availability and Implementation

The python package and examples are available onhttps://github.com/EngBioNUS/BMSS2. A web page which allows users to browse and download the models (SBML format) in MBase is also available with the link provided on GitHub.

Supplementary Information

Supplementary data is available.
What is the evidence available to support our knowledge about threats to the conservation of Galliformes in the Greater Himalaya?
Authors: Gupta Garima , Grainger Matthew , Dunn Jonathon C. , Sanderson Roy , McGowan Philip J.K.
Published: February 2021

1.

Biodiversity is at a heightened risk of extinction and we are losing species faster than any other time. It is important to understand the threats that drive a species towards extinction in order to address those drivers. In this paper, we assess our knowledge of the threats faced by 24 Himalayan Galliformes species by undertaking a review to identify threats reported in the published literature and the supporting evidence that the threat is having an impact on the species population. Only 24 papers were deemed suitable to be included in the study. We found that biological resource use, agriculture and aquaculture are the predominant threats to the Galliformes in the Greater Himalaya but the evidence available in the studies is quite poor as only one paper quantified the impact on species. This study shows that major gaps exist in our understanding of threats to species and it is imperative to fill those gaps if we want to prevent species from going extinct.
Identification of host antiviral genes differentially induced by clinically diverse strains of Tick-Borne Encephalitis Virus
Authors: Goonawardane Niluka , Upstone Laura , Harris Mark , Jones Ian M
Published: February 2021

Tick Borne Encephalitis Virus (TBEV) is an important human arthropod-borne virus, which causes tick-borne encephalitis (TBE), an acute viral infection of the central nervous system (CNS) that causes neurological symptoms of varying severity. TBEV is prevalent in large parts of central- and northern-Europe as well as Northern Asia, and strains of varying pathogenicity have been described. Both host and viral specific characteristics have been postulated to determine the outcome of TBEV infection, but the exact basis of their clinical variability remains undefined.

Here, we report the generation of Spinach RNA aptamer labelled TBEV replicons of high (Hypr) and low (Vs) pathogenicity isolates and perform the first direct comparison of both strains in cell culture. We show that pathogenic Hypr replicates to higher levels than Vs in mammalian cells, but not in arthropod cells, and that the basis of this difference maps to the NS5 region, encoding the methyltransferase and RNA polymerase. For both Hypr and Vs strains, NS5 and the viral genome localized to defined intracellular structures typical of positive strand RNA viruses, but Hypr was associated with significant activation of IRF-3, caspase-3 and caspase-8, whilst Vs activated Akt, affording protection against caspase-mediated apoptosis. Activation of TIAR and the formation of cytoplasmic stress granules were an additional early feature of Vs but not Hypr replication. Taken together, these findings highlight NS5 and novel host cell responses as key underling factors for the differential clinical characteristics of TBEV strains.

Importance

Tick-borne encephalitis virus (TBEV) is an emerging virus of the flavivirus family spread by ticks. Tick bite can transfer the virus and lead to a febrile infection, Tick-borne encephalitis, of varying severity. There is no specific therapeutic treatment and control in endemic areas is by vaccination. The basis of the different pathologies shown following TBEV infection, from mild to fatal, is not clear although the virus genotype clearly has a role. Mapping the basis of their differential effects would allow focus on the stages of the replication cycle responsible, which might guide the development of therapeutic interventions or the creation of purposefully attenuated strains as candidate vaccines.
The immunophilin protein FKBPL and its peptide derivatives are novel regulators of vascular integrity and inflammation via NF-κB signaling
Authors: Annett Stephanie , Spence Shaun , Garciarena Carolina , Campbell Ciaran , Dennehy Margaret , Drakeford Clive , Lai Jacqueline , Dowling Jennifer , Moore Gillian , Yakkundi Anita , Short Amy , Sharpe Danny , Furlong Fiona , O’Donnell James S. , Cavalleri Gianpiero , Kerrigan Steve , Tikhonova Irina G. , Johnson Pauline , Kissenpfennig Adrien , Robson Tracy
Published: February 2021

A breakdown in vascular integrity and excessive inflammation are hallmarks of serious pathological conditions including sepsis, acute respiratory distress syndrome (ARDs) and most recently, severe COVID-19. FK506 – binding protein like (FKBPL) is a member of the immunophilin protein superfamily with potent anti-tumor activity through inhibition of angiogenesis and cancer stemness. An FKBPL-based 23mer peptide, ALM201, displayed a good safety and pharmacokinetic profile in a Phase 1a oncology clinical trial and was subsequently designated orphan drug status by the FDA in ovarian cancer. Here we describe a novel role for FKBPL and its peptides in regulating vascular integrity and cytokine production though modulating NF-κB signaling. FKBPL knockdown promoted endothelial cell barrier permeability, which was further exacerbated upon stimulation with lipopolysaccharide (LPS) and accompanied by increased expression of TNF mRNA and phosphorylation of p65(RelA). Whilst treatment with the FKBPL based pre-clinical peptide, AD-01, increased VE-cadherin endothelial tight junctions following LPS stimulation. Bone marrow derived macrophages (BMDM) from FKBPL haploinsufficient mice (Fkbpl+/−) also demonstrated increased phosphorylation of p65(RelA) in response to LPS stimulation compared to wild-type mice. Furthermore, treatment with AD-01 inhibited p65(RelA) phosphorylation following LPS stimulation resulting in reduced NF-κB target gene expression and proinflammatory cytokine production. In anin vivoLPS survival model,Fkbpl+/−mice have reduced survival compared to wild-type mice. Moreover, treatment of wild-type mice with the clinical FKBPL-based peptide, ALM201, following LPS injection resulted in a 100% survival rate in mice at experimental endpoint, as well as an abrogation of production of pro-inflammatory cytokines, TNF and IL-6, in peritoneal lavage washings. Analysis of human genetic biobanks found an association between common genetic variants associated with FKBPL and traits associated with inflammatory disorders such as psoriasis, rheumatoid arthritis and high lymphocyte count. In summary, for the first time, we describe a novel role for FKBPL as a regulator of inflammation and vascular integrity through modulating NF-κB signaling and FKBPL based therapies demonstrate potent anti-inflammatory activity.
Truly Privacy-Preserving Federated Analytics for Precision Medicine with Multiparty Homomorphic Encryption
Authors: Froelicher David , Troncoso-Pastoriza Juan R. , Raisaro Jean Louis , Cuendet Michel A. , Sousa Joao Sa , Cho Hyunghoon , Berger Bonnie , Fellay Jacques , Hubaux Jean-Pierre
Published: February 2021

Using real-world evidence in biomedical research, an indispensable complement to clinical trials, requires access to large quantities of patient data that are typically held separately by multiple healthcare institutions. Centralizing those data for a study is often infeasible due to privacy and security concerns. Federated analytics is rapidly emerging as a solution for enabling joint analyses of distributed medical data across a group of institutions, without sharing patient-level data. However, existing approaches either provide only limited protection of patients’ privacy by requiring the institutions to share intermediate results, which can in turn leak sensitive patient-level information, or they sacrifice the accuracy of results by adding noise to the data to mitigate potential leakage. We propose FAMHE, a novel federated analytics system that, based on multiparty homomorphic encryption (MHE), enables privacy-preserving analyses of distributed datasets by yielding highly accurate results without revealing any intermediate data. We demonstrate the applicability of FAMHE to essential biomedical analysis tasks, including Kaplan-Meier survival analysis in oncology and genome-wide association studies in medical genetics. Using our system, we accurately and efficiently reproduce two published centralized studies in a federated setting, enabling biomedical insights that are not possible from individual institutions alone. Our work represents a necessary key step towards overcoming the privacy hurdle in enabling multi-centric scientific collaborations.
Targeted Drug Repurposing Against the SARS-CoV-2 E channel Identifies Blockers Within vitroAntiviral Activity
Authors: Tomar Prabhat Pratap Singh , Krugliak Miriam , Arkin Isaiah Tuvia
Published: February 2021

It is difficult to overstate the impact that COVID-19 had on humankind. The pandemic’s etiological agent, SARS-CoV-2, is a member of the Coronaviridae, and as such, is an enveloped virus with ion channels in its membrane. Therefore, in an attempt to provide an option to curb the viral spread, we searched for blockers of its E protein viro-porin. Using three bacteria-based assays, we identified eight compounds that exhibited activity after screening a library of ca. 3000 approved-for-human-use drugs. Reassuringly, analysis of viral replication in tissue culture indicated that most of the compounds could reduce infectivity to varying extents. In conclusion, targeting a particular channel in the virus for drug repurposing may increase our arsenal of treatment options to combat COVID-19 virulence.

Significance Statement

The goal of our study was to expand the treatment arsenal against COVID-19. To that end, we have decided to focus on drug therapy, and as a target - the E protein, an ion channel in the virus. Ion channels as a family are excellent drug targets, but viral channels have been underexploited for pharmaceutical point intervention. To hasten future regulatory requirements and focus the chemical search space, we screened a library of ca. 3000 approved-for-human-use drugs using three independent bacteria-based assays. Our results yielded eight compounds, which were subsequently tested for antiviral activity in tissue culture. Gratifyingly, most compounds were able to reduce viral replication, and as such, both validate our approach and potentially augment our anti-COVID tool kit.
Structural and Functional Diversity among Agonist-Bound States of the GLP-1 Receptor
Authors: Cary Brian P. , Zhao Peishen , Truong Tin T. , Piper Sarah J. , Belousoff Matthew J. , Danev Radostin , Sexton Patrick M. , Wootten Denise , Gellman Samuel H.
Published: February 2021

Recent advances in G protein-coupled receptor (GPCR) structural elucidation have strengthened previous hypotheses that multi-dimensional signal propagation mediated by these receptors is, in part, dependent on their conformational mobility. However, the relationship between receptor function and static structures determined via crystallography or cryo-electron microscopy is not always clear. This study examines the contribution of peptide agonist conformational plasticity to activation of the glucagon-like peptide-1 receptor (GLP-1R), an important clinical target. We employ variants of the peptides GLP-1 and exendin-4 to explore the interplay between helical propensity near the agonist N-terminus and the ability to bind to and activate the receptor. Cryo-EM analysis of a complex involving an exendin-4 analogue, the GLP-1R and Gsprotein revealed two receptor conformers with distinct modes of peptide-receptor engagement. Our functional and structural data suggest that receptor conformational dynamics associated with flexibility of the peptide N-terminal activation domain may be a key determinant of agonist efficacy.
REVA as a Well-curated Database for Human Expression-modulating Variants
Authors: Wang Yu , Shi Fang-Yuan , Liang Yu , Gao Ge
Published: February 2021

More than 80% of disease- and trait-associated human variants are noncoding. By systematically screening multiple large-scale studies, we compiled REVA, a manually curated database for over 11.8 million experimentally tested noncoding variants with expression-modulating potentials. We provided 2424 functional annotations that could be used to pinpoint plausible regulatory mechanism of these variants. We further benchmarked multiple state-of-the-art computational tools and found their limited sensitivity remains a serious challenge for effective large-scale analysis. REVA provides high-qualify experimentally tested expression-modulating variants with extensive functional annotations, which will be useful for users in the noncoding variants community. REVA is available at http://reva.gao-lab.org.
Nanomechanics of negatively supercoiled diaminopurine-substituted DNA
Authors: Salerno Domenico , Mantegazza Francesco , Cassina Valeria , Cristofalo Matteo , Shao Qing , Finzi Laura , Dunlap David
Published: February 2021

Single molecule experiments have demonstrated a progressive transition from a B- to an L-form helix as DNA is gently stretched and progressively unwound. Since the particular sequence of a DNA segment influences both base stacking and hydrogen bonding, the conformational dynamics of B-to-L transitions should be tunable. To test this idea, DNA with diaminopurine replacing adenine was synthesized to produce linear fragments with triply hydrogen-bonded A:T base pairs. Triple hydrogen bonding stiffened the DNA by 30% flexurally. In addition, DAP-substituted DNA formed plectonemes with larger gyres for both B- and L-form helices. Both unmodified and DAP-substituted DNA transitioned from a B- to an L-helix under physiological conditions of mild tension and unwinding. This transition avoids writhing by DNA stretched and unwound by enzymatic activity. The intramolecular nature and ease of this transition likely prevent cumbersome topological rearrangements in genomic DNA that would require topoisomerase activity to resolve. L-DNA displayed about tenfold lower persistence length indicating it is much more contractile and prone to sharp bends and kinks. However, left-handed DAP DNA was twice as stiff as unmodified L-DNA. Thus, significantly doubly and triply hydrogen bonded segments have very distinct mechanical dynamics at physiological levels of negative supercoiling and tension.
A genome-wide CRISPR screen identifies interactors of the autophagy pathway as conserved coronavirus targets
Authors: Kratzel Annika , Kelly Jenna N. , Brueggemann Yannick , Portmann Jasmine , V’kovski Philip , Todt Daniel , Ebert Nadine , Steinmann Eike , Dijkman Ronald , Zimmer Gert , Pfaender Stephanie , Thiel Volker
Published: February 2021

Over the past 20 years, the emergence of three highly pathogenic coronaviruses (CoV) – SARS-CoV, MERS-CoV, and most recently SARS-CoV-2 – has shown that CoVs pose a serious risk to human health and highlighted the importance of developing effective therapies against them. Similar to other viruses, CoVs are dependent on host factors for their survival and replication. We hypothesized that evolutionarily distinct CoVs may exploit similar host factors and pathways to support their replication cycle. Here, we conducted two independent genome-wide CRISPR/Cas9 knockout screens to identify pan-CoV host factors required for the replication of both endemic and emerging CoVs, including the novel CoV SARS-CoV-2. Strikingly, we found that several autophagy-related genes, including the immunophilin FKBP8, TMEM41B, and MINAR1, were common host factors required for CoV replication. Importantly, inhibition of the immunophilin family with the compounds Tacrolimus, Cyclosporin A, and the non-immunosuppressive derivative Alisporivir, resulted in dose-dependent inhibition of CoV replication in primary human nasal epithelial cell cultures that resemble the natural site of virus replication. Overall, we identified host factors that are crucial for CoV replication and demonstrate that these factors constitute potential targets for therapeutic intervention by clinically approved drugs.