bluuebunny/crossref_metadata_2025 huggingface dataset:
Civilian Ballistic Femoral Shaft Fractures Compared With Blunt Femur Shaft Fractures
Authors: Patch David A. , Levitt Eli B. , Andrews Nicholas A. , Heatherly Alex R. , Bonner Henry V. , Halstrom Jared R. , Watson Jared B. , Spitler Clay A.
Published: December 2021

Objective:

To assess ballistic femoral shaft fracture outcomes in comparison with closed and open femoral shaft fractures sustained by blunt mechanisms. We hypothesized that ballistic femoral shaft fractures would have similar outcomes to blunt open fractures.

Design:

Retrospective cohort study.

Setting:

Academic Level I trauma center.

Participants:

Patients 16 years and older presenting with ballistic (140), blunt closed (317), or blunt open (71) femoral shaft fractures.

Main Outcomes:

Unplanned return to operating room, fracture-related infection, soft tissue reconstruction, nonunion, implant failure, length of stay, Injury Severity Scores, hospital charges, and compartment syndrome.

Results:

A total of 528 femoral shaft fractures were identified. A group of 140 ballistic fractures and comparison groups of all femoral shaft fractures sustained by blunt mechanisms and treated with intramedullary nailing were included in the analysis. Among the 2 subgroups of nonballistic injuries, 317 were blunt closed fractures and 71 were blunt open fractures. The ballistic group was associated with a 3-fold increase in overall complications (30%) compared with the blunt closed group (10%, P < 0.001), had a higher occurrence of thigh compartment syndrome (P < 0.001), and required more soft tissue reconstruction (P < 0.001) than either of the blunt fracture groups.

Conclusions:

Ballistic femoral shaft fractures do not perfectly fit with blunt closed or open femoral fractures. A high index of suspicion for the development of thigh compartment syndrome should be maintained in ballistic femoral shaft fractures. The overall rates of nonunion and infection were comparable between all groups, but the all-cause complication rate was significantly higher in the ballistic group compared with the blunt closed group.

Level of Evidence:

Prognostic Level III. See Instructions for Authors for a complete description of levels of evidence.
Extra-articular Unstable Iliac Fractures: Associated Injuries, Fixation Strategies, and Outcomes
Authors: Stevens Nicole M. , Tyler Andrew F. , Boyce Robert H. , Mitchell Phillip M.
Published: December 2021

Objective:

To characterize the associated injuries, fixation constructs, and outcomes of extra-articular unstable iliac fractures.

Design:

Retrospective cohort study.

Setting:

Level I trauma center.

Patients:

Thirty-three extra-articular unstable iliac fractures treated over a 20-year period.

Intervention:

Percutaneous or open fixation of iliac fractures at the pelvic brim AND/OR iliac crest.

Main Outcome Measures:

Incidence of union, fixation failure, and angiography at the time of injury.

Results:

Twenty-five patients were treated operatively with appropriate follow-up. Four patients had fixation failure with displacement, all in the group with only brim OR crest fixation (4/8 patients, 50% rate). In patients with both crest AND brim fixation (n = 17), there were no cases of implant failure or late displacement. In displaced fractures (n = 22), 4 patients (18%) required embolization by interventional radiology. In all 4 cases, the superior gluteal artery was embolized. In patients with both crest AND brim fixation, all went on to uneventful union with an average Visual Analog Scale (VAS) pain score of 0.9 (range, 0-5) at final follow-up.

Conclusions:

Extra-articular unstable iliac fractures are high-energy injuries that demonstrate a high rate of union when both pelvic brim AND iliac crest fixation is used. Approximately 1 in 5 patients with a displaced iliac fracture presented with a superior gluteal artery disruption requiring embolization. Pelvic brim OR iliac crest fixation used in isolation was associated with a fixation failure rate of 50%, supporting previous biomechanical work.

Level of Evidence:

Therapeutic Level III. See Instructions for Authors for a complete description of levels of evidence.
The COVID-19 pandemic and unemployment, subsistence needs and mental health among adults with HIV in the United States
Authors: Beer Linda , Tie Yunfeng , Dasgupta Sharoda , McManus Tim , Chowdhury Pranesh P. , Weiser John
Published: December 2021

Objective:

To evaluate whether reported prevalence of unemployment, subsistence needs, and symptoms of depression and anxiety among adults with diagnosed HIV during the COVID-19 pandemic were higher than expected.

Design:

The Medical Monitoring Project (MMP) is a complex sample survey of adults with diagnosed HIV in the United States.

Methods:

We analyzed 2015–2019 MMP data using linear regression models to calculate expected prevalence, along with corresponding prediction intervals (PI), for unemployment, subsistence needs, depression, and anxiety for June–November 2020. We then assessed whether observed estimates fell within the expected prediction interval for each characteristic, overall and among specific groups.

Results:

Overall, the observed estimate for unemployment was higher than expected (17% vs. 12%) and exceeded the upper limit of the PI. Those living in households with incomes ≥400% of FPL were the only group where the observed prevalence of depression and anxiety during the COVID-19 period was higher than the PIs; in this group, the prevalence of depression was 9% compared with a predicted value of 5% (75% higher) and the prevalence of anxiety was 11% compared with a predicted value 5% (137% higher). We did not see elevated levels of subsistence needs, although needs were higher among Black and Hispanic compared with White persons.

Conclusions:

Efforts to deliver enhanced employment assistance to persons with HIV and provide screening and access to mental health services among higher income persons may be needed to mitigate the negative effects of the US COVID-19 pandemic.
Molecular profiling of breast and lung cancer in women with HIV reveals high tumor mutational burden
Authors: Caro-Vegas Carolina , Ramirez Catalina , Landis Justin , Adimora Adaora A. , Strickler Howard , French Audrey L. , Ofotokun Igho , Fischl Margaret , Seaberg Eric C. , Wang Chia-ching J. , Spence Amanda B. , Dittmer Dirk P.
Published: December 2021

Objective:

This study compared the mutation profile and tumor mutational burden (TMB) in women with HIV (WWH) diagnosed with lung adenocarcinoma (n = 8) or breast ductal neoplasm (n = 13) who were enrolled into the Women's Interagency HIV Study (WIHS).

Design:

Previous studies tended to focus on single institutions based on sample availability. This study is based on a representative, multicenter cohort that represents the racial and ethnic composition of women with HIV in the United States

Methods:

The study sequenced the complete human exome of n = 26 cancer samples from HIV-positive women, using Ion torrent next-generation sequencing. The study cohort was compared with a HIV-negative cohort obtained from the Genomic Data Commons Data Portal of the NCI.

Results:

There were no differences in known cancer mutations between breast cancer and lung cancer that developed in WWH and those that developed in HIV-negative (HIV-) women; however, WWH presented a significantly higher TMB in comparison to HIV- patients. Seventy-five percent of lung cancers and 61% of breast cancers were defined as TMB-high (more than 10 mutation/mb of DNA).

Conclusion:

This study affirms the recommendation that WWH be included in clinical trials of novel treatments for these cancers. Although these data are preliminary, the high TMB in WLHV suggests, paradoxically, that this immune challenged population may benefit greatly from immune checkpoint inhibitor therapies.
Prevalence and Correlates of Electrocardiographic Abnormalities in Adults With HIV: Insights From the Randomized Trial to Prevent Vascular Events in HIV (REPRIEVE)
Authors: Bloomfield Gerald S. , Weir Isabelle R. , Ribaudo Heather J. , Fitch Kathleen V. , Fichtenbaum Carl J. , Moran Laura E. , Bedimo Roger , de Filippi Christopher , Morse Caryn G. , Piccini Jonathan , Zanni Markella V. , Lu Michael T. , Hoffmann Udo , Grinspoon Steven K. , Douglas Pamela S.
Published: December 2021

Background:

People with HIV (PWH) are at increased risk of cardiovasvular disease (CVD) and sudden cardiac death. Previous work has suggested an association between HIV infection and electrocardiographic (ECG) abnormalities. There are limited data on the burden of ECG abnormalities among PWH in a multiracial, multiethnic globally representative population.

Setting:

One hundred twenty sites in the Randomized Trial to Prevent Vascular Events in HIV (REPRIEVE).

Methods:

ECG findings were grouped into clinically relevant categories using sex-specific thresholds when indicated. We used the Fisher exact tests to assess associations of demographic characteristics and ECG abnormalities. We used logistic regression model to assess associations between demographic and HIV management measures, with adjustment.

Results:

We analyzed data for 7720 PWH (99% of participants) (median age 50 years, 69% male participants). There were 3346 (43%) Black or African American, 2680 (35%) White, and 1139 (15%) Asian participants. Most of the participants (97%) had viral load that was <400 copies/mL or <lower limits of quantification. Nearly half of the participants had at least one ECG abnormality (44%). QTc prolongation was more common among male than female participants (9% vs. 6%, P = 0.001) and nearly twice as common among Asian participants (12%) when compared with other racial groups (7%) (P < 0.0001). Participants with viral load >400 copies/mL had approximately twice the odds of prolonged QTc compared with those that were undetectable (adjusted OR: 2.05, 95% CI: 1.22 to 3.45).

Conclusions:

Prolonged QTc is common among male, Asian, and REPRIEVE participants with higher viral loads. These relationships warrant future investigation of linkages to ensuing CVD events among PWH.
Evaluation of the Viability of Untreated Leiomyomas Using Computed Tomography–Detected Calcification Patterns
Authors: Crane Erin P. , Fenlon Edward P. , Ascher Susan M. , Balaji Dhiksha , Siegelman Evan S.
Published: December 2021

Objective

To evaluate the relationship between computed tomography (CT)-detected calcification patterns and Magnetic Resonance Imaging (MRI) enhancement as a surrogate for viability in untreated uterine leiomyomas.

Methods

We queried 2 university hospital databases to identify patients with: (1) at least 1 calcified leiomyoma on CT greater than 1 cm (2) contrast-enhanced MRI of the pelvis performed within 5 years of the CT, and (3) no prior history of uterine fibroid embolization (UFE). Computed tomography was used to analyze calcification pattern and contrast-enhanced MRI to analyze size and viability.

Results

There were 12,862 reports that fit the criteria. After exclusion, 50 patients with 74 calcified untreated leiomyomas were analyzed. Three calcification patterns were identified: rim (n = 22), diffuse (n = 9), and coarse either less than or greater than 50% (n = 43). Four of 22 (18%) of leiomyomas with rim calcification were viable. Three of 9 (33%) of leiomyomas with diffuse calcification were viable. All leiomyomas with coarse calcifications were viable, 43 of 43 (100%).

Conclusions

Leiomyomas with coarse calcifications are viable, whereas the majority with rim or diffuse calcification are not. This information may be helpful when triaging symptomatic women to treatment.
The Combined Interpretation of 68Ga-DOTATATE PET/CT and 18F-FDG PET/CT in Metastatic Gastroenteropancreatic Neuroendocrine Tumors
Authors: Hayes Aimee R. , Furtado O'Mahony Luke , Quigley Ann-Marie , Gnanasegaran Gopinath , Caplin Martyn E. , Navalkissoor Shaunak , Toumpanakis Christos
Published: December 2021

Purpose

Gastroenteropancreatic neuroendocrine neoplasms (GEP NEN) are widely heterogeneous in their biological behavior, and predicting prognosis and optimal treatment strategies can be challenging. 68Ga-DOTATATE PET/CT is a sensitive imaging modality for well-differentiated NEN and indicates a favorable prognosis, whereas 18F-FDG PET/CT avidity indicates disease that is potentially more aggressive. There has been emerging interest in the combined interpretation of 68Ga-DOTATATE and 18F-FDG PET and its prognostic significance. We aimed to assess the prognostic utility of a classification system that incorporates the complex findings of 68Ga-DOTATATE and 18F-FDG PET interpreted side-by-side in patients with metastatic GEP NEN.

Methods

We defined 3 68Ga-DOTATATE/18F-FDG “dual-tracer PET” groups: D1 (68Ga-DOTATATE positive/18F-FDG negative), D2 (68Ga-DOTATATE positive/18F-FDG positive), and D3 (68Ga-DOTATATE negative/18F-FDG positive). We retrospectively assessed the association between the dual-tracer PET classification and progression-free and overall survival (OS) using Kaplan-Meier analysis. Univariate and multivariate analyses were performed using the Cox proportional hazards model.

Results

Eighty-seven patients with metastatic GEP NEN and contemporaneous 68Ga-DOTATATE and 18F-FDG PET were included. The dual-tracer PET classification was an independent predictor of OS (multivariate P = 0.016) and also predicted progression-free survival (univariate P = 0.030). Other independent predictors of OS included chromogranin A and World Health Organization (WHO) grade. WHO grade was not associated with OS from the time of dual-tracer PET but was an independent predictor of OS from the date of histological diagnosis (multivariate P = 0.003).

Conclusion

Our study demonstrates that a classification system combining the complex findings of 68Ga-DOTATATE and 18F-FDG PET is correlated with prognosis. Further research is needed to prospectively validate these findings and to explore whether dual-tracer PET scores may also be able to predict response to treatment.
Potential and Most Relevant Applications of Total Body PET/CT Imaging
Authors: Alavi Abass , Saboury Babak , Nardo Lorenzo , Zhang Vincent , Wang Meiyun , Li Hongdi , Raynor William Y. , Werner Thomas J. , Høilund-Carlsen Poul F. , Revheim Mona-Elisabeth
Published: December 2021

The introduction of total body (TB) PET/CT instruments over the past 2 years has initiated a new and exciting era in medical imaging. These instruments have substantially higher sensitivity (up to 68 times) than conventional modalities and therefore allow imaging the entire body over a short period. However, we need to further refine the imaging protocols of this instrument for different indications. Total body PET will allow accurate assessment of the extent of disease, particularly, including the entire axial and appendicular skeleton. Furthermore, delayed imaging with this instrument may enhance the sensitivity of PET for some types of cancer. Also, this modality may improve the detection of venous thrombosis, a common complication of cancer and chemotherapy, in the extremities and help prevent pulmonary embolism. Total body PET allows assessment of atherosclerotic plaques throughout the body as a systematic disease. Similarly, patients with widespread musculoskeletal disorders including both oncologic and nononcologic entities, such as degenerative joint disease, rheumatoid arthritis, and osteoporosis, may benefit from the use of TB-PET. Finally, quantitative global disease assessment provided by this approach will be superior to conventional measurements, which do not reflect overall disease activity. In conclusion, TB-PET imaging may have a revolutionary impact on day-to-day practice of medicine and may become the leading imaging modality in the future.
Prospective Paired Comparison of 123I-FP-CIT SPECT Images Obtained With a 360°-CZT and a Conventional Camera
Authors: Piatkova Yuliya , Payoux Pierre , Boursier Caroline , Bordonne Manon , Roch Veronique , Marie Pierre-Yves , Hossu Gabriela , Imbert Laëtitia , Verger Antoine
Published: December 2021

Purpose

This study aimed to compare 123I-FP-CIT SPECT imaging obtained from a 360° cadmium-zinc-telluride (CZT) camera with different focus configurations and from a conventional Anger camera.

Methods

This prospective study (NCT03980418) included patients referred to 123I-FP-CIT SPECT imaging who consecutively underwent a 30-minute acquisition on a conventional camera immediately followed by two 15-minute acquisitions on the 360°-CZT camera with, respectively, striatum and brain focus and reconstruction parameters to give equivalent contrast ratios, albeit with higher spatial resolution for the CZT camera. Tomographic count sensitivities were calculated. The images were analyzed through visual, according to 5 independent physicians, and automatic semiquantitative analyses.

Results

Ninety-two patients were included in this study. The 360°-CZT camera tomographic count sensitivities showed increases of +25% and +18% for striatum and brain focus, respectively, as well as significantly higher quality scores (P ≤ 0.04) in comparison to the conventional camera. The κ scores of consensual visual analysis were 0.80 and 0.85, and correlation coefficients of semiquantitative analysis for striatum uptakes were 0.75 and 0.76 for the comparisons of images obtained with the 2 cameras, with striatum and brain focus, respectively, for the CZT camera. Advanced age was the single predictor of discordant cases (10/92 [11%]) showing systematically abnormal scans with the conventional camera, potentially as a result of partial volume effect.

Conclusions

Irrespective of focus mode, this high-sensitivity 360°-CZT camera provides concordant 123I-FP-CIT SPECT results when compared with a conventional camera, but with shorter acquisition times, higher image quality, and few discordant cases possibly explained by its higher spatial resolution.
Statistical Inferences and Analysis based on the COVID-19 Data from the United States
Authors: Rethnakar Nivedita
Published: December 2021

This paper investigates the mortality statistics of the COVID-19 pandemic from the United States perspective. We bring out several exciting and glaring aspects of the pandemic, otherwise hidden, using empirical data analysis and statistical inference tools. First, specific patterns seen in demographics such as race/ethnicity are analyzed qualitatively and quantitatively. We looked at the role of factors such as population density in mortality rates. A detailed study of the connections between COVID-19 and other respiratory diseases is also covered. Finally, we examine the temporal dynamics of the COVID-19 outbreak and vaccines’ stellar impact in controlling the pandemic. Statistical inference such as the ones gathered in this paper would be helpful for better scientific understanding, policy preparation, and thus adequately preparing, should a similar situation arise in the future.
TRAWLING: a Transcriptome Reference Aware of spLIciNG events
Authors: Nanni Noemi Di , Reyes Alejandro , Ho Daniel , Ihry Robert , Kauffmann Audrey , Durand Eric Y. , de Weck Antoine
Published: December 2021

Alternative splicing is critical for human gene expression regulation and plays an important role in multiple human diseases. In this context, RNA sequencing has emerged as powerful approach to detect alternative splicing events.

In parallel, fast alignment-free methods have emerged as a viable alternative to quantify gene and transcript level abundance from RNAseq data. However, the ability to detect differential splicing events is dependent on the annotation of the transcript reference provided by the user.

Here, we introduce a new reference transcriptome aware of splicing events, TRAWLING, which simplifies the detection of aberrant splicing events in a fast and simple way. In addition, we evaluate the performances and the benefits of aligning transcriptome data to TRAWLING using three different RNA sequencing datasets: whole transcriptome sequencing, single cell RNA sequencing and Digital RNA with pertUrbation of Genes.

Collectively, our comprehensive evaluation underlines the value of using TRAWLING in transcriptomic data analysis.

Availability and implementation

Our code is available athttps://github.com/Novartis/TRAWLING
The human brain networks mediating the vestibular sensation of self-motion
Authors: Hadi Zaeem , Pondeca Yuscah , Calzolari Elena , Mahmud Mohammad , Chepisheva Mariya , Smith Rebecca M , Rust Heiko , Sharp David J , Seemungal Barry M
Published: December 2021

Vestibular Agnosia - where peripheral vestibular activation triggers the usual reflex nystagmus response but with attenuated or no self-motion perception - is found in brain disease with disrupted cortical network functioning, e.g. traumatic brain injury (TBI) or neurodegeneration (Parkinson’s Disease). Patients with acute focal hemispheric lesions (e.g. stroke) do not manifest vestibular agnosia. Thus brain network mapping techniques, e.g. resting state functional MRI (rsfMRI), are needed to interrogate functional brain networks mediating vestibular agnosia. Whole-brain rsfMRI was acquired from 39 prospectively recruited acute TBI patients with preserved peripheral vestibular function, along with self-motion perceptual thresholds during passive yaw rotations in the dark. Following quality-control checks, 25 patient scans were analyzed. TBI patients were classified as having vestibular agnosia (n = 11) or not (n = 14) via laboratory testing of self-motion perception. Using independent component analysis, we found altered functional connectivity in the right superior longitudinal fasciculus and left rostral prefrontal cortex in vestibular agnosia. Moreover, regions of interest analyses showed both inter-hemispheric and intra-hemispheric network disruption in vestibular agnosia. In conclusion, our results show that vestibular agnosia is mediated by bilateral anterior and posterior network dysfunction and reveal the distributed brain mechanisms mediating vestibular self-motion perception.
High School Science Fair: Ethnicity Trends in Student Participation and Experience
Authors: Grinnell Frederick , Dalley Simon , Reisch Joan
Published: December 2021

In this paper, we report ethnicity trends in student participation and experience in high school science and engineering fair (SEFs). SEF participation showed significant ethnic diversity. For survey students, the approximate distribution was Asian-32%; Black-11%; Hispanic-20%; White-33%; Other-3%. Comparing the SEF level at which students competed from school to district to region to state levels, we observed that black students made up only 4.5% of the students who participated in SEF beyond the school level, whereas students from other ethnic groups were more equally represented at all levels. The lower percentage of Black students resulted from a combination of lower overall participation in SEF and lower percentage of those students who did participate to advance to SEFs beyond the school level. Students who advanced to SEFs beyond the school level frequently received help from scientists, coaching for the interview, and were not required to participate in SEF. Black students received the least help from scientists, were least likely to receive coaching for the interview, and were most likely to be required to participate in SEF. They also were most likely to receive no help from parents, teachers, or scientists. Asian and Hispanic students (63.8% and 56.8%) indicated a greater interest in careers in science and engineering (S&E) compared to Black and White students (43.7% & 50.7%). In addition to career interest, the most important experiences that correlated with students who indicated that SEF increased their interests in S&E were getting help from the internet, books and magazines; getting help fine tuning the report; and overcoming obstacles by doing more background research, making a timeline, and perseverance. Black students did not report a positive effect of any of these strategies but experienced time pressure as more of an obstacle than did other students. Our findings identify a wide range of student experiences associated with positive SEF outcomes that could be enhanced for all students but especially Black students. More involvement of scientists in helping students who participate in SEFs would be particularly valuable.
MitoVisualize: A resource for analysis of variants in human mitochondrial RNAs and DNA
Authors: Lake Nicole J. , Zhou Lily , Xu Jenny , Lek Monkol
Published: December 2021

We present MitoVisualize, a new tool for analysis of the human mitochondrial DNA (mtDNA). MitoVisualize enables visualization of: (1) the position and effect of variants in mitochondrial transfer RNA (tRNA) and ribosomal RNA (rRNA) secondary structures alongside curated variant annotations, (2) data across RNA structures, such as to show all positions with disease-associated variants or with post-transcriptional modifications, and (3) the position of a base, gene or region in the circular mtDNA map, such as to show the location of a large deletion. All visualizations can be easily downloaded as figures for reuse. MitoVisualize can be useful for anyone interested in exploring mtDNA variation, though is designed to facilitate mtDNA variant interpretation in particular. MitoVisualize can be accessed via https://www.mitovisualize.org/. The source code is available at https://github.com/leklab/mito_visualize/.
Elucidating design principles for engineering cell-derived vesicles to inhibit SARS-CoV-2 infection
Authors: Gunnels Taylor F. , Stranford Devin M. , Mitrut Roxana E. , Kamat Neha P. , Leonard Joshua N.
Published: December 2021

The ability of pathogens to develop drug resistance is a global health challenge. The SARS-CoV-2 virus presents an urgent need wherein several variants of concern resist neutralization by monoclonal antibody therapies and vaccine-induced sera. Decoy nanoparticles—cell-mimicking particles that bind and inhibit virions—are an emerging class of therapeutics that may overcome such drug resistance challenges. To date, we lack quantitative understanding as to how design features impact performance of these therapeutics. To address this gap, here we perform a systematic, comparative evaluation of various biologically-derived nanoscale vesicles, which may be particularly well-suited to sustained or repeated administration in the clinic due to low toxicity, and investigate their potential to inhibit multiple classes of model SARS-CoV-2 virions. A key finding is that such particles exhibit potent antiviral efficacy across multiple manufacturing methods, vesicle subclasses, and virus-decoy binding affinities. In addition, these cell-mimicking vesicles effectively inhibit model SARS-CoV-2 variants that evade monoclonal antibodies and recombinant protein-based decoy inhibitors. This study provides a foundation of knowledge that may guide the design of decoy nanoparticle inhibitors for SARS-CoV-2 and other viral infections.
SARS-CoV-2 infection of olfactory epithelial cells and neurons drives acute lung injury and lethal COVID-19 in mice
Authors: Tang Alan T. , Buchholz David W. , Szigety Katherine M. , Imbhiaka Brian , Gao Siqi , Frankfurter Maxwell , Wang Min , Yang Jisheng , Hewins Peter , Mericko-Ishizuka Patricia , Adrian Leu N , Sterling Stephanie , Monreal Isaac A. , Sahler Julie , August Avery , Zhu Xuming , Jurado Kellie A. , Xu Mingang , Morrisey Edward E. , Millar Sarah E. , Aguilar Hector C. , Kahn Mark L.
Published: December 2021

Lethal COVID-19 is associated with respiratory failure that is thought to be caused by acute respiratory distress syndrome (ARDS) secondary to pulmonary infection. To date, the cellular pathogenesis has been inferred from studies describing the expression of ACE2, a transmembrane protein required for SARS-CoV-2 infection, and detection of viral RNA or protein in infected humans, model animals, and cultured cells. To functionally test the cellular mechanisms of COVID-19, we generated hACE2fl animals in which human ACE2 (hACE2) is expressed from the mouse Ace2 locus in a manner that permits cell-specific, Cre-mediated loss of function. hACE2fl animals developed lethal weight loss and hypoxemia within 7 days of exposure to SARS-CoV-2 that was associated with pulmonary infiltrates, intravascular thrombosis and patchy viral infection of lung epithelial cells. Deletion of hACE2 in lung epithelial cells prevented viral infection of the lung, but not weight loss, hypoxemia or death. Inhalation of SARS-CoV-2 by hACE2fl animals resulted in early infection of sustentacular cells with subsequent infection of neurons in the neighboring olfactory bulb and cerebral cortex— events that did not require lung epithelial cell infection. Pharmacologic ablation of the olfactory epithelium or Foxg1Cre mediated deletion of hACE2 in olfactory epithelial cells and neurons prevented lethality and neuronal infection following SARS-CoV-2 infection. Conversely, transgenic expression of hACE2 specifically in olfactory epithelial cells and neurons in Foxg1Cre; LSL-hACE2 mice was sufficient to confer neuronal infection associated with respiratory failure and death. These studies establish mouse loss and gain of function genetic models with which to genetically dissect viral-host interactions and demonstrate that lethal disease due to respiratory failure may arise from extrapulmonary infection of the olfactory epithelium and brain. Future therapeutic efforts focused on preventing olfactory epithelial infection may be an effective means of protecting against severe COVID-19.
A deep learning-based multisite neuroimage harmonization framework established with traveling-subject dataset
Authors: Tian Dezheng , Zeng Zilong , Sun Xiaoyi , Tong Qiqi , Li Huanjie , He Hongjian , Gao Jiahong , He Yong , Xia Mingrui
Published: December 2021

The accumulation of multisite large-sample MRI datasets collected by large brain research projects in the last decade has provided a critical resource for understanding the neurobiological mechanisms underlying cognitive functions and brain disorders. However, the significant site effects, observed in the imaging data and their derived structural and functional features, has prevented the derivation of consistent findings across different studies. The development of harmonization methods that can effectively eliminate complex site effects while maintaining biological characteristics in neuroimaging data has become a vital and urgent requirement for multisite imaging studies. Here, we proposed a deep learning-based framework to harmonize imaging data from pairs of sites, in which site factors and brain features can be disentangled and encoded. We trained the proposed framework with a publicly available traveling-subject dataset from SRPBS and harmonized the gray matter volume maps from eight source sites to a target site. The proposed framework significantly eliminated inter-site differences in gray matter volume. The embedded encoders successfully captured both the abstract texture of site factors and the concrete brain features. Moreover, the proposed framework exhibited outstanding performance relative to conventional statistical harmonization methods in site effect removal, data distribution homogenization, and intra-subject similarity improvement. Together, the proposed method offers a powerful and interpretable deep learning-based harmonization framework for multisite neuroimaging data that could enhance reliability and reproducibility in multisite studies for brain development and brain disorders.
Met/HGFR triggers detrimental reactive microglia in TBI
Authors: Rehman Rida , Miller Michael , Krishnamurthy Sruthi Sankari , Kjell Jacob , Elsayed Lobna , olde Heuvel Florian , Conquest Alison , Chandrasekar Akila , Ludolph Albert , Boeckers Tobias , Mulaw Medhanie A , Goetz Magdalena , Morganti-Kossmann Maria Cristina , Takeoka Aya , Roselli Francesco
Published: December 2021

The complexity of the signaling events, cellular responses unfolding in neuronal, glial and immune cells upon Traumatic brain injury (TBI) constitutes an obstacle in elucidating pathophysiological links and targets for intervention. We used array phosphoproteomics in a murine mild blunt TBI to reconstruct the temporal dynamics of tyrosine-kinase signaling in TBI and then to scrutinize the large-scale effects of the perturbation of cMet/HGFR, VEGFR1 and Btk signaling by small molecules. cMet/HGFR emerged as a selective modifier of the early microglial response, and cMet/HGFR blockade prevented the induction of microglial inflammatory mediators, of reactive microglia morphology and of TBI-associated responses in neurons, vessels and brain extracellular matrix. Acute or prolonged cMet/HGFR inhibition ameliorated neuronal survival and motor recovery. Early elevation of HGF itself in the CSF of TBI patients suggest that this mechanism has translational value in human subjects. Our findings identify cMet/HGFR as a modulator of early neuroinflammation in TBI with translational potential and indicate several RTK families as possible additional targets for TBI treatment.

Controlling neuroinflammation in neurotrauma is an important but unachieved goal. This study exploits a moderate TBI model and array-based proteomics to identify cMet as a new inducer of reactive microglia. A small-molecule inhibitor of cMet contains microglial reactivity, reduces neuronal and vascular alterations, limits behavioural disturbances and accelerates recovery.

Highlights

Met is activated in microglia upon TBI and drives microglial reactivity.

A Met inhibitor reduces motor dysfunction upon TBI and promotes recovery.

Blockade of MET prevents the appearance of a reactive microglia.

The cMET inhibitor reduces the sub-acute neuronal loss after TBI.
scBERT as a Large-scale Pretrained Deep Language Model for Cell Type Annotation of Single-cell RNA-seq Data
Authors: Yang Fan , Wang Wenchuan , Wang Fang , Fang Yuan , Tang Duyu , Huang Junzhou , Lu Hui , Yao Jianhua
Published: December 2021

Annotating cell types based on the single-cell RNA-seq data is a prerequisite for researches on disease progress and tumor microenvironment. Here we show existing annotation methods typically suffer from lack of curated marker gene lists, improper handling of batch effect, and difficulty in leveraging the latent gene-gene interaction information, impairing their generalization and robustness. We developed a pre-trained deep neural network-based model scBERT (single-cell Bidirectional Encoder Representations from Transformers) to overcome the challenges. Following BERT’s approach of pre-train and fine-tune, scBERT obtains a general understanding of gene-gene interaction by being pre-trained on huge amounts of unlabeled scRNA-seq data and is transferred to the cell type annotation task of unseen and user-specific scRNA-seq data for supervised fine-tuning. Extensive and rigorous benchmark studies validated the superior performance of scBERT on cell type annotation, novel cell type discovery, robustness to batch effect, and model interpretability.
Effects of chronic exposure to fluoxetine, eicosapentaenoic acid, and lipopolysaccharide on behavior and hippocampal transcriptome in the rat model of prolonged chronic unpredictable stress
Authors: Demin Konstantin A. , Kolesnikova Tatiana O. , Galstyan David S. , Krotova Nataliya A. , Ilyin Nikita P. , Derzhavina Ksenia A. , Seredinskaya Maria , Kositsyn Yuriy M. , Sorokin Dmitry V. , Nerush Maria O. , Khaybaev Abubakar-Askhab S. , Pushkareva Sofia A. , Petersen Elena V. , de Abreu Murilo S. , Masharsky Alexey , Kalueff Allan V.
Published: December 2021

Animal models are widely used to study stress-induced affective disorders and associated with them neuroinflammation and other neuroimmune processes. Here, we examined rat behavioral and hippocampal transcriptomic responses to prolonged chronic unpredictable stress (PCUS), as well as following a 4-week treatment with a classical antidepressant fluoxetine, an anti-inflammatory agent eicosapentaenoic acid (EPA), a pro-inflammatory agent lipopolysaccharide (LPS) and their combinations. Overall, PCUS evoked an anxiety-like behavioral phenotype in rats (corrected by chronic fluoxetine alone or combined with other drugs), EPA was anxiolytic and LPS promoted anxiety in this model. PCUS evoked pronounced transcriptomic responses in rat hippocampi, including >200 differentially expressed genes. While pharmacological manipulations did not affect hippocampal gene expression markedly,Gpr6,Drd2andAdora2awere downregulated in stressed rats treated with fluoxetine+EPA, suggesting G protein-coupled receptor 6, dopamine D2 receptor and adenosine A2A receptor as potential evolutionarily conserved targets in chronic stress. Overall, these findings support the validity of rat PCUS paradigm as a useful tool to study stress-related affective pathologies and calls for further research probing how various conventional and novel drugs modulate behavioral and neurotranscriptomic biomarkers of chronic stress.
Prdm16 amplifies Notch signaling and suppresses venous lineage specification to prevent arteriovenous malformations during vascular development
Authors: Van Wauwe Jore , Craps Sander , Ashmita KC , Asuncion Lisabel , Vrancaert Pieter , Daems Margo , Finck Chris , Wright Shane , Müller Christian , Leigh Nicholas D. , Frye Maike , MacRae Calum A. , Luttun Aernout , Beerens Manu
Published: December 2021

Proper arterial versus venous endothelial lineage identity is required to establish a hierarchical network of arteries and veins and prevent the occurrence of life-threatening arteriovenous malformations. The molecular mechanisms that govern arteriovenous lineage specification remain however incompletely understood. Here, we demonstrate that the transcription factor Prdm16 is expressed in arterial but not venous endothelial cells (ECs) from the earliest stages of development, where it actively promotes arterial EC identity by enhancing canonical Notch activity, while simultaneously suppressing the alternative venous cell fate. Concordantly, our results in zebrafish show that Prdm16 coordinates proper arterial development and arteriovenous lineage specification together with canonical Notch signaling, as combined loss of prdm16 and notch in zebrafish invariably leads to arteriovenous malformations (AVMs). Although the arterializing effect of Prdm16 in human ECs is dependent on the absolute levels of the cleaved intracellular domain of the Notch receptors (NICD), Prdm16 does not increase NICD levels per se. Rather, Prdm16 physically and functionally interacts with NICD to potentiate its effect. Prdm16 further finetunes Notch signaling and arterial development by complexing with the Notch downstream effector Hey2, which regulates arterial lineage specification and development across species. Together, our data demonstrate that Prdm16 act as a rheostat for endothelial Notch activity and suggest that Prdm16 signaling may constitute a novel therapeutic target for AVMs.
Constructing a multiple-layer interactome for SARS-CoV-2 in the context of lung disease: Linking the virus with human genes and co-infecting microbes
Authors: Lou Shaoke , Li Tianxiao , Gerstein Mark
Published: December 2021

The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) pandemic has caused millions of deaths worldwide. Many efforts have focused on unraveling the mechanism of the viral infection to develop effective strategies for treatment and prevention. Previous studies have provided some clarity on the protein-protein interaction linkages occurring during the life cycle of viral infection; however, we lack a complete understanding of the full interactome, comprising human miRNAs and protein-coding genes and co-infecting microbes. To comprehensively determine this, we developed a statistical modeling method using latent Dirichlet allocation (called MLCrosstalk, for multiple-layer crosstalk) to fuse many types of data to construct the full interactome of SARS-CoV-2. Specifically, MLCrosstalk is able to integrate samples with multiple layers of information (e.g., miRNA and microbes), enforce a consistent topic distribution on all data types, and infer individual-level linkages (i.e., differing between patients). We also implement a secondary refinement with network propagation to allow our microbe-gene linkages to address larger network structures (e.g., pathways). Using MLCrosstalk, we generated a list of genes and microbes linked to SARS-CoV-2. Interestingly, we found that two of the identified microbes, Rothia mucilaginosa and Prevotella melaninogenica, show distinct patterns representing synergistic and antagonistic relationships with the virus, respectively. We also identified several SARS-COV-2-associated pathways, including the VEGFA-VEGFR2 and immune response pathways, which may provide potential targets for drug design.
Type-I interferon signaling is essential for robust metronomic chemo-immunogenic tumor regression in murine triple-negative breast cancer
Authors: Vergato Cameron , Doshi Kshama A. , Roblyer Darren , Waxman David J.
Published: December 2021

Triple-negative breast cancer (TNBC) is characterized by poor prognosis and aggressive growth, with limited therapeutic options for many patients. Here, we use two syngeneic mouse TNBC models, 4T1 and E0771, to investigate the chemo-immunogenic potential of cyclophosphamide and the mechanistic contributions of cyclophosphamide-activated type-I interferon (IFN) signaling to therapeutic activity.

Chemically-activated cyclophosphamide induced robust IFNα/β receptor-1-dependent signaling linked to hundreds of IFN-stimulated gene responses in both TNBC lines. Further, in 4T1 tumors, cyclophosphamide given on a medium-dose, 6-day intermittent metronomic schedule induced strong IFN signaling but comparatively weak immune cell infiltration associated with long-term tumor growth stasis. Induction of IFN signaling was somewhat weaker in E0771 tumors but was followed by extensive downstream gene responses, robust immune cell infiltration and prolonged tumor regression. The immune dependence of these effective anti-tumor responses was established by CD8 T-cell immunodepletion, which blocked cyclophosphamide-induced E0771 tumor regression and led to tumor stasis followed by regrowth. Strikingly, IFNα/β receptor-1 antibody blockade was even more effective in preventing E0771 immune cell infiltration and blocked the major tumor regression induced by cyclophosphamide treatment. Type-I IFN signaling is thus essential for the robust chemo-immunogenic response of these TNBC tumors to cyclophosphamide administered on a metronomic schedule.

Significance

TNBC has poor prognosis and few therapeutic options. We show that cyclophosphamide treatment can induces extensive tumor regression in syngeneic mouse models of TNBC via a chemo-immunogenic mechanism linked to type-I IFN production. Our findings establish that IFN signaling is essential for the robust anti-tumor actions of cyclophosphamide and suggest that treatment resistance may stem from silencing the IFN pathway. This suggests a new avenue for improving TNBC treatment efficacy.
Bat teeth illuminate the diversification of mammalian tooth classes
Authors: Sadier Alexa , Anthwal Neal , Krause Andrew L. , Dessalles Renaud , Lake Michael , Bentolila Laurent , Haase Robert , Nieves Natalie , Santana Sharlene , Sears Karen
Published: December 2021

Tooth classes are a mammalian innovation that has contributed to the evolutionary success of mammals. However, our understanding of how tooth classes have evolved and diversified remains limited. Here, we use the evolutionary radiation of noctilionoid bats, the most diverse clade of mammals in terms of diet type, as a model system to show how the tooth developmental program evolved during the adaptation to new diet types. We combined morphological, developmental, cellular, and modeling approaches, to investigate the developmental differences between two tooth classes, molars and premolars and the mechanisms driving their diversification. We demonstrate that tooth classes develop through independent developmental cascades that deviate from classical models. Then we showed that the dramatic diversification of tooth number and size is driven by the modulation of the growth rate of the jaw, explaining the rapid gain/loss of teeth during the evolution of this clade. Finally, we propose a mathematical model that recapitulates the successive appearance of tooth buds and supports the hypothesis that growth acts as a key driver of the evolution of tooth number and size by tinkering with reaction/diffusion processes. Our results demonstrate developmental independence between mammalian tooth classes and provide a mechanism to explain their rapid diversification. More broadly, these results reveal how simple modifications of one developmental mechanism by another can drive the evolution of repeated structures during adaptive radiations.
Characterization of epigenetic alterations in esophageal cancer by whole-genome bisulfite sequencing
Authors: Pan Feng , Yu Shuai-Xia , Wang Xuan , Huang He-Cheng , Cai Zeng-Ying , Wang Jia-Min , Lin Shu-Yuan , Gao Yu-Lin , Li En-Min , Xu Li-Yan
Published: December 2021

Esophageal carcinoma is a common and aggressive malignancy, and its patients have dismal clinical outcomes. The epigenetic dysregulation in both major subtypes, esophageal squamous cell carcinoma (ESCC) and adenocarcinoma (EAC), awaits further characterization. Here, we perform whole-genome bisulfite sequencing (WGBS) on a total of 43 esophageal cancer and normal samples, generating one of the largest WGBS datasets in this cancer to date. Focusing on hypomethylated regions in cancer, we show that they are associated with increased chromatin activity and enhancer RNA expression. Using this large collection of WGBS dataset, we reveal and validate novel clusters in both ESCC and EAC. We further identify specific molecular features in each cluster, with potential clinical implications. These data together advance our understanding of the epigenetic alterations in esophageal cancer and provide a rich resource for the research community of this disease.
Association of Egg Consumption, Metabolic Markers, and Risk of Cardiovascular Diseases
Authors: Pan Lang , Chen Lu , Lv Jun , Pang Yuanjie , Guo Yu , Pei Pei , Du Huaidong , Yang Ling , Millwood Iona Y. , Walters Robin G. , Chen Yiping , Gong Weiwei , Chen Junshi , Yu Canqing , Chen Zhengming , Li Liming ,   the China Kadoorie Biobank Collaborative Group
Published: December 2021

Objective

To simultaneously explore the associations of self-reported egg consumption with plasma metabolic markers and these markers with CVD risk.

Methods

Totally 4,778 participants (3,401 CVD cases subdivided into subtypes and 1,377 controls) aged 30-79 were selected from a nested case-control study based on the China Kadoorie Biobank. Targeted nuclear magnetic resonance was used to quantify 225 metabolites and derived traits in baseline plasma samples. Linear regression was conducted to assess associations between self-reported egg consumption and metabolic markers, which were further compared with associations between metabolic markers and CVD risk.

Results

Egg consumption was associated with 24 out of 225 markers, including positive associations for apolipoprotein A1, acetate, mean HDL diameter, and lipid profiles of very large and large HDL, and inverse associations for total cholesterol and cholesterol esters in small VLDL. Among these 24 markers, 14 of them were associated with CVD risk. In general, the associations of metabolic markers with egg consumption and of metabolic markers with CVD risk showed opposite patterns.

Conclusions

In the Chinese population, egg consumption is associated with several metabolic markers, which may partially explain the protective effect of egg consumption on CVD.