bluuebunny/crossref_metadata_2025 huggingface dataset:
Nutrition priorities in obese critically ill patients
Authors: Al-Dorzi Hasan M. , Stapleton Renee D. , Arabi Yaseen M.
Published: December 2021

Purpose of review

During critical illness, several neuroendocrine, inflammatory, immune, adipokine, and gastrointestinal tract hormone pathways are activated; some of which are more intensified among obese compared with nonobese patients. Nutrition support may mitigate some of these effects. Nutrition priorities in obese critically ill patients include screening for nutritional risk, estimation of energy and protein requirement, and provision of macronutrients and micronutrients.

Recent findings

Estimation of energy requirement in obese critically ill patients is challenging because of variations in body composition among obese patients and absence of reliable predictive equations for energy expenditure. Whereas hypocaloric nutrition with high protein has been advocated in obese critically ill patients, supporting data are scarce. Recent studies did not show differences in outcomes between hypocaloric and eucaloric nutrition, except for better glycemic control. Sarcopenia is common among obese patients, and the provision of increased protein intake has been suggested to mitigate catabolic changes especially after the acute phase of critical illness. However, high-quality data on high protein intake in these patients are lacking. Micronutrient deficiencies among obese critically ill patients are common but the role of their routine supplementation requires further study.

An individualized approach for nutritional support may be needed for obese critically ill patients but high-quality evidence is lacking. Future studies should focus on nutrition priorities in this population, with efficient and adequately powered studies.
Toward a Standardized and Individualized Laboratory-Based Protocol for Wheelchair-Specific Exercise Capacity Testing in Wheelchair Athletes
Authors: Janssen Rowie J. F. , de Groot Sonja , Van der Woude Lucas H. V. , Houdijk Han , Vegter Riemer J. K.
Published: December 2021

Previous studies on handrim wheelchair–specific (an)aerobic exercise capacity in wheelchair athletes have used a diversity of participants, equipment, and protocols. Therefore, test results are difficult to compare among studies. The first aim of this scoping review is to provide an overview of the populations studied, the equipment and protocols used, and the reported outcomes from all laboratory-based studies on wheelchair-specific exercise capacity in wheelchair athletes. The second aim is to synthesize these findings into a standardized, yet individualized protocol. A scoping literature search resulted in 10 anaerobic and 38 aerobic protocols. A large variety in equipment, protocol design, and reported outcomes was found. Studies that systematically investigated the influence of protocol features are lacking, which makes it difficult to interpret and compare test outcomes among the heterogeneous group of wheelchair athletes. Protocol design was often dependent on a priori participant knowledge. However, specific guidelines for individualization were missing. However, the common protocol features of the different studies were united into guidelines that could be followed when performing standardized and individualized wheelchair-specific exercise capacity tests in wheelchair athletes. Together with guidelines regarding reporting of participant characteristics, used equipment, and outcome measures, we hope to work toward more international agreement in future testing.
Treatment of Sagittal Craniosynostosis Using Osteoplastic Parietal Craniotomy Flap With Distraction Osteogenesis: A Variation on Technique
Authors: Habarth-Morales Theodore E. , Piatt Joseph H. , Caterson Edward J.
Published: December 2021

Late presentation sagittal craniosynostosis presents a unique challenge due to the decreased ability of the skull to repair the bony defects created by standard of care techniques. Distraction osteogenesis is a viable strategy to correct this defect in late presenting cases. The authors describe a variation in technique in which the temporalis muscle origin is retained, creating an osteoplastic bone flap with retained vascularity through the tem-poralis muscle. This may improve postoperative bony healing of bony defects in this compromised population. The authors present two patients who presented to them late with sagittal synostosis who were treated with distraction osteogenesis in which vascular continuity to the parietal bones is preserved through the temporalis muscle.
Drug Induced Sleep Endoscopy Versus Awake Endoscopy in Retrolingual Obstruction Assessment in Obstructive Sleep Apnea Patients: A Comparative Study
Authors: Pérez-Martín Nuria , Bosco Gabriela , Navarro Andrés , Morato Marta , Racionero Miguel A. , Fernandez-Sanjuan Patricia , O’Connor-Reina Carlos , Plaza Guillermo
Published: December 2021

The aim of this study is to evaluate the correlation of retrolingual obstruction determined by drug induced sleep endoscopy (DISE) and awake endoscopy evaluation of Muller maneuver (MM) and lingual tonsil hypertrophy (LTH) in patients with obstructive sleep apnea.

A prospective cohort of 100 patients with obstructive sleep apnea who underwent DISE was assessed. The inclusion criteria were age between 18 and 70 years, and apnea-hypopnea index higher than 5. Friedman staging, LTH and MM were determined by awake endoscopy, as other physical findings. The authors evaluated the correlation of retrolingual obstruction determined by DISE using velum oropharynx tongue, epiglottis (VOTE) and nose, oropharynx, hypopharynx, larynx (NOHL) classification.

When retrolingual MM was assessed, significant changes between awake and DISE were observed (P = 0.000). Conversely, Friedman stage had no significant changes to DISE retrolingual findings (P = 0.868). Analyzing LTH and DISE retrolingual findings according to NOHL and VOTE, if a cutoff value was established at 50%, DISE findings differ from awake: NOHL (P<0.001) and VOTE (P = 0.004). Nevertheless, if a restrictive cutoff at 75% was attached, DISE findings were similar to awake: NOHL (P = 0.124) and VOTE (P = 0.123).

This study demonstrates that awake endoscopy determining LTH and Friedman stage is a mild predictor of collapse at retrolingual level, showing significant correlation to DISE only when severe retrolingual collapse is present. Our findings suggest that in-office awake endoscopy may have certain predictive value to select surgical patients.
Correlation Between Sports-Related Maxillofacial Injuries and Head Injuries: A Five-Year Retrospective Study
Authors: Park Han-Kyul , Shriya Jaiswai M. , Jeon Min-A. , Choi Na-Rae , Chen Chun-Ming , Park Jin-Young , Hwang Dae-Seok
Published: December 2021

Purpose:

As sports have become more diverse and demanding, the number of patients with a maxillofacial injury accompanied by a cranial injury or neurological symptoms has increased. This study examined the correlation between sports-related maxillofacial injuries and head injuries.

Patients and Methods:

Among the patients who visited the emergency department of Pusan National University Dental Hospital due to a maxillofacial injury from sporting activities between 2014 and 2018, those who additionally had head injuries were retrospectively examined. Sporting activities were classified according to the American Academy of Pediatrics classification, and severity of injuries was determined using the Facial Injury Severity Scale (FISS). Patients whose medical records showed neurological symptoms and who underwent brain computed tomography for concomitant head injury were selected. The association between each of these variables, including age and gender, was statistically analyzed.

Results:

A total of 95 patients were included in this study, most of whom were male teenagers, and cycling was the most common cause of injuries. The meanFISS score was 0.79. Brain computed tomography was conducted for 91 patients, and 28 patients reported neurological symptoms. Only 11 patients underwent advanced evaluation in the neurology or neurosurgery department. Most patients were diagnosed with contusion and concussion and were monitored without any treatment.

Conclusions:

Higher FISS values did not reflect the severity of maxillofacial and head injury. In this study, there were some patients with cranial fracture and cerebral hemorrhage with mild neurosurgical symptoms of facial trauma. Although the incidence of head trauma is not high, the necessity of wearing protective equipment cannot be overemphasized because severe trauma is permanent. Neurological signs and symptoms of patients with maxillofacial trauma should not be overlooked and require a thorough evaluation.
Seminal Studies in Facial Reanimation Surgery: Consensus and Controversies in the Top 50 Most Cited Articles
Authors: Boonipat Thanapoom , Asaad Malke , Al-Mouakeh Ahmad , Muro-Cardenas Jose , Mardini Samir , Stotland Mitchell A. , Glass Graeme E.
Published: December 2021

Facial paralysis can impair one's ability to form facial expressions that are congruent with internal emotion. This hinders communication and the cognitive processing of emotional experience. Facial reanimation surgery, which aims to restore full facial expressivity is a relatively recent undertaking which is still evolving. Due in large part to published techniques, refinements, and clinical outcomes in the scientific literature, consensus on best practice is gradually emerging, whereas controversies still exist.

Taking stock of how the discipline reached its current state can help delineate areas of agreement and debate, and more clearly reveal a path forward. To do this, the authors have analyzed the 50 seminal publications pertaining to facial reanimation surgery. In longstanding cases, the free gracilis transfer emerges as a clear muscle of choice but the nerve selection remains controversial with prevailing philosophies advocating cross facial nerve grafts (with or without the support of an ipsilateral motor donor) or an ipsilateral motor donor only, of which the hypoglossal and nerve to masseter predominate. The alternative orthodoxy has refined the approach popularized by Gillies in 1934 and does not require the deployment of microsurgical principles. Although this citation analysis does not tell the whole story, surgeons with an interest in facial reanimation will find that this is a good place to start.
The MLL3/4 complexes and MiDAC act antagonistically as genome-wide regulators of H4K20ac to control a specific gene expression program
Authors: Wang Xiaokang , Rosikiewicz Wojciech , Sedkov Yurii , Mondal Baisakhi , Kallappagoudar Satish , Tvardovskiy Andrey , Bajpai Richa , Xu Beisi , Pruett-Miller Shondra M , Schneider Robert , Herz Hans-Martin
Published: December 2021

The mitotic deacetylase complex MiDAC has recently been shown to play a vital physiological role in embryonic development and neurite outgrowth. However, how MiDAC functionally intersects with other chromatin-modifying regulators is poorly understood. Here, we describe a physical interaction between the histone H3K27 demethylase UTX, a complex-specific subunit of the enhancer-associated MLL3/4 complexes, and MiDAC. We demonstrate that UTX bridges the association of the MLL3/4 complexes and MiDAC by interacting with ELMSAN1, a scaffolding subunit of MiDAC. Our data shows that MiDAC constitutes a negative genome-wide regulator of H4K20ac, an activity which is counteracted by the MLL3/4 complexes. MiDAC and the MLL3/4 complexes co-localize at many genomic regions, that are enriched for H4K20ac and the enhancer marks H3K4me1, H3K4me2 and H3K27ac. We find that MiDAC antagonizes the recruitment of the MLL3/4 complexes to negatively regulate H4K20ac, H3K4me2 and H3K27ac resulting in transcriptional attenuation of associated genes. In summary, our findings provide a paradigm how the opposing roles of chromatin-modifying components, such as MiDAC and the MLL3/4 complexes, balance the transcriptional output of specific gene expression programs.
Modeling osteoporosis to design and optimize pharmacologic therapies comprising multiple drug types
Authors: Jörg David J. , Fürtinger Doris H. , Cherif Alhaji , Bushinsky David A. , Mermelstein Ariella , Raimann Jochen G. , Kotanko Peter
Published: December 2021

For the treatment of postmenopausal osteoporosis, several drug classes with different mechanisms of action are available. Since only a limited set of dosing regimens and drug combinations can be tested in clinical trials, it is currently unclear whether common medication strategies achieve optimal bone mineral density gains or are outperformed by alternative dosing schemes and combination therapies that have not been explored so far. Here we develop a mathematical framework of drug interventions for postmenopausal osteoporosis that unifies fundamental mechanisms of bone remodeling and the mechanisms of action of four drug classes: bisphosphonates, parathyroid hormone (PTH) analogs, sclerostin inhibitors and receptor activator of NF-κB ligand (RANKL) inhibitors. Using data from several clinical trials, we calibrate and validate the model, demonstrating its predictive capacity for complex medication scenarios including sequential and parallel drug combinations. Via simulations, we reveal that there is a large potential to improve gains in bone mineral density by exploiting synergistic interactions between different drug classes, without increasing the total amount of drug administered.
Agonists to ions: Efficiency suggests ‘zipper’ mechanism for nicotinic receptor activation
Authors: Auerbach Anthony
Published: December 2021

Agonists are classified by the strength at which they bind to their target sites (affinity) and their ability to activate receptors once bound to those sites (efficacy). Efficiency is a third fundamental agonist property that is a measure of the correlation between affinity and efficacy. Efficiency is the percent of agonist binding energy that is converted into energy for receptor activation (‘gating’). In the muscle nicotinic acetylcholine receptor, agonists belong to families having discrete efficiencies of 54%, 51%, 42% or 35%. Efficiency depends on the size and composition of both the agonist and binding site, and can be estimated from, and used to interpret, concentration-response curves. A correlation between affinity and efficacy indicates that the agonist’s energy changes that take place within binding and gating processes are linked. Efficiency suggests that receptors turn on and off by progressing through a sequence of energy-linked domain rearrangements, as in a zipper.
A highly sensitive cell-based luciferase assay for high-throughput automated screening of SARS-CoV-2 nsp5/3CLpro inhibitors
Authors: Chen KY , Krischuns T , Varga L Ortega , Harigua-Souiai E , Paisant S , Zettor A , Chiaravalli J , Courtney D , O’Brien A , Baker SC , Isel C , Agou F , Jacob Y , Blondel A , Naffakh N
Published: December 2021

Effective drugs against SARS-CoV-2 are urgently needed to treat severe cases of infection and for prophylactic use. The main viral protease (nsp5 or 3CLpro) represents an attractive and possibly broad-spectrum target for drug development as it is essential to the virus life cycle and highly conserved among betacoronaviruses. Sensitive and efficient high-throughput screening methods are key for drug discovery. Here we report the development of a gain-of-signal, highly sensitive cell-based luciferase assay to monitor SARS-CoV-2 nsp5 activity and show that it is suitable for high-throughput screening of compounds in a 384-well format. A benefit of miniaturisation and automation is that screening can be performed in parallel on a wild-type and a catalytically inactive nsp5, which improves the selectivity of the assay. We performed molecular docking-based screening on a set of 14,468 compounds from an in-house chemical database, selected 359 candidate nsp5 inhibitors and tested them experimentally. We identified four molecules, including the broad-spectrum antiviral merimepodib/VX-497, which show anti-nsp5 activity and inhibit SARS-CoV-2 replication in A549-ACE2 cells with IC50 values in the 4-21 µM range. The here described assay will allow the screening of large-scale compound libraries for SARS-CoV-2 nsp5 inhibitors. Moreover, we provide evidence that this assay can be adapted to other coronaviruses and viruses which rely on a viral protease.
The P3 O-Tert-Butyl-Threonine is Key to High Cellular and Antiviral Potency for Aldehyde-Based SARS-CoV-2 Main Protease Inhibitors
Authors: Ma Yuying , Yang Kai S. , Geng Zhi Zachary , Alugubelli Yugendar R. , Shaabani Namir , Vatansever Erol C. , Ma Xinyu R. , Cho Chia-Chuan , Khatua Kaustav , Blankenship Lauren , Yu Ge , Sankaran Banumathi , Li Pingwei , Allen Robert , Ji Henry , Xu Shiqing , Liu Wenshe Ray
Published: December 2021

As an essential enzyme to SARS-CoV-2, main protease (MPro) is a viable target to develop antivirals for the treatment of COVID-19. By varying chemical compositions at both P2 and P3 sites and the N-terminal protection group, we synthesized a series of MPro inhibitors that contain β-(S-2-oxopyrrolidin-3-yl)-alaninal at the P1 site. These inhibitors have a large variation of determined IC50 values that range from 4.8 to 650 nM. The determined IC50 values reveal that relatively small side chains at both P2 and P3 sites are favorable for achieving high in vitro MPro inhibition potency, the P3 site is tolerable toward unnatural amino acids with two alkyl substituents on the α-carbon, and the inhibition potency is sensitive toward the N-terminal protection group. X-ray crystal structures of MPro bound with 16 inhibitors were determined. All structures show similar binding patterns of inhibitors at the MPro active site. A covalent interaction between the active site cysteine and a bound inhibitor was observed in all structures. In MPro, large structural variations were observed on residues N142 and Q189. All inhibitors were also characterized on their inhibition of MPro in 293T cells, which revealed their in cellulo potency that is drastically different from their in vitro enzyme inhibition potency. Inhibitors that showed high in cellulo potency all contain O-tert-butyl-threonine at the P3 site. Based on the current and a previous study, we conclude that O-tert-butyl-threonine at the P3 site is a key component to achieve high cellular and antiviral potency for peptidyl aldehyde inhibitors of MPro. This finding will be critical to the development of novel antivirals to address the current global emergency of concerning the COVID-19 pandemic.
The N-Terminal Carbamate is Key to High Cellular and Antiviral Potency for Boceprevir-Based SARS-CoV-2 Main Protease Inhibitors
Authors: Alugubelli Yugendar R. , Geng Zhi Zachary , Yang Kai S. , Shaabani Namir , Khatua Kaustav , Ma Xinyu R. , Vatansever Erol C. , Cho Chia-Chuan , Ma Yuying , Blankenship Lauren , Yu Ge , Sankaran Banumathi , Li Pingwei , Allen Robert , Ji Henry , Xu Shiqing , Liu Wenshe Ray
Published: December 2021

Boceprevir is an HCV NSP3 inhibitor that has been explored as a repurposed drug for COVID-19. It inhibits the SARS-CoV-2 main protease (MPro) and contains an α-ketoamide warhead, a P1 β-cyclobutylalanyl moiety, a P2 dimethylcyclopropylproline, a P3 tert-butyl-glycine, and a P4 N-terminal tert-butylcarbamide. By introducing modifications at all four positions, we synthesized 20 boceprevir-based MPro inhibitors including PF-07321332 and characterized their MPro inhibition potency in test tubes (in vitro) and human host cells (in cellulo). Crystal structures of MPro bound with 10 inhibitors and antiviral potency of 4 inhibitors were characterized as well. Replacing the P1 site with a β-(S-2-oxopyrrolidin-3-yl)-alanyl (opal) residue and the warhead with an aldehyde leads to high in vitro potency. The original moieties at P2, P3 and the P4 N-terminal cap positions in boceprevir are better than other tested chemical moieties for high in vitro potency. In crystal structures, all inhibitors form a covalent adduct with the MPro active site cysteine. The P1 opal residue, P2 dimethylcyclopropylproline and P4 N-terminal tert-butylcarbamide make strong hydrophobic interactions with MPro, explaining high in vitro potency of inhibitors that contain these moieties. A unique observation was made with an inhibitor that contains an P4 N-terminal isovaleramide. In its MPro complex structure, the P4 N-terminal isovaleramide is tucked deep in a small pocket of MPro that originally recognizes a P4 alanine side chain in a substrate. Although all inhibitors show high in vitro potency, they have drastically different in cellulo potency in inhibiting ectopically expressed MPro in human 293T cells. All inhibitors including PF-07321332 with a P4 N-terminal carbamide or amide have low in cellulo potency. This trend is reversed when the P4 N-terminal cap is changed to a carbamate. The installation of a P3 O-tert-butyl-threonine improves in cellulo potency. Three molecules that contain a P4 N-terminal carbamate were advanced to antiviral tests on three SARS-CoV-2 variants. They all have high potency with EC50 values around 1 μM. A control compound with a nitrile warhead and a P4 N-terminal amide has undetectable antiviral potency. Based on all observations, we conclude that a P4 N-terminal carbamate in a boceprevir derivative is key for high antiviral potency against SARS-CoV-2.
Mutational analysis of SARS-CoV-2. ORF8 and the evolution of the Delta and Omicron variants
Authors: Trieu Gopika , Trieu Vuong N
Published: December 2021

SARS-CoV-2 the virus responsible for the current pandemic. This virus is continually evolving, adapting to both innate and acquired immune responses and therapeutic drugs. Therefore, it is important to understand how the virus evolving to design the appropriate therapeutic and vaccine in preparation for future variants. Here, we used the online SARS-CoV-2 databases, Nextstrain and Ourworld, to map the evolution and epidemiology of the virus. We identified 30 high entropy residues which underwent a progressive evolution to arrive at the current dominant variant - Delta variant. The virus underwent mutational waves with the first wave made up of structural proteins important in its infectivity and the second wave made up of the ORFs important for its contagion. The most important driver of the second wave is ORF8 mutations at residue 119 and 120. Further mutations of these two residues are creating new clades that are offshoots from the Delta backbone. More importantly the further expansion of the S protein in the Omicron variant is now followed with the acquisition of ORF8 mutations 119 and 120. These findings demonstrate how SARS-CoV-2 mutates and points to two evolutionary paths; 1) Mutational expansion on the Delta backbone among the ORFs and 2) Mutational expansion of the S protein on other backbone follow with mutational wave among the ORFs. Both are happening at the same time right now with the Omicron variant early in the first wave to follow with a more aggressive second wave of mutations.

HIGHLIGHTS

Mutational waves in the evolution of SARS-CoV-2. S protein as the driver of the first wave improving the minimum inhaled viral load required to cause infection and ORF8 mutations 119 and 120 as the driver of the second mutational wave to improve the Contagion Airborne Transmission value.
COVID-19 pandemic dynamics in South Africa and epidemiological characteristics of three variants of concern (Beta, Delta, and Omicron)
Authors: Yang Wan , Shaman Jeffrey
Published: December 2021

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) variants of concern (VOCs) have been key drivers of new coronavirus disease 2019 (COVID-19) pandemic waves. To better understand variant epidemiologic characteristics, here we apply a model-inference system to reconstruct SARS-CoV-2 transmission dynamics in South Africa, a country that has experienced three VOC pandemic waves (i.e. Beta, Delta, and Omicron). We estimate key epidemiologic quantities in each of the nine South African provinces during March 2020 – Feb 2022, while accounting for changing detection rates, infection seasonality, nonpharmaceutical interventions, and vaccination. Model validation shows that estimated underlying infection rates and key parameters (e.g., infection-detection rate and infection-fatality risk) are in line with independent epidemiological data and investigations. In addition, retrospective predictions capture pandemic trajectories beyond the model training period. These detailed, validated model-inference estimates thus enable quantification of both the immune erosion potential and transmissibility of three major SARS-CoV-2 VOCs, i.e., Beta, Delta, and Omicron. These findings help elucidate changing COVID-19 dynamics and inform future public health planning.
A lineage-specific Exo70 is required for receptor kinase-mediated immunity in barley
Authors: Holden Samuel , Bergum Molly , Green Phon , Bettgenhaeuser Jan , Hernández-Pinzón Inmaculada , Thind Anupriya , Clare Shaun , Russell James M. , Hubbard Amelia , Taylor Jodi , Smoker Matthew , Gardiner Matthew , Civolani Laura , Cosenza Francesco , Rosignoli Serena , Strugala Roxana , Molnár István , Šimková Hana , Doležel Jaroslav , Schaffrath Ulrich , Barrett Matthew , Salvi Silvio , Moscou Matthew J.
Published: December 2021

In the evolution of land plants, the plant immune system has experienced expansion in immune receptor and signaling pathways. Lineage-specific expansions have been observed in diverse gene families that are potentially involved in immunity, but lack causal association. Here, we show that Rps8-mediated resistance in barley to the fungal pathogen Puccinia striiformis f. sp. tritici (wheat stripe rust) is conferred by a genetic module: LRR-RK and Exo70FX12, which are together necessary and sufficient. The Rps8 LRR-RK is the ortholog of rice extracellular immune receptor Xa21 and Exo70FX12 is a member of the Poales-specific Exo70FX clade. The Exo70FX clade emerged after the divergence of the Bromeliaceae and Poaceae, and comprises from 2 to 75 members in sequenced grasses. These results demonstrate the requirement of a lineage-specific Exo70FX12 in Rps8 LRR-RK immunity and suggest that the Exo70FX clade may have evolved a specialized role in receptor kinase signaling.
Epidemiology study of SARS-CoV-2 pandemic in India, the first and second wave
Authors: Chaudhuri Dwaipayan , Datta Joyeeta , Majumder Satyabrata , Giri Kalyan
Published: December 2021

Background and objectives

SARS-CoV-2 has wrecked the world for the past 17 months. India has been hit by the second wave of the virus which has been characterized by new symptoms. This study focuses on the pattern of infection over the last 13 months utilizing epidemic model to predict course of the pandemic.

Material and methods

The data was collected from covid19india.org to perform analysis based on age and gender distribution. Statistical analysis was performed to determine the relation between confirmed and recovered cases while SIR epidemic model was used to determine the course of the pandemic in the country and the changes that have occurred from the first to the second wave.

Results and discussions

Results show infectivity rate to be higher in ages 20-50 while mortality is higher in 50-80 age group while 60-70% of the infected population are males. Each of the 9 states have their own salient feature curves of infection. It was seen that the confirmed and recovered cases are more correlated at present than previous wave. The curves for both waves show a polynomial distribution while the reproduction number data shows an almost U-shaped curve indicating decrease of infection spread in the middle phase when the first wave was on a decline before picking up again owing to the second wave.

Interpretations and conclusion

The gender and age distribution shows that although lower age group is more infected, mortality is high for higher age groups, on the other hand males are more prone to the infection. The statistical analysis shows the nature of spread of the disease, the data of which is quantified by the SIR model based study.
Increased risk of infection with SARS-CoV-2 Omicron compared to Delta in vaccinated and previously infected individuals, the Netherlands, 22 November to 19 December 2021
Authors: Eggink Dirk , Andeweg Stijn P. , Vennema Harry , van Maarseveen Noortje , Vermaas Klaas , Vlaemynck Boris , Schepers Raf , van Gageldonk-Lafeber Arianne B. , van den Hof Susan , Reusken Chantal B.E.M. , Knol Mirjam J.
Published: December 2021

Infections by the Omicron SARS-CoV-2 variant are rapidly increasing worldwide. Among 70,983 infected individuals (age ≥ 12 years), we observed an increased risk of S-gene target failure, predictive of the Omicron variant, in fully vaccinated (odds ratio: 5.0; 95% confidence interval: 4.0-6.1) and previously infected individuals (OR: 4.9: 95% CI: 3.1-7.7) compared with infected naïve individuals. This suggests a substantial decrease in protection from vaccine- or infection-induced immunity against SARS-CoV-2 infections caused by the Omicron variant compared with the Delta variant.
O-methylated N-glycans Distinguish Mosses from Vascular Plants
Authors: Stenitzer David , Mocsai Reka , Zechmeister Harald , Reski Ralf , Decker Eva L. , Altmann Friedrich
Published: December 2021

In the animal kingdom, a stunning variety of N-glycan structures has emerged with phylogenetic specificities of various kinds. In the plant kingdom, however, N-glycosylation appears as strictly conservative and uniform. From mosses to all kinds of gymno- and angiosperms, land plants mainly express structures with the common pentasaccharide core substituted with xylose, core α1,3-fucose, maybe terminal GlcNAc residues and Lewis A determinants. In contrast, green algae biosynthesize unique and unusual N-glycan structures with uncommon monosaccharides, a plethora of different structures and various kinds of O-methylation. Mosses, a group of plants that are separated by at least 400 million years of evolution from vascular plants, were hitherto seen as harbouring an N-glycosylation machinery identical to that of vascular plants. To challenge this view, we have analysed the N-glycomes of several moss species using MALDI-TOF/TOF, PGC-MS/MS and GC-MS. While all species contained the plant-typical heptasaccharide with no, one or two terminal GlcNAc residues (MMXF, MGnXF and GnGnXF, respectively), many species exhibited MS signals with 14.02 Da increments as characteristic for O-methylation. Throughout all analysed moss N-glycans the level of methylation differed strongly even in the same family. In some species, methylated glycans dominated, while others had no methylation at all. GC-MS revealed the main glycan from Funaria hygrometrica to contain 2,6-O-methylated terminal mannose. Some mosses additionally presented very large, likewise methylated complex-type N-glycans. This first finding of methylation of N-glycans in land plants mirrors the presumable phylogenetic relation of mosses to green algae, where O-methylation of mannose and many other monosaccharides is a common trait.
Neonatal enthesis healing involves non-inflammatory formation of acellular scar through ECM secretion by resident cells
Authors: Vinestock Ron Carmel , Felsenthal Neta , Assaraf Eran , Katz Eldad , Rubin Sarah , Heinemann-Yerushalmi Lia , Krief Sharon , Dezorella Nili , Levin-Zaidman Smadar , Tsoory Michael , Thomopoulos Stavros , Zelzer Elazar
Published: December 2021

Wound healing is a well-orchestrated process that typically recruits the immune and vascular systems to restore the structure and function of the injured tissue. Injuries to the enthesis, a hypocellular and avascular tissue, often result in fibrotic scar formation and loss of mechanical properties, thereby severely affecting musculoskeletal function and life quality. This raises questions about the healing capabilities of the enthesis.

Here, we established an injury model to the Achilles entheses of neonatal mice to study the possibility that at an early age, the enthesis can heal more effectively. Histology and immunohistochemistry analyses revealed an atypical process that did not involve inflammation or angiogenesis. Instead, neonatal enthesis healing was mediated by secretion of collagen types I and II by resident cells, which formed a permanent hypocellular and avascular scar. Transmission electron microscopy showed that the cellular response to injury, including ER stress, autophagy and cell death, varied between the tendon and cartilage ends of the enthesis. Single-molecule in situ hybridization, immunostaining, and TUNEL assays verified these differences. Finally, gait analysis showed that these processes effectively restored function of the injured leg.

Collectively, these findings reveal a novel healing mechanism in neonatal entheses, whereby local ECM secretion by resident cells forms an acellular ECM deposit in the absence of inflammation markers, allowing gait restoration. These insights into the healing mechanism of a complex transitional tissue may lead to new therapeutic strategies for adult enthesis injuries.
OligoTRAFTACs: A Generalizable Method for Transcription Factor Degradation
Authors: Samarasinghe Kusal T. G. , An Elvira , Genuth Miriam A. , Chu Ling , Holley Scott A. , Crews Craig M.
Published: December 2021

Dysregulated transcription factors (TFs) that rewire gene expression circuitry are frequently identified as key players in disease. Although several TFs have been drugged with small molecules, the majority of oncogenic TFs are not currently pharmaceutically tractable due to their paucity of ligandable pockets. The first generation of transcription factor targeting chimeras (TRAFTACs) was developed to target TFs for proteasomal degradation by exploiting their DNA binding ability. In the current study, we have developed the second generation TRAFTACs (“oligoTRAFTACs”) comprised of a TF- binding oligonucleotide and an E3 ligase-recruiting ligand. Herein, we demonstrate the development of oligoTRAFTACs to induce the degradation of two oncogenic TFs, c-Myc and brachyury. In addition, we show that brachyury can be successfully degraded by oligoTRAFTACs in chordoma cell lines. Furthermore, zebrafish experiments demonstrate in vivo oligoTRAFTAC activity. Overall, our data demonstrate oligoTRAFTACs as a generalizable platform towards difficult-to-drug TFs and their degradability via the proteasomal pathway.
FUCCI-based live imaging platform reveals cell cycle dynamics and identifies pro-proliferative compounds in human iPSC-derived cardiomyocytes
Authors: Murganti Francesca , Derks Wouter , Baniol Marion , Simonova Irina , Neumann Katrin , Khattak Shahryar , Guan Kaomei , Bergmann Olaf
Published: December 2021

One of the major goals in cardiac regeneration research is to replace lost ventricular tissue with new cardiomyocytes. However, cardiomyocyte proliferation drops to low levels in neonatal hearts and is no longer efficient in compensating for the loss of functional myocardium in heart disease. We generated a human induced pluripotent stem cell (iPSC)-derived cardiomyocyte-specific cell cycle indicator system (TNNT2-FUCCI) to characterize regular and aberrant cardiomyocyte cycle dynamics. We visualized cell cycle progression in TNNT2-FUCCI and found G2 cycle arrest in endoreplicating cardiomyocytes. Moreover, we devised a live-cell compound screening platform to identify pro-proliferative drug candidates. We found that the alpha-adrenergic receptor agonist clonidine induced cardiomyocyte proliferation in vitro and increased cardiomyocyte cell cycle entry in neonatal mice. In conclusion, the TNNT2-FUCCI system is a valuable tool to characterize cardiomyocyte cell cycle dynamics and identify pro-proliferative candidates with regenerative potential in the mammalian heart.
The influence factors of mean particle size and positive quality control of bacterial filtration efficiency system
Authors: Yi Yayi , Shi Dianlong
Published: December 2021

Background

The Coronavirus Disease 2019 (COVID-19) has swept the whole world with high mortality. Since aerosol transmission is the main route of transmission, wearing a mask serves as a crucial preventive measure. An important parameter to evaluate the performance of a mask is the bacteria filtration efficiency (BFE). Aerosol mean particle size (MPS) and positive quality control value are two key indexes of BFE system.

Aim

To study the major influence factors of the mean particle size of bacterial aerosols and positive quality control value of BFE system.

Method and Results

In this study, we investigated the influence of Anderson sampler, spray flow, medium thickness, and peristaltic pump flow on the MPS of bacterial aerosols and positive quality control value of BFE system, respectively. The results show that the machining accuracy of Anderson sampler has great influence on aerosol MPS and positive quality control value. With the increase of aerosol spray flow rate, the positive quality control value will increase gradually, but the effect on aerosol MPS is not a simple linear relationship. As the agar medium thickness increased, the positive quality control value and aerosol MPS increased gradually. With the increase of peristaltic pump flow, the positive quality control value increased gradually, while the aerosol MPS was basically in a downward trend. When the peristatic pump flow rate was 0.1mL/min, the spray flow rate was 7.2L/min, the agar plate thickness was 27mL, and the Anderson sampler of Beijing Mingjie was used for the experiment, the aerosol MPS and positive quality control value were both within the acceptable range and were the optimal parameters.

Conclusions

This study provides guidance for the manufacturers of the BFE system and improves the protective performance of masks, which is important for the human health, especially during the occurrence of viral pandemics such as “COVID-19”.

Abstract Figure
Quantitative detection of SARS-CoV-2 Omicron BA.1 and BA.2 variants in wastewater through allele-specific RT-qPCR
Authors: Lee Wei Lin , Gu Xiaoqiong , Armas Federica , Wu Fuqing , Chandra Franciscus , Chen Hongjie , Xiao Amy , Leifels Mats , Chua Feng Jun Desmond , Kwok Germaine WC , Tay Joey YR , Lim Claire YJ , Thompson Janelle , Alm Eric J
Published: December 2021

On November 26, 2021, the World Health Organisation classified the B.1.1.529 SARS-CoV-2 variant as the Omicron variant of concern (VOC). Reports of higher transmissibility and potential immune evasion triggered flight bans and heightened health control measures across the world to stem its distribution. Wastewater-based surveillance has demonstrated to be a useful complement for community-based tracking of SARS-CoV-2 variants. Using design principles of our previous assays that detect VOCs (Alpha and Delta), here we report three allele-specific RT-qPCR assays that can quantitatively detect and discriminate the Omicron BA.1 and BA.2 variants in wastewater. The first assay targets the nine-nucleotide deletion at the L24-A27S of the spike protein for detection of BA.2. The second targets the six-nucleotide deletion at 69-70 of the spike protein for detection of the Omicron BA.1 variant, and the third targets the stretch of mutations from Q493R to Q498R for simultaneous detection of both Omicron BA.1 and BA.2. This method is open-sourced, can be implemented using commercially available RT-qPCR protocols, and would be an important tool for tracking the introduction and spread of the Omicron variants BA.1 and BA.2 in communities for informed public health responses.
Early assessment of the clinical severity of the SARS-CoV-2 Omicron variant in South Africa
Authors: Wolter Nicole , Jassat Waasila , Walaza Sibongile , Welch Richard , Moultrie Harry , Groome Michelle , Amoako Daniel Gyamfi , Everatt Josie , Bhiman Jinal N. , Scheepers Cathrine , Tebeila Naume , Chiwandire Nicola , du Plessis Mignon , Govender Nevashan , Ismail Arshad , Glass Allison , Mlisana Koleka , Stevens Wendy , Treurnicht Florette K. , Makatini Zinhle , Hsiao Nei-yuan , Parboosing Raveen , Wadula Jeannette , Hussey Hannah , Davies Mary-Ann , Boulle Andrew , von Gottberg Anne , Cohen Cheryl
Published: December 2021

Background

The SARS-CoV-2 Omicron variant of concern (VOC) almost completely replaced other variants in South Africa during November 2021, and was associated with a rapid increase in COVID-19 cases. We aimed to assess clinical severity of individuals infected with Omicron, using S Gene Target Failure (SGTF) on the Thermo Fisher Scientific TaqPath COVID-19 PCR test as a proxy.

Methods

We performed data linkages for (i) SARS-CoV-2 laboratory tests, (ii) COVID-19 case data, (iii) genome data, and (iv) the DATCOV national hospital surveillance system for the whole of South Africa. For cases identified using Thermo Fisher TaqPath COVID-19 PCR, infections were designated as SGTF or non-SGTF. Disease severity was assessed using multivariable logistic regression models comparing SGTF-infected individuals diagnosed between 1 October to 30 November to (i) non-SGTF in the same period, and (ii) Delta infections diagnosed between April and November 2021.

Results

From 1 October through 6 December 2021, 161,328 COVID-19 cases were reported nationally; 38,282 were tested using TaqPath PCR and 29,721 SGTF infections were identified. The proportion of SGTF infections increased from 3% in early October (week 39) to 98% in early December (week 48). On multivariable analysis, after controlling for factors associated with hospitalisation, individuals with SGTF infection had lower odds of being admitted to hospital compared to non-SGTF infections (adjusted odds ratio (aOR) 0.2, 95% confidence interval (CI) 0.1-0.3). Among hospitalised individuals, after controlling for factors associated with severe disease, the odds of severe disease did not differ between SGTF-infected individuals compared to non-SGTF individuals diagnosed during the same time period (aOR 0.7, 95% CI 0.3-1.4). Compared to earlier Delta infections, after controlling for factors associated with severe disease, SGTF-infected individuals had a lower odds of severe disease (aOR 0.3, 95% CI 0.2-0.5).

Conclusion

Early analyses suggest a reduced risk of hospitalisation among SGTF-infected individuals when compared to non-SGTF infected individuals in the same time period. Once hospitalised, risk of severe disease was similar for SGTF- and non-SGTF infected individuals, while SGTF-infected individuals had a reduced risk of severe disease when compared to earlier Delta-infected individuals. Some of this reducton is likely a result of high population immunity.
Breakthrough Covid-19 infections during periods of circulating Beta, Delta and Omicron variants of concern, among health care workers in the Sisonke Ad26.COV2.S vaccine trial, South Africa
Authors: Goga Ameena , Bekker Linda-Gail , Garrett Nigel , Reddy Tarylee , Yende-Zuma Nonhlanhla , Fairall Lara , Moultrie Harry , Takalani Azwidihwi , Trivella Valentina , Faesen Mark , Bailey Veronique , Seocharan Ishen , Gray Glenda E
Published: December 2021

Background

We report breakthrough infections (BTIs) during periods of circulating Beta, Delta and Omicron variants of concern, among health care workers (HCW) participating in the Sisonke phase 3B Ad26.COV2.S vaccine trial (ClinicalTrials.gov number, NCT04838795). Data were gathered between 17 February and 15 December 2021. Duration of each period in this study was 89 days for Beta, 180 days or Delta and 30 days for Omicron.

Results

A total of 40 538 BTIs were observed, with 609 during Beta, 22 279 during Delta and 17 650 during Omicron. By 15 December, daily infections during Omicron were three times that seen during the peak observed during Delta. However, unlike the Delta period, with Omicron there was a clear and early de-coupling of hospitalisation from cases as a percentage of the Delta peak curves. Omicron significantly infected a greater proportion of HCW in the 18-30 year age-group, compared with the 55+ age group. There were 1 914 BTI-related hospitalisations - 77, 1 429 and 408 in the Beta (89 days), Delta (180 days) and Omicron (30 days) periods, respectively. During Omicron, 91% hospitalized HCWs required general ward care, 6% high care and 3% intensive care, compared with 89% general ward care, 4% high care and 7% intensive care, during Delta and 78% general care, 7% high care and 16% intensive care during Beta (p<0.001). During Beta and Beta 43% of hospitalized HCW needed supplementary oxygen and 7-8% needed ventilation, compared with 16% and 0.2% respectively during the Omicron period (p<0.001). Median length of hospitalization was significantly lower with Omicron compared with Beta and Delta (3 days compared with 5-6 days, p<0.001).

Conclusions

We illustrate more BTIs but reassuringly less severe Covid-19 with Omicron. Re-infections and Omicron-driven primary infections were likely driven by high population SARS-CoV-2 seroprevalence, waning vaccine effectiveness over time, increased Omicron infectivity, Omicron immune evasion or a combination of these and need further investigation. Follow-up of this cohort will continue and reports will be updated, as time and infections accrue.
OMA1 mediates local and global stress responses against protein misfolding in CHCHD10 mitochondrial myopathy
Authors: Shammas Mario K. , Huang Xiaoping , Wu Beverly P. , Song Insung , Randolph Nicholas , Li Yan , Bleck Christopher K. E. , Springer Danielle A. , Fratter Carl , Barbosa Ines A. , Powers Andrew F. , Quirós Pedro M. , Lopez-Otin Carlos , Poulton Joanna , Narendra Derek P.
Published: December 2021

Mitochondrial stress triggers a response in the cell’s mitochondria and nucleus, but how these stress responses are coordinated in vivo is poorly understood. Here, we characterize a family with myopathy caused by a dominant p.G58R mutation in the mitochondrial protein CHCHD10. To understand the disease etiology, we developed a novel knock-in mouse model and found that mutant CHCHD10 aggregates in affected tissues, applying a toxic protein stress to the inner mitochondrial membrane. Unexpectedly, survival of CHCHD10 knock-in mice depended on a protective stress response mediated by OMA1. The OMA1 stress response acted both locally within mitochondria, inhibiting mitochondrial fusion, and signaled outside the mitochondria, activating the integrated stress response. We additionally identified an isoform switch in the terminal complex of the electron transport chain as a novel component of this response. Our results demonstrate that OMA1 is essential for neonatal survival conditionally in the setting of inner mitochondrial membrane stress, coordinating local and global stress responses to reshape the mitochondrial network and proteome.

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