bluuebunny/crossref_metadata_2025 huggingface dataset:
Combinatorial treatment of sophoraflavanone G and rhein with ampicillin, oxacillin, or oxytetracycline synergistically increased antibacterial activity against oral bacteria
Authors: Kim Daseul , Kim Ki-young
Published: June 2021

Various antibacterial agents have been developed to prevent dental diseases but many oral bacteria have been come out with resistance. In this study, antibacterial activities of sophoraflavanone G and rhein were investigated against oral bacteria using the microdilution assay, the checkerboard assay, the growth curve assay, and the disc diffusion assay. Minimum inhibitory concentration(MIC) values of sophoraflavanone G were 1.56 μg/ml against Streptococcus mutans and Fusobacterium nucleatum, 3.125 μg/ml against Streptococcus sobrinus and Actinomyces viscosus, and more than 100 μg/ml against Porphyromonas gingivalis after 24 h treatment, respectively. MIC values of rhein were 100 μg/ml against Strep. mutans and Strep. sobrinus, and 25 μg/ml against A. viscosus, F. nucleatum and Porphyromonas gingivalis after 24 h treatment, respectively. As both of the compounds showed antibacterial activity, combined treatment was accomplished to know synergistic activity between sophoraflavanone G and rhein, and with commercially available antibacterial agents, such as ampicillin, oxacillin, and oxytetracycline. Sophoraflavanone G with rhein showed synergistic antibacterial activity [fractional inhibitory concentration index (FICI) < 0.5] against all tested oral bacteria. Sophoraflavanone G with antibiotics usually showed additive antibacterial activity (0.5 < FICI < 1.0) but interestingly sophoraflavanone G showed strong synergistic activity with ampicillin, which showed resistance against all tested strains, and with oxacillin, which showed resistance against Strep. mutans, and Strep. sobrinus. Even though rhein possessed low antibacterial activity, it showed synergistic activity with ampicillin and oxacillin against drug-resistant strain. These results suggest that sophoraflavanone G and rhein combined with other antibacterial agents may be beneficial and provide the better option to treat the oral bacteria.
Normative Data for Nonstrabismic Binocular Vision Parameters in African Schoolchildren
Authors: Darko-Takyi Charles , Moodley Vanessa R. , Boadi-Kusi Samuel B.
Published: June 2021

SIGNIFICANCE

With reported population differences in parameters of nonstrabismic binocular vision, the present study investigated and reports normative data among a sample of African children.

PURPOSE

This study aimed to determine expected binocular visual function data among schoolchildren in the Central Region of Ghana.

METHODS

The study used a prospective cross-sectional design and used a multistage cluster sampling approach. Eligible normal participants selected through the administration of Convergence Insufficiency Symptom Survey questionnaire (score <16) and preliminary vision screening underwent comprehensive binocular vision testing. Only data for participants who expressed no difficulty with the specific procedures were analyzed.

RESULTS

A total of 1261 normal participants (11 to 17 years [mean, 14.75 ± 1.530 years]) were selected for comprehensive binocular vision testing in the normative data study. The means with ±1 standard deviation for normative data for the nonstrabismic binocular vision parameters include the following: accommodative target near point of convergence (NPC) break (6.10 ± 1.67 cm), NPC recovery (8.17 ± 1.67 cm), fixation light with red-green anaglyph (RG NPC) break (8.51 ± 2.43 cm), RG NPC recovery (10.95 ± 2.60 cm), cover test distance phoria (0.12 ± 0.79 exophoria), cover test near phoria (2.1 ± 2.3 exophoria), modified Thorington test near phoria (1.9 ± 2.5 exophoria), negative relative accommodation (+2.54 ± 0.75 D), positive relative accommodation (−2.58 ± 0.81 D), and the accommodative convergence over accommodation ratio (2.80 ± 1.07:1). Age (in years)-predicted normal linear regression equations for NPC break (5.13 + 0.07 × age), RG NPC break (10.00 − 0.10 × age), RG NPC recovery (12.83 − 0.13 × age), positive relative accommodation (2.05 + 0.04 × age), and the gradient accommodative convergence over accommodation ratio (3.97 − 0.08 × age) serve as a guide.

CONCLUSIONS

The study provides expected data that optometrists may use with similar aged Black African populations.
Clinical Features, Molecular Alterations and Prognosis of Colorectal Adenocarcinoma With Mucinous Component in Chinese Patients
Authors: Jia Xiaoli , Li Bin , Wang Hui , Yan Zhe
Published: June 2021

Mucinous adenocarcinoma (MAC) is conventionally diagnosed by WHO definition when the extracellular mucin is >50% of the tumor area, while tumors with <50% mucin are designated as having a mucinous component. The study is aimed at analyzing the clinicopathologic characteristics, mutation spectrum, and prognosis of colorectal adenocarcinoma with mucinous component (CAWMC). Mutation analyses for exon 2 to 4 of KRAS gene and exon 15 of BRAF gene were performed by Sanger sequencing. Expression of DNA mismatch repairs and P53 proteins were evaluated by immunohistochemistry. Density of tumor-infiltrating lymphocyte (TIL) status was scored. We also evaluated the percentage of glands producing mucin and the morphology of the different tumor cell types in mucin pools. We retrospectively analyzed the prognosis of 43 patients with stage II/III. The overall frequencies of KRAS and BRAF mutations were 36% and 8%, respectively. Patients with MAC exhibiting high levels of mucin were related to the increase of tumor diameter (P=0.038) but were not associated with any of the other clinicopathologic parameters. The proportion or variable morphology of mucinous component did not stratify progression-free survival in stage II/III cases. TIL was the most significant predictor of progression-free survival among stage II/III CAWMC. It is interesting to note that signet ring cell carcinoma does not portend a worse prognosis for patients with high TIL levels. Combining use the grade of TIL status with the WHO grade of the entire tumor can help identify patients with a high risk of recurrence more accurately.
Community Assessment for Public Health Emergency Response (CASPER) Following Hurricane Michael, Bay and Gulf Counties, Florida, 2019
Authors: Rodriguez Edda , Duclos Chris , Joiner Jessica , Jordan Melissa , Reid Keshia , Kintziger Kristina W
Published: June 2021

Context:

On October 10, 2018, Hurricane Michael made landfall near Mexico Beach, Florida, as one of the strongest storms on record to hit the US mainland. Hurricane Michael brought strong winds, heavy rain, and life-threatening storm surge, causing extensive damage across the Florida Panhandle.

Objectives:

To assess community preparedness and effects experienced by Panhandle residents, including structural and economic losses, injury and illness, health care access, and suicide risk and ideation in the counties most severely impacted by Hurricane Michael.

Design:

The Florida Department of Health conducted a Community Assessment for Public Health Emergency Response (CASPER) in October and November 2019, a year after Hurricane Michael made landfall. CASPER is a 2-stage cluster sampling method designed to provide household-level information about a community's needs in a timely, inexpensive, and representative manner.

Setting:

A total of 30 clusters were randomly selected from Bay and Gulf Counties, Florida.

Participants:

In total, 178 face-to-face interviews were completed with adult residents 18 years or older.

Main Outcome Measures:

Hurricane-related impacts, including structural and economic losses, injury and illness, health care access; and mental health.

Results:

Almost half of respondents did not evacuate despite mandatory evacuation orders. Most houses (78.1%) received some damage, with more than half still not repaired 1 year later. Access to emergency supply kits, water, nonperishable foods, medications, and health care was common, though many reported needing supplies not included in their kit. Less than half reported having working household carbon monoxide detectors. Injuries and illnesses associated with the hurricane were uncommon; however, anxiety, depression, and insomnia were reported as occurring or worsening by more than one-third of respondents posthurricane.

Conclusions:

Increased education and communication regarding hurricane preparedness and recovery, which include clearer messaging on evacuation, improving emergency supply kits, importance of carbon monoxide detectors, and proper generator use, could enhance the safety of the community.
Everyday Discrimination and Mental Stress–Induced Myocardial Ischemia
Authors: McKinnon Izraelle I. , Shah Amit J. , Lima Bruno , Moazzami Kasra , Young An , Sullivan Samaah , Almuwaqqat Zakaria , Garcia Mariana , Elon Lisa , Bremner J. Douglas , Raggi Paolo , Quyyumi Arshed A. , Vaccarino Viola , Lewis Tené T.
Published: June 2021

Objective

Mental stress–induced myocardial ischemia (MSIMI), a transient myocardial ischemic response to mental stress, is associated with poorer outcomes among patients with coronary heart disease and is more likely to occur among women. However, predictors of MSIMI are not well explored. The current study investigated the association between experiences of everyday discrimination and MSIMI among patients with recent myocardial ischemia and contrasted the results with conventional stress–induced myocardial ischemia (CSIMI). We examined sex differences in associations.

Methods

We studied 295 post-MI patients (145 women, 150 men). Provocation of myocardial ischemia with mental stress (speech task) and conventional stress (exercise or pharmacologic) was assessed by myocardial perfusion imaging. Frequency of exposure to everyday discrimination was assessed via questionnaire using the Everyday Discrimination Scale (EDS).

Results

The mean age was 51 years in both women and men, and the EDS score ranged from 10 to 38 (mean [standard deviation] = 17 [6] years). After multivariable analysis, each standard deviation increase in the EDS score (more frequent exposure) was associated with an increased odds of MSIMI (odds ratio [OR] = 1.57 [1.10–2.23]). The EDS score was not associated with CSIMI (OR = 0.86 [0.64–1.17]). Women demonstrated a twofold increase (OR = 1.96 [1.13–3.38], p = .02) in the adjusted odds of MSIMI, with each standard deviation increase in the EDS score compared with a 1.4-fold increase (OR = 1.40 [0.80–2.44], p = .24) among men; however, interaction was not statistically significant.

Conclusions

Among post-MI patients, everyday discrimination was positively associated with occurrence of MSIMI, but not with CSIMI; associations were more pronounced among women.
The impact of COVID-19 infection on outcomes after injury in a state trauma system
Authors: Kaufman Elinore J. , Ong Adrian W. , Cipolle Mark D. , Whitehorn Gregory , Ratnasekera Asanthi , Stawicki Stanislaw P. , Martin Niels D.
Published: June 2021

BACKGROUND

The COVID-19 pandemic reshaped the health care system in 2020. COVID-19 infection has been associated with poor outcomes after orthopedic surgery and elective, general surgery, but the impact of COVID-19 on outcomes after trauma is unknown.

METHODS

We conducted a retrospective cohort study of patients admitted to Pennsylvania trauma centers from March 21 to July 31, 2020. The exposure of interest was COVID-19 (COV+) and the primary outcome was inpatient mortality. Secondary outcomes were length of stay and complications. We compared demographic and injury characteristics between positive, negative, and not-tested patients. We used multivariable regression with coarsened exact matching to estimate the impact of COV+ on outcomes.

RESULTS

Of 15,550 included patients, 8,170 (52.5%) were tested for COVID-19 and 219 (2.7%) were positive (COV+). Compared with COVID-19–negative (COV−) patients, COV+ patients were similar in terms of age and sex, but were less often white (53.5% vs. 74.7%, p < 0.0001), and more often uninsured (10.1 vs. 5.6%, p = 0.002). Injury severity was similar, but firearm injuries accounted for 11.9% of COV+ patients versus 5.1% of COV− patients (p < 0.001). Unadjusted mortality for COV+ was double that of COV− patients (9.1% vs. 4.7%, p < 0.0001) and length of stay was longer (median, 5 vs. 4 days; p < 0.001). Using coarsened exact matching, COV+ patients had an increased risk of death (odds ratio [OR], 6.05; 95% confidence interval [CI], 2.29–15.99), any complication (OR, 1.85; 95% CI, 1.08–3.16), and pulmonary complications (OR, 5.79; 95% CI, 2.02–16.54) compared with COV− patients.

CONCLUSION

Patients with concomitant traumatic injury and COVID-19 infection have elevated risks of morbidity and mortality. Trauma centers must incorporate an understanding of these risks into patient and family counseling and resource allocation during this pandemic.

LEVEL OF EVIDENCE

Level II, Prognostic Study.
Rapid and sustained decline in CXCL-10 (IP-10) annotates clinical outcomes following TNF-α antagonist therapy in hospitalized patients with severe and critical COVID-19 respiratory failure
Authors: Hachem Hilal , Godara Amandeep , Schroeder Courtney , Fein Daniel , Mann Hashim , Lawlor Christian , Marshall Jill , Klein Andreas , Poutsiaka Debra , Breeze Janis L. , Joshi Raghav , Mathew Paul
Published: June 2021

Background

A feed-forward pathological signaling loop generated by TNFα and IFN-γ in inflamed lung tissue, driving CXCL-10 (IP-10) and CXCL-9 chemokine-mediated activated T-cell and monocyte/macrophage tissue recruitment, may define, sustain and amplify the inflammatory biology of lethal COVID-19 respiratory failure.

Methods

To assess TNFα-antagonist therapy, 18 hospitalized adults with hypoxic respiratory failure and COVID-19 pneumonia received single-dose infliximab-abda therapy 5mg/kg intravenously between April and December 2020. The primary endpoint was time to increase in oxygen saturation to fraction of inspired oxygen ratio (SpO2/FiO2) by ≥ 50 compared to baseline and sustained for 48 hours. Secondary endpoints included 28-day mortality, dynamic cytokine profiles (Human Cytokine 48-Plex Discovery Assay, Eve Technologies), secondary infections, duration of supplemental oxygen support and hospitalization.

Findings

Patients were predominantly in critical respiratory failure (15/18, 83%), male (14/18, 78%), above 60 years (median 63 yrs, range 31-80), race-ethnic minorities (13/18, 72%), lymphopenic (13/18, 72%), steroid-treated (17/18, 94%), with a median ferritin of 1953ng/ml. Sixteen patients (89%) met the primary endpoint within a median of 4 days, 15/18 (83%) recovered from respiratory failure, and 14/18 (78%) were discharged in a median of 8 days and were alive at 28-day follow-up. Deaths among three patients ≥ 65yrs age with pre-existing lung disease or multiple comorbidities were attributed to secondary lung infection. Mean plasma IP-10 levels declined sharply from 9183 pg/ml to 483 pg/ml at Day 3 and further to 146 pg/ml at Day 14/discharge. Significant declines in IFN-γ, TNFα, IL-27, CRP and ferritin were specifically observed at Day 3 whereas other cytokines were unmodified. IL-6 levels declined sharply among patients with baseline levels >10 pg/ml. Among 13 lymphopenic patients, six (46%) had resolution of lymphopenia by day 3, and 11 by day 14. CXCR3-ligand (IP-10 and CXCL-9) declines were strongly correlated among patients with lymphopenia reversal (Day 3, Pearson r: 0.98, p-value: 0.0006).

Interpretation

Consistent with a pathophysiological role of TNFα, the clinical and cytokine data indicate that infliximab-abda may rapidly abrogate pathological inflammatory signaling to facilitate clinical recovery in severe and critical COVID-19. Randomized studies are required to formally assess mortality outcomes. Funding: National Center for Advancing Translational Sciences
Job stress and loneliness among remote workers
Authors: Miyake Fuyu , Odgerel Chimed-Ochir , Hino Ayako , Ikegami Kazunori , Nagata Tomohisa , Tateishi Seiichiro , Tsuji Mayumi , Matsuda Shinya , Ishimaru Tomohiro
Published: June 2021

Background

To prevent the spread of coronavirus disease 2019 (COVID-19), physical distancing and isolation are crucial strategies in society. However, this response to the pandemic promotes loneliness. Previous studies have reported an increase in loneliness since the outbreak of COVID-19, but there is little evidence on the relationship between job stress and loneliness among remote workers.

Aims

To assess the relationship between job stress and loneliness among remote workers.

Methods

This study is a part of nation-wide cross-sectional online survey evaluating the impact of the COVID-19 pandemic in Japan. A total of 27,036 full-time workers completed the self-administrated questionnaire in December 2020. We extracted data on 4,052 desk workers who indicated that they were doing remote work. Loneliness was assessed using a single question and job stress was measured using the Job Content Questionnaire. Multiple logistic regression was performed.

Results

Frequency of remote work was moderately associated with loneliness (adjusted odds ratio [AOR] = 1.60, 95% confidence interval [CI]: 1.04–2.46, P = 0.033). Participants who reported of having a low level of co-worker or supervisor support had greater odds of feeling lonely than those who were highly supported (co-worker support: AOR = 4.06, 95% CI: 2.82–5.84, P <0.001; supervisor support: AOR = 2.49, 95% CI: 1.79–3.47, P <0.001).

Conclusions

Co-worker support and supervisor support were strongly associated with loneliness, whereas frequency of remote work was moderately associated with feeling lonely. Support from co-workers and supervisors may be crucial factors to prevent loneliness caused by remote work.
Head, facial and neck cooling as per-cooling modalities to improve exercise performance in the heat: A narrative review and practical applications
Authors: Cao Yinhang , Lei Tze-Huan , Wang Faming , Yang Bin
Published: June 2021

It has been well established that athletic performance is greatly affected by environmental heat. Numerous studies have attempted to find reliable cooling strategies to improve athletic performance while exercising in the heat. Whole-body pre-cooling has been found to enhance endurance performance in both dry and humid heat. Nevertheless, positive physiological alternations induced by pre-cooling gradually disappear during exercise. Hence, there is a great need to find effective per-cooling strategies to improve athletic performance in the heat. Unfortunately, it’s impractical to adopt pre-cooling approaches as a per-cooling modality to improve athletic performance due to inherent issues of practicality. Thus, a narrative review was conducted to examine the impact of head, neck and facial cooling on athletic performance in the heat. Based on current evidences, head, neck and facial cooling could greatly decrease local skin temperature at those areas where cooling was applied and thereby, local perceptual sensations were greatly enhanced. Neck cooling during exercise is found effective to improve athletic performance for both endurance and team sports athletes in the heat. Besides, neck cooling is preferred over the head, facial & combined head/facial & neck cooling for both endurance and team sport athletes in the heat from a practical application viewpoint. Research is lacking on the systematically selection of per-cooling modalities to improve athletic performance based on environmental conditions and nature of the sports activity. In addition, powerful but portable head, neck and facial cooling systems are urgently required to help athletes improving performance in the heat.

Key points

Neck cooling during exercise is effective to enhance endurance performance for endurance athletes in the heat.

Neck cooling during exercise could improve repeated sprint performance for team sport athletes in the heat.

Head, neck & facial cooling could largely reduce local skin temperature and thereby improving local perceptual responses.

Neck cooling is preferred over the head, facial & combined head/facial & neck cooling for both endurance and team sport athletes.

It’s challenging to adopt facial or head cooling to cool athletes during exercise due to inherent issues of practicality.
Impaired Humoral Immunity to SARS-CoV-2 Vaccination in Non-Hodgkin Lymphoma and CLL Patients
Authors: Diefenbach Catherine , Caro Jessica , Koide Akiko , Grossbard Michael , Goldberg Judith D. , Raphael Bruce , Hymes Kenneth , Moskovits Tibor , Kreditor Maxim , Kaminetzky David , Fleur-Lominy Shella Saint , Choi Jun , Thannickal Sara A. , Stapleford Kenneth A. , Koide Shohei
Published: June 2021

Patients with hematologic malignancies are a high priority for SARS-CoV-2 vaccination, yet the benefit they will derive is uncertain. We investigated the humoral response to vaccination in 53 non-Hodgkin lymphoma (NHL), Hodgkin lymphoma (HL), or CLL patients. Peripheral blood was obtained 2 weeks after first vaccination and 6 weeks after second vaccination for antibody profiling using the multiplex bead-binding assay. Serum IgG, IgA, and IgM antibody levels to the spike specific receptor binding domain (RBD) were evaluated as a measure of response. Subsequently, antibody-positive serum were assayed for neutralization capacity against authentic SARS-CoV-2. Histology was 68% lymphoma and 32% CLL; groups were: patients receiving anti-CD20-based therapy (45%), monitored with disease (28%), receiving BTK inhibitors (19%), or chemotherapy (all HL) (8%). SARS-CoV-2 specific RBD IgG antibody response was decreased across all NHL and CLL groups: 25%, 73%, and 40%, respectively. Antibody IgG titers were significantly reduced (p < 0.001) for CD20 treated and targeted therapy patients, and (p = 0.003) for monitored patients. In 94% of patients evaluated after first and second vaccination, antibody titers did not significantly boost after second vaccination. Only 13% of CD20 treated and 13% of monitored patients generated neutralizing antibodies to SARS-CoV-2 with ICD50s 135 to 1767, and 445 and > 10240. This data has profound implications given the current guidance relaxing masking restrictions and for timing of vaccinations. Unless immunity is confirmed with laboratory testing, these patients should continue to mask, socially distance, and to avoid close contact with non-vaccinated individuals.

Statement of Translational Relevance

Non Hodgkin lymphoma (NHL) and Chronic Lymphocytic leukemia (CLL) patients who are treated with anti-CD20 antibody therapy, BTK inhibitor therapy, or who are monitored with active disease, have decreased antibody response to SARS-CoV-2 vaccination and decreased antibody titers compared to healthy controls. Antibody titers do not boost following second vaccination, and very few patients generate neutralizing antibodies against SARS-CoV-2. This data is of particular importance, given the recent guidance from the CDC that vaccinated patients no longer need to be masked indoors as well as outdoors. Patients with NHL or CLL who fall into these categories should not consider their immunity from vaccination to be assured. If infected with SARS-CoV-2, they should be a high priority for monoclonal antibody directed therapy. Unless immune response to vaccination is confirmed with laboratory testing, they should continue to mask, socially distance, and to avoid close contact with non-vaccinated individuals.
Vitamin D receptor polymorphisms in overweight/obese chronic kidney disease patients undergoing hemodialysis
Authors: Bagci Gokhan , Huzmeli Can , Candan Ferhan
Published: June 2021

Background

Many studies were carried out to investigate the relationship between single nucleotide polymorphisms (SNPs) in vitamin D receptor (VDR) gene with obesity. However, little is known about the role of VDR gene polymorphism with obesity in hemodialysis (HD) patients. Therefore, we aimed to investigate VDR gene TaqI, ApaI and FokI SNPs in overweight/obese HD patients.

Methods

Seventy one normal weight and 68 overweight/obese HD patients were included in study. PCR-RFLP method was used for genotyping. Demographic and laboratory data obtained from medical records of patients.

Results

For all three SNPs, no significant association was found between normal and overweight/obese patients (P>0.05). Lower HDL concentrations and higher levels of triglyceride (TG) and glucose were detected in the obese/overweight patients compared to normal weight (p<0.001 for HDL, and TG and p=0.023 for glucose). In obese/overweight patients, subjects with CC genotype of TaqI showed higher PTH level (717.1±616.4 pg/ml) than those TC genotype (342.7±360.8 pg/ml) and TT genotype (310.2±323.4 pg/ml) (p=0.028); higher TG level was found in patients with CC genotype of ApaI (627.3±653.0 mg/dl) compared to AA (223.3±156.6) and AC genotypes (193.1±85.4) (p<0.001). Obese/overweight patients carrying FokI TT genotype had higher glucose concentration compared to those carrying CC and CT genotypes (CC=183.4±128.4 mg/dl; TT=151.9±66.1 mg/dl; CT=107.6±41.9 mg/dl, p=0.008).

Conclusions

Our study suggest that VDR TaqI, ApaI and FokI polymorphisms are not associated with obesity in HD patients. However, they might be increase the risk of secondary hyperparathyroidism, dyslipidemia, and hyperglycemia, which are among the most common obesity related comorbidities of chronic kidney disease.
Efficacy of ancestral receptor-binding domain, S1 and trimeric spike protein vaccines against SARS-CoV-2 variants B.1.1.7, B.1.351, and B.1.617.1
Authors: Yang Yong , Zang Jinkai , Xu Shiqi , Zhang Xueyang , Yuan Sule , Lavillette Dimitri , Zhang Chao , Huang Zhong
Published: June 2021

The ongoing coronavirus disease 2019 (COVID-19) pandemic is caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). The current SARS-CoV-2 vaccines are based on spike (S) protein, S1 subunit, or receptor-binding domain (RBD) of prototype strain. Emergence of several novel SARS-CoV-2 variants has raised concern about potential immune escape. In this study, we performed an immunogenicity comparison of ancestral RBD, S1, and S ectodomain trimer (S-trimer) antigens and tested the efficacy of these prototype vaccines against the circulating variants, especially B.1.617 that has been linked to India’s current COVID-19 surge. We found that RBD and S-trimer proteins could induce significantly higher neutralizing antibody titers than S1 protein. For the three vaccines, the neutralizing titers decreased over time, but still remained high for at least five months after immunization. Importantly, the three prototype vaccines were still effective in neutralizing the variants of concern, although B.1.351 and B.1.617.1 lineages showed varying degrees of reduction in neutralization by the immune sera. The vaccines-induced sera were shown to block receptor binding and inhibit S protein-mediated membrane fusion. In addition, the immune sera did not promote antibody-dependent enhancement (ADE) in vitro. Our work provides valuable information for development of SARS-CoV-2 subunit vaccines and also supports the continued use of ancestral RBD or S-based vaccines to fight the COVID-19 epidemic.
Cardiac and respiratory muscle responses to dietary N-acetylcysteine in rats consuming a high-saturated fat, high-sucrose diet
Authors: Kelley Rachel C. , Muscato Derek R. , Hahn Dongwoo , Christou Demetra D. , Ferreira Leonardo F.
Published: June 2021

BACKGROUND

Exertional dyspnea is a significant clinical concern in individuals with overweight or obesity. The pathophysiology of dyspnea is multifactorial and complex. Previous data suggest that diaphragm and cardiac abnormalities should be considered as likely contributors to obesity-related exertional dyspnea. Additionally, oxidative stress is a causative factor in the general etiology of obesity as well as skeletal and cardiac muscle pathology. Thus, this preclinical study aimed to define diaphragm and cardiac morphological and functional alterations following an obesogenic diet in rats and the therapeutic potential of an antioxidant supplement, N-acetylcysteine (NAC).

METHODS

Male Wistar rats (∼7 weeks old) consumed ad libitum either lean (20% protein, 70% carbohydrate, 10% fat) or high-saturated fat, high-sucrose (HFHS, 20% protein, 35% carbohydrate, 45% fat) diets for ∼22 weeks. Rats receiving HFHS diet were randomized to drink control water or water with NAC (2 mg/ml) for the last eight weeks of the dietary intervention: Lean, HFHS, and HFHS+NAC (n = 8 per group). We evaluated diaphragm bundles (in vitro function and histology) and hearts (weights and echocardiography) for all groups.

RESULTS

Final body weights of HFHS rats, but not HFHS+NAC rats, were significantly higher than Lean controls. Neither HFHS diet nor NAC supplementation affected diaphragm specific force (N/cm2), peak power (W/kg), or morphology. In cardiac muscle, right and left ventricle weights (normalized to tibia length) of HFHS rats were greater than those of Lean controls and HFHS+NAC rats. Cardiac functional abnormalities were also present in HFHS rats, with left ventricular fractional shortening (%) and posterior wall maximal shortening velocity (cm/s) increasing compared to Lean controls, but HFHS+NAC rats did not demonstrate these markers of hypercontractility. HFHS rats showed an elevated deceleration rate of early transmitral diastolic velocity (E/DT) consistent with diastolic dysfunction, but NAC eliminated this effect.

CONCLUSION

Our data suggest that an HFHS diet does not compromise diaphragm muscle morphology or in vitro function, suggesting other possible contributors to breathing abnormalities in obesity (e.g., neuromuscular transmission abnormalities). However, an HFHS diet resulted in cardiac hypertrophy, hypercontractility, and diastolic dysfunction. Supplementation with NAC did not affect diaphragm morphology or function but attenuated cardiac abnormalities in the HFHS diet. Our findings support future studies testing NAC supplementation in clinical trials of humans with obesity.
High activity and high functional connectivity are mutually exclusive in resting state zebrafish and human brains
Authors: Zarei Mahdi , Xie Dan , Jiang Fei , Abigrove Adil , Huang Bo , Raj Ashish , Nagarajan Srikantan , Guo Su
Published: June 2021

Active neurons impact cell types with which they are functionally connected. Both activity and functional connectivity are heterogeneous across the brain, but the nature of their relationship is not known. Here we employ brain-wide calcium imaging at cellular resolution in larval zebrafish to record spontaneous activity of >12,000 neurons in the forebrain. By classifying their activity and functional connectivity into three levels (high, medium, low), we find that highly active neurons have low functional connections and highly connected neurons are of low activity. Intriguingly, deploying the same analytical methods on functional magnetic resonance imaging (fMRI) data from the resting state human brain, we uncover a similar relationship between activity and functional connectivity, that is, regions of high activity are non-overlapping with those of high connectivity. These findings reveal a previously unknown and evolutionarily conserved brain organizational principle that have implications for understanding disease states and designing artificial neuronal networks.
The VIL gene CRAWLING ELEPHANT controls maturation and differentiation in tomato via polycomb silencing
Authors: Shwartz Ido , Yahav Chen , Kovetz Neta , Israeli Alon , Bar Maya , Levy Matan , Duval Katherine L. , Jiménez-Gómez José M. , Deal Roger B. , Ori Naomi
Published: June 2021

VERNALIZATION INSENSITIVE 3-LIKE (VIL) proteins are PHD-finger proteins that recruit the repressor complex Polycomb Repressive Complex 2 (PRC2) to the promoters of target genes. Most known VIL targets are flowering repressor genes. Here, we show that the tomato VIL gene CRAWLING ELEPHANT (CREL) promotes differentiation throughout plant development by facilitating the trimethylation of Histone H3 on lysine 27 (H3K27me3). We identified the crel mutant in a screen for suppressors of the simple-leaf phenotype of entire (e), a mutant in the AUX/IAA gene ENTIRE/SlIAA9, involved in compound-leaf development in tomato. crel mutants have increased leaf complexity, and suppress the ectopic blade growth of e mutants. In addition, crel mutants are late flowering, and have delayed and aberrant stem, root and flower development. Consistent with a role for CREL in recruiting PRC2, crel mutants present altered H3K27me3 modifications at a subset of PRC2 targets throughout the genome. Our results uncover a wide role for CREL in plant and organ differentiation in tomato and suggest that CREL is required for targeting PRC2 activity to, and thus silencing, a specific subset of polycomb targets.

Author summary

Plants form organs continuously throughout their lives, and the number and shape of their organs is determined in a flexible manner according to the internal and external circumstances. Alongside this flexibility, plants maintain basic developmental programs to ensure proper functioning. Among the ways by which plants achieve flexible development is by tuning the pace of their maturation and differentiation, at both the plant and organ levels. One of the ways plants regulate the rate of maturation and differentiation is by changing gene expression. Here, we identified a gene that promotes plant and organ maturation and differentiation. This gene, CRAWLING ELEPHANT (CREL) acts by bringing a repressing complex to target genes. We show the importance of CREL in multiple developmental processes and in the expression of multiple genes throughout the tomato genome.
Brain mitochondrial diversity and network organization predict anxiety-like behavior in mice
Authors: Rosenberg Ayelet M , Saggar Manish , Monzel Anna S , Devine Jack , Rogu Peter , Limoges Aaron , Junker Alex , Sandi Carmen , Mosharov Eugene V , Dumitriu Dani , Anacker Christoph , Picard Martin
Published: June 2021

The brain and behavior are under energetic constraints, limited by mitochondrial energy transformation capacity. However, the mitochondria-behavior relationship has not been systematically studied on a brain-wide scale. Here we examined the association between multiple features of mitochondrial respiratory chain capacity and stress-related behaviors in mice with diverse behavioral phenotypes. Miniaturized assays of mitochondrial respiratory chain enzyme activities and mitochondrial DNA (mtDNA) content were deployed on 571 samples across 17 brain areas, defining specific patterns of mito-behavior associations. By applying multi-slice network analysis to our brain-wide mitochondrial dataset, we identified three large-scale networks of brain areas with shared mitochondrial signatures. A major network composed of cortico-striatal areas exhibited the strongest mitochondria-behavior correlations, accounting for up to 50% of animal-to-animal behavioral differences, suggesting that this mito-based network is functionally significant. The mito-based brain networks also overlapped with regional gene expression and structural connectivity and quantitatively diverged in their molecular mitochondrial phenotype signatures. Therefore, this work provides convergent multimodal evidence anchored in enzyme activities, gene expression, and animal behavior that distinct, behaviorally-relevant mitochondrial phenotypes exist across the mouse brain.
In an “ecological-belonging” intervention to reduce inequities in STEM, context matters
Authors: Hammarlund Sarah P. , Scott Cheryl , Binning Kevin R. , Cotner Sehoya
Published: June 2021

Doubts about belonging in the classroom are often shouldered disproportionately by students from historically marginalized groups, which can lead to underperformance. Ecological-belonging interventions use a classroom-based activity to instill norms that adversity is normal, temporary and surmountable. Building on prior studies, we sought to identify the conditions under which such interventions are effective. In a chemistry course (Study 1), students from underrepresented ethnic backgrounds underperformed relative to their peers in the absence of the intervention. This performance gap was eliminated by the intervention. In an introductory biology course (Study 2), there were no large performance gaps in the absence of the intervention, and the intervention had no effect. Study 2 also explored the role of the instructor that delivers the intervention. The intervention boosted scores in classrooms of instructors with a fixed (versus growth-oriented) intelligence mindset. Our results suggest that ecological-belonging interventions are more effective in more threatening classroom contexts.
GlyConnect: a glycan-based conjugation extension of the GlycoDelete technology
Authors: Van Breedam Wander , Thooft Karel , Santens Francis , Vanmarcke Sandrine , Wyseure Elise , Laukens Bram , Van Moer Berre , Nerinckx Wim , Devos Simon , Madder Annemieke , Callewaert Nico
Published: June 2021

Recently, our lab developed GlycoDelete, a technology suite that allows a radical simplification of eukaryotic N-glycosylation. The technology allows to produce glycoproteins that carry single GlcNAc, LacNAc, or LacNAc-Sia type glycans on their N-linked glycosylation sequons. GlycoDelete-type N-glycans are uniquely suited for glycan-based conjugation purposes, as these provide a short, homogeneous and hydrophilic link to the protein backbone. Targeting GlycoDelete-glycans allows for highly site-specific conjugation at sites in the protein which are normally occupied by bulky glycans, thus ensuring minimal interference with protein structure and function. The current manuscript describes the evaluation and optimization of both chemical and chemo-enzymatic conjugation of molecules onto the GlycoDelete-type glycans of a limited set of benchmark proteins.
Characterization of the interaction domains between the phosphoprotein and the nucleocapsid of human Metapneumovirus
Authors: Decool Hortense , Bardiaux Benjamin , Ruano Luis Checa , Sperandio Olivier , Fix Jenna , Gutsche Irina , Richard Charles-Adrien , Bajorek Monika , Eléouët Jean-François , Galloux Marie
Published: June 2021

Human metapneumovirus (HMPV) causes severe respiratory diseases in young children. The HMPV RNA genome is encapsidated by the viral nucleoprotein, forming an RNA-N complex (NNuc), which serves as template for genome replication and mRNA transcription by the RNA-dependent RNA polymerase (RdRp). The RdRp is formed by the association of the large polymerase subunit (L), which has RNA polymerase, capping and methyltransferase activities, and the tetrameric phosphoprotein (P). P plays a central role in the RdRp complex by binding to NNuc and L, allowing the attachment of the L polymerase to the nucleocapsid template. During infection these proteins concentrate in cytoplasmic inclusion bodies (IBs) where viral RNA synthesis occurs. By analogy to the closely related pneumovirus respiratory syncytial virus (RSV), it is likely that the formation of IBs depends on the interaction between P and NNuc. However, the HMPV P-NNuc interaction still remains to characterize. Here, we finely characterized the binding domains involved in HMPV P and NNuc interaction by studying binding between recombinant proteins, combined with the use of a functional assay of the polymerase complex activity and the study of the recruitment of these proteins to IBs by immunofluorescence. We show that the last 6 C-terminal residues of HMPV P are necessary and sufficient for binding to NNuc, that P binds the N-terminal domain of N (NNTD), and identified conserved N residues critical for the interaction. Our results allowed to propose a structural model of the HMPV P-NNuc interaction.

IMPORTANCE

Like respiratory syncytial virus (RSV), human metapneumovirus (HMPV) is a leading cause of severe respiratory infections in children but also affects human populations of all ages worldwide. Nowadays, no vaccine or efficient antiviral treatments are available for these two pneumoviruses. A better understanding of the molecular mechanisms involved in viral replication could help the design or discovery of specific antiviral compounds. In this work we have investigated the interaction between two major viral proteins involved in HMPV RNA synthesis, the N and P proteins. We finely characterized their domains of interaction, in particular a pocket on the surface of the N protein that could be used as a template for the design of compounds interfering with N-P complexes and viral replication.
Noisy metabolism can drive the evolution of microbial cross-feeding
Authors: Lopez Jaime G. , Wingreen Ned S.
Published: June 2021

Cross-feeding, the exchange of nutrients between organisms, is ubiquitous in microbial communities. Despite its importance in natural and engineered microbial systems, our understanding of how cross-feeding arises is incomplete, with existing theories limited to specific scenarios. Here, we introduce a novel theory for the evolution of cross-feeding, which we term noise-averaging cooperation (NAC). NAC is based on the idea that, due to their small size, bacteria are prone to noisy regulation of metabolism which limits their growth rate. To compensate, related bacteria can share metabolites with each other to “average out” noise and improve their collective growth. This metabolite sharing among kin then allows for the evolution of metabolic interdependencies via gene deletions (this can be viewed as a generalization of the Black Queen Hypothesis). We first characterize NAC in a simple model of cell metabolism, showing that metabolite leakage can in principle substantially increase growth rate in a community context. Next, we develop a generalized framework for estimating the potential benefits of NAC among real bacteria. Using single-cell protein abundance data, we predict that bacteria suffer from substantial noise-driven growth inefficiencies, and may therefore benefit from NAC. Finally, we review existing evidence for NAC and outline potential experimental approaches to detect NAC in microbial communities.
Predicting localized affinity of RNA binding proteins to transcripts with convolutional neural networks
Authors: Kitaygorodsky Alexander , Jin Emily , Shen Yufeng
Published: June 2021

RNA binding proteins (RBPs) are important regulators of transcriptional and post-transcriptional processes. Computational prediction of localized RBP binding affinity with transcripts is important for interpretation of genetic variation, especially variants outside of protein coding region. Here we describe POLARIS (PredictionOfLocalizedAffinity forRBPsInSequence), a new deep-learning method for achieving fast, site-specific binding affinity predictions of RNA-binding proteins (RBPs) to the transcribed genome. POLARIS has two modules: 1. a convolutional neural network (CNN) to predict overall RBP binding within a region based on transcript sequence content and expression level; 2. a Gradient-weighted Class Activation Mapping (GradCAM) implementation for efficient signal backpropagation to individual sequence positions. We trained the model using enhanced crosslinking and immunoprecipitation (eCLIP) data from ENCODE. POLARIS has good performance with a median AUC ~ 0.96 for 160 RBPs across three different cell lines, substantially higher than selected popular published methods trained and tested on the same data sets. When tested on data from a different cell line with the same RBPs, the overall performance is maintained, supporting the ability of cell-type specific affinity prediction. Finally, the GradCAM module allows the model to identify the informative sites in a region that drive prediction. The localized prediction facilitates interpretation of the results and provides basis for inference of functional impact of noncoding variants.
Optimizing microtubule arrangements for rapid cargo capture
Authors: Mogre Saurabh , Christensen Jenna R. , Reck-Peterson Samara L. , Koslover Elena F.
Published: June 2021

Cellular functions such as autophagy, cell signaling and vesicular trafficking involve the retrograde transport of motor-driven cargo along microtubules. Typically, newly formed cargo engages in slow diffusive movement from its point of origin before attaching to a microtubule. In some cell types, cargo destined for delivery to the perinuclear region relies on capture at dynein-enriched loading zones located near microtubule plus-ends. Such systems include extended cell regions of neurites and fungal hyphae, where the efficiency of the initial diffusive loading process depends on the axial distribution of microtubule plus-ends relative to the initial cargo position. We use analytic mean first passage time calculations and numerical simulations to model diffusive capture processes in tubular cells, exploring how the spatial arrangement of microtubule plus-ends affects the efficiency of retrograde cargo transport. Our model delineates the key features of optimal microtubule ar-rangements that minimize mean cargo capture times. Namely, we show that configurations with a single long microtubule and broad distribution of additional microtubule plus-ends allow for efficient capture in a variety of different scenarios for retrograde transport. Live-cell imaging of microtubule plus-ends in Aspergillus nidulans hyphae indicates that their distributions exhibit these optimal qualitative features. Our results highlight important coupling effects between microtubule length distribution and retrograde cargo transport, providing guiding principles for the spatial arrangement of microtubules within tubular cell regions.
Insights into cisplatin-induced neurotoxicity and mitochondrial dysfunction in Caenorhabditis elegans
Authors: Martínez-Fernández Carmen , Bergamino Milana , Brena David , Ventura Natascia , Honnen Sebastian , Villanueva Alberto , Nadal Ernest , Cerón Julián
Published: June 2021

Cisplatin is the most common drug in first-line chemotherapy against solid tumors. We and others have previously used the nematode Caenorhabditis elegans to identify genetic factors influencing the sensitivity and resistance to cisplatin. In this study, we take advantage of C. elegans to explore cisplatin effects on mitochondrial functions and investigate cisplatin-induced neurotoxicity through a high-resolution semi-automated system for evaluating locomotion. Firstly, we report that a high-glucose diet sensitizes C. elegans to cisplatin at the physiological level and that mitochondrial CED-13 protects the cell from cisplatin-induced oxidative stress. Additionally, by assessing mitochondrial function with a Seahorse Analyzer, we observed a detrimental additive effect of cisplatin and glucose in mitochondrial respiration. Secondly, since we previously found that catechol-O-methyltransferases (involved in dopamine degradation) were upregulated upon cisplatin exposure, we studied the protective role of the FDA-approved drug dopamine against cisplatin-induced neurotoxicity. To implement the use of the Tierpsy Tracker system for measuring neurotoxicity in C. elegans, we showed that abnormal displacements and body postures in cat-2 mutants, which have the dopamine synthesis pathway disrupted, can be rescued by adding dopamine. Then, we used such a system to demonstrate that dopamine treatment protects from the dose-dependent neurotoxicity caused by cisplatin.