bluuebunny/crossref_metadata_2025 huggingface dataset:
TBIO-05. R-loops in pediatric brain tumors
Authors: Wang Shanzheng , Gopisetty Apurva , Jäger Natalie , Pfister Stefan , Kool Marcel
Published: June 2022

R-loops are structures containing DNA-RNA hybrids and displaced single-stranded DNA, which are widely distributed across genomic regions. The generation and removal of R-loops is dynamically regulated by several factors including helicases and topoisomerases. Previously, we have identified high levels of R-loops associated with genomic instability in Embryonal Tumors with Multilayered Rosettes (ETMR) (Lambo et al. 2019), which is associated with a sensitivity to drugs targeting topoisomerases and DNA repair. However, it is unknown whether there are other pediatric cancers with high levels of R-loops, and whether R-loops in these tumors are also associated with genomic instability and sensitivity to specific treatments. Here, we have used real R-loops sequencing data sets, including ETMR DRIP-seq data, and the bioinformatic tool QmRLFS-finder (Wongsurawat et al. 2012), which can predict R-loops forming sequences (RLFSs) based on DNA sequence composition. By performing bioinformatic analyses of DRIP-seq data sets and integrating these with RLFSs from human reference genome simulations, we aim to analyze how reliable the different methods are to measure and predict R-loops and what role they have in cancer genomes. In ETMR, R-loops signals from DRIP-seq data were enriched around transcriptional start sites (TSS), comparable to R-loops distribution and enrichment in other published cell models. However, the overlap with RLFSs was limited, indicating that more validations with real DRIP-seq data from more ETMRs and other pediatric cancers are needed to validate the different methods. Taken together, until now, we developed methods to (semi-)quantify R-loops by combining real sequencing data and computational simulation approaches to investigate R-loops distribution in cancer genomes and to investigate whether R-loops are associated with breakpoints or other genetic aberrations in pediatric cancer entities.
The Characterization of Pathotypes in Grapevine Downy Mildew Provides Insights into the Breakdown of Rpv3, Rpv10, and Rpv12 Factors in Grapevines
Authors: Paineau Manon , Mazet Isabelle D. , Wiedemann-Merdinoglu Sabine , Fabre Frédéric , Delmotte François
Published: June 2022

We describe a standard method for characterizing the virulence profile of Plasmopara viticola, the causal agent of grapevine downy mildew. We used 33 European strains to inoculate six grapevine varieties carrying the principal factors for resistance to downy mildew (Rpv1, Rpv3.1, Rpv3.2, Rpv5, Rpv6, Rpv10, and Rpv12) and the susceptible Vitis vinifera ‘Chardonnay’. For each interaction, we characterized the level of sporulation by image analysis and the intensity of the grapevine hypersensitive response by visual score. We propose a definition for the breakdown of grapevine quantitative resistances combining these two traits. Among the 33 strains analyzed, 28 are virulent on at least one resistance factor. We identified five different pathotypes across the 33 strains analyzed: two pathotypes overcoming a single resistance factor (vir3.1 and vir3.2) and three complex pathotypes overcoming multiple resistance factors (vir3.1,3.2; vir3.2,12; vir3.1,3.2,10). Our findings confirm the widespread occurrence of P. viticola strains overcoming the Rpv3 haplotypes (28 strains). We also detected the first breakdown of resistance to the Rpv10 by a strain from Germany and the breakdown of Rpv12 factors by a strain from Hungary. The pathotyping method proposed here and the associated differential host range lay the groundwork for the early detection of resistance breakdown in grapevines. This approach will also facilitate the monitoring of the evolution of P. viticola populations at large spatial scales. This is an essential step forward to promoting durable management of the resistant grapevine varieties currently available.
A pan‐cancer analysis identifies HDAC11 as an immunological and prognostic biomarker
Authors: Li Ran , Wu Xiaolu , Zhao Ping , Xue Kai , Li Junmin
Published: June 2022

Histone deacetylase 11 (HDAC11) is aberrantly expressed in many types of cancer, and such abnormalities are associated with tumor immunity and heterogeneous clinical outcomes. Here, we explore the prognostic value and immunological function of HDAC11 across 33 cancer types. We observe HDAC11 is aberrantly expressed in 25 cancer types and positively or negatively associated with prognosis in different cancers. HDAC11 played a protective prognostic role in KIRP, KIRC, LGG, PCPG, READ, and UVM, which was contrary to the conventional opinion that HDAC11 was an oncogenic gene. Moreover, HDAC11 is negatively associated with tumor immune components, most immune checkpoint genes, and key cytokine expression. HDAC11 is correlated with tumor mutational burden in 11 cancer types and with microsatellite instability in 9 cancer types, suggesting HDAC11 may affect a patient's response to immune checkpoint inhibitor (ICI) therapy. In addition, HDAC11 is negatively correlated with the drug sensitivity of oxaliplatin, carmustine, ifosfamide, imexon, lomustine, and BN‐2629, indicating the potential synergy between HDAC11 inhibitors and these anti‐tumor drugs. In vitro assays indicate that HDAC11 inhibitor SIS17 combined with oxaliplatin shows a synergistic cytotoxic role in K562 cells while SIS17 has an antagonistic effect on the cytotoxic role of oxaliplatin in 769P cells. HDAC11 is also associated with hallmark pathways, including epithelial mesenchymal transition, IL‑6/JAK/STAT3, and allograft rejection pathways. Overall, we provide clues regarding the key role of HDAC11 in multiple cancers.
Retardation of Myopia by Multifocal Soft Contact Lens and Orthokeratology: A 1-Year Randomized Clinical Trial
Authors: Fang Jianxia , Huang Zhu , Long Yan , Zhu Miaomiao , Wu Qin , Chen Xiaojun , Xv Wei , Du Chixin
Published: June 2022

Objectives:

This randomized, single-blind, clinical trial compared the effectiveness of multifocal soft contact lenses (MFSCLs), orthokeratology contact lenses (Ortho-kCLs), and single vision spectacles (SVSs) for myopia control.

Methods:

Sixty-six eligible Chinese subjects, aged 7 to 15 years old with cycloplegic refraction measurements between −1.00 and −8.00 diopters (D), astigmatism not more than 1.00 D, and no history of myopia control treatment, were randomly assigned to wear MFSCLs, Ortho-kCLs, or SVSs for 1 year. For all three groups, baseline measurements of cycloplegic refraction, axial length (AL), and corneal endothelial cell density (CECD) were made. At the 6- and 12-month follow-up visits, changes in cycloplegic refraction, AL, and CECD were measured in the MFSCL and SVS groups. For the Ortho-kCL group, only changes in the AL were measured at 6 and 12 months, and CECD was measured at the 12-month follow-up visit.

Results:

After 1 year of lens wear, myopia progression of the SVS group, −0.938±0.117 D, was greater than that of the MFSCLs group, −0.591±0.106 D (P=0.032). Thus, MFSCLs reduced the rate of myopia progression by 37.0% compared with the SVSs. The AL elongations after 1 year were 0.30±0.03 mm for MFSCLs (P=0.027 vs SVSs), 0.31±0.04 mm for Ortho-kCLs (P=0.049 vs SVSs), and 0.41±0.04 mm for SVSs. Compared with the SVS group, the reduction in AL elongation was 26.8% and 24.4% in the MFSCL and Ortho-kCL groups, respectively. There were no significant differences in CECD among the three groups (P>0.05).

Conclusions:

Compared with SVSs, wearing MFSCLs and Ortho-kCLs significantly delayed myopia progression. MFSCLs and Ortho-kCLs are safe and promising methods of myopia control (chictr.org number, ChiCTR2100048452).
The Coexistence of Upper and Lower Body Segmental Infantile Hemangiomas
Authors: Shayegan Leila H. , Frieden Ilona J. , Davies Olivia M. T. , Drolet Beth A. , Siegel Dawn H. , Chamlin Sarah L. , Maguiness Sheilagh M. , Powell Julie , Shawber Carrie , Garzon Maria C.
Published: June 2022

Objectives:

PHACE and LUMBAR are distinct regional malformation sequences with a suspected shared pathogenesis. A dedicated case series illustrating an overlap between these entities has not been published. The purpose of this study was to characterize patients with both upper and lower body segmental infantile hemangiomas (sIHs) and congenital anomalies in an effort to further elucidate their etiology.

Methods:

We conducted a retrospective review of cases at 6 centers carrying a diagnosis of upper and lower body sIHs. A study instrument, including a map of cutaneous hemangiomas and congenital anomalies, was completed for each patient. A literature review for similar cases was conducted.

Results:

We identified 13 patients with both upper and lower body sIHs. 85% were female. Upper body sIH most commonly involved the periauricular region (62%), frontotemporal (54%), maxillary (54%), and mandibular (54%) segments. Lower body sIH were most frequently on the buttocks (77%), posterior thigh (62%), and anterior thigh (54%). Cerebrovascular (69%) and cardiac abnormalities (38%) were common. All 8 previously unreported cases demonstrated minimal, arrested growth (IH-MAG) of at least 1 sIH. We identified an additional 9 cases only partially meeting our criteria.

Conclusions:

In our cohort, certain reproducible embryological vascular patterns described in the literature seem to govern the distribution of sIH. The prevalence of periauricular involvement deserves additional exploration. Our characterization of patients only partially meeting criteria supports the concept that segmental patterns themselves carry risk for congenital anomalies and may merit additional evaluation.
Prediction of Future Health Care Utilization Through Note-extracted Psychosocial Factors
Authors: Dorr David A. , Quiñones Ana R. , King Taylor , Wei Melissa Y. , White Kellee , Bejan Cosmin A.
Published: June 2022

Background:

Persons with multimorbidity (≥2 chronic conditions) face an increased risk of poor health outcomes, especially as they age. Psychosocial factors such as social isolation, chronic stress, housing insecurity, and financial insecurity have been shown to exacerbate these outcomes, but are not routinely assessed during the clinical encounter. Our objective was to extract these concepts from chart notes using natural language processing and predict their impact on health care utilization for patients with multimorbidity.

Methods:

A cohort study to predict the 1-year likelihood of hospitalizations and emergency department visits for patients 65+ with multimorbidity with and without psychosocial factors. Psychosocial factors were extracted from narrative notes; all other covariates were extracted from electronic health record data from a large academic medical center using validated algorithms and concept sets. Logistic regression was performed to predict the likelihood of hospitalization and emergency department visit in the next year.

Results:

In all, 76,479 patients were eligible; the majority were White (89%), 54% were female, with mean age 73. Those with psychosocial factors were older, had higher baseline utilization, and more chronic illnesses. The 4 psychosocial factors all independently predicted future utilization (odds ratio=1.27–2.77, C-statistic=0.63). Accounting for demographics, specific conditions, and previous utilization, 3 of 4 of the extracted factors remained predictive (odds ratio=1.13–1.86) for future utilization. Compared with models with no psychosocial factors, they had improved discrimination. Individual predictions were mixed, with social isolation predicting depression and morbidity; stress predicting atherosclerotic cardiovascular disease onset; and housing insecurity predicting substance use disorder morbidity.

Discussion:

Psychosocial factors are known to have adverse health impacts, but are rarely measured; using natural language processing, we extracted factors that identified a higher risk segment of older adults with multimorbidity. Combining these extraction techniques with other measures of social determinants may help catalyze population health efforts to address psychosocial factors to mitigate their health impacts.
Data-Driven Nurse Staffing in the Neonatal Intensive Care Unit
Authors: Feldman Keith , Rohan Annie J.
Published: June 2022

The challenge of nurse staffing is amplified in the acute care neonatal intensive care unit (NICU) setting, where a wide range of highly variable factors affect staffing. A comprehensive overview of infant factors (severity, intensity), nurse factors (education, experience, preferences, team dynamics), and unit factors (structure, layout, shift length, care model) influencing pre-shift NICU staffing is presented, along with how intra-shift variability of these and other factors must be accounted for to maintain effective and efficient assignments. There is opportunity to improve workload estimations and acuity measures for pre-shift staffing using technology and predictive analytics. Nurse staffing decisions affected by intra-shift factor variability can be enhanced using novel care models that decentralize decision-making. Improving NICU staffing requires a deliberate, systematic, data-driven approach, with commitment from nurses, resources from the management team, and an institutional culture prioritizing patient safety.
Angle κ Measurement and Its Correlation with Other Ocular Parameters in Normal Population by a New Imaging Modality
Authors: Gharieb Ibrahim Hani M. , Gharieb Hesham Mohamed , Othman Ihab Saad
Published: June 2022

SIGNIFICANCE

This study obtained normative database for angle κ using Orbscan 3. The average angle κ values were 2.3 ± 1.34° in the whole sample, 2.23 ± 1.36° in myopic eyes, and 3.3 ±1.5° in hyperopic eyes. This is very important to optimize refractive surgery outcomes.

PURPOSE

The aim of this cross-sectional study was to obtain the value of mean angle κ in normal eyes of patients seeking laser vision correction, by the Orbscan 3.

METHODS

The study was conducted on healthy eyes of people seeking laser refractive surgery. A total of 1815 eyes of 908 candidates were included. These were examined as a part of pre-operative assessment. Orbscan 3 was used to measure angle κ and its XY intercepts, keratometry readings, central corneal thickness, thinnest location, white-to-white diameter, and corneal asphericity of front surface (Qf) and back surface (Qb).

RESULTS

The mean ± standard deviation angle κ in all eyes was 2.3 ± 1.34°. The values were 2.23 ± 1.36° in myopic eyes, 3.3 ±1.5° in hyperopic eyes, and 2.9 ±1.6° in emmetropic eyes. Positive correlation was found between angle κ and age, spherical equivalent, subjective sphere, and white-to-white diameter. On the other hand, axial length, average keratometry, central corneal thickness, pupil diameter, and asphericity Q front were negatively correlated with angle κ.

CONCLUSIONS

The mean ± standard deviation angle κ value measured by the Orbscan 3 was 2.3 ± 1.34°. This could be attributed to different software used, in addition to the relatively high axial length in the studied eyes.
International Perspectives on Joint Hypermobility
Authors: Nicholson Leslie L. , Simmonds Jane , Pacey Verity , De Wandele Inge , Rombaut Lies , Williams Cylie M. , Chan Cliffton
Published: June 2022

There is exponential clinical and research interest in joint hypermobility due to recognition of the complexity of identification, assessment, and its appropriate referral pathways, ultimately impacting management. This state-of-the-science review provides an international, multidisciplinary perspective on the presentation, etiology, and assessment of joint hypermobility, as it presents in those with and without a systemic condition. We synthesize the literature, propose standardizing the use of terminology and outcome measures, and suggest potential management directions. The major topics covered are (i) historical perspectives; (ii) current definitions of hypermobility, laxity, and instability; (iii) inheritance and acquisition of hypermobility; (iv) traditional and novel assessments; (v) strengths and limitations of current assessment tools; (vi) age, sex, and racial considerations; (vii) phenotypic presentations; (viii) generalized hypermobility spectrum disorder and hypermobility Ehlers-Danlos syndrome; and (ix) clinical implications and research directions. A thorough understanding of these topics will equip the reader seeking to manage individuals presenting with joint hypermobility, while mindful of its etiology. Management of generalized joint hypermobility in the context of a complex, multisystem condition will differ from that of acquired hypermobility commonly seen in performing artists, specific athletic populations, posttrauma, and so on. In addition, people with symptomatic hypermobility present predominantly with musculoskeletal symptoms and sometimes systemic symptoms including fatigue, orthostatic intolerance, and gastrointestinal or genitourinary issues. Some also display skeletal deformities, tissue and skin fragility, and structural vascular or cardiac differences, and these warrant further medical follow-up. This comprehensive review on the full spectrum of joint hypermobility will assist clinicians, coaches/sports trainers, educators, and/or researchers in this area.
Societal COVID-19 epidemic counter measures and activities associated with SARS-CoV-2 infection in an adult unvaccinated population – a case-control study in Denmark, June 2021
Authors: Munch Pernille Kold , Espenhain Laura , Hansen Christian Holm , Krause Tyra Grove , Ethelberg Steen
Published: June 2022

Measures to restrict physical inter-personal contact in the community have been widely implemented during the COVID-19 pandemic. We studied determinants for infection with SARS-CoV-2 with the aim of testing the efficiency of such measures.

We conducted a national matched case-control study among unvaccinated persons aged 18-49 years. Cases were selected among those testing positive for SARS-CoV-2 by RT-PCR over a five-day period in June 2021. Controls were selected from the national population register and were individually matched on age, sex and municipality of residence and had not previously tested positive. Cases and controls were interviewed via telephone about contact with other persons and exposures in the community. We included 500 cases and 529 controls and determined odds ratios (ORs) and 95% confidence intervals (95%CIs) by conditional logistical regression with adjustment for household size and immigration status.

We found having had contact with another individual with a known infection as the main determinant for SARS-CoV-2 infection. Reporting close contact with an infected person who either had or did not have symptoms resulted in ORs of 20 (95%CI:9.8-39) and 8.5 (95%CI 4.5-16) respectively. In contrast, community exposures were generally not associated with disease; several exposures were negatively associated. Exceptions were: attending fitness centers, OR=1.4 (95%CI:1.0-2.0) and consumption of alcohol in restaurants or cafés, OR=2.3 (95%CI:1.3–4.2).

For reference, we provide a timeline of non-pharmaceutical interventions in place in Denmark from February 2020 to March 2022. Fitness centers and alcohol consumption were mildly associated with infection, in agreement with findings of our similar study conducted six month earlier (Epidemiology & Infection 2021;150:e9.). Transmission of disease through involvement in community activities appeared to occur only rarely, suggesting that community restrictions in place were efficient. Instead, transmission appeared to primarily take place in a confined space via contact to known persons.
Volumetric bioluminescence imaging of cellular dynamics with deep learning based light-field reconstruction
Authors: Morales-Curiel Luis Felipe , Castro-Olvera Gustavo , Gonzalez Adriana , Lin Lynn , El-Quessny Malak , Porta-de-la-Riva Montserrat , Severino Jacqueline , Battle Laura , Ramallo Diego , Ruprecht Verena , Loza-Alvarez Pablo , Krieg Michael
Published: June 2022

The application of genetically encoded fluorophores for microscopy has afforded one of the biggest revolutions in the biosciences. Bioluminescence microscopy is an appealing alternative to fluorescence microscopy, because it does not depend on external illumination, and consequently does neither produce spurious background autofluorescence, nor perturb intrinsically photosensitive processes in living cells and animals. The low quantum yield of known luciferases, however, limit the acquisition of high signal-noise images of fast biological dynamics. To increase the versatility of bioluminescence microscopy, we present an improved low-light microscope in combination with deep learning methods to increase the signal to noise ratio in extremely photon-starved samples at millisecond exposures for timelapse and volumetric imaging. We apply our method to image subcellular dynamics in mouse embryonic stem cells, the epithelial morphology during zebrafish development, and DAF-16 FoxO transcription factor shuttling from the cytoplasm to the nucleus under external stress. Finally, we concatenate neural networks for denoising and light-field deconvolution to resolve intracellular calcium dynamics in three dimensions of freely movingCaenorhabditis eleganswith millisecond exposure times. This technology is cost-effective and has the potential to replace standard optical microscopy where external illumination is prohibitive.
The mIAA7 degron improves auxin-mediated degradation in C. elegans
Authors: Sepers Jorian J. , Verstappen Noud H. M. , Vo An A. , Ragle James Matthew , Ruijtenberg Suzan , Ward Jordan D. , Boxem Mike
Published: June 2022

Auxin-inducible degradation (AID) is a powerful tool for the targeted degradation of proteins with spatiotemporal control. One limitation of the AID system is that not all proteins are degraded efficiently. Here, we demonstrate that an alternative degron sequence, termed mIAA7, improves the efficiency of degradation in C. elegans, as previously reported in human cells. We tested depletion of a series of proteins with various sub-cellular localizations in different tissue types and found that the use of the mIAA7 degron resulted in faster depletion kinetics for five out of six proteins tested. The exception was the nuclear protein HIS-72, which was depleted with similar efficiency as with the conventional AID* degron sequence. The mIAA7 degron also increased the leaky degradation for two of the tested proteins. To overcome this problem, we combined the mIAA7 degron with the C. elegans AID2 system (C.e.AID2), which resulted in complete protein depletion without detectable leaky degradation. Finally, we show that degradation of ERM-1, a highly stable protein that is challenging to deplete, could be improved further by using multiple mIAA7 degrons. Taken together, the mIAA7 degron further increases the power and applicability of the AID system. To facilitate the generation of mIAA7-tagged proteins using CRISPR/Cas9 genome engineering, we generated a toolkit of plasmids for the generation of dsDNA repair templates by PCR.
Longitudinal Electrocochleography as an Objective Measure of Serial Behavioral Audiometry in Electro-Acoustic Stimulation Patients
Authors: Tejani Viral D. , Kim Jeong-Seo , Etler Christine P. , Skidmore Jeffrey , Yuan Yi , He Shuman , Hansen Marlan R. , Gantz Bruce J. , Abbas Paul J. , Brown Carolyn J.
Published: June 2022

Minimally traumatic surgical techniques and advances in cochlear implant (CI) electrode array designs have allowed acoustic hearing present in a CI candidate prior to surgery to be preserved post-operatively. As a result, these patients benefit from combined electric-acoustic stimulation (EAS) post-operatively. However, 30-40% of EAS CI users experience a partial loss of hearing up to 30 dB after surgery. In the present study, electrocochleography (ECoG) was used to study cochlear microphonic (hair cell response) and auditory nerve neurophonic (neural response) in patients with preserved hearing and patients with loss of hearing. These measures were obtained longitudinally over the course of CI use. At each test session, ECoG amplitude growth functions for several low-frequency stimuli were obtained. The threshold, slope, and suprathreshold amplitude at a fixed stimulation level was obtained from each growth function at each time point. Subjects were categorized as having stable hearing or loss of hearing. Longitudinal linear mixed effects models were used study trends in ECoG thresholds, slopes, and amplitudes for these two categories of subjects. Results showed that CM and ANN thresholds and amplitudes were stable in CI users with preserved residual hearing. CM and ANN thresholds increased (worsened) while CM and ANN amplitudes decreased (worsened) for those with delayed hearing loss. The slope did not distinguish between subjects with stable hearing and subjects with delayed loss of hearing. These results provide a new application of post-operative ECoG as an objective tool to monitor residual hearing and understand the pathophysiology of delayed hearing loss.
Genistein effect on cognition in early Alzheimer’s disease patients. The GENIAL clinical trial
Authors: Viña José , Escudero Joaquín , Baquero Miquel , Carbonell-Asíns JA , Tarazona-Santabalbina Francisco J. , Cebrián Mónica , Muñoz José Enrique , Satorres Encarnación , Melendez Juan Carlos , Rebolleda José Ferrer , del Puig Cózar Santiago Ma. , Santabárbara Gomez Jose Manuel , Jové Mariona , Pamplona Reinald , Borrás Consuelo
Published: June 2022

Background

Delaying the transition from minimal cognitive impairment to Alzheimer’s dementia is a major concern in Alzheimer’s disease (AD) therapeutics.

Pathological signs of AD occur years before the onset of clinical dementia. Thus, long-term therapeutic approaches, with safe, minimally invasive, and yet effective substances are recommended. There is a need to develop new drugs to delay Alzheimer’s dementia. We have taken a nutritional supplement approach with genistein, a chemically defined polyphenol that acts by multimodal specific mechanisms. Our group previously showed that genistein supplementation is effective to treat the double transgenic (APP/PS1) AD animal model.

Methods

In this double-blind, placebo-controlled, bicentric clinical trial we evaluated the effect of daily oral supplementation with 120 mg of genistein for 12 months on 24 early symptomatic Alzheimer’s patients. We used a battery of validated neurocognitive tests: Mini-Mental State Exam (MMSE), Memory Alteration Test (M@T) Clock-drawing test, Complutense Verbal Learning Test (TAVEC), Barcelona Test-Revised (TBR), and Rey Complex Figure Test.

Results

We report that genistein treatment results in a significant improvement in two of the tests used (dichotomized direct TAVEC, p=0.031; dichotomized delayed centil REY copy p=0.002 and a tendency to improve in all the rest of them.

The amyloid-beta deposition was analyzed using 18F-flutemetamol uptake which showed that genistein-treated patients did not increase their uptake in the anterior cingulate gyrus after treatment (p = 0.878) while placebo-treated did increase it (p=0.036) We did not observe significant changes in other brain areas studied

Conclusions

This study shows that genistein may have a role in therapeutics to delay the onset of Alzheimer’s dementia in patients with mild cognitive impairment. These encouraging results indicate that this should be followed up by a new study with more patients to further validate the conclusion that arises from this study.

Trial registration

NCT01982578
Longitudinal profiles of plasma gelsolin, cytokines and antibody expression predict COVID-19 severity and hospitalization outcomes
Authors: Asare-Werehene Meshach , McGuinty Michaeline , Vranjkovic Agatha , Galipeau Yannick , Cowan Juthaporn , Cameron Bill , Cooper Curtis L. , Langlois Marc-André , Crawley Angela M. , Tsang Benjamin K.
Published: June 2022

Background

Prognostic markers for COVID-19 disease outcome are currently lacking. Plasma gelsolin (pGSN) is an actin-binding protein and an innate immune marker involved in disease pathogenesis and viral infections. Here, we demonstrate the utility of pGSN as a prognostic marker for COVID-19 disease outcome; a test performance that is significantly improved when combined with cytokines and antibodies compared to other conventional markers such as CRP and ferritin.

Methods

Blood samples were longitudinally collected from hospitalized COVID-19 patients as well as COVID-19 negative controls and the levels of pGSN in μg/mL, cytokines and anti-SARS-CoV-2 spike protein antibodies assayed. Mean±SEM values were correlated with clinical parameters to develop a prognostic platform.

Results

pGSN levels were significantly reduced in COVID-19 patients compared to healthy individuals. Additionally, pGSN levels combined with plasma IL-6, IP-10 and M-CSF significantly distinguished COVID-19 patients from healthy individuals. While pGSN and anti-spike IgG titers together strongly predict COVID-19 severity and death, the combination of pGSN and IL-6 was a significant predictor of milder disease and favorable outcomes.

Conclusion

Taken together, these findings suggest that multi-parameter analysis of pGSN, cytokines and antibodies could predict COVID-19 hospitalization outcomes with greater certainty compared with conventional clinical laboratory markers such as CRP and ferritin. This research will inform and improve clinical management and health system interventions in response to SARS-CoV-2 infection.

Trial Registration

N/A

Funding

The Ottawa Hospital Department of Medicine - Special Pandemic Agile Research Competition
Impact of the Pandemic: Screening for Social Risk Factors in the Intensive Care Unit
Authors: Ge Derek , Weber Alec M. , Vatson Jayanth , Andrews Tracy , Levytska Natalia , Shu Carol , Hussain Sabiha
Published: June 2022

Due to limitations in data collected through electronic health records, the social risk factors (SRF) that predate severe illness and restrict access to critical care services are poorly understood. This study explored the feasibility and utility of directly eliciting SRF in the ICU by implementing a screening program. 566 critically ill patients at the medical ICU of Robert Wood Johnson University Hospital from July 1, 2019, to September 31, 2021, were screened for seven SRF. We compared characteristics between those with and without each SRF through Chi-squared tests and Wilcoxon Rank Sum tests. Overall, 39.58% of critically ill patients reported at least one SRF. Age, socioeconomic status, insurance type, and severity score differed significantly depending on the SRF. Most notably, the prevalence of SRF, overall and individually, changed after March 2020 which represented the onset of the COVID-19 pandemic. Our findings indicate that SRF can induce low-risk severe illnesses and restrict access to critical care services.
Comparative ultrasonographic anatomy of “medial-oblique” probe position with classic “short axis” probe position for ultrasound guided axillary vein cannulation: A cross-over study
Authors: Maitra Souvik , Bhattacharjee Sulagna , Baidya Dalim K. , Ray Bikash R
Published: June 2022

Study objective

Subclavian vein cannulation in the infraclavicular region may be a preferred approach as it is associated with less infection than internal jugular or femoral venous access in critically ill patients. ‘Short-axis view” has a problem that shaft of the puncture needle is not visualized and tip of the needle is only seen as ‘dot’; hence posterior wall of the vein puncture is always possible with ‘short-axis approach’. We have designed this study to know the ultrasonographic anatomy of subclavian vein in short axis and medial oblique view.

Design

Prospective randomized, cross-over.

Setting

Operating room.

Patients

One hundred consecutive patients aged between 18-50yrs of either sex, ASA PS I-III undergoing elective surgery under general anesthesia.

Intervention

The ultrasonographic anatomy of axillary vein cannulation in infraclavicular region in one hundred patients was assessed as per randomization sequence in medial oblique probe position and short-axis probe position.

Measurements

Antero-posterior and transverse diameter of axillary vein, pleural line visibility.

Main Results

Transverse diameter of subclavian vein was higher in ‘medial-oblique’ view [mean difference (95% confidence interval) 0.12 cm (0.09-0.16) cm; p<0.0001]. However, mean (standard deviation) antero-posterior diameter was similar in two views [0.72(0.15) cm in short axis versus 0.68 (0.16) cm in medial oblique; p=0.07]. Visibility of pleural line was similar in both the view (p=0.84, Chi-square test).

Conclusion

Medial-oblique view may be useful in axillary approach of subclavian vein cannulation. Further clinical studies are required to know whether medial oblique view can reduce complications and increase success rate of ultrasound guided subclavian vein cannulation over short axis view.
Genomic Insights of Bruneian Malays
Authors: Azmi Mirza , Chen Lie , Idris Adi , Lu Zen H.
Published: June 2022

The Malays and their many sub-ethnic groups collectively make up one of the largest population groups in Southeast Asia. However, their genomes, especially those from Brunei, remain very much underrepresented and understudied. Here, we analysed the publicly available WGS and genotyping data of two and 39 Bruneian Malay individuals, respectively. NGS reads from the two individuals were first mapped against the GRCh38 human reference genome and their variants called. Of the total ∼5.28 million short nucleotide variants and indels identified, ∼217K of them were found to be novel; with some predicted to be deleterious and associated with risk factors of common non-communicable diseases in Brunei. Unmapped reads were next mapped against the recently reported novel Chinese and Japanese genomic contigs and de novo assembled. ∼227 Kbp genomic sequences missing in GRCh38 and a partial open reading frame encoding a potential novel small zinc finger protein were successfully discovered. Interestingly, although the Malays in Brunei, Singapore and Malaysia share >83% common variants, principal component and admixture analysis comparing the genetic structure of the local Malays against other Asian population groups suggested that they are genetically closer to some Filipino ethnic groups than the Malays in Malaysia and Singapore. Taken together, our work provides the first comprehensive insight into the genomes of the Bruneian Malay population.
A reference single-cell map of freshly dissociated human synovium in inflammatory arthritis with an optimized dissociation protocol for prospective synovial biopsy collection
Authors: Edalat Sam G. , Gerber Reto , Houtman Miranda , Kuret Tadeja , Ižanc Nadja , Micheroli Raphael , Burki Kristina , Burja Blaž , Pauli Chantal , Rotar Žiga , Tomšič Matija , Čučnik Saša , Distler Oliver , Ospelt Caroline , Sodin-Semrl Snežna , Robinson Mark D. , Bertoncelj Mojca Frank
Published: June 2022

Single-cell RNA-sequencing is advancing our understanding of synovial pathobiology in inflammatory arthritis. Here, we optimized the protocol for the dissociation of fresh synovial biopsies and created a reference single-cell map of fresh human synovium in inflammatory arthritis. We utilized the published method for dissociating cryopreserved synovium and optimized it for dissociating small fresh synovial biopsies. The optimized protocol enabled the isolation of a good yield of consistently highly viable cells, minimizing the dropout rate of prospectively collected biopsies. Our reference synovium map comprised over 100’000 unsorted single-cell profiles from 25 synovial tissues of patients with inflammatory arthritis. Synovial cells formed 11 lymphoid, 15 myeloid and 16 stromal cell clusters, including IFITM2+ synovial neutrophils. Using this reference map, we successfully annotated published synovial scRNA-seq datasets. Our dataset uncovered endothelial cell diversity and identified SOD2highSAA1+SAA2+ and SERPINE1+COL5A3+ fibroblast clusters, expressing genes linked to cartilage breakdown (SDC4) and extracellular matrix remodelling (LOXL2, TGFBI, TGFB1), respectively. We broadened the characterization of tissue resident FOLR2+COLEC12highand LYVE1+SLC40A1+ macrophages, inferring their extracellular matrix sensing and iron recycling activities. Our research brings an efficient synovium dissociation protocol and a reference annotation resource of fresh human synovium, while expanding the knowledge about synovial cell diversity in inflammatory arthritis.
scMuffin: an R package for disentangling solid tumor heterogeneity from single-cell expression data
Authors: Nale Valentina , Chiodi Alice , Di Nanni Noemi , Cifola Ingrid , Moscatelli Marco , Cocola Cinzia , Gnocchi Matteo , Piscitelli Eleonora , Sula Ada , Zucchi Ileana , Reinbold Rolland , Milanesi Luciano , Mezzelani Alessandra , Pelucchi Paride , Mosca Ettore
Published: June 2022

INTRODUCTION

Single-cell (SC) gene expression analysis is crucial to dissect the complex cellular heterogeneity of solid tumors, which is one of the main obstacles for the development of effective cancer treatments. Such tumors typically contain a mixture of cells with aberrant genomic and transcriptomic profiles affecting specific sub-populations that might have a pivotal role in cancer progression, whose identification eludes bulk RNA-sequencing approaches. We presentscMuffin, an R package that enables the characterization of cell identity in solid tumors on the basis of a various and complementary analyses on SC gene expression data.

RESULTS

scMuffin provides a series of functions to calculate qualitative and quantitative scores, such as: expression of marker sets for normal and tumor conditions, pathway activity, cell state trajectories, CNVs, transcriptional complexity and proliferation state. Thus, scMuffin facilitates the combination of various evidences that can be used to distinguish normal and tumoral cells, define cell identities, cluster cells in different ways, link genomic aberrations to phenotypes and identify subtle differences between cell subtypes or cell states. We analysed public SC expression datasets of human high-grade gliomas as a proof-of-concept to show the value of scMuffin and illustrate its user interface. Nevertheless, these analyses lead to interesting findings, which suggest that some chromosomal amplifications might underlie the invasive tumor phenotype and the presence of cells that possess tumor initiating cells characteristics.

CONCLUSIONS

The analyses offered by scMuffin and the results achieved in the case study show that our tool helps addressing the main challenges in the bioinformatics analysis of SC expression data from solid tumors.
The BDNF Val68Met polymorphism causes a sex specific alcohol preference over social interaction and also acute tolerance to the anxiolytic effects of alcohol, a phenotype driven by malfunction of BDNF in the ventral hippocampus of male mice
Authors: Moffat Jeffrey J. , Sakhai Samuel A. , Hoisington Zachary W. , Ehinger Yann , Ron Dorit
Published: June 2022

The brain-derived neurotrophic factor (BDNF) Valine 66 to Methionine human polymorphism results in impaired activity-dependent BDNF release and has been linked to psychiatric disorders including depression and anxiety. We previously showed that male knock-in mice carrying the mouse Methionine homolog (Met68BDNF) exhibit excessive and compulsive alcohol drinking behaviors as compared to the wild-type Val68BDNF mice. Here, we set out to determine the potential mechanism for the heightened and compulsive alcohol drinking phenotypes detected in Met68BDNF mice. We found that male, but not female Met68BDNF mice exhibit social anxiety-like behaviors. We further show that male Met68BDNF mice exhibit a preference for alcohol over social interaction. In contrast, alcohol place preference without an alternative social reward, is similar in male Met68BDNF and Val68BDNF mice. Since the Met68BDNF mice show social anxiety phenotypes, we tested whether alcohol reliefs anxiety similarly in Met68BDNF and Val68BDNF mice and found that male, but not female Met68BDNF mice are insensitive to the acute anxiolytic action of alcohol. Finally, we show that this acute tolerance to alcohol-dependent anxiolysis can be restored by overexpressing wild-type Val68BDNF in the ventral hippocampus (vHC) of Met68BDNF mice. Together, our results suggest that excessive alcohol drinking in the Met68BDNF may be attributed, in part, to heighted social anxiety and a lack of alcohol-dependent anxiolysis, a phenotype that is associated with malfunction of BDNF signaling in thevHC of male Met68BDNF mice.
Inter-regional delays fluctuate in the human cerebral cortex
Authors: Moon Joon-Young , Müsch Kathrin , Schroeder Charles E. , Valiante Taufik A. , Honey Christopher J.
Published: June 2022

The flow of information between cortical regions depends on the excitability at each site, which is reflected in fluctuating field potentials. It remains uncertain how global changes in field potentials affect the latency and strength of cortico-cortical couplings. Therefore, we measured changes in oscillations and inter-regional couplings by recording intracranially from the human cerebral cortex. As participants listened to an auditory narrative, global increases in low-frequency (4-14 Hz) power were associated with stronger and more delayed inter-regional couplings. Conversely, increases in broadband high-frequency power were associated with weaker coupling and zero lag. In network oscillator models, these changes in cortico-cortical latency can be generated by varying the effective influence of inter-regional projections relative to intra-regional dynamics. Altogether, low-frequency oscillations appear to modulate information flow across the human cerebral cortex, as they covary with the timing of peak excitability between regions, and this process may be regulated by nonspecific ascending projections.
Hi-TrAC reveals fine-scale chromatin structures organized by transcription factors
Authors: Liu Shuai , Cao Yaqiang , Cui Kairong , Tang Qingsong , Zhao Keji
Published: June 2022

The three-dimensional genomic structure plays a critical role in gene expression, cellular differentiation, and pathological conditions. It is pivotal to elucidate fine-scale chromatin architectures, especially interactions of regulatory elements, to understand the temporospatial regulation of gene expression. In this study, we report Hi-TrAC as a proximity ligation free, robust, and sensitive technique to profile genome-wide chromatin interactions at high-resolution among accessible regulatory elements. Hi-TrAC detects chromatin looping among accessible chromatin regions at single nucleosome resolution. With almost half-million identified loops, we constructed a comprehensive interaction network of regulatory elements across the genome. After integrating chromatin binding profiles of transcription factors, we discovered that cohesin complex and CTCF are responsible for organizing long-range chromatin loops, related to domain formation; whereas ZNF143 and HCFC1 are involved in structuring short-range chromatin loops between regulatory elements, which directly regulate gene expression. Thus, we developed a new methodology to identify a delicate and comprehensive network of cis-regulatory elements, revealing the complexity and a division of labor of TFs in chromatin looping for genome organization and gene expression.
Genetic or transcranial magnetic stimulation of B-RAF–MEK signaling promotes CST axon sprouting and functional regeneration
Authors: Boato Francesco , Guan Xiaofei , Zhu Yanjie , Ryu Youngjae , Voutounou Mariel , Rynne Christopher , Freschlin Chase R. , Zumbo Paul , Betel Doron , Matho Katie , Makarov Sergey N. , Wu Zhuhao , Son Young-Jin , Nummenmaa Aapo , Huang Josh Z. , Edwards Dylan J. , Zhong Jian
Published: June 2022

Facilitating axon regeneration in the injured central nervous system remains a challenging task. RAF–MEK signaling plays an important role in axon elongation during nervous system development. Here we show that activation of B-RAF in mature corticospinal neurons elicited the expression of a discrete set of transcription factors previously implicated in the regeneration of zebrafish optic nerve axons. Genetic activation of B-RAF–MEK signaling promoted robust regeneration and sprouting of corticospinal tract axons after injury. Newly sprouting axon collaterals formed synaptic connections with spinal interneurons, correlating with the recovery of skilled motor function. Seeking a non-invasive way to stimulate axon regeneration, we found that suprathreshold high-frequency repetitive transcranial magnetic stimulation activates the B-RAF canonical effectors MEK1/2 and requires MEK1/2 activity to promote corticospinal axon regeneration and sprouting after injury. These data demonstrate a central role of neuron-intrinsic RAF–MEK signaling in enhancing the growth capacity of mature corticospinal neurons and propose HF-rTMS as a potential therapy for spinal cord injury.

One Sentence Summary

Genetic or HF-rTMS-mediated activation of B-RAF– MEK signaling promotes CST axon sprouting and functional regeneration after a spinal cord injury.
Comparative phyloproteomics identifies conserved plasmodesmal proteins
Authors: Johnston Matthew G. , Breakspear Andrew , Samwald Sebastian , Zhang Dan , Papp Diana , Faulkner Christine , de Keijzer Jeroen
Published: June 2022

Plasmodesmata connect neighbouring plant cells across the cell wall. They are cytosolic bridges, lined by the plasma membrane and traversed by endoplasmic reticulum to connect these cell components between cells and tissues. While plasmodesmata are notoriously difficult to extract, tissue fractionation and proteomic analyses have yielded valuable knowledge of their composition. Most proteomic profiles originate from cell suspension cultures in which simple plasmodesmata dominate and have been exclusively generated from dicotyledonous plant species. Here we have generated two novel proteomes to expand tissue and taxonomic representation of plasmodesmata: one from mature Arabidopsis leaves and one from the moss Physcomitrium patens. We have leveraged these and existing data to perform a comparative analysis that, owing to comparing proteomes from an expanded taxonomic tree, allowed us to identify conserved protein families that are associated with plasmodesmata that likely serve as core structural or functional components. Thus, we identified β-1,3-glucanases, C2 lipid-binding proteins and tetraspanins as core plasmodesmal components, with proteins from P. patens and Arabidopsis maintaining plasmodesmal association across diverse species. Our approach has not only identified elements of a conserved, core plasmodesmal proteome, but also demonstrated the added power offered by comparative analysis. Conserved plasmodesmal proteins establish a basis upon which ancient plasmodesmal function can be further investigated to determine the essential roles these structures play in multicellular organism physiology in the green lineages.
Genomic analysis of the recent monkeypox outbreak
Authors: Giorgi Federico M. , Pozzobon Daniele , Di Meglio Antonio , Mercatelli Daniele
Published: June 2022

The Monkeypox virus is the etiological cause of a recent multi-country outbreak, with nearly one hundred distinct cases detected outside the endemic areas of Africa in May 2022. In this article, we analyze the sequences of two full genomes of Monkeypox virus from Portugal and Belgium, and compare them with all available Monkeypox sequences, annotated by year and geographic origin, as well as related Cowpox and Variola (smallpox) virus sequences. Our results show that the recent outbreak is most likely originating from the West African clade of Monkeypox, with >99% sequence identity with sequences derived from historical and recent cases, dating from 1971 to 2017. We analyze specific mutations occurring in viral proteins A42R (for which a crystal structure is available) and H3L (an important epitope in host immune recognition), highlighting specific amino acids varying between the current outbreak, previous Monkeypox and Cowpox sequences and the historical Variola virus. Genome-wide sequence analysis of the recent outbreak and other monkeypox/cowpox/variola viruses shows a very high conservation, with 97.9% (protein-based) and 97.8% (nucleotide-based) sequence identity.