bluuebunny/crossref_metadata_2025 huggingface dataset:
Research and the real world: Analyzing the short- and long-term impact of knowledge transfer
Authors: Caves Katherine , Lueling Sarah
Published: April 2021

Knowledge exchange interventions are an important driver of research impact. This study examines 5 years of intensive knowledge-exchange ‘reform labs’ in the field of education policy. Using qualitative analysis and a regression analysis approach applied to rich case data and quantitative results, we find that the reform labs have a significant impact on both participants and their reform projects in the short-term immediately after the event and in the medium term up to 5 years later. We also find evidence that the impact on individuals and projects drives broader social impact. We take a holistic approach to the knowledge brokerage of designing the reform labs and find that across contexts and project phases, but highly costly. In comparing the reform labs to best practices identified in the literature, we find evidence that knowledge exchange interventions of longer duration, with case-focused teamwork, and involving intensive researcher–participant interaction are more impactful. Additionally, we observe that diverse participants can drive impact and their needs must be considered.
Probiotics in food allergy
Authors: Mennini Maurizio , Arasi Stefania , Artesani Maria Cristina , Fiocchi Alessandro Giovanni
Published: April 2021

Purpose of review

To perform a nonsystematic review of the literature on the possible role of probiotics for food allergy (FA).

Recent findings

Animal model and in vitro evidence suggest that the gut microbiome could protect against FA and that probiotics could be a valid instrument. There is no consistent evidence in identifying the specific species, the dosage, and the optimal duration to obtain the correct immunomodulation. Early life supplementation with specific ‘missing’ immunomodulatory microbes – derived from machine learning approach to birth cohort studies – might represent a novel approach to the primary prevention of multiple human atopic diseases. However, further studies are needed.

Currently, there is no positive recommendation from the main scientific societies to use probiotics neither for the treatment nor for the prevention of FA.
Physeal Fractures of Distal Tibia: A Systematic Review and Meta-analysis
Authors: Jalkanen Jenni , Sinikumpu Juha-Jaakko , Puhakka Jani , Laaksonen Topi , Nietosvaara Yrjänä , Kosola Jussi , Stenroos Antti
Published: April 2021

Background:

Fractures involving the distal tibia growth plate are common in children. Injury or treatment that damages the growth plate may result in progressive angular deformity or leg length discrepancy. There is no consensus on treatment and follow-up of these injuries. This study aims to describe which factors increase the risk of premature physeal closure (PPC).

Material and Methods:

A systematic review and meta-analysis were performed. Altogether 395 articles were reviewed, and ultimately 12 of them were found eligible, comprising 1997 patients. The most usual type of fracture was Salter-Harris (SH) II (n=855, 49%) followed by SH III (n=296, 17%) and SH I (n=261, 15%). The risk of PPC according to number of reduction attempts, method of treatment, and residual displacement was the primary outcome.

Results:

The total rate of PPC was 13% (n=245). The PPC rate varied from 0.2% to 42% across the studies. Patients with SH IV fractures were most likely to develop PPC (20%), followed by those with SH II (12%) (P<0.05) and repeated (>2) reduction maneuvers were associated with a higher risk of PPC (pooled odds ratio, 8.5; 95% confidence interval, 6.3-12.17; P<0.05). Open reduction was associated with a lower risk of PPC when analyzing only displaced fractures (odds ratio, 0.63; 95% confidence interval, 0.38-0.91; P<0.05).

Interpretation:

This meta-analysis implies that residual displacement after reduction is the most significant factor in predicting PPC. It seems that open reduction might reduce the PPC rate among patients with dislocated fractures. In addition, there is some evidence that a higher number of reduction attempts correlates positively with the risk of PPC.
Correlations between alterations of T-helper 17 cells and treatment efficacy after concurrent radiochemotherapy in locally advanced cervical cancer (stage IIB–IIIB): a 3-year prospective study
Authors: Liu Yi , Guo Qiu-Fen , Chen Jin-Long , Li Xi-Rui , Hou Fei , Liu Xiao-Yan , Zhang Wen-Jing , Zhang Yan , Gao Fu-Feng , Zhang You-Zhong , Cui Bao-Xia , Liu Nai-Fu
Published: April 2021

Background:

Recently, T-helper 17 (Th17) cells have been proved to play an important role in promoting cervical cancer. But, till now, few study has been carried out to understand the involvement of these cells in efficacy of anti-tumor treatments. This study aimed to investigate the alterations in the percentage of circulating Th17 cells and related cytokines in locally advanced cervical cancer (LACC) patients before and after concurrent chemoradiotherapy (cCRT) and to analyze the correlations between the alterations in Th17 cells and treatment efficacy.

Methods:

A prospective study with 49 LACC (International federation of gynecology and obstetrics [FIGO] stage IIB–IIIB) patients and 23 controls was conducted. Patients received the same cCRT schedule and were followed up for 3 years. Circulating Th17 cells (CD3+CD8– interleukin [IL]-17+ T cells) and related cytokines IL-17, transforming growth factor-β (TGF-β), IL-10, IL-23, IL-6, and IL-22 were detected before and after cCRT. Correlations between alterations of circulating Th17 cells and treatment efficacy were analyzed. Kaplan-Meier analysis was used for overall survival (OS) and progression-free survival (PFS).

Results:

We found that 40 patients finished the entire cCRT schedule and met the endpoint of this study. The percentage of circulating Th17 cells in the LACC patients was higher than that in the controls, and it significantly decreased after cCRT (P < 0.05). After cCRT, patients were divided into two groups based on the average of the Th17 cells declined. The subgroup of patients with a prominent decrease in circulating Th17 cells after cCRT had a higher treatment efficacy and longer PFS and OS times. Compared with the control patients, LACC patients had higher IL-6, IL-10, IL-22, TGF-β levels and a lower IL-23 level (P < 0.05). After cCRT, IL-6, IL-10, IL-17, IL-23 level significantly increased and TGF-β level significantly decreased compared with the levels before cCRT (P < 0.05).

Conclusion:

Circulating Th17 cells in the LACC patients (FIGO stage IIB–IIIB) were higher than those in the controls, but they generally decreased after cCRT. A more pronounced decrease in circulating Th17 cells after cCRT was correlated with better therapeutic effect and longer PFS and OS times.
CLINICAL SIGNIFICANCE OF RETINAL VASCULAR OCCLUSION IN MOYAMOYA DISEASE
Authors: Seong Hyo Jin , Lee Ji Hwan , Heo Ji Hoe , Kim Dong Seok , Kim Yong Bae , Lee Christopher Seungkyu
Published: April 2021

Purpose:

Although moyamoya disease primarily affects the carotid artery in the ophthalmic artery bifurcation area, retinal vascular abnormalities in moyamoya disease have rarely been reported. The purpose of this report is to describe clinical findings of patients with retinal vascular occlusion in patients with moyamoya disease and present its clinical significance.

Methods:

We reviewed and analyzed patients with moyamoya disease with retinal vascular occlusions. For this, a retrospective medical chart review was performed in a tertiary medical center and a literature search was performed using PubMed and EMBASE until September 2020.

Results:

Patients with retinal artery occlusion (RAO) were significantly younger than patients with retinal vein occlusion (25.0 vs. 40.1 years, P = 0.023). Of 14 patients, retinal vascular occlusion was the presenting sign of moyamoya disease in 8 (57.1%) patients. The occlusion site at the carotid artery was proximal to the ophthalmic artery bifurcation area in 8 (57.1%) patients. Legal blindness occurred in 8 (57.1%) patients at final visits.

Conclusion:

Retinal vascular occlusion is a rare but sight-threatening ocular complication in patients with moyamoya disease. Overall, younger age may be a risk factor for RAO, whereas older age for retinal vein occlusion. Retinal vascular occlusion can be an important indicator of moyamoya disease screening, especially in relatively younger and healthy patients.
OPTIC DISK COLOBOMA AND CONTRALATERAL OPTIC DISK PIT MACULOPATHY TREATED BY VITRECTOMY IN A PATIENT WITH NOONAN SYNDROME WITH MULTIPLE LENTIGINES
Authors: Van den Heurck Jonas J. , Boven Kim B. , Claes Carl C.
Published: April 2021

Purpose:

To report a case of Noonan syndrome with multiple lentigines with unusual ocular features.

Methods:

The authors describe a case of a 7-year-old girl with Noonan syndrome with multiple lentigines and anomalous optic disks.

Results:

A 7-year-old girl with genetically proven Noonan syndrome with multiple lentigines (PTPN11 gene mutation) and anomalous optic disks was referred for treatment of persistent macular detachment after 1 year of conservative follow-up. The right eye demonstrated an optic disk coloboma with the best-corrected visual acuity of 20/32, the left eye demonstrated an optic disk pit with serous macular detachment (best-corrected visual acuity 20/50–20/80). Optical coherence tomography demonstrated a neurosensory detachment. Twenty-five gauge pars plana vitrectomy was performed with posterior hyaloid detachment, drainage over disk pit area, and SF6 20% gas tamponade. Surgery resulted in subretinal fluid reduction and improvement of the visual acuity to 20/32.

Conclusion:

A case of Noonan syndrome with multiple lentigines with optic disk coloboma in the right eye and optic disk pit with related maculopathy in the left eye. To the best of the authors' knowledge, this is the first reported case describing the association of Noonan syndrome with multiple lentigines and congenital optic disk anomalies. Optic disk pit maculopathy was managed surgically because of its longstanding nature with the deteriorating visual acuity.
Telemedicine Medical Screening Evaluation Expedites the Initiation of Emergency Care for Children
Authors: Friedman Jonathan , Lame Maria , Clark Sunday , Gogia Kriti , Platt Shari L. , Kim Ji Won
Published: April 2021

Objective

Prior studies show that staffing a physician at triage expedites care in the emergency department. Our objective was to describe the novel application and effect of a telemedicine medical screening evaluation (Tele-MSE) at triage on quality metrics in the pediatric emergency department (PED).

Methods

We conducted a retrospective quasi-experimental pre-post intervention study of patients presenting to an urban PED from December 2017 to November 2019 who received a Tele-MSE at triage. We analyzed 4 diagnostic cohorts: gastroenteritis, psychiatry evaluation, burn injury, and extremity fracture. We matched cases with controls who received standard triage, from December 2015 to November 2017, by age, diagnosis, weekday versus weekend, and season of presentation. Outcome measures included door-to-provider time, time-to-intervention order, and PED length of stay (LOS).

Results

We included 557 patients who received Tele-MSE during the study period. Compared with controls, patients who received a Tele-MSE at triage had a shorter median door-to-provider time (median difference [MD], 8.4 minutes; 95% confidence interval [CI], 6.0–11.0), time-to-medication order (MD, 27.3 minutes; 95% CI, 22.9–35.2), time-to-consult order (MD, 10.0 minutes; 95% CI, 5.3–12.7), and PED LOS (MD, 0.4 hours; 95% CI, 0.3–0.6).

Conclusions

A Tele-MSE is an innovative modality to expedite the initiation of emergency care and reduce PED LOS for children. This novel intervention offers potential opportunities to optimize provider and patient satisfaction and safety during the COVID-19 pandemic.
Avoidable Adverse Events Related to Ignoring the Do-Not-Do Recommendations: A Retrospective Cohort Study Conducted in the Spanish Primary Care Setting
Authors: Mira José Joaquín , Carrillo Irene , Pérez-Pérez Pastora , Astier-Peña Maria Pilar , Caro-Mendivelso Johanna , Olivera Guadalupe , Silvestre Carmen , Nuín Mª Angeles , Aranaz-Andrés Jesús M. ,   on behalf the SOBRINA Research Team
Published: April 2021

Objective

This study aimed to measure the frequency and severity of avoidable adverse events (AAEs) related to ignoring do-not-do recommendations (DNDs) in primary care.

Methods

A retrospective cohort study analyzing the frequency and severity of AAEs related to ignoring DNDs (7 from family medicine and 3 from pediatrics) was conducted in Spain. Data were randomly extracted from computerized electronic medical records by a total of 20 general practitioners and 5 pediatricians acting as reviewers; data between February 2018 and September 2019 were analyzed.

Results

A total of 2557 records of adult and pediatric patients were reviewed. There were 1859 (72.7%) of 2557 (95% confidence interval [CI], 71.0%–74.4%) DNDs actions in 1307 patients (1507 were performed by general practitioners and 352 by pediatricians). Do-not-do recommendations were ignored more often in female patients (P < 0.0001). Sixty-nine AAEs were linked to ignoring DNDs (69/1307 [5.3%]; 95% CI, 4.1%–6.5%). Of those, 54 (5.1%) of 1062 were in adult patients (95% CI, 3.8%–6.4%) and 15 (6.1%) of 245 in pediatric patients (95% CI, 3.1%–9.1%). In adult patients, the majority of AAEs (51/901 [5.7%]; 95% CI, 4.2%–7.2%) occurred in patients 65 years or older. Most AAEs were characterized by temporary minor harm both in adult patients (28/54 [51.9%]; 95% CI, 38.5%–65.2%) and pediatric patients (15/15 [100%]).

Conclusions

These findings provide a new perspective about the consequences of low-value practices for the patients and the health care systems. Ignoring DNDs could place patients at risk, and their safety might be unnecessarily compromised.

Trial Registration Number

NCT03482232.
Closure of Challenging Pediatric Scalp Wounds by a Tension-Relief System
Authors: Olshinka Asaf , Ad-El Dean , Kalish Eyal , Shay Tamir , Yaacobi Dafna Shilo
Published: April 2021

Pediatric scalp defects may be challenging, due to their variant tension level and specific etiologies. Tissue characteristics and pre- and post-management considerations may pose difficulties to reconstruction in the pediatric patient. Primary closure is the preferred surgical technique but is not always possible. Various techniques have been described for facilitating primary wound closure, by reducing tension from the skin wound margins. The authors use a tension-relief system in some challenging scalp wounds when simple primary closure cannot be achieved. This enables primary closure without tension on the surgical margins, and may thus preclude the need for other closure techniques such as tissue-expanders, grafts, and flaps. The authors describe our use of a tension-relief system in 21 pediatric patients treated during 2017–2020, for congenital deformities, vascular malformations and other skin lesions, traumatic wounds, burn scars, and complicated surgical wounds with and without hardware exposure. A tension-relief system is a prompt, simple-to-use, safe, and low-cost surgical solution that offers several advantages over other techniques when tension-free primary intention closure is not possible. These benefits include less extensive surgery, fewer surgeries and associated anesthesia, shorter treatment period and hospitalization, better scarring, lower distress and burden to patients and their families, better pain-control, the absence of donor-site with its comorbidities, and less bleeding and risk of damaging adjacent structures. Based on our experience and the system characteristics detailed, the authors recommend using the described technique, which is convenient, accessible, and reliable, to close challenging scalp wounds in pediatric patients.
Changes in the Transcriptome and Proteome of Cartilage in Microtia
Authors: Dong Weiwei , Jiang Haiyue , He Leren , Pan Bo , Yang Qinghua
Published: April 2021

Congenital microtia is a severe physiological defect and is among the most common craniofacial defects. It is characterized by severe auricle dysplasia, external auditory canal atresia or stenosis, and middle ear malformation, though inner ear development is mostly normal with some hearing occurring through bone conduction. Auricular reconstruction is the only treatment for congenital microtia. In this study, the authors integrated messenger ribonucleic acid and mass spectrometry data of cartilage obtained from the affected and unaffected sides of 16 unilateral microtia patients who had undergone ear reconstruction surgery. The authors next performed functional analyses to investigate differences in the proteome of the affected and unaffected ears to elicit molecular pathways involved in microtia pathogenesis. The authors collected 16 pairs samples. Proteomic and transcriptomic analyses identified 47 genes that were differentially expressed in affected and unaffected cartilage. Integrated pathway analysis implicated the involvement of genes related to cell adhesion, extracellular matrix organization, and cell migration in disease progression. Through the integration of gene and protein expression data in human primary chondrocytes, the authors identified molecular markers of microtia progression that were replicated across independent datasets and that have translational potential.
Association Between Anterior Cingulate Cortex Neurochemical Profile and Clinical Remission After Electroconvulsive Treatment in Major Depressive Disorder
Authors: Ermis Cagatay , Aydin Burc , Kucukguclu Semih , Yurt Aysegul , Renshaw Perry F. , Yildiz Aysegul
Published: April 2021

Background

The aim of the study was to assess anterior cingulate cortex (ACC) neurochemical profile of patients with unipolar major depressive disorder (MDD) before and after electroconvulsive therapy (ECT) by using 1H magnetic resonance spectroscopy (1H-MRS).

Method

Using 1H-MRS, the metabolite levels of choline, glutamate + glutamine (Glx), myo-inositol, N-acetylaspartate, and total creatine were measured in ACC before and after 4-week ECT. The Montgomery-Åsberg Depression Rating Scale (MADRS) was implemented by blind raters to evaluate the efficacy of the treatment. Electroconvulsive therapy–remitter (ER) and nonremitter groups were compared using the 1-way repeated measures analysis of variance.

Results

Thirty patients with unipolar MDD (aged 41.3 ± 10.0 years, 66.7% female) were included in the study. The ER group (n = 16, 53.3%) and NR group did not differ regarding baseline Global Assessment of Functioning and MADRS scores. At the end of 4-week ECT treatment, results did not suggest any significant difference for metabolite levels in ACC. When compared with the NR group, the ER group had higher baseline levels of Glx (8.8 ± 1.8 vs 6.3 ± 2.0, P = 0.005) and total creatine (5.3 ± 0.6 vs 4.7 ± 0.5, P = 0.010). In addition, elevated baseline Glx (r = −0.68, P = 0.002) was associated with lower MADRS scores at the end treatment. Finally, the change in Glx levels was correlated with change in MADRS scores after ECT (r = 0.47, P = 0.049).

Limitations

Modest sample size and 1H-MRS at 1.5 Tesla are limitations of the study.

Conclusions

Results suggested that Glx levels could be a predictor of remission. Studies with larger samples should explore neurochemical correlates of ECT in unipolar MDD.
HIV-1 evolutionary dynamics under non-suppressive antiretroviral therapy
Authors: Kemp Steven A. , Charles Oscar J. , Derache Anne , Smidt Werner , Martin Darren P. , Pillay Deenan , Goldstein Richard A. , Gupta Ravindra K.
Published: April 2021

Prolonged virologic failure on 2nd-line protease inhibitor (PI) based ART without emergence of major protease mutations is well recognised and provides an opportunity to study within-host evolution in long-term viraemic individuals. Using next-generation sequencing and in silico haplotype reconstruction we analysed whole genome sequences from longitudinal plasma samples of eight chronically infected HIV-1 individuals failing 2nd-line regimens from the ANRS 12249 TasP trial. On non-suppressive ART, there were large fluctuations in synonymous and non-synonymous variant frequencies despite stable viraemia. Reconstructed haplotypes provided evidence for selective sweeps during periods of partial adherence, and viral haplotype competition during periods of low drug exposure. Drug resistance mutations in reverse transcriptase (RT) were used as markers of viral haplotypes in the reservoir and their distribution over time indicated recombination. We independently observed linkage disequilibrium decay, indicative of recombination. These data highlight dramatic changes in virus population structure that occur during stable viremia under non suppressive ART.
CoVac501, a self-adjuvanting peptide vaccine conjugated with TLR7 agonists, against SARS-CoV-2 induces protective immunity
Authors: Long Yiru , Sun Jianhua , Liu Tingting , Tang Feng , Zhang Xinxin , Qin Qiuping , Miao Yunqiu , Zhu Weiliang , Pan Xiaoyan , An Qi , Qin Mian , Tong Xiankun , Peng Xionghua , Yu Pan , Zhu Peng , Zhang Yachun , Zhang Leike , Xiao Gengfu , Zuo Jianping , Tang Wei , Zhou Ji , Xu Zhijian , Gan Yong , Ren Jin , Huang Wei , Jin Guangyi , Gong Likun
Published: April 2021

Safe, economical and effective vaccines against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) are needed to achieve adequate herd immunity and halt the pandemic. We have constructed a novel SARS-CoV-2 vaccine, CoVac501, which is a self-adjuvanting peptide vaccine conjugated with Toll-like receptor 7 (TLR7) agonists. The vaccine contains two immunodominant peptides screened from receptor-binding domain (RBD) and is fully chemically synthesized. And the vaccine has optimized nanoemulsion formulation, outstanding stability and safety. In non-human primates (NHPs), CoVac501 elicited high and persistent titers of RBD-specific and protective neutralizing antibodies (NAbs), which were also effective to RBD mutations. CoVac501 was found to elicit the increase of memory T cells, antigen-specific CD8+T cell responses and Th1-biased CD4+T cell immune responses in NHPs. More importantly, the sera from the immunized NHPs can prevent infection of live SARS-CoV-2 in vitro.

One-Sentence Summary

A novel SARS-CoV-2 vaccine we developed, CoVac501, which is a fully chemically synthesized and self-adjuvanting peptides conjugated with TLR7 agonists, can induce high-efficient humoral and cellular immune responses against SARS-CoV-2.
Interannual temporal patterns of DeSoto Canyon macrofauna and evaluation of influence from the Deepwater Horizon
Authors: Shantharam Arvind K. , Baco Amy R.
Published: April 2021

Submarine canyons are highly dynamic and productive ecosystems, but time-series studies of metazoan benthic communities in canyons are scarce. Deep-sea macrofauna from the DeSoto Canyon in the northern Gulf of Mexico were sampled annually from 2012 through 2014 from five stations within the Canyon and from two stations in 2013 and 2014 on the adjacent open slope, for analysis of interannual dynamics, temporal variability, and potential influence of the Deepwater Horizon oil spill (DwH), which occurred nearby in 2010. At a few sites, elevated abundance was observed at the start of the time-series for overall macrofauna and for deposit feeder abundance. However, diversity metrics showed no difference within stations among time points. Community and feeding guild structure varied by station, as expected, but showed no statistical difference among time points within a station. Some temporal variability was visible in temporal trajectory overlays. Cluster analyses showed grouping more by station than by time point. Metrics utilized for measuring potential oil contamination impact and overall community stress including the benthic polychaete/amphipod ratio, feeding guild abundance, macrofaunal indicators designed from the DwH, and community dispersion, generally exhibited a paucity of evidence of impact, both yearly and with site-to-site comparisons. This suggests low levels of impact in the canyon consistent with the low deposition of hydrocarbons, the timing of sampling, and quick recovery of canyon foraminifera. Taken together these results suggest relatively low levels of temporal variability within the DeSoto Canyon macrofauna with little evidence of oil influence on these sites within the studied time range.
Single-cell profiling of environmental enteropathy reveals signatures of epithelial remodeling and immune activation in severe disease
Authors: Kummerlowe Conner , Wallach Thomas , Mwakamui Simutanyi , Hughes Travis K. , Mulugeta Nolawit , Mudenda Victor , Besa Ellen , Zyambo Kanekwa , Fleming Ira , Vukovic Marko , Doran Ben A. , Aicher Toby P. , Wadsworth Marc H. , Bramante Juliet Tongue , Uchida Amiko M. , Fardoos Rabiah , Asowata Osaretin E. , Herbert Nicholas , Kløverpris Henrik N. , Garber John J. , Ordovas-Montanes Jose , Gartner Zev , Shalek Alex K. , Kelly Paul
Published: April 2021

Environmental enteropathy (EE) is a subclinical condition of the small intestine that is highly prevalent in low- and middle-income countries. It is thought to be a key contributing factor to childhood malnutrition, growth-stunting, and diminished oral vaccine responses. While EE has been shown to be the by-product of recurrent enteric infection, its full pathophysiology remains unclear. Here, we mapped the cellular and molecular correlates of EE severity by performing high-throughput single-cell RNA-sequencing on 33 small intestinal biopsies from 11 adults with EE from Lusaka, Zambia (8 HIV-negative, 3 HIV-positive), 6 adults without EE in Boston, USA, and 2 adults from Durban, South Africa, which we complemented with published data from 3 additional South African adults from the same clinical site. By using these data to reanalyze previously-defined bulk-transcriptomic signatures of reduced villus height and decreased plasma LPS levels in EE, we found that these signatures may be driven by an increased abundance of surface mucosal cells – a gastric-like subset previously implicated in epithelial repair in the gastrointestinal tract. In addition, we identified several cell subsets whose fractional abundances associate with histologically determined EE severity, small intestinal region, and HIV infection. Furthermore, by comparing distal duodenal EE samples with those from three control cohorts, we identified dysregulated WNT and MAPK signaling in the EE epithelium and a T cell subset highly expressing a transcriptional signature of tissue-resident memory cells but with increased pro-inflammatory cytokine expression in the EE cohort. Altogether, our work illuminates epithelial and immune correlates of EE and provides new molecular targets for intervention.

One Sentence Summary

Using single-cell RNA-sequencing, we characterize the pathophysiology of environmental enteropathy (EE) – a highly prevalent condition of the small intestine that is thought to be a primary cause of global growth-stunting cases and a key contributing factor to childhood malnutrition and diminished oral vaccine responses – to derive insights into the epithelial and immune correlates of disease severity, suggesting new therapeutic targets for future investigation.
Adhesion dynamics regulate cell intercalation behaviour in an active tissue
Authors: Nestor-Bergmann Alexander , Blanchard Guy B. , Hervieux Nathan , Fletcher Alexander G. , Étienne Jocelyn , Sanson Bénédicte
Published: April 2021

Cell intercalation is a key cell behaviour of morphogenesis and wound healing, where local cell neighbour exchanges can cause dramatic tissue deformations such as body axis extension. Here, we develop a mechanical model to understand active cell intercalation behaviours in the context of an epithelial tissue. Extending existing descriptions, such as vertex models, the junctional actomyosin cortex of every cell is modelled as a continuum morphoelastic rod, explicitly representing cortices facing each other at bicellular junctions. Cells are described directly in terms of the key subcellular constituents that drive dynamics, with localised stresses from the contractile actomyosin cortex and adhesion molecules coupling apposed cortices. This multi-scale apposed-cortex formulation reveals key behaviours that drive tissue dynamics, such as cell-cell shearing and flow of junctional material past cell vertices. We show that cell neighbour exchanges can be driven by purely junctional mechanisms. Active contractility and viscous turnover in a single bicellular junction are sufficient to shrink and remove a junction. Next, the 4-way vertex is resolved and a new, orthogonal junction extends passively. The adhesion timescale defines a frictional viscosity that is an important regulator of these dynamics, modulating tension transmission in the tissue as well as the speeds of junction shrinkage and growth. The model additionally predicts that rosettes, which form when a vertex becomes common to many cells, are likely to occur in active tissues with high adhesive friction.

SIGNIFICANCE

Cell intercalation, or neighbour exchange, is a crucial behaviour that can drive tissue deformations, dissipate stress and facilitate wound healing. Substantial experimental work has identified the key molecular players facilitating intercalation, but there remains a lack of consensus and understanding of their physical roles. Existing biophysical models that represent cell-cell contacts with single edges cannot study the continuous dynamics of intercalation, involving shear between coupled cell cortices. Deriving a continuum description of the cell cortex, explicitly coupling neighbouring cortices with adhesions, we define the biophysical conditions required for successful neighbour exchanges. Furthermore, we show how the turnover of adhesion molecules specifies a viscous friction that regulates active tissue dynamics.
Prediction and evolution of the molecular fitness of SARS-CoV-2 variants: Introducing SpikePro
Authors: Pucci Fabrizio , Rooman Marianne
Published: April 2021

The understanding of the molecular mechanisms driving the fitness of the SARS-CoV-2 virus and its mutational evolution is still a critical issue. We built a simplified computational model, called SpikePro, to predict the SARS-CoV-2 fitness from the amino acid sequence and structure of the spike protein. It contains three contributions: the viral transmissibility predicted from the stability of the spike protein, the infectivity computed in terms of the affinity of the spike protein for the ACE2 receptor, and the ability of the virus to escape from the human immune response based on the binding affinity of the spike protein for a set of neutralizing antibodies. Our model reproduces well the available experimental, epidemiological and clinical data on the impact of variants on the biophysical characteristics of the virus. For example, it is able to identify circulating viral strains that, by increasing their fitness, recently became dominant at the population level. SpikePro is a useful instrument for the genomic surveillance of the SARS-CoV-2 virus, since it predicts in a fast and accurate way the emergence of new viral strains and their dangerousness. It is freely available in the GitHub repository github.com/3BioCompBio/SpikeProSARS-CoV-2.
Caenorhabditis elegansLET-413 Scribble is essential in the epidermis for growth, viability, and directional outgrowth of epithelial seam cells
Authors: Riga Amalia , Cravo Janine , Schmidt Ruben , Pires Helena R. , Castiglioni Victoria G. , van den Heuvel Sander , Boxem Mike
Published: April 2021

The conserved adapter protein Scribble (Scrib) plays essential roles in a variety of cellular processes, including polarity establishment, proliferation, and directed cell migration. While the mechanisms through which Scrib promotes epithelial polarity are beginning to be unraveled, its roles in other cellular processes including cell migration remain enigmatic. InC. elegans, the Scrib ortholog LET-413 is essential for apical–basal polarization and junction formation in embryonic epithelia. However, whether LET-413 is required for postembryonic development or plays a role in migratory events is not known. Here, we use inducible protein degradation to investigate the functioning of LET-413 in larval epithelia. We find that LET-413 is essential in the epidermal epithelium for growth, viability, and junction maintenance. In addition, we identify a novel role for LET-413 in the polarized outgrowth of the epidermal seam cells. These stem cell-like epithelial cells extend anterior and posterior directed apical protrusions in each larval stage to reconnect to their neighbors. We show that the role of LET-413 in seam cell outgrowth is mediated at least in part by the junctional component DLG-1 discs large, which appears to restrict protrusive activity to the apical domain. Finally, we demonstrate that the Rho-family GTPases CED-10 Rac and CDC-42 can regulate seam cell outgrowth and may also function downstream of LET-413. Our data uncover multiple essential functions for LET-413 in larval development and shed new light on the regulation of polarized outgrowth of the seam cells.
Early Patellofemoral Cartilage and Bone Degeneration in a Rat Model of Noninvasive Anterior Cruciate Ligament Rupture
Authors: Hartner Samantha E. , Newton Michael D. , Fleischer Mackenzie M. , Baker Kevin C. , Maerz Tristan
Published: April 2021

Background

Anterior cruciate ligament rupture (ACLR) is a well-known risk factor for the development of post-traumatic osteoarthritis (PTOA). While clinical and pre-clinical studies have characterized the onset and progression of PTOA in the tibiofemoral joint compartment, very little is known about degenerative changes in the patellofemoral compartment after ACL injury.

Hypothesis/Purpose

To evaluate the extent to which ACL rupture induces acute patellofemoral joint degeneration by quantifying articular cartilage morphology and remodeling of subchondral and trabecular bone microarchitecture in the patellofemoral compartment.

Study Design

Descriptive laboratory study.

Methods

Adult female Lewis rats were randomized to undergo either a non-surgical ACL rupture or a Sham procedure (n = 6 per group).Ex vivocontrast-enhanced micro-computed tomography (µCT) and histological evaluation of the patellofemoral compartment were performed at 2-weeks post-injury, representing a timepoint of documented early PTOA in the tibiofemoral compartment in this model.

Results

ACL rupture causes osteophyte formation in the patella and mild degeneration in the superficial zone of articular cartilage (AC), including surface fibrillation, fissures, increased cellularity, and abnormal chondrocyte clustering at two weeks post-injury. Contrast-enhanced µCT analysis demonstrates significant increases in AC thickness of patellar and trochlear cartilage. Loss of subchondral bone thickness, bone volume fraction, and tissue mineral density, as well as changes to trabecular microarchitecture in both the patella and trochlea, were indicative of catabolic bone remodeling.

Conclusion

These results demonstrate that the patellofemoral joint develops mild but evident degenerative changes in the acute time period following ACL rupture, extending the utility of this rat model to the study of degenerative patellofemoral changes following joint trauma.

Clinical Relevance

ACL rupture causes mild degeneration and swelling of articular cartilage, coupled with catabolic bone remodeling in the patellofemoral compartment. Characterizing the pathophysiology of patellofemoral PTOA in its early stages may provide a better understanding of disease progression and provide opportunities for preventative therapeutic intervention.
Characterizing the effect of small-scale topographic variability on co-existing native and invasive species in a heterogeneous grassland using airborne hyperspectral remote sensing
Authors: Dao Phuong D. , Axiotis Alexander , He Yuhong
Published: April 2021

Characterizing the distribution, mechanism, and behaviour of invasive species is crucial to implementing an effective plan for the protection and management of native grassland ecosystems. Hyperspectral remote sensing has been used for mapping and monitoring invasive species at various spatial and temporal scales. However, most studies focus either on invasive tree species mapping or on the landscape-level using low-spatial resolution remote sensing imagery. These low-resolution images are not fine enough to distinguish individual invasive grasses, especially in a heterogeneous environment where invasive species are small, fragmented, and co-existing with native plants with similar color and texture.

To capture the small yet highly dynamic invasive plants at different stages of the growing season and under various topography and hydrological conditions, we use airborne high-resolution narrow-band hyperspectral imagery (HrHSI) to map invasive species in a heterogeneous grassland ecosystem in southern Ontario, Canada.

The results show that there is high spectral and textural separability between invasive species and between invasive and native plants, leading to an overall species classification accuracy of up to 89.6%. The combination of resultant species-level maps and the digital elevation model (DEM) showed that seasonality is the dominant factor that drives the distribution of invasive species at the landscape level, while small-scale topographic variations partially explain local patches of invasive species.

This study provides insights into the feasibility of using HrHSI in mapping invasive species in a heterogeneous ecosystem and offers the means to understand the mechanism and behaviour of invasive species for a more effective grassland management strategy.
The human sperm basal body is a complex centrosome important for embryo pre-implantation development
Authors: Amargant Farners , Pujol Aïda , Ferrer-Vaquer Anna , Durban Mercè , Martínez Meritxell , Vassena Rita , Vernos Isabelle
Published: April 2021

The mechanism of conversion of the human sperm basal body to a centrosome after fertilization, and its role in supporting human early embryogenesis has not been directly addressed so far. Using proteomics and immunofluorescence studies we show here that the human zygote inherits a basal body enriched with centrosomal proteins from the sperm, establishing the first functional centrosome of the new organism. Injection of human sperm tails containing the basal body into human oocytes followed by parthenogenetically activation, showed that the centrosome contributes to the robustness of the early cell divisions, increasing the probability of parthenotes reaching the compaction stage. In the absence of the sperm-derived centrosome, pericentriolar (PCM) components stored in the oocyte can formde novostructures after genome activation, suggesting a tight PCM expression control in zygotes. Our results reveal that the sperm basal body is a complex organelle which converts to a centrosome after fertilization, ensuring the early steps of embryogenesis and successful compaction. However, more experiments are needed to elucidate the exact molecular mechanisms of centrosome inheritance in humans.
In vitrosynthesis and reconstitution using mammalian cell-free lysates enables the systematic study of the regulation of LINC complex assembly
Authors: Majumder Sagardip , Hsu Yen-Yu , Moghimianavval Hossein , Andreas Michael , Giessen Tobias W. , Luxton G.W. Gant , Liu Allen P.
Published: April 2021

Membrane proteins perform numerous important functions in cells and tissues. Approximately 20% of the human genome encodes for membrane proteins, which represent the majority of targets for clinically relevant small molecules. Consequently, understanding their structure and structure-function relationships is a fundamental problem in biomedical research. Given the difficulties inherent to performing mechanistic biochemical and biophysical studies of membrane proteinsin vitro, we previously developed a facile HeLa cell-based cell-free expression (CFE) system that enables the efficient reconstitution of full-length (FL) functional membrane proteins in supported lipid bilayers. Despite having shown the directional reconstitution of CFE-synthesized FL inner nuclear membrane SUN proteins (i.e. SUN1 and SUN2), which directly interact with outer nuclear membrane KASH proteins within the nuclear envelope lumen to form linker of nucleoskeleton and cytoskeleton (LINC) complexes that mechanically couple the cytoskeleton and nucleus, the mechanism underlying regulated LINC complex assembly remains unclear. Here, we provide evidence that suggests that the reconstitution of CFE-synthesized FL membrane proteins in supported lipid bilayers occurs primarily through the fusion of endoplasmic reticulum-derived microsomes present within our CFE reactions with our supported lipid bilayers. In addition, we demonstrate the ease with which our synthetic biology platform can be used to investigate the impact of the chemical environment (e.g. calcium ions and redox state) on the ability of CFE-synthesized FL SUN proteins reconstituted in supported lipid bilayers to interact with the luminal domain of the KASH protein nesprin-2. Moreover, we use our platform to study the molecular requirements for the homo- and hetero-typic interactions that can occur between SUN1 and SUN2. Finally, we show that our platform can be used to simultaneously reconstitute three different CFE-synthesized FL membrane proteins in a single supported lipid bilayer. Overall, these results establish our HeLa cell-based CFE and supported lipid bilayer reconstitution platform as a powerful tool for performing mechanistic dissections of the oligomerization and function of FL membrane proteinsin vitro. While our platform is not a substitute for cell-based studies of membrane protein biochemistry and function, it does provide important mechanistic insights into the biology of difficult-to-study membrane proteins.

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New insights of glycosylation role on variable domain of antibody structures
Authors: Melo-Braga Marcella Nunes , Carvalho Milene Barbosa , Ferreira Manuela Cristina Emiliano , Felicori Liza Figueiredo
Published: April 2021

N-glycosylation at antibody variable domain (FvN-glyco) has emerged as an important modification for antibody function such as stability and antigen recognition, but it is also associated with autoimmune disease and IgE-mediated hypersensitivity reaction. However, the information related to its role and regulation is still scarce. Therefore, we investigated new insights in this regarding using solved antibodies structures presenting in the Protein Data Bank (PDB). From 130 FvN-glycostructures, we observed significant findings as a higher prevalence of N-glycosylation in human and mouse antibodies containing IGHV1-8 and IGHV2-2 germline genes, respectively. We also speculate the influence of activation-induced cytidine deaminase (AID) in introducing N-glycosylation sites during somatic hypermutation, specifically on threonine to asparagine substitution. Moreover, we highlight the enrichment of anti-HIV antibodies containing N-glycosylation at antibody variable domain and where we showed a possible important role of N-glycosylation, besides to antigen-antibody interactions, in antibody chain pair and antibody-antibody interactions. These could be a positive secondary effect of glycosylation to enhance antigen binding and further neutralization, including an additional mechanism to form Fab-dimers. Overall, our findings extend the knowledge on the characteristics and diverse role of N-glycosylation at antibody variable domain.

Key Points

Prevalence of FvN-glycoin human IGHV1-8 and mouse IGHV2-2 germline genes.

Enrichment of antibody FvN-glycoagainst virus, especially anti-HIV-1.

FvN-glycoin the interface with antigen, antibody pair chain, and another antibody.
Glycogen-dependent demixing of frog egg cytoplasm at increased crowding
Authors: Pelletier James F. , Field Christine M. , Coughlin Margaret , Ryazanova Lillia , Sonnett Matthew , Wühr Martin , Mitchison Timothy J.
Published: April 2021

Crowding increases the tendency of macromolecules to aggregate and phase separate, and high crowding can induce glass-like states of cytoplasm. To explore the effect of crowding in a well-characterized model cytoplasm we developed methods to selectively concentrate components larger than 25 kDa fromXenopusegg extracts. When crowding was increased 1.4x, the egg cytoplasm demixed into two liquid phases of approximately equal volume. One of the phases was highly enriched in glycogen while the other had a higher protein concentration. Glycogen hydrolysis blocked or reversed demixing. Quantitative proteomics showed that the glycogen phase was enriched in proteins that bind glycogen, participate in carbohydrate metabolism, or are in complexes with especially high native molecular weight. The glycogen phase was depleted of ribosomes, ER and mitochondria. These results inform on the physical nature of a glycogen-rich cytoplasm and suggest a role of demixing in the localization of glycogen particles in tissue cells.
Development of highly potent neutralising nanobodies against multiple SARS-CoV-2 variants including the variant of concern B.1.351
Authors: Sziemel Agnieszka M , Hwa Shi-Hsia , Sigal Alex , Tyson Grace , Logan Nicola , Willett Brian J. , Durcan Peter J
Published: April 2021

The pathogenic severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has caused a global pandemic. During the years of 2020-2021, millions of humans have died due to SARS-CoV-2 infection and severe economic damage to the global economy has occurred. Unprecedented rapid investments in vaccine development have been made to counter the spread of SARS-CoV-2 among humans. While vaccines are a key pillar of modern medicine, SARS-CoV-2 has mutated as it spread among humans. Vaccines previously developed and approved by regulators are becoming less effective against new variants. One variant of SARS-CoV-2 known as B.1.351 that was first reported to be present in South Africa significantly reduces the efficacy of vaccines developed to date. Therapeutic options that work against the B.1.351 variant are therefore urgently needed to counteract reduced vaccine efficacy. We present here the discovery of recombinant alpaca antibodies that neutralise live virus of B.1.351 and other SARS-CoV-2 variants potently. The antibodies described here may be a useful tool for clinicians who are treating patients infected with B.1.351 and other SARS-CoV-2 for which there is currently no known highly effective treatment.
CST interacts with the cohesin complex and promotes chromosome cohesion
Authors: Schuck P. Logan , Stewart Jason A.
Published: April 2021

Sister chromatid cohesion (SCC) is established during DNA replication by loading of the cohesin complex on newly replicated chromatids. Cohesin must then be maintained until mitosis to prevent segregation defects and aneuploidy. How SCC is established and maintained until mitosis remains incompletely understood and emerging evidence suggests that replication stress can lead to premature SCC loss. Here, we report that the single-stranded DNA-binding protein CTC1-STN1-TEN1 (CST) aids in SCC. CST primarily functions in telomere length regulation but also has known roles in replication restart and DNA repair. Following depletion of CST subunits, we observed an increase in the complete loss of SCC. Additionally, we determined that CST interacts with the cohesin complex. Unexpectedly, we did not find evidence of defective cohesion establishment or mitotic progression in the absence of CST. However, we did find that treatment with various replication inhibitors increased the association between CST and cohesin. Since replication stress was recently shown to induce SCC loss, we supposed that CST may be required to maintain SCC following fork stalling. In agreement with this idea, SCC loss was greatly increased in CST-depleted cells following exogenous replication stress. Based on our findings, we propose that CST aids in the maintenance of SCC at stalled replication forks to prevent premature cohesion loss.