bluuebunny/crossref_metadata_2025 huggingface dataset:
DOLAMA study
Authors: Hidalgo-Tenorio Carmen , Cortés Luis López , Gutiérrez Alicia , Santos Jesús , Omar Mohamed , Gálvez Carmen , Sequera Sergio , Jesús Samantha Eisabeth De , Téllez Franciso , Fernández Elisa , García Coral , Pasquau Juan
Published: August 2019

Dolutegravir (DTG) has shown effectiveness in combination with rilpivirine in with experience of antiretroviral therapy (ART) and with 3TC in naïve patients (GEMINI trial). The main objectives of this real-life study were to analyze the effectiveness and safety of 3TC plus DTG in virologically suppressed HIV-1 patients and to conduct a pharmacoeconomic analysis.

We conducted an observational, retrospective and multicenter study of HIV+ patients pretreated for at least 6 months with ART that was then simplified to 3TC + DTG for any reason. We gathered data on viral loads (VLs) during exposure to the DT, calculating the rate with VL < 50 copies/mL at week 48, and on associated adverse effects.

The 177 HIV+ patients were collected, 77.4% male, with average age of 48.5 years and mean count of 252.2cell/μL CD4+ nadir lymphocytes; 96.6% had VL < 50 copies/mL and 674 cells/μL CD4+ lymphocytes. Median time since HIV diagnosis was 15 years, and median ART duration was 13 years, and 34.5% of patients were on mono- or dual-therapy before the switch. At week 48, 82.4% of patients had VL < 50 cop/μL using an intention-to-treat (ITT) analysis, 89.6% according to mITT, and 96.7% according to Per-Protocol analysis. 3.3% patients had virological failure (VF). These effectiveness data and costs were compared with those for 2 reference triple therapies (DTG/ABC/3TC and EVG/cobi/FTC/TAF) in a cost minimization analysis, showing cost savings with administration of DTG+3TC (2741 €/year vs DTG/ABC/3TC and 4164 €/year vs EVG/cobi/FTC/TAF) and in a cost-effectiveness analysis, finding the DT to be the most cost-effective approach (ICER = −548 vs DTG/ABC/3TC and ICER = −4,627€ vs EVG/cobi/FTC/TAF)

The combination of 3TC with DTG appears to be a safe and effective option for the simplification of ART in pretreated and virologically stable HIV-positive patients, being cost-effective and offering the same effectiveness as the triple therapy it replaces.
Stress and Health in Nursing Students
Authors: Olvera Alvarez Hector A. , Provencio-Vasquez Elias , Slavich George M. , Laurent Jose Guillermo Cedeño , Browning Matthew , McKee-Lopez Gloria , Robbins Leslie , Spengler John D.
Published: August 2019

Background

Evidence suggests that behavioral, social, and environmental factors may modify the effects of life stress on health and performance of new nurses as they transition to hospitals.

Objectives

The aim of this study was to describe the methods of a project designed to investigate the role of social, behavioral, and environmental factors in modifying the adverse effects of stress on new nurses and to discuss demographic, health, and life stress characteristics of the cohort at baseline.

Methods

A prospective cohort design was used to conduct a comprehensive assessment of health endpoints, life stress, behaviors, personal traits, social factors, indicators of engagement and performance, and environmental exposures in nursing students. Adjusted odds ratios and analyses of covariance were used to examine associations between these factors at baseline.

Results

Health indicators in the cohort were comparable or better than in the broader United States population, and lifetime stress exposure was lower than among students from other majors. Exposure to more lifetime stressors was associated with greater risk for various health conditions, including hypertension, diabetes, and depression. Conversely, better social, environmental, behavioral, and personal profiles were associated with protective effects for the same health conditions.

Discussion

These data comprehensively summarize the lives of predominately Hispanic nursing students and highlight risk and resilience factors associated with their health and well-being. The findings are timely, as the nursing field diversifies in preparation to care for a diverse and aging population. Comprehensively assessing stress–health relationships among student nurses ought to inform the policies, practices, and curricula of nursing schools to better prepare nurses to thrive in the often-strenuous healthcare environment.
Review of Recent Physical Activity Guidelines During Pregnancy to Facilitate Advice by Health Care Providers
Authors: Evenson Kelly R. , Mottola Michelle F. , Artal Raul
Published: August 2019

Importance

Physical activity during pregnancy can offer many maternal and fetal health benefits.

Objective

The aim was to summarize American, Canadian, and international recommendations published recently on physical activity during pregnancy to aid health care providers in their delivery of advice on the topic.

Evidence Acquisition

A descriptive review of 3 national guidelines and 1 international guideline on physical activity during pregnancy was conducted. The guidelines included the 2019 Canadian recommendations, the 2018 United States' Physical Activity Guidelines for Americans (second edition), the 2015 (reaffirmed in 2017) American College of Obstetrics and Gynecology guideline, and the 2016–2018 International Olympic Committee recommendations for recreational and elite athletes.

Results

For apparently healthy women, under the guidance of their health care provider, moderate-intensity physical activity using both aerobic and muscle conditioning activities is recommended. The guidelines recommended at least 150 min/wk spread throughout the week (Canada, United States) or at least 20 to 30 min/d (American College of Obstetrics and Gynecology).

Conclusions and Relevance

This summary of 4 recent guidelines can facilitate use of updated recommendations by health care providers regarding physical activity during pregnancy. More detailed evidence-based guidelines on physical activity during postpartum are needed.

Target Audience

Obstetricians and gynecologists, family physicians

Learning Objectives

After completing this activity, the learner should be better able to describe the most recent recommendations for physical activity during pregnancy; explain the relative and absolute contraindications to physical activity during pregnancy; and identify the warning signs for pregnant women to stop physical activity.
Nocebo Effects in Concussion
Authors: Polich Ginger , Iaccarino Mary A. , Kaptchuk Ted J. , Morales-Quezada Leon , Zafonte Ross
Published: August 2019

Nocebo effects refer to new or worsening symptoms that develop in response to negative health-related information, beliefs, and/or experiences. In recent years, research on concussion pathophysiology has significantly advanced. Through health campaigns and media coverage, emerging knowledge on the risks of this injury has been quickly disseminated to the public, and nowadays, the public perceives concussions as more hazardous to health than ever before. Although advancements in concussion-related research and care are of great importance and value, we ask in this article whether the increasing negative publicity regarding concussion also carries any latent costs. Are additional nocebo effects being fostered? To do so, we will review the literature on the psychological and neurobiological processes underlying nocebo effects, present a series of clinical studies demonstrating the ways in which nocebos may impact concussion outcomes both clinically and societally, then speculate on further potential mechanisms for nocebo effects in concussion. We conclude with an outline of the specific efforts one may take to minimize nocebo effects in concussion-related care.
Personal Phone Calls Lead to Decreased Rates of Missed Appointments in an Adolescent/Young Adult Practice
Authors: Penzias Rebecca , Sanabia Virginia , Shreeve Kyra M. , Bhaumik Urmi , Lenz Caitlin , Woods Elizabeth R. , Forman Sara F.
Published: August 2019

Introduction:

Nationally, hospital practice missed appointment rates are high. Our goal was to reduce the rate of missed appointments in an Adolescent/Young Adult Practice through quality improvement methods.

Methods:

During the 12-month intervention period, administrative staff called patients the day before their primary or specialty care appointments to remind them of the date, time, and location, as well as patients who did not attend their appointments to ask about the reason for their missed appointment. We implemented Plan-Do-Study-Act interventions and analyzed data to compare missed appointment rates between the 12 months before and after February 1, 2017, the project intervention date.

Results:

Results showed significant reductions in the missed appointment rate for the Adolescent/Young Adult Practice. A control chart showed a shift in the mean overall percent of completed appointments from 76.7% to 79.2%. The most common reasons for missed appointments included forgetting (39.2%), conflicts with work/school (11.0%), or emailing the provider without contacting administrative staff (7.8%). There were significant reductions in missed appointment rates for both males and females as well as patients who were ≥20 years old, identified English or Spanish as their primary language, had public or private insurance, identified as Black or Hispanic, or did or did not require an interpreter.

Conclusion:

These data show that targeted interventions such as personalized reminder calls can be effective in reducing patient missed appointment rates in Adolescent/Young Adult Practices.
Trigeminal nerve and white matter brain abnormalities in chronic orofacial pain disorders
Authors: Moayedi Massieh , Hodaie Mojgan
Published: August 2019

The orofacial region is psychologically important, given that it serves fundamental and important biological purposes. Chronic orofacial pain disorders affect the head and neck region. Although some have clear peripheral etiologies, eg, classic trigeminal neuralgia, others do not have a clear etiology (eg, muscular temporomandibular disorders). However, these disorders provide a unique opportunity in terms of elucidating the neural mechanisms of these chronic pain conditions: both the peripheral and central nervous systems can be simultaneously imaged. Diffusion-weighted imaging and diffusion tensor imaging have provided a method to essentially perform in vivo white matter dissections in humans, and to elucidate abnormal structure related to clinical correlates in disorders, such as chronic orofacial pains. Notably, the trigeminal nerve anatomy and architecture can be captured using diffusion imaging. Here, we review the trigeminal somatosensory pathways, diffusion-weighted imaging methods, and how these have contributed to our understanding of the neural mechanisms of chronic pain disorders affecting the trigeminal system. We also discuss novel findings indicating the potential for trigeminal nerve diffusion imaging to develop diagnostic and precision medicine biomarkers for trigeminal neuralgia. In sum, diffusion imaging serves both an important basic science purpose in identifying pain mechanisms, but is also a clinically powerful tool that can be used to improve treatment outcomes.
Disentangling Associations Between Serum Muscle Biomarkers and Sarcopenia in the Presence of Pain and Inflammation Among Patients With Osteoarthritis
Authors: Kurita Noriaki , Kamitani Tsukasa , Wada Osamu , Shintani Ayumi , Mizuno Kiyonori
Published: August 2019

Background/Objective

Reduction of muscle markers, such as creatine phosphokinase (CK), in rheumatic diseases and its association with reduced muscle mass may be of clinical importance in osteoarthritis (OA). Considering the complexity of secondary sarcopenia, clarifying the association between muscle markers and sarcopenia and disentangling the involvement of OA-related conditions are of clinical importance. We investigated the association between serum muscle biomarkers and sarcopenia among patients with OA, considering the presence of pain and inflammation.

Methods

Overall, 1425 patients with knee and hip OA scheduled for joint replacement surgery were included in a single-center cross-sectional study from Screening for People Suffering Sarcopenia in Orthopedic cohort of Kobe study. Primary outcome was sarcopenia defined by 2 criteria (the Asian Working Group for Sarcopenia and the European Working Group on Sarcopenia in Older People). Pain and inflammation were measured using the numeric rating scale and serum C-reactive protein (CRP) levels, respectively. Associations between the biomarkers (serum CK, aspartate aminotransferase, alanine aminotransferase) and sarcopenia were examined using logistic regression models.

Results

Sarcopenia by the Asian Working Group for Sarcopenia criteria was present in 4.0% of patients. In adjusted analyses, sarcopenia was negatively associated with higher serum CK levels, but not with serum aspartate aminotransferase or alanine aminotransferase levels independent of pain score and serum CRP. Neither pain score nor serum CRP level was associated with sarcopenia. Similar results were found when the European Working Group on Sarcopenia in Older People criteria were used.

Conclusions

Serum CK was associated with sarcopenia, suggesting the potential usefulness for sarcopenia detection regardless of pain or inflammation in OA.
Unexpected Race and Ethnicity Differences in the US National Veterans Affairs Kidney Transplant Program
Authors: Myaskovsky Larissa , Kendall Kellee , Li Xingyuan , Chang Chung-Chou H. , Pleis John R. , Croswell Emilee , Ford C. Graham , Switzer Galen E. , Langone Anthony , Mittal-Henkle Anuja , Saha Somnath , Thomas Christie P. , Adams Flohr Jareen , Ramkumar Mohan , Dew Mary Amanda
Published: August 2019

Background.

Racial/ethnic minorities have lower rates of deceased kidney transplantation (DDKT) and living donor kidney transplantation (LDKT) in the United States. We examined whether social determinants of health (eg, demographics, cultural, psychosocial, knowledge factors) could account for differences in the Veterans Affairs (VA) Kidney Transplantation (KT) Program.

Methods.

We conducted a multicenter longitudinal cohort study of 611 Veterans undergoing evaluation for KT at all National VA KT Centers (2010–2012) using an interview after KT evaluation and tracking participants via medical records through 2017.

Results.

Hispanics were more likely to get any KT (subdistribution hazard ratios [SHR] [95% confidence interval (CI)]: 1.8 [1.2-2.8]) or DDKT (SHR [95% CI]: 2.0 [1.3-3.2]) than non-Hispanic white in univariable analysis. Social determinants of health, including marital status (SHR [95% CI]: 0.6 [0.4-0.9]), religious objection to LDKT (SHR [95% CI]: 0.6 [0.4-1.0]), and donor preference (SHR [95% CI]: 2.5 [1.2-5.1]), accounted for some racial differences, and changes to Kidney Allocation System policy (SHR [95% CI]: 0.3 [0.2-0.5]) mitigated race differences in DDKT in multivariable analysis. For LDKT, non-Hispanic African American Veterans were less likely to receive an LDKT than non-Hispanic white (SHR [95% CI]: 0.2 [0.0-0.7]), but accounting for age (SHR [95% CI]: 1.0 [0.9-1.0]), insurance (SHR [95% CI]: 5.9 [1.1-33.7]), presenting with a living donor (SHR [95% CI]: 4.1 [1.4-12.3]), dialysis duration (SHR [95% CI]: 0.3 [0.2-0.6]), network of potential donors (SHR [95% CI]: 1.0 [1.0-1.1]), self-esteem (SHR [95% CI]: 0.4 [0.2-0.8]), transplant knowledge (SHR [95% CI]: 1.3 [1.0-1.7]), and changes to Kidney Allocation System policy (SHR [95% CI]: 10.3 [2.5-42.1]) in multivariable analysis eliminated those disparities.

Conclusions.

The VA KT Program does not exhibit the same pattern of disparities in KT receipt as non-VA centers. Transplant centers can use identified risk factors to target patients who may need more support to ensure they receive a transplant.
Shear-sensitive adhesion enables size-independent adhesive performance in stick insects
Authors: Labonte David , Struecker Marie-Yon , Birn-Jeffery Aleksandra , Federle Walter
Published: August 2019

The ability to climb with adhesive pads conveys significant advantages, and is hence widespread in the animal kingdom. The physics of adhesion predict that attachment is more challenging for large animals, whereas detachment is harder for small animals, due to the difference in surface-to-volume ratios. Here, we use stick insects to show that this problem is solved at both ends of the scale by linking adhesion to the applied shear force. Adhesive forces of individual insect pads, measured with perpendicular pull-offs, increased approximately in proportion to a linear pad dimension across instars. In sharp contrast, whole-body force measurements suggested area-scaling of adhesion. This discrepancy is explained by the presence of shear forces during whole-body measurements, as confirmed in experiments with pads sheared prior to detachment. When we applied shear forces proportional to either pad area or body weight, pad adhesion also scaled approximately with area or mass, respectively, providing a mechanism that can compensate for the size-related loss of adhesive performance predicted by isometry. We demonstrate that the adhesion-enhancing effect of shear forces is linked to pad sliding, which increased the maximum adhesive force per area sustainable by the pads. As shear forces in natural conditions are expected to scale with mass, sliding is more frequent and extensive in large animals, thus ensuring that large animals can attach safely, while small animals can still detach their pads effortlessly. Our results therefore help to explain how nature’s climbers maintain a dynamic attachment performance across seven orders of magnitude in body weight.
Altered theta / beta frequency synchrony links abnormal anxiety-related behavior to synaptic inhibition in Neuroligin-2 knockout mice
Authors: Cruces-Solis Hugo , Babaev Olga , Ali Heba , Chatain Carolina Piletti , Mykytiuk Vasyl , Balekoglu Nursen , Wenger Sally , Krueger-Burg Dilja
Published: August 2019

Inhibitory synaptic transmission plays a key role in the circuits underlying anxiety behaviors, but the network mechanisms by which disruptions in synaptic inhibition contribute to pathological anxiety processing remain largely unknown. Here we addressed this question in mice lacking the inhibitory synapse-specific adhesion protein Neuroligin-2 (Nlgn2), which display widespread reduction in inhibitory synaptic transmission as well as a pronounced anxiety phenotype. To investigate how the lack of synaptic inhibition alters the communication between key brain regions in anxiety processing, we recorded local field potentials (LFPs) simultaneously from a network of brain regions involved in anxiety processing, including the basolateral amygdala (BLA), centromedial amygdala, bed nucleus of the stria terminalis, prefrontal cortex and ventral hippocampus (vHPC). We found that LFP power in the vHPC was profoundly increased while vHPC-directed theta frequency synchrony was disrupted in Nlgn2 KO mice under anxiogenic conditions. Instead, deletion of Nlgn2 increased beta frequency synchrony across the anxiety network, and the theta / beta synchrony ratio strongly predicted anxiety behaviors in an open field paradigm. Local deletion of Nlgn2 in the vHPC and BLA revealed that they encode distinct aspects of the anxiety phenotype of the Nlgn2 KO mice, with vHPC linked to anxiety induced freezing and BLA linked to reduction in exploratory activity. Together, our data demonstrate that alterations in long-range functional connectivity link synaptic inhibition to abnormal anxiety behaviors, and that Nlgn2 KO mice represent an interesting model to study the role of inhibitory synaptic transmission in the circuits underlying anxiety disorders.
Structural models of full-length JAK2 kinase
Authors: Ayaz Pelin , Hammarén Henrik M. , Raivola Juuli , Sharon Dina , Hubbard Stevan R. , Silvennoinen Olli , Shan Yibing , Shaw David E.
Published: August 2019

The protein JAK2 is a prototypical member of the Janus kinase family, and mediates signals from numerous cytokine receptors. The constitutively active V617F mutant of JAK2 is prevalent in many bone marrow disorders, blood cancers, and autoimmune diseases, and is an important drug target. Structures have been determined for each of the four individual domains making up JAK2, and for certain pairs of these domains, but no structure of full-length JAK2 is available, and thus the mechanisms underlying JAK2 regulation and the aberrant activity of the V617F mutant have been incompletely understood. Here we propose structural models of full-length JAK2 in both its active and inactive forms. Construction of these models was informed by long-timescale molecular dynamics simulations. Subsequent mutagenesis experiments showed that mutations at the putative interdomain interfaces modulated JAK2 activity. The models provide a structural basis for understanding JAK2 autoinhibition and activation, and suggest that the constitutive activity of the V617F mutant may arise from a dual effect of destabilizing the inactive conformation and stabilizing the active conformation.
Comparing the microbial communities of natural and supplemental nests of an endangered ecosystem engineer
Authors: Thoemmes Megan S. , Cove Michael V.
Published: August 2019

Supplemental nests are often used to restore habitats for a variety of rare and endangered taxa. However, though supplemental nests mimic the function of natural nests, they vary in design and building material. We know from previous research on human homes and other buildings that these differences in architecture can alter the types of microbes to which inhabitants are exposed, and these shifts in microbial interactions can be detrimental for health and well-being. Yet, no one has tested whether microbial communities in supplemental structures are distinct from those found in natural nests. Here we sampled the bacteria from inside supplemental nests of the endangered Key Largo woodrat (Neotoma floridana smalli). We then compared the diversity and composition of those bacteria to those collected from natural stick-nests and the forest floor in Key Largo, Florida. In addition, we sampled woodrat bodies to assess the microbiota of nest inhabitants. We observed distinct bacterial communities in Key Largo woodrat nests, relative to the forest environment; however, we could not differentiate between the microbial communities collected from supplemental and natural nests. Furthermore, when we considered genera known to contain bacterial pathogens of wild rodents, supplemental and natural nests exhibited similarly low relative abundances of these taxa. Where we expected to see an accumulation of pathogens, we instead observed high relative abundances of bacteria from antimicrobial-producing groups (i.e., Pseudonocardiaceae and Streptomycetaceae). The microbial biota of Key Largo woodrat individuals resembled those of their nests, with low relative abundances of potentially pathogenic bacteria and high abundances of antimicrobial-producing groups. Our results suggest that, although there is some microbial interaction between nests and nest inhabitants, there are no detectable differences in the types of bacteria to which Key Largo woodrats are exposed in supplemental and natural nest structures.
Conserved CxnC motifs in Kaposi’s sarcoma-associated herpesvirus ORF66 are required for viral late gene expression and mediate its interaction with ORF34
Authors: Didychuk Allison L. , Castañeda Angelica F. , Kushnir Lola O. , Huang Carolyn J. , Glaunsinger Britt A.
Published: August 2019

Late gene transcription in the beta- and gammaherpesviruses depends on a set of virally-encoded transcriptional activators (vTAs) that hijack the host transcriptional machinery and direct it to a subset of viral genes that are required for completion of the viral replication cycle and capsid assembly. In Kaposi’s sarcoma-associated herpesvirus (KSHV), these vTAs are encoded by ORF18, ORF24, ORF30, ORF31, ORF34, ORF66. Assembly of the vTAs into a complex is critical for late gene transcription, and thus deciphering the architecture of the complex is central to understanding its transcriptional regulatory activity. Here, we generated an ORF66-null virus and confirmed that it fails to produce late genes and infectious virions. We show that ORF66 is incorporated into the vTA complex primarily through its interaction with ORF34, which is mediated by a set of four conserved cysteine-rich motifs in the C-terminal domain of ORF66. While both ORF24 and ORF66 occupy the canonical K8.1 late gene promoter, their promoter occupancy requires the presence of the other vTAs, suggesting that sequence-specific, stable binding requires assembly of the entire complex on the promoter. Additionally, we find that ORF24 expression is impaired in the absence of a stable vTA complex. This work extends our knowledge about the architecture of the KSHV vPIC and suggests that it functions as a complex to recognize late gene promoters.

IMPORTANCE

Kaposi’s sarcoma-associated herpesvirus (KSHV; human herpesvirus 8) is an oncogenic gammaherpesvirus that is the causative agent of multiple human cancers. Release of infectious virions requires production of capsid proteins and other late genes, whose production are transcriptionally controlled by a complex of six virally-encoded proteins that hijack the host transcription machinery. It is poorly understood how this complex assembles or what function five of its six components play in transcription. Here, we demonstrate that ORF66 is an essential component of this complex in KSHV and that its inclusion in the complex is mediated through its C-terminal domain, which contains highly conserved cysteine-rich motifs reminiscent of zinc finger motifs. Additionally, we examine assembly of the viral pre-initiation complex at late gene promoters and find that while sequence-specific binding of late gene promoters requires ORF24, it additionally requires a fully assembled viral pre-initation complex.
Single-particle view of stress-promoters induction dynamics: an interplay between MAPK signaling, chromatin and transcription factors
Authors: Wosika Victoria , Pelet Serge
Published: August 2019

Precise regulation of gene expression in response to environmental changes is crucial for cell survival, adaptation and proliferation. In eukaryotic cells, extracellular signal integration is often carried out by Mitogen-Activated Protein Kinases (MAPK). Despite a robust MAPK signaling activity, downstream gene expression can display a great variability between single cells. Using a live mRNA reporter, we monitored the dynamics of transcription in Saccharomyces cerevisiae upon hyper-osmotic shock. The transient activity of the MAPK Hog1 opens a temporal window where stress-response genes can be activated. Here we show that the first minutes of Hog1 activity are essential to control the activation of a promoter. The chromatin repression on a locus slows down this transition and contributes to the variability in gene expression, while binding of transcription factors increases the level of transcription. However, soon after Hog1 activity peaks, negative regulators promote chromatin closure of the locus and transcription progressively stops.
The association between caesarean section delivery and later life obesity in 21-24 year olds in an Urban South African birth cohort
Authors: Sogunle Eniola , Masukume Gwinyai , Nelson Gill
Published: August 2019

Background

Obesity is an important public health problem and rates have reached epidemic proportions in many countries. Studies have explored the association between infants delivered by caesarean section and their later life risk of obesity, in many countries outside Africa. As a result of the increasing caesarean section and obesity rates in South Africa, we investigated the association in this country.

Methods

This was a retrospective analysis of data that were collected from a prospective South African birth cohort (Birth to Twenty Plus), established in 1990. A total of 889 young adults aged 21-24 years were included in the analysis. Multiple logistic regression models were fitted to assess the association between mode of delivery and early adulthood obesity.

Results

Of the 889 young adults, 106 (11.9%) were obese while 72 (8.1%) were delivered by CS; of which 14 (19.4%) were obese. Caesarean section delivery was significantly associated with obesity in young adults after adjusting for potential confounders like gestational age (at delivery), birth weight, sex, maternal age, parity and education (OR 1.99, 95% CI 1.00–3.94, p=0.049).

Conclusion

The association of caesarean section with early adulthood obesity should be interpreted with caution because data on certain key confounding factors such as mothers’ pre-pregnancy body mass index and gestational diabetes were not available. Further research from Africa, with larger sample sizes and databases with useful linking of maternal and infant data, should be conducted.
Paternal Indifference and neglect in early life and Creativity: Exploring the Moderating Role ofTPH1genotype and Offspring’s Gender
Authors: Yu Qi , Si Si , Zhang Shun , Zhang Jinghuan
Published: August 2019

For further understanding the joint contribution of environment, heredity and gender to creativity, the present research examined the prospective impact of paternal indifference & neglect in early life,TPH1rs623580, offspring’s gender, and the interaction effects thereof on creativity in five hundred and thirty-nine unrelated healthy Chinese undergraduate students. Paternal indifference & neglect in early life was assessed on the Parental Bonding Instrument (PBI) and creativity on the Runco Creativity Assessment Battery (rCAB). Results showed significant paternal indifference & neglect ×TPH1genotype andTPH1genotype × offspring’s gender interaction effects when predicting creativity. Specifically, paternal indifference & neglect in early life negatively predicted creativity in youth when individuals carry A allele ofTPH1(rs623580). In addition, male individuals who carry A allele were linked with lower level of flexibility compared to TT homozygote individuals. No significant three-way interaction was found. Findings from the current study suggested that the A allele ofTPH1(rs623580) might be a risk allele for creativity, and the long-term negative influence of paternal indifference & neglect in early life on individuals’ creativity in youth depending onTPH1genotype.
Oxidative stress in alpha and beta cells as a selection criterion for biocompatible biomaterials
Authors: Sthijns Mireille M.J.P.E. , Jetten Marlon J. , Mohammed Sami G. , Claessen Sandra M.H. , de Vries Rick , Stell Adam , de Bont Denise , Engelse Marten A. , Mumcuoglu Didem , van Blitterswijk Clemens A. , Dankers Patricia Y.W. , de Koning Eelco J.P. , van Apeldoorn Aart A. , LaPointe Vanessa L.S.
Published: August 2019

The clinical success of islet transplantation is limited by factors including acute ischemia, stress upon transplantation, and delayed vascularization. Islets experience high levels of oxidative stress due to delayed vascularization after transplantation and this can be further aggravated by their encapsulation and undesirable cell-biomaterial interactions. To identify biomaterials that would not further increase oxidative stress levels and that are also suitable for manufacturing a beta cell encapsulation device, we studied five clinically approved polymers for their effect on oxidative stress and islet (alpha and beta cell) function. We found that 300 poly(ethylene oxide terephthalate) 55/poly(butylene terephthalate) 45 (PEOT/PBT300) was more resistant to breakage and more elastic than other biomaterials, which is important for its immunoprotective function. In addition, PEOT/PBT300 did not induce oxidative stress or reduce viability in MIN6 beta cells, and even promoted protective endogenous antioxidant expression over 7 days. Importantly, PEOT/PBT300 is one of the biomaterials we studied that did not interfere with insulin secretion in human islets. These data indicate that PEOT/PBT300 may be a suitable biomaterial for an islet encapsulation device.
Identification of cerebellar afferent projections in a nonhuman primate using CAV-2 vectors
Authors: Dopeso-Reyes Iria Gonzalez , Junyent Felix , Mestre-Francés Nadine , Whebi Amani , Beucher Bertrand , Kremer Eric J
Published: August 2019

Until relatively recently, the cerebellum was considered primarily as modulator of fine motor functions. This has changed during the last 20 years, and now the cerebellum has been shown to be involved in learning and cognition. With this renewed interest comes the need to better understand and potentially modify its input-output connections. In this pilot study, we tested the efficacy of a canine adenovirus type 2 (CAV-2) vector in the cerebellum of a nonhuman primate (NHP). Consistent with other reports, we found a preferentially transduction of cells with neuron-like morphology at the site of injection and efficient retrograde transport into several structures in the midbrain. These data will help identify cerebellar circuits and may lay the foundation for studies of human pathologies, such as ataxias, autism, and schizophrenia.
Cyclin Dependent Kinase 5 (CDK5) Regulates the Circadian Clock
Authors: Brenna Andrea , Olejniczak Iwona , Chavan Rohit , Ripperger Jürgen A. , Langmesser Sonja , Cameroni Elisabetta , Hu Zehan , De Virgilio Claudio , Dengjel Jörn , Albrecht Urs
Published: August 2019

Circadian oscillations emerge from transcriptional and post-translational feedback loops. An important step in generating rhythmicity is the translocation of clock components into the nucleus, which is regulated in many cases by kinases. In mammals, the kinase promoting the nuclear import of the key clock component Period 2 (PER2) is unknown. Here we show that the cyclin-dependent kinase 5 (CDK5) regulates the mammalian circadian clock involving phosphorylation of PER2. Knock-down ofCdk5in the suprachiasmatic nuclei (SCN), the main coordinator site of the mammalian circadian system, shortened the free-running period in mice. CDK5 phosphorylated PER2 at serine residue 394 (S394) in a diurnal fashion. This phosphorylation facilitated interaction with Cryptochrome 1 (CRY1) and nuclear entry of the PER2-CRY1 complex. Taken together, we found that CDK5 drives nuclear entry of PER2, which is critical for establishing an adequate circadian period of the molecular circadian cycle. Therefore, CDK5 is critically involved in the regulation of the circadian clock and may represent a link to various diseases affected by the circadian clock.
Polygenic risk scores of several subtypes of epilepsies in a founder population
Authors: Moreau Claudia , Rébillard Rose-Marie , Wolking Stefan , Michaud Jacques , Tremblay Frédérique , Girard Alexandre , Bouchard Joanie , Minassian Berge , Laprise Catherine , Cossette Patrick , Girard Simon
Published: August 2019

Importance

Epilepsy is defined as a group of neurological disorders characterized by epileptic seizures, brief episodes of symptoms that are caused by abnormal or excessive neuronal activity in the brain. Epilepsy affects around 3 percent of individuals. In the past 10 years, many groups have been working to better understand the complex genetic mechanisms underlying epilepsy. Together, they studied many different genetic mechanisms, but there is still a substantial missing heritability component in epilepsy genetics.

Objective

Here, we used polygenic risk scores (PRS) to quantify the cumulative effects of a number of variants, which may individually have a very small effect on susceptibility.

Design

We calculated PRS in 522 French-Canadian epilepsy patients divided into seven subtypes and French-Canadian controls.

Setting

All study participants (cases and controls) were selected based on their French-Canadian ancestry.

Participants

The epilepsy cohort was composed of families of at least three affected individuals with Idiopathic Generalized Epilepsy (IGE) or Non-acquired Focal Epilepsy (NAFE) previously collected and diagnosed by neurologists following the International League Against Epilepsy (ILAE) criteria.

Exposures

All samples were processed on a common genotyping array.

Main outcomes and Results

We show that the area under the curve (AUC) is almost always slightly greater than 0.5, especially in patients with IGE and subtypes. We also looked at the association of the PRS with the different phenotypes using a linear mixed effects model estimated by generalized estimating equation (GEE) with the pairwise identity-by-descent (IBD) matrix as a random effect. P-values of GEE were consistent with AUC calculations.

Conclusions and Relevance

Globally, we support the notion that PRS and SNP-based heritability provide reliable measures to rightfully estimate the contribution of genetic factors to the pathophysiological mechanism of epilepsies, but further studies are needed on PRS before they can be used clinically.
Constraints and limitations on the transcriptional response downstream of the Bicoid morphogen gradient
Authors: Tran Huy , Walczak Aleksandra M. , Dostatni Nathalie
Published: August 2019

The regulation of thehunchbackpromoter expression by the maternal Bicoid gradient has been studied as a model system in development for many years. Yet, at the level of quantitative agreement between data and theoretical models, even the first step of this regulation, transcription, continues to be challenging. This situation is slowly progressing, thanks to quantitative live-imaging techniques coupled to advanced statistical data analysis and modelling. Here we outline the current state of our knowledge of this apparently “simple” step, highlighting the newly appreciated role of bursty transcription dynamics and its regulation.
Assessment of the Utility of Gene Positioning Biomarkers in the Stratification of Prostate Cancers
Authors: Meaburn Karen J. , Misteli Tom
Published: August 2019

In eukaryotic cells, the genome is spatially organized in a non-random fashion within the confines of the interphase nucleus, and most genes occupy preferred nuclear positions. For some genomic loci these positioning patterns are context specific, reflected in the distinct location of certain genes and chromosomes in different cell types and in disease. Disease-related differential spatial positioning of genes has led to the hypothesis that the spatial reorganization of the genome may be utilized as a diagnostic biomarker. In keeping with this possibility, the positioning patterns of specific genes can be used to reproducibly discriminate benign tissues from cancerous ones. In addition to the use of spatial genome organization for diagnostic purposes, we explore here the potential use of spatial genome organization as a prognostic tool. This is a pressing need since in many cancer types there is a lack of accurate markers to predict the aggressiveness of individual tumors. We find that directional repositioning of SP100 and TGFB3 gene loci stratifies prostate cancers of differing Gleason scores. A more peripheral position of SP100 and TGFB3 in the nucleus, compared to benign tissues, is associated with low Gleason score cancers, whereas more internal positioning correlates with higher Gleason scores. Conversely, LMNA is more internally positioned in many non-metastatic prostate cancers, while its position is indistinguishable from benign tissue in metastatic cancer. Our findings of subtype-specific gene positioning patterns in prostate cancer provides a proof-of-concept for the potential usefulness of spatial gene positioning as a prognostic biomarker.
Multiple changes underlie allelic divergence of CUP2 between Saccharomyces species
Authors: Li Xueying C. , Fay Justin C.
Published: August 2019

Under the model of micromutationism, phenotypic divergence between species is caused by accumulation of many small-effect changes. While mapping the causal changes to single nucleotide resolution could be difficult for diverged species, genetic dissection via chimeric constructs allows us to evaluate whether a large-effect gene is composed of many small-effect nucleotide changes. In a previously described non-complementation screen, we found allele difference of CUP2, a copper-binding transcription factor, underlie divergence in copper resistance between Saccharomyces cerevisiae and S. uvarum. Here, we tested whether the allele effect of CUP2 was caused by multiple nucleotide changes. By analyzing chimeric constructs containing four separate regions in the CUP2 gene, including its distal promoter, proximal promoter, DNA binding domain and transcriptional activation domain, we found that all four regions of the S. cerevisiae allele conferred copper resistance, with the proximal promoter showing the largest effect, and that both additive and epistatic effects are likely involved. These findings support a model of multiple changes underlying evolution and suggest an important role of both protein coding and cis-regulatory changes in evolution.
Atypical neuromagnetic resting activity associated with thalamic volume and cognitive outcome in very preterm children
Authors: Nunes Adonay S. , Kozhemiako Nataliia , Hutcheon Evan , Chau Cecil , Ribary Urs , Grunau Ruth E , Doesburg Sam M
Published: August 2019

Children born very preterm, even in the absence of overt brain injury or major impairment, are at risk of cognitive difficulties. This risk is associated with disruption of ongoing critical periods involving development of the thalamocortical system while in the neonatal intensive care unit. The thalamus is an important structure that not only relays sensory information but acts as a hub integrating cortical activity, and through this integration, it regulates cortical power at different frequency bands. In this study, we investigate the association between atypical power at rest in children born very preterm at school age, neurocognitive function and structural alterations related to the thalamus. Our results indicate that children born extremely preterm have higher power at low frequencies and lower power at high frequencies, compared to controls born full-term. A similar pattern of spectral power was found to be associated with poorer neurocognitive outcomes. This pattern of spectral power was also associated with normalized T1 intensity and the volume of the thalamus. Overall, this study provides evidence of the relation between structural alterations related to very preterm birth, atypical oscillatory power at rest and neurocognitive difficulties at school-age children born very preterm.
Negative frequency-dependent selection maintains coexisting genotypes during fluctuating selection
Authors: Turner Caroline B. , Buskirk Sean W. , Harris Katrina B. , Cooper Vaughn S.
Published: August 2019

Natural environments are rarely static; rather selection can fluctuate on time scales ranging from hours to centuries. However, it is unclear how adaptation to fluctuating environments differs from adaptation to constant environments at the genetic level. For bacteria, one key axis of environmental variation is selection for planktonic or biofilm modes of growth. We conducted an evolution experiment withBurkholderia cenocepacia, comparing the evolutionary dynamics of populations evolving under constant selection for either biofilm formation or planktonic growth with populations in which selection fluctuated between the two environments on a weekly basis. Populations evolved in the fluctuating environment shared many of the same genetic targets of selection as those evolved in constant biofilm selection, but were genetically distinct from the constant planktonic populations. In the fluctuating environment, mutations in the biofilm-regulating geneswspAandrpfRrose to high frequency in all replicate populations. A mutation inwspAfirst rose rapidly and nearly fixed during the initial biofilm phase but was subsequently displaced by a collection ofrpfRmutants upon the shift to the planktonic phase. ThewspAandrpfRgenotypes coexisted via negative frequency-dependent selection around an equilibrium frequency that shifted between the environments. The maintenance of coexisting genotypes in the fluctuating environment was unexpected. Under temporally fluctuating environments coexistence of two genotypes is only predicted under a narrow range of conditions, but the frequency-dependent interactions we observed provide a mechanism that can increase the likelihood of coexistence in fluctuating environments.
Cryptococcus neoformansrecovered from olive trees (Olea europaea) in Turkey reveal allopatry with African and South American lineages
Authors: Ergin Çağrı , Şengül Mustafa , Aksoy Levent , Döğen Aylin , Sun Sheng , Averette Anna F. , Cuomo Christina A. , Seyedmousavi Seyedmojtaba , Heitman Joseph , Ilkit Macit
Published: August 2019

Cryptococcusspecies are life-threatening human fungal pathogens that cause cryptococcal meningoencephalitis in both immunocompromised and healthy hosts. The natural environmental niches ofCryptococcusinclude pigeon (Columba livia) guano, soil, and a variety of tree species such asEucalyptus camaldulensis, Ceratonia siliqua, Platanus orientalis, andPinusspp. Genetic and genomic studies of extensive sample collections have provided insights into the population distribution and composition of differentCryptococcusspecies in geographic regions around the world. However, few such studies examinedCryptococcusin Turkey. We sampled 388Olea europaea(olive) and 132E. camaldulensistrees from 7 locations in coastal and inland areas of the Aegean region of Anatolian Turkey in September 2016 to investigate the distribution and genetic diversity present in the naturalCryptococcuspopulation. We isolated 84Cryptococcus neoformansstrains (83MATα and 1MATa) and 3Cryptococcus deneoformansstrains (allMATa) from 87 (22.4% of surveyed)O. europaeatrees; a total of 32C. neoformansstrains were isolated from 32 (24.2%) of theE. camaldulensistrees, all of which wereMATα. A statistically significant difference was observed in the frequency ofC. neoformansisolation between coastal and inland areas (P< 0.05). Thus,O. europaeatrees could represent a novel niche forC. neoformans. Interestingly, theMATaC. neoformansisolate was fertile in laboratory crosses with VNI and VNBMATα tester strains and produced robust hyphae, basidia, and basidiospores, thus suggesting potential sexual reproduction in the natural population. Sequencing analyses of theURA5gene identified at least 5 different genotypes among the isolates. Population genetics and genomic analyses revealed that most of the isolates in Turkey belong to the VNBII lineage ofC. neoformans, which is predominantly found in southern Africa; these isolates are part of a distinct minor clade within VNBII that includes several isolates from Zambia and Brazil. Our study provides insights into the geographic distribution of differentC. neoformanslineages in the Mediterranean region and highlights the need for wider geographic sampling to gain a better understanding of the natural habitats, migration, epidemiology, and evolution of this important human fungal pathogen.