bluuebunny/crossref_metadata_2025 huggingface dataset:
A clinical study of artery of Percheron infarction
Authors: Chiang Yi-Kuan , Ling Yu-Hsiang , Chang Feng-Chi , Fuh Jong-Ling
Published: November 2022

Artery of Percheron (AOP) infarction, a rare cause of acute altered mental status (AMS), is characterized by bilateral paramedian thalamic infarction. The aim of this study was to review the clinical manifestation, radiological patterns, treatment, and prognosis of patients with AOP infarction. This retrospective case series included patients with AOP infarction from 2009 to 2020 from a medical center in Taiwan. We defined AOP infarction as acute bilateral paramedian thalamic infarction from magnetic resonance imaging, and patients were further categorized by their additional AOP territorial involvements. We determined outcomes with the modified Rankin Scale at discharge. Among the 10 included patients, AMS was the most common presentation (90%). We identified two patients with bilateral vertebral artery (VA), five with unilateral posterior cerebral artery (PCA), and one with bilateral PCA occlusion. Atherosclerosis was the most common presumed etiology (60%). Two and eight patients had favorable and unfavorable prognoses, respectively. PCA occlusion, rather than VA and BA occlusion, was common in angiography. Residual symptoms often resulted in significant disability at discharge. Basilar tip syndrome may share indistinguishable thalamic infarct patterns with AOP infarction but could be differentiated by angiography and other infarcted territories.
Inferiorly based nasolabial flap for reconstruction of full-thickness medium-sized lower lip and commissural defects following ablative cancer surgery
Authors: Tsai Chien-Sheng , Chang Chan-Chi , Hsiao Jenn-Ren
Published: November 2022

Background:

Information regarding the design and usage of inferiorly based nasolabial flap for lower lip and commissural defect reconstruction following ablative cancer surgery remains limited. This study aimed to provide our design and experiences for such reconstructive purpose.

Methods:

Patients with lower lip or oral commissural cancer who received curative surgery involving reconstruction with inferiorly based nasolabial flap were included. The demographic data and clinical outcomes of these patients were obtained by retrospective chart review.

Results:

A total of eight patients were enrolled in this study. All patients received ablative surgery at the National Cheng Kung University Hospital during May 2019 to May 2021, with their surgical defects reconstructed with unilateral inferiorly based nasolabial flap successfully. Among the five patients with lower lip cancer, one had a limited area of necrosis at flap tip. Another patient had a small orocutaneous fistula that healed spontaneously. No trismus or oral incompetence was noted following recovery. For the three patients with commissural cancer, a second stage commisuroplasy was needed after primary reconstruction. One patient had limited wound dehiscence at mouth angle following surgery, resulting in mild oral incompetence. Although mild trismus was noted in these three commissural cancer patients, all patients resumed normal diet during follow-up.

Conclusion:

Inferiorly based nasolabial flap is an excellent local flap for lower lip reconstruction following cancer ablative surgery. It is also a viable option for reconstruction of oral commissural defects. Minimal donor side morbidity, good functional recovery, and esthetic outcomes can be achieved with meticulous flap design.
Eliciting blinks by transcutaneous electric nerve stimulation improves tear fluid in healthy video display terminal users: A self-controlled study
Authors: Zeng Weiting , Lou Han , Huang Quanbin , Li Kunke , Liu Xiuping , Wu Kaili
Published: November 2022

We aimed to elicit strong blinks among healthy video display terminal (VDT) users by periorbital transcutaneous electric nerve stimulation (TENS) and evaluate its impact on the tear fluid and visual task. Appropriate TENS conditions were evaluated to evoke strong blinks under minimum discomfort. Seventeen healthy VDT users with noninvasive Keratograph first breakup time (NIKf-BUT) 5-15 s and Ocular Surface Disease Index (OSDI) scores < 15 were recruited in this study. Before the trial, noninvasive Keratograph average breakup time (NIKa-BUT), tear meniscus height (TMH) and OSDI scores were evaluated. Before each TENS session, the volunteers played Tetris while the corresponding blink rate and Tetris scores were recorded. Then, the participants underwent 30 minutes of TENS, which evoked blinking of their right eye 20 times per minute. Tetris scores were evaluated again during TENS. The Tetris scores and corresponding blink rate were assessed after each TENS session while NIKa-BUT, TMH and OSDI scores were recorded after the third and sixth TENS sessions. We found that OSDI scores declined significantly after the sixth TENS (P = .003). The NIKa-BUT of the right eye was promoted after the sixth TENS (P = .02), and the TMH was higher after the third and sixth TENS in both eyes (P = .03, P = .03 for right eyes respectively, P = .01, P = .01 for left eyes respectively). There was no significant difference between the adjusted Tetris scores before and during TENS (P = .12). The blink rate before and after TENS were unaffected after 6 sessions (P = .61). The results indicated that periorbital TENS effectively ameliorated ocular irritation and improved tear secretion and tear film stability by eliciting strong blinks in healthy VDT users without disturbing the visual task.
Serum pro-oxidant/antioxidant balance in term versus preterm neonates
Authors: Boskabadi Hassan , Ghayour-Mobarhan Majid , Saeidinia Amin
Published: November 2022

The oxidant/antioxidant status balance is a process that begins before birth and premature infants are particularly susceptible to oxidative stress. According to the mechanisms of oxidative stress and lack of study in this field, in this prospective study, we aimed to compare the levels of serum pro-oxidant/antioxidant balance (PAB) in preterm versus term babies. This was a prospective cross-sectional study that was performed in Ghaem hospital, a university tertiary hospital, in Mashhad, Iran. The study population included all term and preterm neonates who were admitted to the hospital within birth time. In our study, 324 neonates were included. One hundred ninety-eight neonates were preterm (61.1%) and others were term (38.9%). There was a significant difference between PAB levels in term and preterm neonates. Serum PAB level was significantly lower in preterm neonates rather than in term neonates (21.86 ± 21.01 vs 50.33 ± 31.69; P = .001). There was also a significant negative correlation between PAB levels and gestational age. According to previous investigations, we showed for the first time in our study that PAB is lower in preterm newborns rather than in term ones.
Development of eosinophilic granulomatosis with polyangiitis during the clinical course of microscopic polyangiitis: A case report
Authors: Ide Hiroyuki , Shimizu Toshimasa , Koike Yuta , Abe Kuniko , Shigematsu Kazuto , Nishihata Shinya , Kojima Kanako , Ichinose Kunihiro , Kawakami Atsushi
Published: November 2022

Rationale:

Eosinophilic granulomatosis with polyangiitis (EGPA) is belongs to the antineutrophil cytoplasmic autoantibody (ANCA)-associated vasculitis (AAV) subgroups. EGPA, unlike other subgroups of AAV, including microscopic polyangiitis (MPA) and granulomatosis with polyangiitis, has the unique feature that both ANCA and eosinophilic inflammation are involved in its pathogenesis. Although AAV often relapses, there are currently no reports of EGPA developing during other subgroups of AAV. Herein, we document a case of EGPA that developed during the clinical course of MPA.

Patient concerns:

A 61-year-old Japanese woman was diagnosed with MPA based on interstitial lung disease and myeloperoxidase-ANCA positivity. After starting immunosuppression therapy, including prednisolone and tacrolimus, she was expected to achieve clinical remission. Nonetheless, she occasionally experienced MPA relapse, which required an increased prednisolone dose, rituximab, intravenous cyclophosphamide, and plasma exchange. Three years after MPA onset, she developed renal amyloidosis; thus, subcutaneous tocilizumab was added to her regimen. Following clinical remission, the administration interval of her subcutaneous tocilizumab therapy was extended and immunosuppressants were discontinued. She then developed bronchial asthma and mild eosinophilia (eosinophilic count: ~1000/μL). Further, a year later, she underwent total hip replacement using a titanium implant. Subsequently, she developed abnormal sensation in both hands, numbness, and muscle weakness, as well as palpable purpura and massive eosinophilia (eosinophilic count: ~8500/μL).

Diagnosis:

We diagnosed the patient with EGPA based on 5 items (asthma, multiple mononeuropathies, sinus abnormality, and extravascular eosinophils) of the 1990 American College of Rheumatology classification criteria.

Interventions:

We administered 400 mg/kg intravenous immunoglobulin for 5 consecutive days, 300 mg mepolizumab subcutaneously every 4 weeks, and 40 mg/day prednisolone following pulsed methylprednisolone therapy (1000 mg/day for 3 consecutive days).

Outcomes:

After these treatments, the patient’s symptoms improved, and eosinophilic count and inflammatory markers declined.

Lessons:

The present case suggests that EGPA can be induced by the development of eosinophilic inflammation in other subgroups of AAV.
Medication safety in the perioperative setting: A comparison of methods for detecting medication errors and adverse medication events
Authors: Stipp Melanie M. , Deng Hao , Kong Kathy , Moore Sonya , Hickman Ron L. , Nanji Karen C.
Published: November 2022

The purpose of this study was to evaluate perioperative medication-related incidents (medication errors (MEs) and/or adverse medication events (AMEs)) identified by 2 different reporting methods (self-report and direct observation), and to compare the types and severity of incidents identified by each method. We compared perioperative medication-related incidents identified by direct observation in Nanji et al’s 2016 study[1] to those identified by self-report via a facilitated incident reporting system at the same 1046-bed tertiary care academic medical center during the same 8-month period. Incidents, including MEs and AMEs were classified by type and severity. In 277 operations involving 3671 medication administrations, 193 MEs and/or AMEs were observed (5.3% incident rate). While none of the observed incidents were self-reported, 10 separate medication-related incidents were self-reported from different (unobserved) operations that occurred during the same time period, which involved a total of 21,576 operations and approximately 280,488 medication administrations (0.004% self-reported incident rate). The distribution of incidents (ME, AME, or both) did not differ by direct observation versus self-report methodology. The types of MEs identified by direct observation differed from those identified by self-report (P = .005). Specifically, the most frequent types of MEs identified by direct observation were labeling errors (N = 37; 24.2%), wrong dose errors (N = 35; 22.9%) and errors of omission (N = 27; 17.6%). The most frequent types of MEs identified by self-report were wrong dose (N = 5; 50%) and wrong medication (N = 4; 40%). The severity of incidents identified by direct observation and self-report differed, with self-reported incidents having a higher average severity (P < .001). The procedure types associated with medication-related incidents did not differ by direct observation versus self-report methodology. Direct observation captured many more perioperative medication-related incidents than self-report. The ME types identified and their severity differed between the 2 methods, with a higher average incident severity in the self-reported data.
Effect of glomerular filtration rate in patients undergoing percutaneous coronary intervention: A systematic review and meta-analysis
Authors: Zhu Xiang , Zhang Pin , Xiong Jinrui , Wang Nan , Yang Shanlan , Zhu Ruoling , Zhang Langlang , Liu Weixin , Wu Lei
Published: November 2022

Background:

Through meta-analysis of the relationship between glomerular filtration rate and major adverse cardiovascular events (MACE) after percutaneous coronary intervention (PCI), we studied the impact of glomerular filtration rate on the prognosis of PCI.

Methods:

We collected literature on the incidence of MACE in patients with chronic kidney disease (CKD; estimated glomerular filtration rate < 60 mL/minute/1.73 m2) and patients with nonchronic kidney disease undergoing PCI. The search period was from January 1, 2000, to November 1, 2021. The searched databases included CNKI, Chinese Wanfang Data, China Biology Medicine disc, Web of Science, PubMed, and Cochrane Library. We used subgroup analysis and meta-regression to assess heterogeneity.

Results:

Twenty-one eligible studies were included, with 46,255 samples included, 4903 cases of MACE (10.6%), and patients with CKD had a higher risk of MACE after PCI (Risk ratios = 1.67; 95% confidence interval: 1.51–1.85). Multivariate meta regression results show that heterogeneity is related to region. The risk of MACEs in patients with CKD is different in different regions, and North America has the lowest risk, with an risk ratios value of 1.21 (95% confidence interval: 1.08–1.35).

Conclusion:

Chronic kidney disease will increase the probability of MACE in patients with myocardial infarction after PCI and affect the prognosis of PCI. Therefore, clinical attention should be given to assessing glomerular filtration rate effects while treating patients with myocardial infarction with the PCI procedure.
Development of convolutional neural network model for diagnosing tear of anterior cruciate ligament using only one knee magnetic resonance image
Authors: Shin Hyunkwang , Choi Gyu Sang , Chang Min Cheol
Published: November 2022

Deep learning is an advanced machine learning approach used in diverse areas such as image analysis, bioinformatics, and natural language processing. In the current study, using only one knee magnetic resonance image of each patient, we attempted to develop a convolutional neural network (CNN) to diagnose anterior cruciate ligament (ACL) tear. We retrospectively recruited 164 patients who had knee injury and underwent knee magnetic resonance imaging evaluation. Of 164 patients, 83 patients’ ACLs were torn (20 patients, partial tear; 63 patients, complete tear), whereas 81 patients’ ACLs were intact. We used a CNN algorithm. Of the included subjects, 79% were assigned randomly to the training set and the remaining 21% were assigned to the test set to measure the model performance. The area under the curve was 0.941 (95% CI, 0.862–1.000) for the classification of intact and tears of the ACL. We demonstrated that a CNN model trained using one knee magnetic resonance image of each patient could be helpful in diagnosing ACL tear.
Effect of task-oriented training on gross motor function, balance and activities of daily living in children with cerebral palsy: A systematic review and meta-analysis
Authors: Zai Weiyi , Xu Ning , Wu Wei , Wang Yueying , Wang Runfang
Published: November 2022

Background:

To systematically evaluate task-oriented training (TOT) on the improvement of gross motor function, balance and activities of daily living in children with cerebral palsy (CP).

Methods:

A number of randomized controlled trials (RCTs) of TOT in children with CP were searched from Pubmed, Cochrane Library, Web of Science, EmBase, China National Knowledge Infrastructure, Chinese Biology Medicine, Chinese Scientific Journals Database and Wanfang data from the establishment of database to March 2022. The methodological quality of the included studies was evaluated, and meta-analysis was performed by RevMan5.4 software.

Results:

A total of 16 studies were included in the systematic review (n = 893). Meta-analysis showed that the gross motor function measure (GMFM) (MD = 11.05, 95%CI [8.26, 13.83], P < .00001), dimension D (MD = 3.05, 95%CI [1.58, 4.53], P < .0001) of the GMFM, dimension E (MD = 7.36, 95%CI [5.88, 8.84], P < .00001) of the GMFM, the Berg Balance Scale (BBS) (MD = 6.23, 95%CI [3.31, 9.15], P < .0001), the pediatric evaluation of disability inventory (PEDI) mobile function (MD = 6.44, 95%CI [3.85, 9.02], P < .00001) score improved significantly in the TOT group compared with the control group.

Conclusions:

Current evidence shows that TOT could effectively improve gross motor function, balance and activities of daily living in children with CP. Due to the limitations of the number and quality of the included studies, the above conclusions need to be verified by more high-quality studies.
Brief Report: T-Cell Receptor α Repertoire Diversity at Birth After in utero Exposure to HIV Integrase Strand-Transfer Inhibitors
Authors: de Villartay Jean Pierre , Pannier Emmanuelle , Sibiude Jeanne , Frange Pierre , Tubiana Roland , Blanche Stéphane
Published: November 2022

Effectiveness of anti-HIV in the prevention of perinatal transmission has been established. Assessing the tolerance of drug exposure during pregnancy is of the utmost importance given the number of children exposed. HIV integrase and the recombinase-activating gene enzyme involved in the establishment of the T-lymphocyte repertoire show structural similarity. The inhibition of recombinase-activating (RAG) gene by anti-integrases is observed in vitro, in a variable way according to the molecules. Here, we show that in utero exposure to raltegravir did not alter the T-lymphocyte repertoire of 12 newborns. These reassuring data merit verification for other anti-integrases. (ClinicalTrial.org NCT 04024150).
Primary Neuroendocrine Carcinoma of Pineal Gland With Extensive Meningeal Metastasis Detected by 18F-NOTATATE PET/CT
Authors: Deng Yujiao , He Limeng , Gao Hanyan , Deng Ying , Zhang Wei
Published: November 2022

Primary neuroendocrine tumor of the pineal gland is a rare disease. A 44-year-old woman with right cerebellopontine angle metastatic small cell neuroendocrine carcinoma underwent18F-FDG and18F-NOTATATE PET/CT scans.18F-NOTATATE PET/CT showed intense uptake in the pineal gland lesions and multiple foci of intense focus of uptake in the intracranial leptomeningeal and whole spinal canal. However, the lesions are less impressive on18F-FDG PET/CT.
Brain PET Imaging of 11C-Methionine, 18F-FDG, and 18F-THK5351 in a Case of Lymphomatoid Granulomatosis
Authors: Higashihara Mana , Ishibashi Kenji , Tokumaru Aya M. , Ishii Kenji , Iwata Atsushi
Published: November 2022

A 52-year-old woman complained of upper respiratory symptoms and subsequently developed Wallenberg syndrome. Chest CT and brain MRI revealed multiple nodular lesions in the lungs and brain. She was pathologically diagnosed with low-grade lymphomatoid granulomatosis by lung biopsy. Brain PET examinations using 11C-methionine, 18F-FDG, and 18F-THK5351 were performed. Uptake of 11C-methionine and 18F-FDG was slightly increased in some lesions, likely reflecting the degree of inflammatory cell infiltration. 18F-THK5351 uptake was significantly increased in all lesions, likely reflecting the degree of reactive astrogliosis. This case illustrates the utility of PET studies for diagnosing lymphomatoid granulomatosis and provides insight into its pathophysiology.
Diverse Patterns and Clinical Significance of 11C-Methionine PET in Dysembryoplastic Neuroepithelial Tumors
Authors: Kim Joo Whan , Kang Yeon-koo , Paeng Jin Chul , Kim Seung-Ki , Lim Byung Chan , Kim Ki Joong , Phi Ji Hoon
Published: November 2022

Purpose

Dysembryoplastic neuroepithelial tumors (DNETs) are slow-growing epilepsy-associated tumors. Low or normal 11C-methionine (MET) PET uptake helps to differentiate DNETs from other low-grade gliomas. However, diverse MET-PET uptake in DNETs has been observed. The aim of this study is to measure the clinical significance and prognostic value of MET-PET in DNET management.

Patients and Methods

Retrospective review of 26 DNET patients was done. Clinical characteristics, radiologic findings, and visual and quantitative MET-PET results were analyzed. PET uptake was calculated as the tumor–to–homotopic mirror ratio (TNRm) and tumor–to–contralateral cortex ratio (TNRc). The clinical activity of the tumors at the time of PET was classified into active and quiescent groups. The surgical outcome was defined as a composite of 2 different aspects: tumor progression and/or clinical events such as seizure recurrence or tumor bleeding.

Results

Twenty-seven MET-PET examinations (20 initial MET-PET and 7 MET-PET during follow-up) were included. Clinically active tumors at the time of PET presented significantly higher values of TNRm and TNRc than quiescent tumors. High MET-PET uptake by visual grading, TNRm ≥ 1.90, and TNRc ≥ 1.85 exhibited poor prognosis for event-free survival.

Conclusions

MET-PET uptake correlates well with the clinical behavior of DNETs at the time of PET examination. Moreover, High MET-PET uptake is closely related to seizure recurrence if tumors are not entirely resected. Efforts to achieve gross total resection should be made for DNETs with high MET-PET uptake.
Comparisons of Respiratory Syncytial Virus (RSV) and Influenza: Population Characteristics and Clinical Outcomes in Hospitalized Adults
Authors: Begley Katherine M. , Monto Arnold S. , Lamerato Lois E. , Malani Anurag N. , Lauring Adam S. , Talbot H. Keipp , Gaglani Manjusha , McNeal Tresa , Silveira Fernanda P. , Zimmerman Richard K. , Middleton Donald B. , Ghamande Shekhar , Murthy Kempapura , Kim Lindsay , Ferdinands Jill M. , Patel Manish M. , Martin Emily T.
Published: November 2022

Background

Respiratory syncytial virus (RSV) is under-recognized in hospitalized adults. We evaluated severity of acute respiratory illness (ARI) including intensive care unit (ICU) admission and mechanical ventilation in a national surveillance network.

Methods

Hospitalized adults who met a standardized ARI case definition were prospectively enrolled across three respiratory seasons from hospitals participating across all sites of the U.S. Hospitalized Adult Influenza Vaccine Effectiveness Network (HAIVEN, 2016-2019). Multivariable logistic regression was used to test associations between lab-confirmed infection and characteristics and clinical outcomes.

Results

Among 10,311 hospitalized adults, 6% tested positive for RSV (n=622), 18.8% positive for influenza (n=1,940), and 75.1% negative for RSV and influenza (n=7,749). The proportion of adults with Congestive Heart Failure (CHF) or Chronic Obstructive Pulmonary Disease (COPD) was higher among adults with RSV than influenza (CHF: 37.3% vs. 28.8%, p<0.0001; COPD: 47.6% vs. 35.8%, p<0.0001). Patients with RSV had higher odds of experiencing length of stay ≥8 days [OR=1.38 (95% CI: 1.06-1.80), p-value=0.02] and invasive or noninvasive mechanical ventilation [OR=1.45 (95% CI: 1.09-1.93), p-value=0.01] compared with influenza patients.

Conclusions

Our findings suggest patients with RSV might incur worse outcomes than influenza in hospitalized adults, who are likely to have pre-existing cardiopulmonary conditions.
Age variability and time averaging in oyster reef death assemblages
Authors: Durham Stephen R. , Dietl Gregory P. , Hua Quan , Handley John C. , Kaufman Darrell , Clark Cheryl P.
Published: November 2022

A lack of temporal context for paleoecological data from molluscan death assemblages (DAs) makes integrating them with monitoring data from living communities to inform habitat management difficult. Here we illustrate this challenge by documenting the spatial and stratigraphic variability in age and time-averaging of oyster reef death assemblages. We radiocarbon dated a total of 573 oyster shells from samples of two burial depths on 28 oyster reefs around Florida and found 1) that spatial and stratigraphic variability in DA sample ages and time-averaging are of similar magnitude, and 2) that the shallow oyster reef DAs are among the youngest and highest-resolution molluscan DAs documented to-date, with most having time-averaging estimates of decades or less. This information increases the potential usefulness of the DAs for habitat management because measured indicators can be placed in temporal context relative to monitoring data. More broadly, the results highlight the potential to obtain decadal-scale resolution from oyster bioherms in the fossil record.
Complexes Formed by Mixing Tumor-derived Extracellular Vesicles with Polymeric Surfactants for Personalized Therapeutic Vaccine
Authors: Zeng Wenfeng , Tian Hongjian , Wang Zihao , Li Siqi , Jin Lingtao , Liang Wei
Published: November 2022

The personalized therapeutic vaccine is an ideal weapon to eliminate tumors. However, the core steps of manufacturing personalized cancer vaccines are identifying tumor-specific antigens (TSAs, also called neoantigens) and HLA epitope prediction, which is time-consuming and labor-intense. Tumor-derived extracellular vesicles (TEVs) are alternative sources of neoantigens. However, the immunosuppressive nature of TEVs limits their application in such immunotherapy. In this study, we present a new strategy to maintain neoantigens in TEVs and diminish the immunosuppression by deconstructing the structure of TEVs with polymeric surfactant polyethylene glycol-phosphatidylethanolamine (PEG-PE). Together with adjuvant MPLA, the newly formed micelle-like complexes compose a therapeutic vaccine (MLC-V). Results show that MLC-V is capable of eliciting neoantigen-specific T-cell responses, restoring TEV-induced immunosuppression, and preventing lung metastasis of murine melanoma. MLC-V also exhibits outstanding anti-tumor efficacy in multiple tumor models. MLC-V can be used as a personalized therapeutic vaccine in a mimetic pre-clinical MC38 model and the anti-tumor effect of MLC-V was synergistically enhanced by PD-1 mAb. Taken together, the present study demonstrates a time-saving, low-cost, and simplified strategy to produce personalized therapeutic vaccines based on MLC-V platform technology.
Novel inhibitors against COVID-19 main protease suppressed viral infection
Authors: Ramachandran Vijayan , Liu Yanyun , He Qianying , Tang Andrew , Ronaldson Patrick , Schenten Dominik , Chang Rui
Published: November 2022

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), the etiologic agent of COVID-19, can cause severe disease with high mortality rates, especially among older and vulnerable populations. Despite the recent success of vaccines and approval of first-generation anti-viral inhibitor against SARS-CoV-2, an expanded arsenal of anti-viral compounds that limit viral replication and ameliorate disease severity is still urgently needed in light of the continued emergence of viral variants of concern (VOC). The main protease (Mpro) of SARS-CoV-2 is the major non-structural protein required for the processing of viral polypeptides encoded by the open reading frame 1 (ORF1) and ultimately replication. Structural conservation of Mpro among SARS-CoV-2 variants make this protein an attractive target for the anti-viral inhibition by small molecules. Here, we developed a structure-basedin-silicoscreening of approximately 11 million compounds in ZINC15 database inhibiting Mpro, which prioritized 9 lead compounds for the subsequentin vitrovalidation in SARS-CoV-2 replication assays using both Vero and Calu-3 cells. We validated three of these compounds significantly inhibited SARS-CoV-2 replication in the micromolar range. In summary, our study identified novel small-molecules significantly suppressed infection and replication of SARS-CoV-2 in human cells.
Exploring of a novel monitoring tool for injury risk when sidestepping: Using unsupervised learning to characterize movement patterns
Authors: David Sina , Barton Gabor J.
Published: November 2022

The monitoring of athletes is crucial to prevent injuries, identify fatigue or support return-to-play decisions. The purpose of this study was to explore the ability of Kohonen neural network self-organizing maps (SOM) to objectively visualize and characterize different movement patterns during sidestepping and to detect those patterns that are associated with signs of injury risk or fatigue. The marker trajectories of 631 pre-planned sidestepping trials were used to train a SOM. Out of 61913 input vectors, the SOM identified 1250 unique body postures, determined by the 3D marker positions. Visualizing the movement trajectories and adding the latent parameter time, allows for the investigation of different movement patterns. Additionally, the SOM can be used to identify zones with increased injury risk, by adding more latent parameters more directly linked to injuries which opens the option to monitor athletes and give feedback. The results highlight the ability of unsupervised learning to visualize movement patterns and to give further insight into an individual athlete’s status without the necessity to reduce the complexity of the data describing the movement.
The relationship between controllability, optimal testing resource allocation, and incubation-latent period mismatch as revealed by COVID-19
Authors: Demers Jeffery , Fagan William F. , Potluri Sriya , Calabrese Justin M.
Published: November 2022

The severe shortfall in testing supplies during the initial COVID-19 outbreak and ensuing struggle to manage the pandemic have affirmed the critical importance of optimal supply-constrained resource allocation strategies for controlling novel disease epidemics. To address the challenge of constrained resource optimization for managing diseases with complications like pre- and asymptomatic transmission, we develop an integro partial differential equation compartmental disease model which incorporates realistic latent, incubation, and infectious period distributions along with limited testing supplies for identifying and quarantining infected individuals. Our model overcomes the limitations of typical ordinary differential equation compartmental models by decoupling symptom status from model compartments to allow a more realistic representation of symptom onset and presymptomatic transmission. To analyze the influence of these realistic features on disease controllability, we find optimal strategies for reducing total infection sizes that allocate limited testing resources between ‘clinical’ testing, which targets symptomatic individuals, and ‘non-clinical’ testing, which targets non-symptomatic individuals. We apply our model not only to the original, delta, and omicron COVID-19 variants, but also to generically parameterized disease systems with varying mismatches between latent and incubation period distributions, which permit varying degrees of presymptomatic transmission or symptom onset before infectiousness. We find that factors that decrease controllability generally call for reduced levels of non-clinical testing in optimal strategies, while the relationship between incubation-latent mismatch, controllability, and optimal strategies is complicated. In particular, though greater degrees of presymptomatic transmission reduce disease controllability, they may increase or decrease the role of non-clinical testing in optimal strategies depending on other disease factors like transmissibility and latent period length. Importantly, our model allows a spectrum of diseases to be compared within a consistent framework such that lessons learned from COVID-19 can be transferred to resource constrained scenarios in future emerging epidemics and analyzed for optimality.
Neutralization of zoonotic retroviruses by human antibodies: genotype-specific epitopes within the receptor-binding domain from simian foamy virus
Authors: Dynesen Lasse Toftdal , Fernandez Ignacio , Coquin Youna , Delaplace Manon , Montange Thomas , Njouom Richard , Bilonga-Ndongo Chanceline , Rey Felix A. , Gessain Antoine , Backovic Marija , Buseyne Florence
Published: November 2022

Infection with viruses of animal origin pose a significant threat to human populations. Simian foamy viruses (SFVs) are frequently transmitted to humans, in which they establish a life-long infection, with the persistence of replication-competent virus. However, zoonotic SFVs do not induce severe disease nor are they transmitted between humans. Thus, SFVs represent a model of zoonotic retroviruses that lead to a chronic infection successfully controlled by the human immune system. We previously showed that infected humans develop potent neutralizing antibodies (nAbs). Within the viral envelope (Env), the surface protein (SU) carries a variable region that defines two genotypes, overlaps with the receptor binding domain (RBD), and is the exclusive target of nAbs. However, its antigenic determinants are not understood. Here, we characterized nAbs present in plasma samples from SFV-infected individuals living in Central Africa. Neutralization assays were carried out in the presence of recombinant SU that compete with SU at the surface of viral vector particles. We defined the regions targeted by the nAbs using mutant SU proteins modified at the glycosylation sites, RBD functional subregions, and genotype-specific sequences that present properties of B-cell epitopes. We observed that nAbs target conformational epitopes. We identified three major epitopic regions: the loops at the apex of the RBD, which likely mediate interactions between Env protomers to form Env trimers, a loop located in the vicinity of the heparan binding site, and a region proximal to the highly conserved glycosylation site N8. We provide information on how nAbs specific for each of the two viral genotypes target different epitopes. Two common immune escape mechanisms, sequence variation and glycan shielding, were not observed. We propose a model according to which the neutralization mechanisms rely on the nAbs to block the Env conformational change and/or interfere with binding to susceptible cells. As the SFV RBD is structurally different from known retroviral RBDs, our data provide fundamental knowledge on the structural basis for the inhibition of viruses by nAbs.
Transcriptome Data Analysis of Primary Cardiomyopathies Reveals Perturbations in Arachidonic Acid Metabolism
Authors: Chauhan Pankaj Kumar , Sowdhamini R.
Published: November 2022

Cardiomyopathies are complex heart diseases with significant prevalence around the world. Among these, primary forms are the major contributor to heart failure and sudden cardiac death. As the high-energy demanding engine, the heart utilizes fatty acids, glucose, amino acid, lactate and ketone bodies as energy to meet its requirement. However, continuous myocardial stress and cardiomyopathies drive towards metabolic impairment that advances heart failure (HF) pathogenesis. So far, metabolic profile correlation across different cardiomyopathies remains poorly understood. In this study, we systematically explore metabolic differences amongst primary cardiomyopathies. By assessing the metabolic gene expression of all primary cardiomyopathies, we highlight the significantly shared and distinct metabolic pathways that may represent specialized adaptations to unique cellular demands. We utilized publicly available RNA-seq datasets to profile global changes in the above diseases and performed Gene set analysis (GSA). Our analysis demonstrates genes in arachidonic acid metabolism (AA) as significantly perturbated across cardiomyopathy. In particular, arachidonic acid metabolism genePLA2G2Ainteracts with fibroblast marker genes and can potentially influence fibrosis during cardiomyopathy.
Learning predictive models of tissue cellular neighborhoods from cell phenotypes with graph pooling
Authors: Hu Yuxuan , Rong Jiazhen , Xie Runzhi , Xu Yafei , Peng Jacqueline , Gao Lin , Tan Kai
Published: November 2022

It remains poorly understood how different cell types organize and coordinate with each other to support tissue functions. We describe CytoCommunity for identification of tissue cellular neighborhoods (TCNs) based on cell phenotypes and their spatial distributions. CytoCommunity learns a mapping directly from cell phenotype space to TCN space by a graph neural network model without using additional gene or protein expression features and is thus applicable to tissue imaging data with a small number of measured features. By leveraging graph pooling, CytoCommunity enablesde novoidentification of condition-specific TCNs under the supervision of image labels. Using various types of single-cell-resolution spatial proteomics and transcriptomics images, we demonstrate that CytoCommunity can identify TCNs of variable sizes with substantial improvement over existing methods. To further evaluate the ability of CytoCommunity for discovering condition-specific TCNs by supervised learning, we apply it to colorectal and breast cancer tissue images with clinical outcome information. Our analysis reveals novel granulocyte- and cancer associated fibroblast-enriched TCNs specific to high-risk tumors as well as altered tumor-immune and tumor-stromal interactions within and between TCNs compared to low-risk tumors. CytoCommunity represents the first computational tool for end-to-end unsupervised and supervised analyses of single-cell spatial maps and enables direct discovery of conditional-specific cell-cell communication patterns across variable spatial scales.
Whole-body gene expression atlas of an adult metazoan
Authors: Ghaddar Abbas , Armingol Erick , Huynh Chau , Gevirtzman Louis , Lewis Nathan E. , Waterston Robert , O’Rourke Eyleen J.
Published: November 2022

Animals are integrated organ systems composed of interacting cells whose structure and function are in turn defined by their active genes. Understanding what distinguishes physiological and disease states therefore requires systemic knowledge of the gene activities that define the distinct cells that make up an animal. Towards this goal, this study reports the first single-cell resolution transcriptional atlas of a fertile multicellular organism:Caenorhabditis elegans. The scRNA-Seq compendium of wild-type young adultC. eleganscomprises 159 distinct cell types with 18,033 genes expressed across cell types. Fewer than 300 of these genes are housekeeping genes as evidenced by their consistent expression across cell types and conditions, and by their basic and essential functions; 170 of these housekeeping genes are conserved across phyla. The 362 transcription factors with available ChIP-Seq data are linked to patterns of gene expression of different cell types. To identify potential interactions between cell types, we used thein silicotool cell2cell to predict molecular patterns reflecting both known and uncharacterized intercellular interactions across theC. elegansbody. Finally, we present WormSeq (wormseq.org), a web interface that, among other functions, enables users to query gene expression across cell types, identify cell-type specific and potential housekeeping genes, analyze candidate ligand-receptors mediating communication between cells, and study promiscuous and cell-specific transcription factors. The datasets, analyses, and tools presented here will enable the generation of testable hypotheses about the cell and organ-specific function of genes in diverse biological contexts.
Two RhoGEF isoforms with distinct localisation act in concert to control asymmetric cell division
Authors: Montembault Emilie , Deduyer Irène , Claverie Marie-Charlotte , Bouit Lou , Tourasse Nicolas , Dupuy Denis , McCusker Derek , Royou Anne
Published: November 2022

Cytokinesis is essential for the partitioning of cellular contents into daughter cells. It relies on the formation of an acto-myosin contractile ring, whose constriction induces the ingression of the cleavage furrow between the segregated chromatids. Rho1 GTPase and its RhoGEF (Pbl) are essential for this process as they drive the assembly and constriction of the contractile ring. However, how Rho1 is regulated to sustain efficient furrow ingression while maintaining correct furrow position remains poorly defined. Here, we show that during asymmetric division of Drosophila neuroblasts, Rho1 is controlled by two Pbl isoforms with distinct localisation. Spindle midzone- and furrow-enriched Pbl-A focuses Rho1 at the furrow to sustain efficient ingression, while Pbl-B pan-plasma membrane localization promotes the broadening of Rho1 activity and the subsequent enrichment of cortical myosin. This enlarged zone of Rho1 activity becomes essential to adjust furrow position during ingression, thereby preserving correct daughter cell size asymmetry. Our work highlights how the use of isoforms with distinct localisation patterns provides robustness to an essential process.
Identification of Potential DNA Gyrase Inhibitors: Virtual Screening, Extra-Precision Docking and Molecular Dynamics Simulation Study
Authors: Kumar Avinash , Prasun Chakrawarti , Rathi Ekta , Nair Maya S. , Kini Suvarna G
Published: November 2022

DNA gyrase brings negative supercoils into DNA and loosens up certain positive supercoils that collect during replication and transcription and is a notable antibacterial target. To fight against the menace of antibiotic-resistant bacterial infections, we have employed various computational tools like high throughput virtual screening (HTVS), standard precision (SP), extra precision (XP), and molecular dynamics (MD) simulation studies to identify some potential DNA gyrase inhibitors. A focused library of 5968 anti-bacterial compounds was screened using the HTVS docking protocol of the glide module of Maestro. The top 200 docked compounds were further filtered using SP and XP docking protocols and their free binding energies were calculated using MM-GBSA studies. Binding and stability of the top two compounds which showed better docking score than the co-crystallized ligand (clorobiocin) of DNA gyrase (PDB ID: 1KZN) was further probed by MD simulation of 100 ns using GROMACS. MD simulation study suggested that the compounds AM1 and AM5 form a stable complex with DNA gyrase with a good number of hydrogen bonds. XP docking study showed that interaction with the crucial amino acids for compounds AM1 and AM5 was like the co-crystallized ligand. These compounds were also predicted to be drug-like molecules with good water solubility and excellent absorption profiles. Based on the above studies, herein we report compounds AM1 (1R,3S)-1-(2-((3-(ammoniomethyl)phenyl)amino)-2-oxoethyl)-3-carbamoylpiperidin-1-ium and AM5 (1’S,2s,4R)-4-ammonio-6-ethyl-1’-methylspiro[chromane-2,4’-piperidin]-1’-ium as potential DNA gyrase inhibitors which can be further developed as a potential drug against the menace of antibiotic resistance.
Mathematical Modeling of Impacts of Patient Differences on Renin-Angiotensin System and Applications to COVID-19 Lung Fibrosis Outcomes
Authors: Islam Mohammad Aminul , Ford Versypt Ashlee N.
Published: November 2022

Patient-specific premorbidity, age, and sex are significant heterogeneous factors that influence the severe manifestation of lung diseases, including COVID-19 fibrosis. The renin-angiotensin system (RAS) plays a prominent role in regulating the effects of these factors. Recent evidence shows patient-specific alterations of RAS homeostasis concentrations with premorbidity and the expression level of angiotensin-converting enzyme 2 (ACE2) during COVID-19. However, conflicting evidence suggests decreases, increases, or no changes in RAS peptides after SARS-CoV-2 infection. In addition, detailed mechanisms connecting the patient-specific conditions before infection to infection-induced RAS alterations are still unknown. Here, a multiscale computational model was developed to quantify the systemic contribution of heterogeneous factors of RAS during COVID-19. Three submodels were connected—an agent-based model for in-host COVID-19 response in the lung tissue, a RAS dynamics model, and a fibrosis dynamics model to investigate the effects of patient-group-specific factors in the systemic alteration of RAS and collagen deposition in the lung. The model results indicated cell death due to inflammatory response as a major contributor to the reduction of ACE and ACE2. In contrast, there were no significant changes in ACE2 dynamics due to viral-bound internalization of ACE2. The model explained possible mechanisms for conflicting evidence of patient-group-specific changes in RAS peptides in previously published studies. Simulated results were consistent with reported RAS peptide values for SARS-CoV-2-negative and SARS-CoV-2-positive patients. RAS peptides decreased for all virtual patient groups with aging in both sexes. In contrast, large variations in the magnitude of reduction were observed between male and female virtual patients in the older and middle-aged groups. The patient-specific variations in homeostasis RAS peptide concentrations of SARS-CoV-2-negative patients also affected the dynamics of RAS during infection. The model results also showed that feedback between RAS signaling and renin dynamics could restore ANGI homeostasis concentration but failed to restore homeostasis values of RAS peptides downstream of ANGI. In addition, the results showed that ACE2 variations with age and sex significantly altered the concentrations of RAS peptides and led to collagen deposition with slight variations depending on age and sex. This model may find further applications in patient-specific calibrations of tissue models for acute and chronic lung diseases to develop personalized treatments.
Carcinogenicity and testicular toxicity of 2-bromopropane in a 26-week inhalation study using the rasH2 mouse model
Authors: Goto Yuko , Saito Arata , Takanobu Kenji , Senoh Hideki , Saito Misae , Umeda Yumi , Yamano Shotaro
Published: November 2022

2-Bromopropane (2-BP) is a colorless liquid at room temperature and is used in closed systems in factories, mainly as an intermediate for medicines, pesticides, and other chemicals. However, the carcinogenicity of 2-BP is still unknown. The CByB6F1-Tg(HRAS)2Jic (rasH2) transgenic mouse model has been established as an alternative to long-term studies (1.5years-lifetime) to detect carcinogenicity in as short a time as six months. We performed a 26-week inhalation exposure study of 2-BP using the rasH2 mouse model. Male and female rasH2 mice were exposed to 0, 67, 200, or 600 ppm of 2-BP for 6 hours/day, 5 days/week for 26 weeks. All tissues and blood were collected and subjected to biological and histopathological analyses. The results showed a concentration-dependent increase in lung tumor development in male and female rasH2 mice exposed by inhalation to 2-BP, which was significant by Peto’s trend test. Furthermore, in male rasH2 mice, 2-BP was found to be a testicular toxin. This study is the first to demonstrate that 2-BP is carcinogenic in male and female mice and a testicular toxin in male mice in the rasH2 mouse model.