bluuebunny/crossref_metadata_2025_split huggingface dataset:
On the accuracy of the epigenetic copy machine: comprehensive specificity analysis of the DNMT1 DNA methyltransferase
Authors: Adam Sabrina , Klingel Viviane , Radde Nicole E , Bashtrykov Pavel , Jeltsch Albert 
Published: May 2023

Abstract
The specificity of DNMT1 for hemimethylated DNA is a central feature for the inheritance of DNA methylation. We investigated this property in competitive methylation kinetics using hemimethylated (HM), hemihydroxymethylated (OH) and unmethylated (UM) substrates with single CpG sites in a randomized sequence context. DNMT1 shows a strong flanking sequence dependent HM/UM specificity of 80-fold on average, which is slightly enhanced on long hemimethylated DNA substrates. To explain this strong effect of a single methyl group, we propose a novel model in which the presence of the 5mC methyl group changes the conformation of the DNMT1-DNA complex into an active conformation by steric repulsion. The HM/OH preference is flanking sequence dependent and on average only 13-fold, indicating that passive DNA demethylation by 5hmC generation is not efficient in many flanking contexts. The CXXC domain of DNMT1 has a moderate flanking sequence dependent contribution to HM/UM specificity during DNA association to DNMT1, but not if DNMT1 methylates long DNA molecules in processive methylation mode. Comparison of genomic methylation patterns from mouse ES cell lines with various deletions of DNMTs and TETs with our data revealed that the UM specificity profile is most related to cellular methylation patterns, indicating that de novo methylation activity of DNMT1 shapes the DNA methylome in these cells.
Ex vivo to in vivo model of malignant peripheral nerve sheath tumors for precision oncology
Authors: Larsson Alex T , Bhatia Himanshi , Calizo Ana , Pollard Kai , Zhang Xiaochun , Conniff Eric , Tibbitts Justin F , Rono Elizabeth , Cummins Katherine , Osum Sara H , Williams Kyle B , Crampton Alexandra L , Jubenville Tyler , Schefer Daniel , Yang Kuangying , Lyu Yang , Pino James C , Bade Jessica , Gross John M , Lisok Alla , Dehner Carina A , Chrisinger John S A , He Kevin , Gosline Sara J C , Pratilas Christine A , Largaespada David A , Wood David K , Hirbe Angela C 
Published: May 2023

Abstract

Background
Malignant peripheral nerve sheath tumors (MPNST) are aggressive soft tissue sarcomas that often develop in patients with neurofibromatosis type 1 (NF1). To address the critical need for novel therapeutics in MPNST, we aimed to establish an ex vivo 3D platform that accurately captured the genomic diversity of MPNST and could be utilized in a medium-throughput manner for drug screening studies to be validated in vivo using patient-derived xenografts (PDX).

Methods
Genomic analysis was performed on all PDX-tumor pairs. Selected PDX were harvested for assembly into 3D microtissues. Based on prior work in our labs, we evaluated drugs (trabectedin, olaparib, and mirdametinib) ex vivo and in vivo. For 3D microtissue studies, cell viability was the endpoint as assessed by Zeiss Axio Observer. For PDX drug studies, tumor volume was measured twice weekly. Bulk RNA sequencing was performed to identify pathways enriched in cells.

Results
We developed 13 NF1-associated MPNST-PDX and identified mutations or structural abnormalities in NF1 (100%), SUZ12 (85%), EED (15%), TP53 (15%), CDKN2A (85%), and chromosome 8 gain (77%). We successfully assembled PDX into 3D microtissues, categorized as robust (&gt;90% viability at 48 h), good (&gt;50%), or unusable (&lt;50%). We evaluated drug response to “robust” or “good” microtissues, namely MN-2, JH-2-002, JH-2-079-c, and WU-225. Drug response ex vivo predicted drug response in vivo, and enhanced drug effects were observed in select models.

Conclusions
These data support the successful establishment of a novel 3D platform for drug discovery and MPNST biology exploration in a system representative of the human condition.
Missing Americans: Early death in the United States—1933–2021
Authors: Bor Jacob , Stokes Andrew C , Raifman Julia , Venkataramani Atheendar , Bassett Mary T , Himmelstein David , Woolhandler Steffie 
Published: May 2023

AbstractWe assessed how many US deaths would have been averted each year, 1933–2021, if US age-specific mortality rates had equaled the average of 21 other wealthy nations. We refer to these excess US deaths as “missing Americans.” The United States had lower mortality rates than peer countries in the 1930s–1950s and similar mortality in the 1960s and 1970s. Beginning in the 1980s, however, the United States began experiencing a steady increase in the number of missing Americans, reaching 622,534 in 2019 alone. Excess US deaths surged during the COVID-19 pandemic, reaching 1,009,467 in 2020 and 1,090,103 in 2021. Excess US mortality was particularly pronounced for persons under 65 years. In 2020 and 2021, half of all US deaths under 65 years and 90% of the increase in under-65 mortality from 2019 to 2021 would have been avoided if the United States had the mortality rates of its peers. In 2021, there were 26.4 million years of life lost due to excess US mortality relative to peer nations, and 49% of all missing Americans died before age 65. Black and Native Americans made up a disproportionate share of excess US deaths, although the majority of missing Americans were White.
Considering ChatGPT to be the first aid for young adults on mental health issues
Authors: Aminah Siti , Hidayah Nur , Ramli M 
Published: May 2023

Abstract
Providing mental health support and interventions through artificial intelligence can open up more significant space for young people to get good services. ChatGPT’s potential to provide first aid to young adults struggling with mental health issues is noteworthy. Despite its benefits and limitations, today’s technology can be a valuable addition to the mental health support available to young adults.
Low testosterone state inhibits erectile function by downregulating the expression of GIT1 in rat penile corpus cavernosum
Authors: Gu JianBin , Zhu Li-kun , Zhao Xin , Jiang Jun , Jiang Rui 
Published: May 2023

Abstract

Background
The mechanism of erectile dysfunction (ED) caused by a low androgen level is still not clear.

Aim
To explore the influence of the low testosterone state on G protein–coupled receptor kinase interactor 1 (GIT1) and its contact to erectile function.

Methods
Thirty male Sprague-Dawley rats aged 8 weeks were distributed at random into 5 groups: control (sham operated), castration, testosterone supplement after castration, castration + vacant lentiviral transfection, and castration + lentiviral transfection. The testis and epididymis were removed through a scrotal incision to develop castrated rats. Four weeks after castration, a lentivirus carrying the GIT1 gene was injected into the middle of rat penile corpus cavernosum. One week after transfection, maximum intracavernous pressure/mean arterial pressure (ICPmax/MAP), serum testosterone, nitric oxide, GIT1, endothelial nitric oxide synthase (eNOS), phospho-eNOS (p-eNOS), p-eNOS/eNOS, and the interaction between eNOS and GIT1 were assessed in the rats.

Outcomes
The levels of GIT1 in the penile cavernous tissue of castrated rats are significantly lower than that of controls.

Results
GIT1 was expressed in the cytoplasm and cell membrane of vascular endothelial cells and smooth muscle cells in rat penile tissue. In comparison with normal rats, the castrated rats showed lower levels of GIT1 expression, GIT1 and eNOS interaction, p-eNOS/eNOS, nitric oxide, and ICPmax/MAP (P &lt; .01). Overexpression of GIT1 can intensively enhance the expression level of GIT1, the interaction between GIT1 and eNOS, p-eNOS/eNOS, nitric oxide, and ICPmax/MAP in rats (P &lt; .01).

Clinical Translation
Modulating the interaction between eNOS and GIT1 might be a novel method of treating ED caused by a low androgen level.

Strengths and Limitations
The impact of GIT1 phosphorylation on the activity of eNOS and its possible mechanisms affecting erectile function require further study.

Conclusion
A low testosterone state inhibits erectile function in rats by reducing the expression of GIT1 and the protein interaction between GIT1 and eNOS.
Sexual dysfunction is highly prevalent in male survivors of malignant lymphoma
Authors: Micas Pedersen Signe , Nielsen Torsten Holm , Gang Anne Ortved , Poulsen Christian Bjørn , de Nully Brown Peter , Jørgensen Niels , Feltoft Claus Larsen , Pedersen Lars Møller 
Published: May 2023

AbstractBackgroundWith improved survival in patients with lymphoma, long-term toxicity and quality of life (QoL), including sexual health, have become increasingly important.AimWe aimed to (1) determine the prevalence of erectile dysfunction (ED) in adult male lymphoma survivors; (2) determine whether testosterone deficiency, comorbidities, or lifestyle factors were associated; and (3) evaluate their impact on QoL.MethodsA cross-sectional study including 172 male survivors of Hodgkin lymphoma or diffuse large B cell lymphoma diagnosed in adulthood between 2008 and 2018 was performed. Patients were in complete metabolic remission after first-line treatment and remained in remission at follow-up (3-13 years after diagnosis). Participants completed 3 questionnaires measuring sexual health and general QoL. Serum concentrations of total testosterone were measured and thorough medical history and sociodemographic factors were obtained. The Danish SEXUS Project, European Male Ageing Study, and European Organization of Research and Treatment of Cancer (EORTC) Reference Manual were used as reference values of the general population.OutcomesPatient reported outcome measures including the 5-item International Index of Erectile Function, EORTC C30, and EORTC 22-item Sexual Health Questionnaire.ResultsED was reported by 55.2%, which was higher than in an age-matched Danish population cohort (17.5%). Erectile function score (5-item International Index of Erectile Function) was negatively associated with comorbidity, body mass index, smoking, and age and positively with the number of children conceived before treatment and serum concentration of total testosterone. Overt testosterone deficiency in combination with ED was detected in 10 (5.7%) of 176 survivors, including excluded survivors in hormonal treatment, which is higher than for the general population (0.1%-3.2% for men &lt;70 years of age). Mean EORTC C30 global health score for survivors with ED was lower (67.7) than for survivors without ED (80.1) but was comparable to the general population (71.2). Furthermore, a positive association was seen between sexual function and both sexual and general QoL.Clinical implicationsSexual health is important for QoL and related to comorbidities. The focus on improving QoL requires that both sexual health and comorbidities are addressed in the follow-up of lymphoma patients.Strengths and limitationsDespite the relatively high number of included survivors, the cross-sectional design of this study warrants longitudinal studies to clarify the specific underlying causes of sexual dysfunction.ConclusionED was highly prevalent and associated with comorbidity in lymphoma survivors, and more focus on sexual health and treatment related comorbidity is needed to improve sexual and general QoL.
Impact of endometriosis on female sexual function: an updated systematic review and meta-analysis
Authors: Zhu Xiujuan , Wu Yanhui , Jia Jing , Zhao Xinwei , Zhao Xiuping 
Published: May 2023

Abstract

Introduction
Endometriosis can lead to a state of chronic inflammation marked by the presence of scarring and adhesions within the pelvis and/or other parts of the body. Recent estimates suggest that globally this condition affects approximately 10% of women in the reproductive age group.

Aims
In this study we sought updated evidence on the association between endometriosis and sexual function in female patients.

Methods
We used standard assessment tools to conduct a systematic search of the PubMed, EMBASE, and Scopus databases for observational studies that documented the association of endometriosis with female sexual function. A random-effects model was used for the analysis, and effect sizes were reported as the weighted mean difference (WMD) or OR with 95% CIs.

Results
A total of 13 studies were selected for inclusion in our investigation. All of the included studies were cross-sectional in design. The data on sexual function in most of the studies were collected by using the Female Sexual Function Index (FSFI) tool, for which higher scores suggest better sexual function. The risk of sexual dysfunction (based on specific cutoffs for the FSFI score) was higher in women with than in women without endometriosis (OR 1.71; 95% CI, 1.21-2.43). In addition, when we used continuous scores to examine the risk of sexual dysfunction, diagnosis of endometriosis was associated with significantly lower overall FSFI scores (WMD, −3.40; 95% CI, −5.13 to −1.66) and lower scores on all of its 6 domains, ie, desire (WMD, −0.27; 95% CI, −0.53 to −0.02), arousal (WMD, −0.43; 95% CI, −0.79 to −0.07), lubrication (WMD, −0.49; 95% CI, −0.66 to −0.31), orgasm (WMD, −0.65; 95% CI, −1.07 to −0.23), satisfaction (WMD, −0.52; 95% CI, −0.77 to −0.26), and pain (WMD, −1.06; 95% CI, −1.57 to −0.55).

Conclusion
The findings of this study suggest that female patients with endometriosis have suboptimal sexual function compared with healthy female subjects. Patients with endometriosis should be offered sexual counseling and supportive care by a multidisciplinary team of gynecologists, psychologists, and sexual therapists.
0003 Sleep and Circadian Disruption Induced by Simulated Night Shift Work Impair Cardiometabolic Outcomes in Healthy Adults
Authors: Seward Sophie , Higgins Janine , Wright Kenneth , Broussard Josiane 
Published: May 2023

Abstract

Introduction
People who work evening, night or rotating shifts make up 20% of the US workforce and have a heightened risk for Type 2 diabetes (T2D) and cardiovascular disease (CVD) compared to people who work days, possibly due to repeated bouts of sleep and circadian disruption. However, the mechanism(s) by which sleep and circadian disruption impair cardiometabolic health are unclear. We therefore investigated the impact of acute circadian misalignment on factors related to cardiometabolic health including interstitial glucose concentration, glucose tolerance, resting systolic blood pressure (SBP), diastolic blood pressure (DBP) and heart rate (HR).

Methods
Ten healthy adults (6F, 25.0±4.5y, BMI: 22.0±2.2kg/m2; mean±SD) participated in an ongoing 6d inpatient simulated night shift protocol to induce sleep and circadian disruption. Participants lived at the Sleep and Metabolism Laboratory for 2d to simulate day shift work followed by 2d of simulated night shift work. Continuous interstitial glucose monitoring was conducted throughout the study (FreeStyle Libre Pro; Abbott, Alameda, CA, USA). BP and HR were assessed 30 minutes after waketime (Omron HEM-FL31; Omron Healthcare, Kyoto, JP) followed by an oral glucose tolerance tests (OGTT) conducted 1.5h after waketime in both conditions.

Results
Simulated night shift work was associated with significantly higher interstitial glucose area under the curve (AUC) in response to an identical first meal after waking (18,299±1412 v 14,606±2035 [mg/dl]*min; p=0.009; mean±SEM) as well as plasma glucose AUC during the OGTT (23,239±2574 v 18,776±1832; p=0.002) compared to simulated day work. Furthermore, simulated night shift work was associated with a significant increase in resting DBP (75±3 v 66±2; p=0.017) compared to day work. No changes were observed in resting SBP (p=0.40) or HR (p=0.11) between conditions.

Conclusion
Sleep and circadian disruption induced by simulated night shift work appear to impair markers of cardiometabolic health, even in healthy, lean adults. Night shift work is largely unavoidable in modern society, thus is it critical to identify strategies or countermeasures to prevent the impact of circadian misalignment on T2D and CVD risk in a large portion of the population.

Support (if any)
This project was supported in part by R01DK125653 & F31HL165883.
0007 Later circadian phase and increased sleep variability are associated with overnight blood pressure dipping in chronic shiftworkers
Authors: Shafer Brooke , Christopher Desirae , Shea Steven , Olson Ryan , McHill Andrew 
Published: May 2023

Abstract

Introduction
Nighttime shift work is associated with adverse cardiovascular outcomes, including hypertension. Increased sleep variability and circadian disruption may increase sympathetic activity and waking blood pressure (BP), potentially constraining typical BP reductions during overnight sleep. However, the relationships between circadian phase, sleep variability, and overnight BP reduction (dipping) among day vs. chronic nightshift workers is unknown.

Methods
Ambulatory BP was monitored for up to 48-hours among 10 dayshift (mean□SD; age 33.1□7.0y; BMI 26.3□5.4 kg/m2) and 10 chronic (9.3□6.8y of shiftwork) nightshift workers (age 32.7□9.1y; BMI 27.9□7.6 kg/m2). Overnight BP dipping was calculated from the sleeping/waking systolic BP ratio. Variability in sleep timing was defined as the SD of self-reported daily-diary sleep onset across 1-week. Circadian phase was determined by salivary dim-light melatonin onset (DLMO; 3pg/ml threshold). Differences between groups were assessed using independent t-tests and linear mixed-effects models with group and time-from-sleep-onset or circadian phase as fixed-effects, and participant as a random effect. Relationships between overnight BP dipping and DLMO, sleep onset timing variability, and phase angle of entrainment (DLMO to sleep onset during ambulatory BP) were assessed using Pearson correlation analyses.

Results
Chronic nightshift workers had reduced overnight BP dipping (-9.3□1.5 % vs -13.4□4.4 %; p=0.04), later DLMO timing (21:08□0:53 vs 19:21□1:02; p=0.001), smaller phase angle of entrainment (3.7□1.0 h vs 5.0□0.90 h; p=0.02), and greater variability in sleep onset timing (3.2□1.5 h vs 0.87□0.34 h; p&lt; 0.001). Significant group effects for higher systolic BP across circadian phase and time from sleep onset in the nightshift group were observed compared to dayshift (both p&lt; 0.05). DLMO (r=0.49; p=0.04) and phase angle of entrainment (r=0.53; p=0.02) were associated with overnight BP dip magnitude (later circadian phase correlated with less dipping). Sleep onset timing variability was negatively correlated with magnitude of overnight BP dipping in nightshift (r= -0.76; p=0.04) but not dayshift workers (r=0.26; p=0.61).

Conclusion
Attenuated overnight BP dipping among chronic nightshift workers may be indicative of increased cardiovascular risk. Chronic circadian disruptions (i.e., smaller phase angle of entrainment) as a function of higher sleep variability among nightshift workers may mechanistically contribute to poorer health outcomes compared to dayshift workers.

Support (if any)
R01HL105495, K01HL146992
0022 Characterization and Evaluation of Digital Dim Light Melatonin Onset in a Population-Based Sample
Authors: Reis Daniel , Bahraini Nazanin 
Published: May 2023

Abstract

Introduction
Misalignment between circadian phase (i.e., timing) and the desired sleep window is associated with sleep disturbances including insomnia and circadian rhythm sleep-wake disorders. Identifying circadian-driven sleep disruption requires assessment of circadian phase, the gold-standard of which is dim light melatonin onset (DLMO). While DLMO is traditionally measured in the lab using saliva or blood sampled over multiple hours, novel methods of estimating DLMO using activity and light data obtained from wearable sensors (i.e., digital DLMO) have been recently validated in samples with both healthy and disordered sleep. Such methods could potentially provide pragmatic, low-burden ways of assessing circadian phase, which in turn could be used to aid diagnostic decisions and to adjust circadian-targeted interventions in real time. However, digital DLMO has yet to be characterized within the broader adult population, which is needed to differentiate between normative and clinically salient values. Therefore, this study will examine digital DLMO in a large, population-based sample, as well as explore the potential clinical utility of digital biomarkers related to circadian phase.

Methods
This study will be a secondary analysis of data obtained during the ancillary sleep study of the Multi-Ethnic Study of Atherosclerosis (i.e., MESA Sleep). Seven days of activity and light data, measured via wrist-worn actigraphy, were obtained from 2,237 participants. Digital DLMO will be estimated using the extended Kronauer limit-cycle model of the human circadian pacemaker. Phase angles, or the differences in clock time, between digital DLMO and the following will be calculated: self-reported in-bed time; and sleep onset, midpoint, and offset measured by actigraphy. The associations between these phase angles and sleep outcomes (i.e., sleep onset latency, sleep efficiency, and sleep quality) will be explored using linear regression. Covariates will include the age, gender, and race/ethnicity of the participant. Weekend and weekday averages will be evaluated separately.

Results
Results will include the distribution of digital DLMO in a population-based sample, as well as the associations between digital DLMO phase angles and sleep outcomes.

Conclusion
This study will inform future research into the clinical potential of digital circadian biomarkers.

Support (if any)