Transformation of an olfactory placode-derived cell into one with stem cell characteristics by disrupting epigenetic barriers.

The mammalian olfactory neuronal lineage is regenerative, and accordingly, maintains a population of pluripotent cells that replenish olfactory sensory neurons and other olfactory cell types during the life of the animal. Moreover, in response to acute injury, the early transit amplifying cells along the olfactory sensory neuronal lineage are able to de-differentiate to shift resources in support of tissue restoration. In order to further explore plasticity of various cellular stages along the olfactory sensory neuronal lineage, we challenged the epigenetic stability of two olfactory placode-derived cell lines that model immature olfactory sensory neuronal stages. We found that perturbation of the Ehmt2 chromatin modifier transformed the growth properties, morphology, and gene expression profiles towards states with several stem cell characteristics. This transformation was dependent on continued expression of the large T-antigen, and was enhanced by Sox2 over-expression. These findings may provide momentum for exploring inherent cellular plasticity within early cell types of the olfactory lineage, as well as potentially add to our knowledge of cellular reprogramming. SUMMARY STATEMENT: Discovering how epigenetic modifications influence olfactory neuronal lineage plasticity offers insights into regenerative potential and cellular reprogramming.

Delta like 4 regulates cerebrovascular development and endothelial integrity via DLL4-NOTCH-CLDN5 pathway and is vulnerable to neonatal hyperoxia.

The mechanisms governing brain vascularization during development remain poorly understood. A key regulator of developmental vascularization is delta like 4 (DLL4), a Notch ligand prominently expressed in endothelial cells (EC). Exposure to hyperoxia in premature infants can disrupt the development and functions of cerebral blood vessels and lead to long-term cognitive impairment. However, its role in cerebral vascular development and the impact of postnatal hyperoxia on DLL4 expression in mouse brain EC have not been explored. We determined the DLL4 expression pattern and its downstream signalling gene expression in brain EC using Dll4+/+ and Dll4+/LacZ mice. We also performed in vitro studies using human brain microvascular endothelial cells. Finally, we determined Dll4 and Cldn5 expression in mouse brain EC exposed to postnatal hyperoxia. DLL4 is expressed in various cell types, with EC being the predominant one in immature brains. Moreover, DLL4 deficiency leads to persistent abnormalities in brain microvasculature and increased vascular permeability both in vivo and in vitro. We have identified that DLL4 insufficiency compromises endothelial integrity through the NOTCH-NICD-RBPJ-CLDN5 pathway, resulting in the downregulation of the tight junction protein claudin 5 (CLDN5). Finally, exposure to neonatal hyperoxia reduces DLL4 and CLDN5 expression in developing mouse brain EC. We reveal that DLL4 is indispensable for brain vascular development and maintaining the blood-brain barrier's function and is repressed by neonatal hyperoxia. We speculate that reduced DLL4 signalling in brain EC may contribute to the impaired brain development observed in neonates exposed to hyperoxia. KEY POINTS: The role of delta like 4 (DLL4), a Notch ligand in vascular endothelial cells, in brain vascular development and functions remains unknown. We demonstrate that DLL4 is expressed at a high level during postnatal brain development in immature brains and DLL4 insufficiency leads to abnormal cerebral vasculature and increases vascular permeability both in vivo and in vitro. We identify that DLL4  regulates endothelial integrity through NOTCH-NICD-RBPJ-CLDN5 signalling. Dll4 and Cldn5 expression are decreased in mouse brain endothelial cells exposed to postnatal hyperoxia.

Rickettsia species identified in adult, host-seeking Dermacentor occidentalis (Acari: Ixodidae) from Baja California, Mexico, and Oregon and Washington, United States.

The Pacific Coast tick (Dermacentor occidentalis Marx, 1892) is a frequently encountered and commonly reported human-biting tick species that has been recorded from most of California and parts of southwestern Oregon, southcentral Washington, and northwestern Mexico. Although previous investigators have surveyed populations of D. occidentalis for the presence of Rickettsia species across several regions of California, populations of this tick have not been surveyed heretofore for rickettsiae from Baja California, Oregon, or Washington. We evaluated 1,367 host-seeking, D. occidentalis adults collected from 2015 to 2022 by flagging vegetation at multiple sites in Baja California, Mexico, and Oregon and Washington, United States, using genus- and species-specific assays for spotted fever group rickettsiae. DNA of Rickettsia 364D, R. bellii, and R. tillamookensis was not detected in specimens from these regions. DNA of R. rhipicephali was detected in D. occidentalis specimens obtained from Ensenada Municipality in Baja California and southwestern Oregon, but not from Washington. All ompA sequences of R. rhipichephali that were amplified from individual ticks in southwestern Oregon were represented by a single genotype. DNA of the Ixodes pacificus rickettsial endosymbiont was amplified from specimens collected in southwestern Oregon and Klickitat County, Washington; to the best of our knowledge, this Rickettsia species has never been identified in D. occidentalis. Collectively, these data are consistent with a relatively recent introduction of Pacific Coast ticks in the northernmost extension of its recognized range.

Early-life stress perturbs the epigenetics of Cd36 concurrent with adult onset of NAFLD in mice.

BACKGROUND: Non-alcoholic fatty liver disease (NAFLD) is one of the most common liver diseases in the U.S. and worldwide. The roles of early postnatal life stress (EPLS) and the fatty acid translocase (CD36) on the pathogenesis of adult-onset NAFLD remain unknown. We hypothesized that EPLS, in the form of neonatal maternal separation (NMS), would predispose mice towards developing adult NAFLD, increase hepatic CD36 expression, and differentially methylate Cd36 promoter concurrently. METHODS: NMS was performed on mice from postnatal day 1 to 21 and a high-fat/high-sucrose (HFS) diet was started at 4 weeks of age to generate four experimental groups: Naive-control diet (CD), Naive-HFS, NMS-CD, and NMS-HFS. RESULTS: NMS alone caused NAFLD in adult male mice at 25 weeks of age. The effects of NMS and HFS were generally additive in terms of NAFLD, hepatic Cd36 mRNA levels, and hepatic Cd36 promoter DNA hypomethylation. Cd36 promoter methylation negatively correlated with Cd36 mRNA levels. Two differentially methylated regions (DMRs) within Cd36 promoter regions appeared to be vulnerable to NMS in the mouse. CONCLUSIONS: Our findings suggest that NMS increases the risk of an individual, particularly male, towards NAFLD when faced with a HFS diet later in life. IMPACT: The key message of this article is that neonatal maternal separation and a postweaning high-fat/high-sucrose diet increased the risk of an individual, particularly male, towards NAFLD in adult life. What this study adds to the existing literature includes the identification of two vulnerable differentially methylated regions in hepatic Cd36 promoters whose methylation levels very strongly negatively correlated with Cd36 mRNA. The impact of this article is that it provides an early-life environment-responsive gene/promoter methylation model and an animal model for furthering the mechanistic study on how the insults in early-life environment are "transmitted" into adulthood and caused NAFLD.

Adverse Maternal Environments Perturb Hepatic DNA Methylome and Transcriptome Prior to the Adult-Onset Non-Alcoholic Fatty Liver Disease in Mouse Offspring.

Exposure to adverse early-life environments (AME) increases the incidence of developing adult-onset non-alcoholic fatty liver disease (NAFLD). DNA methylation has been postulated to link AME and late-onset diseases. This study aimed to investigate whether and to what extent the hepatic DNA methylome was perturbed prior to the development of NAFLD in offspring exposed to AME in mice. AME constituted maternal Western diet and late-gestational stress. Male offspring livers at birth (d0) and weaning (d21) were used for evaluating the DNA methylome and transcriptome using the reduced representation of bisulfite sequencing and RNA-seq, respectively. We found AME caused 5879 differentially methylated regions (DMRs) and zero differentially expressed genes (DEGs) at d0 and 2970 and 123, respectively, at d21. The majority of the DMRs were distal to gene transcription start sites and did not correlate with DEGs. The DEGs at d21 were significantly enriched in GO biological processes characteristic of liver metabolic functions. In conclusion, AME drove changes in the hepatic DNA methylome, which preceded perturbations in the hepatic metabolic transcriptome, which preceded the onset of NAFLD. We speculate that subtle impacts on dynamic enhancers lead to long-range regulatory changes that manifest over time as gene network alternations and increase the incidence of NAFLD later in life.

Recovery of western black-legged tick and vertebrate populations after a destructive wildfire in an intensively-studied woodland in northern California.

Despite increasing severity and frequency of wildfires, knowledge about how fire impacts the ecology of tick-borne pathogens is limited. In 2018, the River Fire burned a forest in the far-western U.S.A. where the ecology of tick-borne pathogens had been studied for decades. Forest structure, avifauna, large and small mammals, lizards, ticks, and tick-borne pathogens (Anaplasma phagocytophilum, Borrelia burgdorferi, Borrelia miyamotoi) were assessed after the wildfire in 2019 and 2020. Burning reduced canopy cover and eliminated the layer of thick leaf litter that hosted free-living ticks, which over time was replaced by forbs and grasses. Tick abundance and the vertebrate host community changed dramatically. Avian species adapted to cavity nesting became most prevalent, while the number of foliage-foraging species increased by 83% as vegetation regenerated. Nine mammalian species were observed on camera traps, including sentinel (black-tailed jackrabbits) and reservoir hosts (western gray squirrels) of B. burgdorferi. One Peromyscus sp. mouse was captured in 2019 but by 2020, numbers were rebounding (n=37), although tick infestations on rodents remained sparse (0.2/rodent). However, western fence lizards (n=19) hosted 8.6 ticks on average in 2020. Assays for pathogens found no B. miyamotoi in either questing or host-feeding ticks, A. phagocytophilum DNA in 4% (1/23) in 2019, and 17% (29/173) in 2020 for questing and host-feeding ticks combined, and B. burgdorferi DNA in just 1% of all ticks collected in 2020 (2/173). We conclude that a moderately severe wildfire can have dramatic impacts on the ecology of tick-borne pathogens, with changes posited to continue for multiple years.

An open trial of VA CONNECT: Caring for Our Nation's Needs Electronically during the COVID-19 Transition.

The COVID-19 pandemic impacted emotional well-being due to safety concerns, grief, employment impacts, and social interaction limitations. Face-to-face mental health treatment restrictions were especially impactful to veterans who often gain social enrichment from Veterans Health Administration (VHA) care. We present results from a novel group-based telehealth intervention, VA Caring for Our Nation's Needs Electronically during the COVID-19 Transition (VA CONNECT), which integrates skills training and social support to develop a COVID-19 Safety & Resilience Plan. Veterans (n â€‹= â€‹29) experiencing COVID-related stress participated in an open trial of this 10-session, manualized group VHA telehealth intervention. We examined whether COVID-19-related stress, adjustment disorder symptoms, and loneliness decreased, and coping strategy use increased after participation in VA CONNECT. Between baseline and two-month follow-up, participants reported a significant reduction in perceived stress and adjustment disorder symptoms, and an increase in planning coping skills use. Significant changes were not observed in loneliness or other specific coping strategies. Findings may support the utility of VA CONNECT as an intervention for pandemic-related stress and improving certain coping skills. Future research should explore group-based telehealth interventions like VA CONNECT with other populations within and outside of the VA, which have value during major disruptions to face-to-face mental healthcare access.

Adverse maternal environment alters Oprl1 variant expression in mouse hippocampus.

An adverse maternal environment (AME) and Western diet (WD) in early life predispose offspring toward cognitive impairment in humans and mice. Cognitive impairment associates with hippocampal dysfunction. An important regulator of hippocampal function is the hippocampal Nociceptin/Orphanin FQ (N/OFQ) system. Previous studies find links between dysregulation of hippocampal N/OFQ receptor (NOP) expression and impaired cognitive function. NOP is encoded by the opioid receptor-like 1 (Oprl1) gene that contains multiple mRNA variants and isoforms. Regulation of Oprl1 expression includes histone modifications within the promoter. We tested the hypothesis that an AME and a postweaning WD increase the expression of hippocampal Oprl1 and select variants concurrent with altered histone code in the promoter. We created an AME-WD model combining maternal WD and prenatal environmental stress plus postweaning WD in the mouse. We analyzed the hippocampal expression of Oprl1, Oprl1 variants, and histone modifications in the Oprl1 promoter in offspring at postnatal day (P) 21 and P100. An AME and an AME-WD significantly increased the total hippocampal expression of Oprl1 and variant V4 concurrently with an increased accumulation of active histone marks in the promoter of male offspring. We concluded that an AME and an AME-WD alter hippocampal Oprl1 expression in offspring through an epigenetic mechanism in a variant-specific and sex-specific manner. Altered hippocampal Oprl1 expression may contribute to cognitive impairment seen in adult males in this model. Epigenetic regulation of Oprl1 is a potential mechanism by which an AME and a WD may contribute to neurocognitive impairment in male offspring.

Detection and Isolation of Rickettsia tillamookensis (Rickettsiales: Rickettsiaceae) From Ixodes pacificus (Acari: Ixodidae) From Multiple Regions of California.

The western black-legged tick (Ixodes pacificus) is the most frequently identified human-biting tick species in the western United States and the principal vector of at least three recognized bacterial pathogens of humans. A potentially pathogenic Rickettsia species, first described in 1978 and recently characterized as a novel transitional group agent designated as Rickettsia tillamookensis, also exists among populations of I. pacificus, although the distribution and frequency of this agent are poorly known. We evaluated DNA extracts from 348 host-seeking I. pacificus nymphs collected from 9 locations in five California counties, and from 916 I. pacificus adults collected from 24 locations in 13 counties, by using a real-time PCR designed specifically to detect DNA of R. tillamookensis. DNA of R. tillamookensis was detected in 10 (2.9%) nymphs (95% CI: 1.6-5.2%) and 17 (1.9%) adults (95% CI: 1.2-3.0%) from 11 counties of northern California. Although site-specific infection rates varied greatly, frequencies of infection remained consistently low when aggregated by stage, sex, habitat type, or geographical region. Four novel isolates of R. tillamookensis were cultivated in Vero E6 cells from individual adult ticks collected from Alameda, Nevada, and Yolo counties. Four historical isolates, serotyped previously as 'Tillamook-like' strains over 40 yr ago, were revived from long-term storage in liquid nitrogen and confirmed subsequently by molecular methods as isolates of R. tillamookensis. The potential public health impact of R. tillamookensis requires further investigation.

Characteristics of suicide attempts associated with lethality and method: A latent class analysis of the Military Suicide Research Consortium.

While suicide prevention is a national priority, particularly among service members and veterans (SMVs), understanding of suicide-related outcomes remains poor. Person-centered approaches (e.g., latent class analysis) have promise to identify unique risk profiles and subgroups in the larger population. The current study identified latent subgroups characterized by prior self-directed violence history and proximal risk factors for suicide among suicide attempt survivors, and compared subgroups on demographics and most-lethal attempt characteristics. Participants included civilians and SMVs reporting lifetime suicide attempt(s) (n = 2643) from the Military Suicide Research Consortium. Two classes emerged from Common Data Elements: suicide attempt and non-suicidal self-injury frequency, suicide attempt method, perceived likelihood of future suicide, suicide disclosure, suicide intent, and perceived and actual lethality of attempt. A Higher-Risk History class was characterized by greater intent to die, certainty about attempt fatality and method lethality, belief injury would be medically unfixable, and likelihood of prior non-suicidal self-injury. A Lower-Risk History class was characterized by greater ambivalence toward death and methods. Higher-Risk class members were more likely to be male, older, SMVs, have less formal education, use firearms as most-lethal attempt method, and require a higher degree of medical attention. Lower-Risk class members were more likely to be female, civilian, use cutting as most-lethal attempt method, and require less medical attention for attempts. Findings have implications for risk assessments and highlight the importance of subjective perceptions about suicidal behavior. Further investigation of real-time individual-level is necessary, especially for SMVs who may be at greatest risk for potentially lethal suicidal behavior.

Adverse maternal environment affects hippocampal HTR2c variant expression and epigenetic characteristics in mouse offspring.

BACKGROUND: An adverse maternal environment (AME) predisposes progeny towards cognitive impairment in humans and mice. Cognitive impairment associates with hippocampal dysfunction. An important regulator of hippocampal function is the hippocampal serotonergic system. Dysregulation of hippocampal serotonin receptor 2c (HTR2c) expression is linked with cognitive impairment. HTR2c contains multiple mRNA variants and isoforms that are epigenetically regulated including DNA methylation, histone modifications, and small nucleolar RNA MBII-52. We tested the hypotheses that AME increases HTR2c variant expression and alters epigenetic modifications along the HTR2c gene locus. METHODS: We create an AME through maternal Western diet and prenatal environmental stress in the mouse. We analyzed hippocampal HTR2c and variants' expression, DNA methylation and histone modifications along the gene locus, and MBII-52 levels in postnatal day 21 offspring. RESULTS: AME significantly increased the expressions of total HTR2c and full-length variants (V201 and V202) concurrently with an altered epigenetic profile along the HTR2c gene locus in male offspring hippocampi. Moreover, increased full-length variants' expression in AME males was in line with increased MBII-52 levels. CONCLUSIONS: AME affects male offspring hippocampal expression of HTR2c and full-length variants via epigenetic mechanisms. Altered hippocampal HTR2c expression may contribute to cognitive impairment seen in adult males in this model. IMPACT: The key message of our article is that an adverse maternal environment increases expression of total HTR2c mRNA and protein, alters proportions of HTR2c mRNA variants, and impacts HTR2c epigenetic modifications in male offspring hippocampi relative to controls. Our findings add to the literature by providing the first report of altered HTR2c mRNA variant expression in association with altered epigenetic modifications in the hippocampus of offspring mice exposed to an adverse maternal environment. Our findings suggest that an adverse maternal environment affects the expression of genes previously determined to regulate cognitive function through an epigenetic mechanism in a sex-specific manner.

Perinatal Research Society's Young Investigator Workshop Prepares the Next Generation of Investigators.

Sustaining impactful research within the field of perinatal biology requires training and retention of the next generations of physician-scientists and basic-scientists. Professional societies such as the Perinatal Research Society (PRS) have a unique role to play in training and retention of perinatal biologists. Here we report outcomes for an innovative Young Investigator Training Workshop created for the PRS. The PRS Workshop uses immersive, active-writing, and active-oral presentation design, with one-on-one feedback from NIH-funded faculty-mentors drawn from the PRS membership. Young investigator data were collected by anonymous surveys of young investigators, NIH RePORTER, and individual young investigator follow-up. Ninety-seven young investigators attended the Workshops over the period 2013-2018. Young investigators were physician- (73%) and PhD- (27%) scientists at the rank of clinical fellow/postdoctoral fellow (27%) or instructor/assistant professor (73%). Participation by underrepresented minority (URM) young investigators was 14%. Young investigators received NIH and non-NIH funding, with 80% of young investigators receiving new funding since the Workshop that they attended. NIH funding was received by 31% of young investigators in the form of K-series awards, R01 equivalents, and other NIH awards. In conclusion, our PRS young investigator Workshop serves as a model to facilitate training of emerging physician- and basic-scientists by scientific societies.

Ending Neglected Surgical Diseases (NSDs): Definitions, Strategies, and Goals for the Next Decade.

While there has been overall progress in addressing the lack of access to surgical care worldwide, untreated surgical conditions in developing countries remain an underprioritized issue. Significant backlogs of advanced surgical disease called neglected surgical diseases (NSDs) result from massive disparities in access to quality surgical care. We aim to discuss a framework for a public health rights-based initiative designed to prevent and eliminate the backlog of NSDs in developing countries. We defined NSDs and set forth six criteria that focused on the applicability and practicality of implementing a program designed to eradicate the backlog of six target NSDs from the list of 44 Disease Control Priorities 3rd edition (DCP3) surgical interventions. The human rights-based approach (HRBA) was used to clarify NSDs role within global health. Literature reviews were conducted to ascertain the global disease burden, estimated global backlog, average cost per treatment, disability-adjusted life-years (DALYs) averted from the treatment, return on investment, and potential gain and economic impact of the NSDs identified. Six index NSDs were identified, including neglected cleft lips and palate, clubfoot, cataracts, hernias and hydroceles, injuries, and obstetric fistula. Global definitions were proposed as a starting point towards the prevention and elimination of the backlog of NSDs. Defining a subset of neglected surgical conditions that illustrates society's role and responsibility in addressing them provides a framework through the HRBA lens for its eventual eradication.

Academic Global Surgery Curricula: Current Status and a Call for a More Equitable Approach.

INTRODUCTION: We aimed to search the literature for global surgical curricula, assess if published resources align with existing competency frameworks in global health and surgical education, and determine if there is consensus around a fundamental set of competencies for the developing field of academic global surgery. METHODS: We reviewed SciVerse SCOPUS, PubMed, African Medicus Index, African Journals Online (AJOL), SciELO, Latin American and Caribbean Health Sciences Literature (LILACS) and Bioline for manuscripts on global surgery curricula and evaluated the results using existing competency frameworks in global health and surgical education from Consortium of the Universities for Global Health (CUGH) and Accreditation Council for Graduate Medical Education (ACGME) professional competencies. RESULTS: Our search generated 250 publications, of which 18 were eligible: (1) a total of 10 reported existing competency-based curricula that were concurrent with international experiences, (2) two reported existing pre-departure competency-based curricula, (3) six proposed theoretical competency-based curricula for future global surgery education. All, but one, were based in high-income countries (HICs) and focused on the needs of HIC trainees. None met all 17 competencies, none cited the CUGH competency on "Health Equity and Social Justice" and only one mentioned "Social and Environmental Determinants of Health." Only 22% (n = 4) were available as open-access. CONCLUSION: Currently, there is no universally accepted set of competencies on the fundamentals of academic global surgery. Existing literature are predominantly by and for HIC institutions and trainees. Current frameworks are inadequate for this emerging academic field. The field needs competencies with explicit input from LMIC experts to ensure creation of educational resources that are accessible and relevant to trainees from around the world.

Olfactory receptor coding sequences cause silencing of episomal constructs in multiple cell lines.

The mammalian olfactory system consists of sensory neurons with specialized odorant-binding capability accomplished by mutually exclusive odorant receptor (OR) expression. Mutually exclusive OR expression is a complex multi-step process regulated by a number of cis and trans factors, including pan-silencing of all OR genes preceding the robust and stable expression of the one OR selected in each sensory neuron. We transfected two olfactory-placode-derived cell lines modeling immature odorant sensory neurons, as well as the GD25 fibroblast cell line, with episomes containing CMV-driven GFP and TK-driven hygromycin reporter genes. We inserted various coding sequences, along with an IRES, immediately upstream of the GFP gene to produce bicistronic mRNAs driven from the local CMV promoter. We found that the presence of several OR coding sequences resulted in significantly diminished episomal expression of GFP in all three cell lines. These findings suggest that OR coding sequences have intrinsic self-silencing capability that might facilitate mutually exclusive OR expression in olfactory sensory neurons by making it less likely that multiple ORs acquire an above-threshold level of expression at once.

Adverse Maternal Environment and Postweaning Western Diet Alter Hepatic CD36 Expression and Methylation Concurrently with Nonalcoholic Fatty Liver Disease in Mouse Offspring.

BACKGROUND: The role of an adverse maternal environment (AME) in conjunction with a postweaning Western diet (WD) in the development of nonalcoholic fatty liver disease (NAFLD) in adult offspring has not been explored. Likewise, the molecular mechanisms associated with AME-induced NAFLD have not been studied. The fatty acid translocase or cluster of differentiation 36 (CD36) has been implicated to play a causal role in the pathogenesis of WD-induced steatosis. However, it is unknown if CD36 plays a role in AME-induced NAFLD. OBJECTIVE: This study was designed to evaluate the isolated and additive impact of AME and postweaning WD on the expression and DNA methylation of hepatic Cd36 in association with the development of NAFLD in a novel mouse model. METHODS: AME constituted maternal WD and maternal stress, whereas the control (Con) group had neither. Female C57BL/6J mice were fed a WD [40% fat energy, 29.1% sucrose energy, and 0.15% cholesterol (wt/wt)] 5 wk prior to pregnancy and throughout lactation. Non invasive variable stressors (random frequent cage changing, limited bedding, novel object, etc.) were applied to WD dams during the last third of pregnancy to produce an AME. Con dams consumed the control diet (CD) (10% fat energy, no sucrose or cholesterol) and were not exposed to stress. Male offspring were weaned onto either CD or WD, creating 4 experimental groups: Con-CD, Con-WD, AME-CD, and AME-WD, and evaluated for metabolic and molecular parameters at 120 d of age. RESULTS: AME and postweaning WD independently and additively increased the development of hepatic steatosis in adult male offspring. AME and WD independently and additively upregulated hepatic CD36 protein and mRNA expression and hypomethylated promoters 2 and 3 of the Cd36 gene. CONCLUSIONS: Using a mouse AME model together with postweaning WD, this study demonstrates a role for CD36 in AME-induced NAFLD in offspring and reveals 2 regions of environmentally induced epigenetic heterogeneity within Cd36.

Prevalence of Babesia canis DNA in Ixodes ricinus ticks collected in forest and urban ecosystems in west-central Poland.

Babesia canis, a widely distributed European tick-borne protozoan haemoparasite, causes canine babesiosis, the most important tick-borne disease afflicting dogs worldwide. The meadow tick, Dermacentor reticulatus, is considered to be the primary vector of this parasite in central Europe. Females of the more broadly distributed and medically important castor bean tick, Ixodes ricinus, also commonly feed upon dogs, but their role in the enzootic transmission cycle of B. canis is unclear. Here, we screened 1,598 host-seeking I. ricinus ticks collected from two different ecosystems, forest stands vs. urban recreational forests, for the presence of B. canis DNA. Ticks were sampled during their two seasonal peaks of activity, spring (May/June) and late summer (September). Babesia species were identified by amplification and sequencing of a hypervariable 18S rRNA gene fragment. Babesia canis was the only piroplasm detected in 13% of 200 larvae and 8.2% of 324 nymphs in the forest ecosystems. In urban recreational areas, B. canis DNA was found in 1.5% of 460 nymphs, 3.5% of 289 females and 3.2% of 280 males. Additionally, three samples, including one female, one male, and one nymph, were co-infected with B. venatorum and one nymph with B. divergens or B. capreoli. Our findings implicate that B. canis can be transmitted transovarially and maintained transstadially within populations of I. ricinus, but the vector competence of I. ricinus for transmitting B. canis remains to be investigated.

Modeling future climate suitability for the western blacklegged tick, Ixodes pacificus, in California with an emphasis on land access and ownership.

In the western United States, Ixodes pacificus Cooley & Kohls (Acari: Ixodidae) is the primary vector of the agents causing Lyme disease and granulocytic anaplasmosis in humans. The geographic distribution of the tick is associated with climatic variables that include temperature, precipitation, and humidity, and biotic factors such as the spatial distribution of its primary vertebrate hosts. Here, we explore (1) how climate change may alter the geographic distribution of I. pacificus in California, USA, during the 21st century, and (2) the spatial overlap among predicted changes in tick habitat suitability, land access, and ownership. Maps of potential future suitability for I. pacificus were generated by applying climate-based species distribution models to a multi-model ensemble of climate change projections for the Representative Concentration Pathway (RCP) 4.5 (moderate emission) and 8.5 (high emission) scenarios for two future periods: mid-century (2026-2045) and end-of-century (2086-2099). Areas climatically-suitable for I. pacificus are projected to expand by 23% (mid-century RCP 4.5) to 86% (end-of-century RCP 8.5) across California, compared to the historical period (1980-2014), with future estimates of total suitable land area ranging from about 88 to 133 thousand km2, or up to about a third of California. Regions projected to have the largest area increases in suitability by end-of-century are in northwestern California and the south central and southern coastal ranges. Over a third of the future suitable habitat is on lands currently designated as open access (i.e. publicly available), and by 2100, the amount of these lands that are suitable habitat for I. pacificus is projected to more than double under the most extreme emissions scenario (from ~23,000 to >51,000 km2). Of this area, most is federally-owned (>45,000 km2). By the end of the century, 26% of all federal land in the state is predicted to be suitable habitat for I. pacificus. The resulting maps may facilitate regional planning and preparedness by informing public health and vector control decision-makers.

DUSP5-mediated inhibition of smooth muscle cell proliferation suppresses pulmonary hypertension and right ventricular hypertrophy.

Pulmonary hypertension (PH) is associated with structural remodeling of pulmonary arteries (PAs) because of excessive proliferation of fibroblasts, endothelial cells, and smooth muscle cells (SMCs). The peptide hormone angiotensin II (ANG II) contributes to pulmonary vascular remodeling, in part, through its ability to trigger extracellular signal-regulated kinase (ERK1/2) activation. Here, we demonstrate that the ERK1/2 phosphatase, dual-specificity phosphatase 5 (DUSP5), functions as a negative regulator of ANG II-mediated SMC proliferation and PH. In contrast to wild-type controls, Dusp5 null mice infused with ANG II developed PH and right ventricular (RV) hypertrophy. PH in Dusp5 null mice was associated with thickening of the medial layer of small PAs, suggesting an in vivo role for DUSP5 as a negative regulator of ANG II-dependent SMC proliferation. Consistent with this, overexpression of DUSP5 blocked ANG II-mediated proliferation of cultured human pulmonary artery SMCs (hPASMCs) derived from patients with idiopathic PH or from failed donor controls. Collectively, the data support a role for DUSP5 as a feedback inhibitor of ANG II-mediated ERK signaling and PASMC proliferation and suggest that disruption of this circuit leads to adverse cardiopulmonary remodeling.NEW & NOTEWORTHY Dual-specificity phosphatases (DUSPs) serve critical roles in the regulation of mitogen-activated protein kinases, but their functions in the cardiovascular system remain poorly defined. Here, we provide evidence that DUSP5, which resides in the nucleus and specifically dephosphorylates extracellular signal-regulated kinase (ERK1/2), blocks pulmonary vascular smooth muscle cell proliferation. In response to angiotensin II infusion, mice lacking DUSP5 develop pulmonary hypertension and right ventricular cardiac hypertrophy. These findings illustrate DUSP5-mediated suppression of ERK signaling in the lungs as a protective mechanism.

Adverse Maternal Environment Alters MicroRNA-10b-5p Expression and Its Epigenetic Profile Concurrently with Impaired Hippocampal Neurogenesis in Male Mouse Hippocampus.

An adverse maternal environment (AME) predisposes adult offspring toward cognitive impairment in humans and mice. However, the underlying mechanisms remain poorly understood. Epigenetic changes in response to environmental exposure may be critical drivers of this change. Epigenetic regulators, including microRNAs, have been shown to affect cognitive function by altering hippocampal neurogenesis which is regulated in part by brain-derived neurotropic factor (BDNF). We sought to investigate the effects of AME on miR profile and their epigenetic characteristics, as well as neurogenesis and BDNF expression in mouse hippocampus. Using our mouse model of AME which is composed of maternal Western diet and prenatal environmental stress, we found that AME significantly increased hippocampal miR-10b-5p levels. We also found that AME significantly decreased DNA methylation and increased accumulations of active histone marks H3 lysine (K) 4me3, H3K14ac, and -H3K36me3 at miR-10b promoter. Furthermore, AME significantly decreased hippocampal neurogenesis by decreasing cell numbers of Ki67+ (proliferation marker), NeuroD1+ (neuronal differentiation marker), and NeuN+ (mature neuronal marker) in the dentate gyrus (DG) region concurrently with decreased hippocampal BDNF protein levels. We speculate that the changes in epigenetic profile at miR-10b promoter may contribute to upregulation of miR-10b-5p and subsequently lead to decreased BDNF levels in a model of impaired offspring hippocampal neurogenesis and cognition in mice.