bluuebunny/crossref_metadata_2025 huggingface dataset:
Contribution of central hemodynamics and end-tidal CO2to cerebrovascular dynamics during aerobic exercise
Authors: Aaron Stacey E. , Whitaker Alicen A. , Billinger Sandra A.
Published: May 2023

During aerobic exercise, central hemodynamics and CO2 partial pressure are central to middle cerebral artery blood velocity (MCAv) response. Still, the extent of their contribution is unknown. The purpose of this study was to characterize and utilize statistical modeling to determine the contribution of heart rate (HR), mean arterial pressure (MAP), and end-tidal CO2(PETCO2) dynamics to MCAv dynamics. Three randomized exercise bouts were completed on a recumbent stepper at 30-40% (Low), 45-55% (Mod1), and 60-70% (Mod2) of estimated HRmax. A 90-s resting period was followed by 6-min of continuous exercise within the estimated HR ranges. HR, MAP, PETCO2, and MCAv exercise dynamics were modeled with a monoexponential curve. From this modeling, the baseline (BL), time delay (TD), time constant (τ), and steady-state (SS) responses were determined. Backward AIC linear regression models determined contributing dynamics. Seventeen healthy adults completed all exercise bouts (28 ± 6 yrs, 8 females). The time from initiation of exercise to an exponential increase in HR (HRTD) was significantly longer for Low than Mod2 (p=0.047). The time constant for the rise in HR (HRτ) was significantly shorter for Low than Mod1 and Mod2 (p=0.01). The absolute change in HR from baseline to steady-state (HRSS) was significantly lower for Low than Mod1 and Mod2 (p<0.001), and Mod1 was significantly lower than Mod2 (p<0.001). MAPSSwas significantly lower for Low than Mod1 (p=0.01) and Mod2 (p<0.001). Exercise intensity, HRTD, and MAPTDaccounted for 17% of variation for MCAvTD(p=0.01). HRTD, PETCO2TD, and MCAvTDaccounted for 21% of variation MCAvτ (p<0.01). MCAvτ, MAPSS, and PETCO2SSaccounted for 60% of variation for MCAvSS(p<0.001). Throughout the MCAv dynamic response pathway central hemodynamics and end-tidal CO2do not account for most MCAv response until the steady-state phase. Thus, other physiological factors should be considered with assessing cerebrovascular function during aerobic exercise.
The effects of oxygenation on acute vasodilator challenge in pulmonary arterial hypertension
Authors: Rockstrom Matthew D , Jin Ying , Peterson Ryan A , Hountras Peter , Badesch David , Gu Sue , Park Bryan , Messenger John , Forbes Lindsay M. , Cornwell William K. , Bull Todd M
Published: May 2023

Background

Identification of long-term calcium channel blocker (CCB) responders with acute vasodilator challenge is critical in the evaluation of patients with pulmonary arterial hypertension. Currently there is no standardized approach for use of supplemental oxygen during acute vasodilator challenge.

Methods

Retrospective analysis of patients identified as acute vasoresponders, treated with CCBs. All patients had hemodynamic measurements in three phases: 1) at baseline; 2) with 100% fractional inspired oxygen; and 3) with 100% fractional inspired oxygen plus inhaled nitric oxide (iNO). Patients were divided into two cohorts. Those meeting the definition of acute vasoresponsiveness from phase 2 to phase 3 were labeled “iNO Responders.” Those who did not reach the threshold of acute vasoresponsiveness from phase 2 to phase 3 but did meet the definition from phase 1 to phase 3 were labeled “Oxygen Responders.” Survival, hospitalization for decompensated right heart failure, duration of CCB monotherapy, and functional data were collected.

Results

iNO Responders, when compared to Oxygen Responders, had superior survival (100% vs 50.1% 5-year survival, respectively), fewer hospitalizations for acute decompensated right heart failure (0% vs 30.4% at 1 year, respectively), longer duration of CCB monotherapy (80% versus 52% at 1 year, respectively), and superior six-minute walk distance.

Conclusion

Current guidelines for acute vasodilator testing do not standardize oxygen coadministration with iNO. This study demonstrates that adjusting for the effects of supplemental oxygen before assessing for acute vasoresponsiveness identifies a cohort with superior functional status, tolerance of CCB monotherapy, and survival while on long-term CCB therapy.
Prognostic utility of rhythmic components in 24-hour ambulatory blood pressure monitoring for the risk stratification of chronic kidney disease patients with cardiovascular co-morbidity
Authors: Jamal Nadim El , Brooks Thomas G. , Cohen Jordana , Townsend Raymond R. , Rodriguez de Sosa Giselle , Shah Vallabh , Nelson Robert G. , Drawz Paul E. , Rao Panduranga , Bhat Zeenat , Chang Alexander , Yang Wei , FitzGerald Garret A. , Skarke Carsten ,   the CRIC Study Investigators
Published: May 2023

Background

Chronic kidney disease (CKD) represents a significant global burden. Hypertension is a modifiable risk factor for rapid progression of CKD.

Methods

We extend the risk stratification by introducing the non-parametric determination of rhythmic components in 24-hour profiles of ambulatory blood pressure monitoring (ABPM) in the African American Study for Kidney Disease and Hypertension (AASK) cohort and the Chronic Renal Insufficiency Cohort (CRIC) using Cox proportional hazards models.

Results

We find that rhythmic profiling of BP through JTK_Cycle analysis identifies subgroups of CRIC participants at advanced risk of cardiovascular death. CRIC participants with a history of cardiovascular disease (CVD) and absent cyclic components in their BP profile had at any time a 3.4-times higher risk of cardiovascular death than CVD patients with cyclic components present in their BP profile (HR: 3.38, 95% CI: 1.45-7.88,p=0.005). This substantially increased risk was independent of whether ABPM followed a dipping or non-dipping pattern whereby non-dipping or reverse dipping were not significantly associated with cardiovascular death in patients with prior CVD (p>0.1). In the AASK cohort, unadjusted models demonstrate a higher risk in reaching end stage renal disease among participants without rhythmic ABPM components (HR:1.80, 95% CI: 1.10-2.96); however, full adjustment abolished this association.

Conclusions

This study proposes rhythmic blood pressure components as a novel biomarker to unmask excess risk among CKD patients with prior cardiovascular disease.
Comparing Providers for the Treatment of Early Childhood Caries with a Value-based Rating Methodology: A Cross-sectional study
Authors: Okuji David , Ben Dor Betty , Jivraj Ashiana , Wu Yinxiang
Published: May 2023

Purpose

An adapted Porter-Teisberg model of value-based health outcomes and cost was applied to comparatively rate providers who treat children with early childhood caries, by treatment modalities, facilities, and geographic location.

Methods

Quality was measured by a Parental-Reported Symptom and Service Quality questionnaire, adapted from the Early Child Oral Health Impact Scale, Child-Oral Impacts on Daily Performance, and Dental Consumer Assessments of Healthcare Providers and Systems tools. Cost was measured by the labor cost for all providers involved in treatment and adjusted by dividing by total relative value units for the types and total number of procedures for all treatment visits. Value was calculated as the quotient of the weighted quality score and the adjusted cost, multiplied by a coefficient. To compare the value score by states and by facilities, Tukey’s multiple comparison test was used and a sensitivity analysis using the non-parametric Dunn’s Kruskal-Wallis multiple comparison test was conducted.

Results

For surgical treatment with general anesthesia, Tennessee ranked the highest, followed by Arizona, Hawaii, and New York. These four states had significantly higher value metrics than Florida, Massachusetts, and Maryland. Maryland had a significantly higher value score for surgical treatment without general anesthesia. While patients were seen for non-surgical treatment only in Maryland and New York, Maryland also had a significantly higher value for this treatment modality.

Conclusion

A value-based rating system of providers, by geographic region and treatment facility, can assist patients to better compare and select providers; third-party payers, such as insurance companies and government programs, to better compare outcomes and costs for provider systems and clinic facilities; and providers to benchmark their comparative ratings on an internal and external basis for continuous quality improvement.

Highlights

Non-surgical management of early childhood caries yields the most value.

Surgical intervention with or without general anesthesia is less valued by patients.

Ranking treatment modalities by value is a useful tool for patients.

Using a parental-reported symptom and service quality questionnaire assesses quality.

Provider value can be determined by dividing quality of care by the cost of delivery.
T cell activation via the CD40 ligand and transferrin receptor and deficits in T regulatory cells are associated with major depressive disorder and severity of depression
Authors: Rachayon Muanpetch , Jirakran Ketsupar , Sodsai Pimpayao , Sughondhabirom Atapol , Maes Michael
Published: May 2023

Major depressive disorder (MDD) is associated with T cell activation (Maes et al. 1990-1993), but no studies have examined the combined effects of T cell activation and deficits in T regulatory (Treg) cells on the severity of acute phase MDD. Using flow cytometry, we determined the percentage and median fluorescence intensity of CD69, CD71, CD40L, and HLADR-bearing CD3+, CD4+, and CD8+ cells, and cannabinoid type 1 receptor (CB1), CD152 and GARP-bearing CD25+FoxP3 T regulatory (Treg) cells in 30 MDD patients and 20 healthy controls in unstimulated and stimulated (anti-CD3/CD28) conditions. Based on cytokine levels, we assessed M1 macrophage, T helper (Th)-1, immune-inflammatory response system (IRS), T cell growth, and neurotoxicity immune profiles. We found that the immune profiles (including IRS and neurotoxicity) were significantly predicted by decreased numbers of CD152 or GARP-bearing CD25+FoxP3 cells or CD152 and GARP expression in combination with increases in activated T cells (especially CD8+CD40L+ percentage and expression). MDD patients showed significantly increased numbers of CD3+CD71+, CD3+CD40L+, CD4+CD71+, CD4+CD40L+, CD4+HLADR+, and CD8+HLADR+ T cells, increased CD3+CD71+, CD4+CD71+ and CD4+HLADR+ expression, and lowered CD25+FoxP3 expression and CD25+FoxP+CB1+ numbers as compared with controls. The Hamilton Depression Rating Scale score was strongly predicted (between 30-40% of its variance) by a lower number of CB1 or GARP-bearing Treg cells and one or more activated T cell subtypes (especially CD8+CD40L+). In conclusion, T helper and cytotoxic cell activation coupled with lowered Treg homeostatic defenses are key components of MDD and contribute towards greater immune responses and consequent neuroimmunotoxicity.
Accelerated Clonal Hematopoiesis in Pediatric and Young Adult Survivors of Childhood Cancer
Authors: Greer Chelsee D. , Kroger Benjamin R. , Hartshorne Taylor N. , Xu Jian , Chung Stephen S. , Dickerson Kathryn E.
Published: May 2023

Clonal hematopoiesis of indeterminate potential(CHIP) is a recognized consequence of aging and a precursor to myelodysplastic syndrome and acute myeloid leukemia which independently increases all-cause mortality in adults. Childhood cancer survivors experience a phenomenon of accelerated aging with increased all-cause mortality; however, the mechanism of this is not known and the prevalence of CHIP not well defined. We prospectively studied 305 pediatric and young adult childhood cancer survivors to determine the prevalence of clonal hematopoiesis(CH). Targeted next-generation sequencing analysis of peripheral blood mononuclear cells elucidated the prevalence of CH (VAF >1%) at a rate of ∼6%, approaching that of adults >50-70 years and much higher than previously reported. This is the first prospective study of CH in pediatric and young adult survivors of childhood cancer and highlights the importance of further investigation to better understand how CH may contribute to treatment-related myeloid neoplasms and other late effects.
Valid, invalid, or somewhere in between? Baseline ImPACT and stand-alone performance validity testing in collegiate athletes
Authors: Higgins Kate L. , Bouchard Heather C. , Maietta Julia E. , Laing-Young Julia M. , Schultz Douglas H.
Published: May 2023

Objective

Baseline cognitive testing is important for sport concussion management. Assessing baseline data for both the validity and reliability is vital to ensuring its utility. Stand-alone performance validity tests (PVT) and embedded validity indicators (EVI) (collectively called “validity measures” hereafter) are commonly used in neuropsychological testing and screening. This study further investigates efficient ways to assess validity of baseline cognitive testing.

Methods

231 NCAA athletes completed baseline assessment with ImPACT and one of two PVT’s: Medical Symptom Validity Test or Rey Dot Counting Test. The relationship between scores on validity measures and cognitive performance, symptoms, and sleep was assessed.

Results

Athletes who failed two or more validity measures performed worse on the Visual Motor Speed Composite while athletes failing three or more measures performed worse on the Reaction Time Composite. Those athletes who failed validity measures and also reported poor sleep performed worse on both composites. Self-reported symptoms and hours of sleep were not independently associated with failing validity measures. Lastly, athletes with self-reported ADHD and/or LD were more likely to fail two+ validity measures (46% versus 27% of neurotypical athletes).

Conclusions

Consistent with previous research, ImPACT Baseline++ only identified 1.7% of the sample’s data as invalid despite 4.8% of the dataset failing a combination of PVT and EVI and an additional 42.9% failing at least EVI alone. Results suggest that assessing validity on a continuum and using multiple validity measures may be useful to identify data validity that falls in the middle of the continuum.

Public Significance Statement

Baseline concussion testing is common and often mandated prior to sport participation, however, a baseline only has utility if it is both a reliable and valid representation of the athlete’s healthy and optimal functioning. This study adds to the growing body of literature demonstrating that baseline testing may frequently have questionable validity. It also provides support to the value of conceptualizing validity as a spectrum, rather than dichotomy and is the first to apply the concept to baseline concussion testing data.
Drug Target Identification in Triple Negative Breast Cancer Stem Cell Pathways: a computational study of gene regulatory pathways using Boolean networks
Authors: Lahiri Aditya , Vundavilli Haswanth , Mondal Madhurima , Bhattacharjee Pranabesh , Decker Brian , Del Priore Giuseppe , Reeves N. Peter , Datta Aniruddha
Published: May 2023

Triple-negative breast cancer (TNBC) is an aggressive form of breast cancer associated with an early age of onset, greater propensity towards metastasis, and poorer clinical outcomes. It accounts for 10% to 20% of newly diagnosed breast cancer cases and disproportionately affects individuals from the African American race. While TNBC is sensitive to chemotherapy, it is also prone to relapse. This is because chemotherapy successfully targets the primary TNBC tumor cell but often fails to target the subpopulation of TNBC stem cells. TNBC stem cells display cancerous traits such as cell cycle progression, survival, proliferation, apoptosis inhibition, and epithelial-mesenchymal transition. To study the cancer initiating behavior of the TNBC stem cells, we studied their underlying signaling pathways using Boolean networks(BN). BNs are effective in capturing the causal interactions taking place in signaling pathways. We built the BN from the pathway literature and used it to evaluate the efficacies of eleven targeted inhibitory drugs in suppressing cancer-promoting genes. We simulated the BN when the pathways had single or multiple mutations, with a maximum of three mutations at a time. Our findings indicated thatSTAT3, GLI, andNF-κBare the most optimal targets for inhibition. These genes are known regulators of the cancer-promoting genes in the pathway,hence our model agrees with the existing biological literature. Therefore inhibiting these three genes has the potential to prevent TNBC relapse. Additionally, our studies found that drug efficacies decreased as mutations increased in the pathway. Furthermore, we noticed that combinations of drugs performed better than single drugs.
A comparative ultrastructure study of the tardigradeRamazzottius varieornatusin the hydrated state, after desiccation and during the process of rehydration
Authors: Galas Simon , Le Goff Emilie , Cazevieille Chantal , Tanaka Akihiro , Cuq Pierre , Baghdiguian Stephen , Kunieda Takekazu , Godefroy Nelly , Richaud Myriam
Published: May 2023

Tardigrades can survive hostile environments such as desiccation by adopting a state of anhydrobiosis. Numerous tardigrade species have been described thus far, and recent genome and transcriptome analyses revealed that several distinct strategies were employed to cope with harsh environments depending on the evolutionary lineages. Detailed analyses at the cellular and subcellular levels are essential to complete these data. In this work, we analyzed a tardigrade species that can withstand rapid dehydration,Ramazzottius varieornatus. Surprisingly, we noted an absence of the anhydrobiotic-specific extracellular structure previously described for theHypsibius exemplarisspecies. BothRamazzottius varieornatusandHypsibius exemplarisbelong to the same evolutionary class of Eutardigrada. Nevertheless, our observations reveal discrepancies in the anhydrobiosis mechanisms between these two species. Interestingly, these discrepancies are correlated with their variations in dehydration resistance.
Strain measures of the left ventricle and left atrium are composite measures of left heart geometry and function
Authors: Frojdh Fredrika , Soundappan Dhnanjay , Sorensson Peder , Sigfridsson Andreas , Maret Eva , Nickander Jannike , Ugander Martin
Published: May 2023

Background: Left ventricular (LV) global longitudinal strain (GLS) and circumferential strain (GCS), and left atrial (LA) strain (LAS) are indicators of poor clinical prognosis. However, it is unclear how they relate to each other and to LV and LA geometry. The aim was to clarify these relationships to inform clinical and research applications. Methods: Patients referred for cardiovascular magnetic resonance imaging were retrospectively identified. Univariable and multivariable linear regression models evaluated associations between GLS, GCS, LAS, LV mass, the volumes and dimensions of the LV and LA, and mitral annular plane systolic excursion (MAPSE). Results: In patients (n=66, median [interquartile range] age 62 [53-72] years, 82% male, LV ejection fraction 48 [34-56]%, range 6-69%), GLS associated with both GCS (R2=0.86, p<0.001) and LAS (R2=0.51, p<0.001), and LAS associated with GCS (R2=0.42, p<0.001). GLS, GCS, and LAS were all univariably associated with MAPSE, LV mass, and the volumes and dimensions of the LV and LA (p<0.001 for all). In multivariable analysis, GLS associated with MAPSE and LV length (R2=0.85, p<0.001); GCS with MAPSE, LV end-systolic volume, and LV mass (R2=0.80, p<0.001); and LAS with LA end-diastolic volume and MAPSE (R2=0.67, p<0.001). Conclusions: MAPSE and LV length alone can accurately estimate GLS. GLS and GCS provide similar information. LV and LA strains can be understood as geometrically coupled composite measures of MAPSE, and the size, function, and dimensions of the LV and LA. The composite of these geometrical relationships likely explains the excellent prognostic strength of strain measures.
Exploring disease-drug pairs in Clinical Trials information for personalized drug repurposing
Authors: Álvarez-Pérez Andrea , Prieto-Santamaría Lucía , Ugarte-Carro Esther , Otero-Carrasco Belén , Ayuso-Muñoz Adrián , Rodríguez-González Alejandro
Published: May 2023

Drug repurposing, the process of finding new uses for existing drugs, has gained considerable attention due to its potential to reduce the time and costs associated with drug development. Personalized drug repurposing, in which drugs are selected based on the characteristics of individual patients, is an emerging approach that holds promise for improving clinical outcomes. In this context, exploring disease-drug pairs in already conducted clinical trials can provide valuable insights to identify promising patient populations for further study that may lead to personalized drug repositioning. Our analysis aims to shed a light into clinical outcomes by selecting the most appropriate repurposed drug based on clinical trials patient groups’ characteristics, such as age and gender. It also gives information about the state of the clinical trials studying these disease-drug pairs, gathering information about the study type, phase and statistical method used to calculate the p-value of the chosen outcome measurement, among others. Overall, this study highlights the importance of using existing knowledge as an initial framework to facilitate further research, particularly in providing patient-specific information. Furthermore, it underlines the importance of building on previous research to facilitate a comprehensive understanding of the research topic, which can eventually improve patient outcomes.
Deciphering the role of brainstem glycinergic neurons during startle and prepulse inhibition
Authors: Huang Wanyun , Cano Jose C. , Fénelon Karine
Published: May 2023

Prepulse inhibition (PPI) of the auditory startle response is the gold standard operational measure of sensorimotor gating. Affected by various neurological and neuropsychiatric illnesses, PPI also declines during aging. While PPI deficits are often associated with cognitive overload, attention impairments and motor dysfunctions, their reversal is routinely used in experimental systems for drug screening. Yet, the cellular and circuit-level mechanisms of PPI remain unclear, even under non-pathological conditions. Recent evidence shows that neurons located in the brainstem caudal pontine reticular nucleus (PnC) expressing the glycine transporter type 2 (GlyT2+) receive inputs from the central nucleus of the amygdala (CeA) and contribute to PPI via an uncharted pathway. Using tract-tracing and immunohistochemical analyses in GlyT2-eGFP mice, we reveal the neuroanatomical location of CeA glutamatergic neurons innervating GlyT2+neurons. Our precisein vitrooptogenetic manipulations coupled to field electrophysiological recordings demonstrate that CeA glutamatergic inputs do suppress auditory neurotransmission in PnC neurons but not via action on transmitter release from auditory afferents. Rather, our data is consistent with excitatory drive onto GlyT2+neurons. Indeed, our PPI experimentsin vivodemonstrate that optogenetic activation of GlyT2+PnC neurons increases PPI and is sufficient to induce PPI, clarifying the crucial role of these neurons in young GlyT2-Cre mice. In contrast, in older GlyT2-Cre mice, PPI is reduced and not further altered by optogenetic inhibition of GlyT2+neurons. We conclude that GlyT2+PnC neurons innervated by CeA glutamatergic inputs are crucial for PPI and we highlight their reduced activity during the age-dependent decline in PPI.

SIGNIFICANCE STATEMENT

Sensorimotor gating is a pre-attentive mechanism that declines with age and that is affected by neuropsychiatric and neurological disorders. Prepulse inhibition (PPI) of startle commonly measures sensorimotor gating to assess cognitive and motor symptoms and to screen drug efficacy. Yet, the neuronal mechanisms underlying PPI are still unresolved, limiting therapeutic advances. Here, we identify brainstem glycinergic neurons essential for PPI using tract tracing,in vitroelectrophysiology and precisein vivooptogenetic manipulations during startle measurements in mice. Innervated by amygdala glutamatergic inputs, we show that these glycinergic neurons are essential and sufficient to induce PPI in young mice. In contrast, these neurons do not contribute to PPI in older mice. We provide new insights to the theoretical construct of PPI.
Effects of TP63 Mutations on Keratinocyte Adhesion and Migration
Authors: Salois Maddison N. , Gugger Jessica A. , Webb Saiphone , Sheldon Christina E. , Parraga Shirley P. , Lewitt G. Michael , Grange Dorothy K. , Koch Peter J. , Koster Maranke I.
Published: May 2023

The goal of this study was to investigate the molecular mechanisms responsible for the formation of skin erosions in patients affected by Ankyloblepharon-ectodermal defects-cleft lip/palate syndrome (AEC). This ectodermal dysplasia is caused by mutations in theTP63gene, which encodes several transcription factors that control epidermal development and homeostasis. We generated induced pluripotent stem cells (iPSC) from AEC patients and corrected theTP63mutations using genome editing tools. Three pairs of the resulting conisogenic iPSC lines were differentiated into keratinocytes (iPSC-K). We identified a significant downregulation of key components of hemidesmosomes and focal adhesions in AEC iPSC-K compared to their gene-corrected counterparts. Further, we demonstrated reduced iPSC-K migration, suggesting the possibility that a process critical for cutaneous wound healing might be impaired in AEC patients. Next, we generated chimeric mice expressing aTP63-AECtransgene and confirmed a downregulation of these genes in transgene-expressing cellsin vivo. Finally, we also observed these abnormalities in AEC patient skin. Our findings suggest that integrin defects in AEC patients might weaken the adhesion of keratinocytes to the basement membrane. We propose that reduced expression of extracellular matrix adhesion receptors, potentially in conjunction with previously identified desmosomal protein defects, contribute to skin erosions in AEC.
Functional GPCR expression in eukaryotic LEXSY system
Authors: Luginina Aleksandra , Maslov Ivan , Khorn Polina , Volkov Oleksandr , Khnykin Andrey , Kuzmichev Pavel , Shevtsov Mikhail , Belousov Anatoliy , Dashevskii Dmitrii , Kornilov Daniil , Bestsennaia Ekaterina , Hofkens Johan , Hendrix Jelle , Gensch Thomas , Cherezov Vadim , Ivanovich Valentin , Mishin Alexey , Borshchevskiy Valentin
Published: May 2023

G protein-coupled receptors (GPCRs) represent an important class of drug targets, and their structural studies facilitate rational drug discovery. However, atomic structures of only about 20% of human GPCRs have been solved to date. Recombinant production of GPCRs for structural studies at a large scale is challenging due to their low expression levels and stability. Here we tested the eukaryotic system LEXSY (Leishmania tarentolae) for GPCR production. We expressed the human A2Aadenosine receptor (A2AAR) in LEXSY, purified it, and compared with the same receptor produced in insect cells, which is the most popular expression system for structural studies of GPCRs. The A2AAR purified from both expression systems showed similar purity, stability, ligand-induced conformational changes and structural dynamics, with a remarkably higher protein yield in the case of LEXSY expression.
Rapamycin-sensitive mechanisms confine the growth of fission yeast below the temperatures detrimental to cell physiology
Authors: Morozumi Yuichi , Mahayot Fontip , Nakase Yukiko , Soong Jia Xin , Yamawaki Sayaka , Sofyantoro Fajar , Imabata Yuki , Oda Arisa H. , Tamura Miki , Kofuji Shunsuke , Akikusa Yutaka , Ohta Kunihiro , Shiozaki Kazuhiro
Published: May 2023

Cells cease to proliferate above their growth-permissible temperatures, a ubiquitous phenomenon generally attributed to protein denaturing and heat damage to other cellular macromolecules. We here report that, in the presence of the macrolide compound rapamycin, the fission yeastSchizosaccharomyces pombecan proliferate at high temperatures that normally arrest its growth. Rapamycin is a potent inhibitor of the protein kinase complex TOR Complex 1 (TORC1), and consistently, mutations to the TORC1 subunit RAPTOR/Mip1 and the TORC1 substrate Sck1 significantly improve cellular heat resistance. These results suggest that TORC1, a well-established growth promoter, restricts the high-temperature growth of fission yeast and that compromised TORC1 signaling allows cell proliferation at higher temperatures. Aiming for a more comprehensive understanding of the negative regulation of high-temperature growth, we conducted genome-wide screens inS. pombe, which identified Sck1 and additional factors that appear to suppress cell proliferation at high temperatures. Our study has uncovered unexpected mechanisms of growth restraint even below the temperatures deleterious to cell physiology. Thus, growth arrest at high temperatures may not directly result from heat damage to cellular components essential for proliferation and viability.

Significance Statement

The immunosuppressant rapamycin is a specific inhibitor of the protein kinase Target Of Rapamycin (TOR), and the drug is known to extend the lifespan of diverse eukaryotic organisms. In this study, we have found that rapamycin confers heat resistance on fission yeast, allowing its proliferation above the normal permissive temperatures. This unexpected observation suggests that TOR, which is known as a growth-promoting kinase, is inhibitory to cell proliferation at high temperatures. Our genome-wide screens have identified additional genes whose deletion leads to improved growth under heat stress. Thus, cells may have mechanisms that restrict proliferation even below the temperatures deleterious to their physiology.
MskAge - An Epigenetic Biomarker of Musculoskeletal Age Derived from a Genetic Algorithm Islands Model
Authors: Green Daniel Charles , Reynard Louise , Henstock James , Reppe Sjur , Gutvik Kaare , Peffers Mandy , Shanley Daryl , Clegg Peter , Canty-Laird Elizabeth
Published: May 2023

Background

Age is a significant risk factor for functional decline and disease of the musculoskeletal system, yet few biomarkers exist to facilitate ageing research in musculoskeletal tissues. Multivariate models based on DNA methylation, termed epigenetic clocks, have shown promise as markers of biological age. However, the accuracy of existing epigenetic clocks in musculoskeletal tissues are no more, and often less accurate than a randomly sampled baseline model.

Results

We developed a highly accurate epigenetic clock, Msk-Age, that is specific to tissues and cells of the musculoskeletal system. MskAge was built using a penalised genetic algorithm islands model that addresses multi-tissue clock bias. The final model was trained on the transformed principal components of CpGs selected by the genetic algorithm, which are significantly enriched for pathways terms related to the skeletal system and mesenchyme development. We show that MskAge tracks epigenetic ageingex vivoandin vitro. Epigenetic age estimates are rejuvenated to zero with cellular reprogramming and are accelerated at a rate of 0.45 years per population doubling. Remarkably, MskAge explains more variance associated within vitroageing of fibroblasts than the purpose-developed skin and blood clock.

Conclusion

The precision of MskAge and its ability to capture perturbations in biological ageing make it a promising research tool for musculoskeletal and ageing biologists.
Method for cycle detection in sparse, irregularly sampled, long-term neuro-behavioral timeseries: Basis pursuit denoising with polynomial detrending of long-term, inter-ictal epileptiform activity
Authors: Balzekas Irena , Trzasko Joshua , Yu Grace , Richner Thomas J. , Mivalt Filip , Sladky Vladimir , Gregg Nicholas M. , Gompel Jamie Van , Miller Kai , Croarkin Paul E. , Kremen Vaclav , Worrell Gregory A.
Published: May 2023

Numerous physiological processes are cyclical, but sampling these processes densely enough to perform frequency decomposition and subsequent analyses can be challenging. Mathematical approaches for decomposition and reconstruction of sparsely and irregularly sampled signals are well established but have been under-utilized in physiological applications. We developed a basis pursuit denoising with polynomial detrending (BPWP) model that recovers oscillations and trends from sparse and irregularly sampled timeseries. We validated this model on a unique dataset of long-term inter-ictal epileptiform discharge (IED) rates from human hippocampus recorded with a novel investigational device with continuous local field potential sensing. IED rates have well established circadian and multiday cycles related to sleep, wakefulness, and seizure clusters. Given sparse and irregular samples of IED rates from multi-month intracranial EEG recordings from ambulatory humans, we used BPWP to compute narrowband spectral power and polynomial trend coefficients and identify IED rate cycles in three subjects. In select cases, we propose that random and irregular sampling may be leveraged for frequency decomposition of physiological signals.

Author Summary

Circadian and multiday cycles are an important part of many long-term neuro-behavioral phenomena such as pathological inter-ictal epileptiform discharges (IEDs) in epilepsy. Long-term, ambulatory, neuro-behavioral monitoring in human patients involves complex recording systems that can be subject to intermittent, irregular data loss and storage limitations, resulting in sparse, irregularly sampled data. Cycle identification in sparse data or irregular data using traditional frequency decomposition techniques typically requires interpolation to create a regular timeseries. Using unique, long-term recordings of pathological brain activity in patients with epilepsy implanted with an investigational device, we developed a method to identify cycles in sparse, irregular neuro-behavioral data without interpolation. We anticipate this approach will enable retrospective cycle identification in sparse neuro-behavioral timeseries and support prospective sparse sampling in monitoring systems to enable long-term monitoring of patients and to extend storage capacity in a variety of ambulatory monitoring applications.
Draft genome sequence of Microbacterium fakhimisp. nov., a novel bacterium associated with the algaChlamydomonas reinhardtii
Authors: Fakhimi Neda , Torres María Jesus , Delgado-Luque Jesús , Fernandez Emilio , Galván Aurora , Dubini Alexandra , González-Ballester David
Published: May 2023

Microbacterium fakhimisp. nov. has been isolated from a contaminated algal culture (Chlamydomonas reinhardtii). Its genome has been fully sequenced (3,753,259 base pairs) and a tentative annotation is provided (3,704 genes). Both, genome information and growth tests suggest thatM. fakhimisp. nov. is auxotroph for biotin and thiamine and unable to use sulfate as sulfur (S) source. S-reduced forms, such as methionine and cysteine can supportM. fakhimisp. nov. growth. The potential biotechnological interest of this bacteria is discussed here and in a related research paper (Fakhimi et al., 2023b).
Phosphorylation of 53BP1 by ATM enforce neurodevelopmental programs in cortical organoids
Authors: Lim Bitna , Djekidel Mohamed Nadhir , Matsui Yurika , Jung Seunghyun , Yuan Zuo-Fei , Wang Xusheng , Yang Xiaoyang , Pilehroud Abbas Shirinifard , Pan Haitao , Wang Fang , Pruett-Miller Shondra , Kavdia Kanisha , Pagala Vishwajeeth , Fan Yiping , Peng Junmin , Xu Beisi , Peng Jamy C.
Published: May 2023

53BP1 is a well-established DNA damage repair factor recently shown to regulate gene expression and critically influence tumor suppression and neural development. For gene regulation, how 53BP1 is regulated remains unclear. Here, we showed that 53BP1-serine 25 phosphorylation by ATM is required for neural progenitor cell proliferation and neuronal differentiation in cortical organoids. 53BP1-serine 25 phosphorylation dynamics controls 53BP1 target genes for neuronal differentiation and function, cellular response to stress, and apoptosis. Beyond 53BP1, ATM is required for phosphorylation of factors in neuronal differentiation, cytoskeleton, p53 regulation, and ATM, BNDF, and WNT signaling pathways for cortical organoid differentiation. Overall, our data suggest that 53BP1 and ATM control key genetic programs required for human cortical development.
Image-based identification and isolation of micronucleated cells to dissect cellular consequences
Authors: DiPeso Lucian , Pendyala Sriram , Huang Heather Z , Fowler Douglas M , Hatch Emily M
Published: May 2023

Recent advances in isolating cells based on visual phenotypes have transformed our ability to identify the mechanisms and consequences of complex traits. Micronucleus (MN) formation is a frequent outcome of genome instability, triggers extensive disease-associated changes in genome structure and signaling coincident with MN rupture, and is almost exclusively defined by visual analysis. Automated MN detection in microscopy images has proved extremely challenging, limiting unbiased discovery of the mechanisms and consequences of MN formation and rupture. In this study we describe two new MN segmentation modules: a rapid model for classifying micronucleated cells and their rupture status (VCS MN), and a robust model for accurate MN segmentation (MNFinder) from a broad range of fluorescence microscopy images. As a proof-of- concept, we define the transcriptome of non-transformed human cells with intact or ruptured MN after inducing chromosome missegregation by combining VCS MN with photoactivation-based cell isolation and RNASeq. Surprisingly, we find that neither MN formation nor rupture triggers a strong unique transcriptional response. Instead, transcriptional changes appear correlated with small increases in aneuploidy in these cell classes. Our MN segmentation modules overcome a significant challenge with reproducible MN quantification, and, joined with visual cell sorting, enable the application of powerful functional genomics assays, including pooled CRISPR screens and time-resolved analyses of cellular and genetic consequences, to a wide-range of questions in MN biology.
DeepPhe-CR: Natural Language Processing Software Services for Cancer Registrar Case Abstraction
Authors: Hochheiser Harry , Finan Sean , Yuan Zhou , Durbin Eric B. , Jeong Jong Cheol , Hands Isaac , Rust David , Kavuluru Ramakanth , Wu Xiao-Cheng , Warner Jeremy L. , Savova Guergana
Published: May 2023

Objective

The manual extraction of case details from patient records for cancer surveillance efforts is a resource-intensive task. Natural Language Processing (NLP) techniques have been proposed for automating the identification of key details in clinical notes. Our goal was to develop NLP application programming interfaces (APIs) for integration into cancer registry data abstraction tools in a computer-assisted abstraction setting.

Methods

We used cancer registry manual abstraction processes to guide the design of DeepPhe-CR, a web-based NLP service API. The coding of key variables was done through NLP methods validated using established workflows. A container-based implementation including the NLP wasdeveloped. Existing registry data abstraction software was modified to include results from DeepPhe-CR. An initial usability study with data registrars provided early validation of the feasibility of the DeepPhe-CR tools.

Results

API calls support submission of single documents and summarization of cases across multiple documents. The container-based implementation uses a REST router to handle requests and support a graph database for storing results. NLP modules extract topography, histology, behavior, laterality, and grade at 0.79-1.00 F1 across common and rare cancer types (breast, prostate, lung, colorectal, ovary and pediatric brain) on data from two cancer registries. Usability study participants were able to use the tool effectively and expressed interest in adopting the tool.

Discussion

Our DeepPhe-CR system provides a flexible architecture for building cancer-specific NLP tools directly into registrar workflows in a computer-assisted abstraction setting. Improving user interactions in client tools, may be needed to realize the potential of these approaches. DeepPhe-CR:https://deepphe.github.io/.
Gender influence on changes of Coagulation factors in cryoprecipitate plasma at Kisii Teaching and Referral Hospital
Authors: Ogolla Collince Odiwuor , Nyanchongi Benson , Momanyi Chrisphine
Published: May 2023

Background

Cryoprecipitate is used without knowing the concentration of coagulation factors it contains which poses danger of circulatory overload with no any improvement if several bags with low factor levels are transfused when the levels changes or drastically reduce.

Objective

The objective was to evaluate gender influence on changes of Coagulation factors in cryoprecipitate plasma at Kisii Teaching and Referral Hospital.

Methods

The study involved time series analysis design involving analysis of cryoprecipitate during storage at -18°C for 5 weeks. Blood collected from the Kisii satellite blood transfusion center was received at Hematology laboratory where factor assays were performed on Erba Mannheim ECL 105 semi-automated coagulation analyzer. Thawing for subsequent coagulation factor analysis and serial testing was done using Stericox Plasma Thawing Bath at 37°C, for 45 mins. Data were entered into Excel and analyzed by SPSS version 25.

Results

The mean rank for cryoprecipitate from week one to week five was in a decreasing trend with 3.00, 1.99 and 1.01 respectively. This confirms a steady statistical significant difference in mean ranks for the time period. The coagulation factors in cryoprecipitate plasma in the donated blood were not affected by the gender of the blood donor.

Conclusion

The gender of the donor has no effect on the coagulation factors in cryoprecipitate plasma
Telomere-to-Telomere Assembly Improves Host Reads Removal in Metagenomic High-Throughput Sequencing of Human Samples
Authors: Wang Lei , Xing Guoning
Published: May 2023

Metagenomic high-throughput sequencing brings revolution to the study of human microbiome, clinical pathogen detection, discovery and infection diagnosis, but clinical samples often contain abundant human nucleic acids, leading to a high proportion of host reads. A high-quality human reference genome is essential for removing host reads to make downstream analyses faster and more accurate. The recently published complete human genome, Telomere-to-Telomere CHM13 assembly (T2T), though achieved great success immediately, has yet to be tested for metagenomic sequencing. In this study, we demonstrated the innovation that T2T brings to the field, using a diverse set of samples containing 4.97 billion reads sequenced from 165 libraries, on short- and long-read platforms. To exclude the effect of algorithms in comparison of the genomes, we benchmarked the per-read performance of state-of-the-art algorithms. For short reads, bwa mem was the best-performing algorithm, with positive median of differences (MD) and adjusted p-values <0.001 for all comparisons, while no consistent difference in overall performance was found for long reads algorithms. T2T, when compared to current reference genomes hg38 and YH, significantly improved the per-read sensitivity (MD: 0.1443 to 0.7238 percentage point, all adjusted p-values < 0.001) in removing host reads for all sequencers, and the per-read Mathew’s correlation coefficient (MCC) with T2T was also higher (MD: 1.063 to 16.41 percentage point, all adjusted p-values <0.001). Genomic location of reads exclusively mappable to T2T concentrated mainly in newly added regions. Misclassified reads generally resulted from low complexity sequences, contaminations in reference genomes and sequencing abnormalities. In downstream microbe detection procedures, T2T did not affect true positive calls but greatly reduced false positive calls. The improvement in the ability to correctly remove host reads foretells the success of T2T to serve as the next prevailing reference genome in metagenomic sequencing of samples containing human nucleic acids.
Age-related changes in the neural processing of semantics, within and beyond the core semantic network
Authors: Wu Wei , Hoffman Paul
Published: May 2023

Ageing is associated with increases in functional activation, which have been interpreted either as compensatory responses to the higher task demands older people experience, or as neural dedifferentiation. Ageing is also characterised by a shift to greater reliance on prior knowledge and less on executive function, whose underlying neural mechanism is poorly understood. This pre-registered fMRI study investigated these questions within the domain of semantic cognition. To disentangle the compensation and dedifferentiation theories, we extracted activation signal in core verbal semantic regions, for young and older participants during semantic tasks. Verbal semantic processing relies heavily on left inferior frontal gyrus (IFG) but older people frequently show additional right IFG activation. We found that right IFG exhibited a similar linear activation-demand relationship as left IFG across age groups and semantic tasks, indicating that age-related over-recruitment of this region may be compensatory in nature. To answer the second question, we examined network-level activity and connectivity changes in semantic and non-semantic tasks. Older people showed more engagement of the default mode network (DMN) and less of the executive multiple demand network (MDN) aligning with their greater reserves of prior knowledge and declined executive control. In contrast, activation was age-invariant in regions contributing specifically to executive control of semantic processing. Older adults also showed a degraded ability to modulate MDN activation as a function of demand in the non-semantic task, but not in the semantic tasks. These findings provide a new perspective on the neural basis of semantic cognition in later life, and suggest that preservation of activation in specialised semantic networks may support preserved performance in this critical domain.
Deciphering the gene regulatory circuitry governing chemoresistance in Triple-Negative Breast Cancer
Authors: Lusby Ryan , Zhang Ziyi , Mahesh Arun , Tiwari Vijay K.
Published: May 2023

Triple-negative breast cancer (TNBC) is the most aggressive breast cancer subtype, due in part to extensive intratumoral heterogeneity, high rates of metastasis and chemoresistance, leading to poor clinical outcomes. Despite progress, the mechanistic basis of chemotherapy resistance in TNBC patients remains poorly understood. Here, using single-cell transcriptome datasets of matched longitudinal TNBC chemoresponsive and chemoresistant patient cohorts, we discover cell subpopulations associated with chemoresistance and the signature genes defining these populations. Notably, we show that the expression of these chemoresistance genes is driven via a set of TNBC super-enhancers and transcription factor networks across TNBC subtypes. Furthermore, genetic screens reveal that a subset of these transcription factors is essential for the survival of TNBC cells and their loss increases sensitivity to chemotherapeutic agents. Overall, our study has revealed transcriptional regulatory networks underlying chemoresistance and suggests novel avenues to stratify and improve the treatment of patients with a high risk of developing resistance.