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Environmental DNA (eDNA) includes a set of rapidly emerging technologies that have the potential to support environmental monitoring and biodiversity conservation through novel, non-invasive, cost-effective and democratic methods and tools. Meanwhile, eDNA researchers are developing international standards for eDNA technologies, methods and data outputs. For eDNA technologies to be accessible, useful and appropriate, we must ensure that any standards developed include a broad conception of users from around the world, a diversity of ecological contexts and locations and, most importantly, a realistic outlook on research capacities and infrastructure. In this article, we assemble perspectives on international standardisation of eDNA from a diverse and global group of users and experts from Africa, South America and the Pacific Islands. The authors of this article collaborated by answering and discussing a set of open-ended questions aimed at eliciting hopes, concerns and experiences regarding eDNA standards. The result is a set of emergent themes and a generative consensus to highlight the need for the creation of adaptable standards, the development of regional capacity, increased sensitising to data sovereignty and the viewing of standardisation as a global capacity-building activity.

Abstract Hoplodactylus delcourti is a presumably extinct species of diplodactylid gecko known only from a single specimen of unknown provenance. It is by far the largest known gekkotan, approximately 50% longer than the next largest-known species. It has been considered a member of the New Zealand endemic genus Hoplodactylus based on external morphological features including shared toe pad structure. We obtained DNA from a bone sample of the only known specimen to generate high-throughput sequence data suitable for phylogenetic analysis of its evolutionary history. Complementary sequence data were obtained from a broad sample of diplodactylid geckos. Our results indicate that the species is not most closely related to extant Hoplodactylus or any other New Zealand gecko. Instead, it is a member of a clade whose living species are endemic to New Caledonia. Phylogenetic comparative analyses indicate that the New Caledonian diplodactylid clade has evolved significantly more disparate body sizes than either the Australian or New Zealand clades. Toe pad structure has changed repeatedly across diplodactylids, including multiple times in the New Caledonia clade, partially explaining the convergence in form between H. delcourti and New Zealand Hoplodactylus. Based on the phylogenetic results, we place H. delcourti in a new genus.

Die dringende Transformation unseres Energiesystems hin zu einer nachhaltigen Infrastruktur der Daseinsvorsorge scheitert in der regionalen Umsetzung regelmäßig an raumbezogenen und gesellschaftlichen Anforderungen des ländlichen Raums. In diesem Beitrag werden am Beispiel eines transdisziplinären Projektes Dilemmata in der partizipativen Umsetzung der regionalen Energiewende identifiziert und Gelingensbedingungen einer raumsensiblen Energiewende-Governance formuliert. Wie mit dem entwickelten Governance-Ansatz zur „Co-Transformation“ gezeigt wird, können kontextsensitive Partizipationsformen der Co-Regulierung, Co-Allokation und Co-Visionierung zur Verfahrens‑, Verteilungs- sowie Zukunftsgerechtigkeit und damit zur Akzeptabilität der regionalen Energiewende als Daseinsvorsorgeinfrastruktur im ländlichen Raum beitragen. Zentrale Maßnahmenfelder sind dabei ergebnisoffene und regional angepasste Formen der Mitwirkung durch die Co-Regulierung im Planungsprozess, Ansätze zur räumlichen Co-Allokation energiewendebezogener Belastungen und lokaler Mehrwerte sowie die Co-Visionierung regionaler Energiezukünfte und daraus abzuleitender regionaler Energievisionen.

Abstract Background ME/CFS is a disorder characterized by recurrent fatigue and intolerance to exertion which manifests as profound post-exertional malaise. Prevalence studies internationally have reported highly variable results due to the 20 + diagnostic criteria. For Australia, the prevalence of ME/CFS based on current case definitions is unknown. Objectives To report prevalence of ME/CFS in patients aged ≥ 13 years attending Australian primary care settings for years 2015–2019, and provide context for patterns of primary care attendance by people living with ME/CFS. Methodology Conducted in partnership with the Patient Advisory Group, this study adopted a mixed methods approach. De-identified primary care data from the national MedicineInsight program were analyzed. The cohort were regularly attending patients, i.e. 3 visits in the preceding 2 years. Crude prevalence rates were calculated for years 2015–2019, by sex, 10-year age groups, remoteness and socioeconomic status. Rates are presented per 100,000population (95% confidence intervals (CI)). Qualitative data was collected through focus groups and in-depth 1:1 interview. Results Qualitative evidence identified barriers to reaching diagnosis, and limited interactions with primary care due to a lack of available treatments/interventions, stigma and disbelief in ME/CFS as a condition. In each year of interest, crude prevalence in the primary care setting ranged between 94.9/100,000 (95% CI: 91.5–98.5) and 103.9/100,000 population (95%CI: 100.3–107.7), equating to between 20,140 and 22,050 people living with ME/CFS in Australia in 2020. Higher rates were observed for age groups 50-59 years and 40-49 years. Rates were substantially higher in females (130.0–141.4/100,000) compared to males (50.9–57.5/100,000). In the context of the qualitative evidence, our prevalence rates likely represent an underestimate of the true prevalence of ME/CFS in the Australian primary care setting. Conclusion ME/CFS affects a substantial number of Australians. Whilst this study provides prevalence estimates for the Australian primary care setting, the qualitative evidence highlights the limitations of these. Future research should focus on using robust case ascertainment criteria in a community setting. Quantification of the burden of disease can be used to inform health policy and planning, for this understudied condition.

BackgroundMany older adults now use technologies such as wearable devices and telehealth services to support their health and well-being while living independently at home. However, older adults vary in how they use these technologies, and there is a lack of knowledge regarding the motivations that influence their acceptance and use of health-related technologies in home environments. ObjectiveThis study aimed to understand the types of technologies that older adults use to support their health and the factors that motivate them to use their chosen technologies to support their health. In addition, we aimed to understand the factors that enable the effective use of technologies for health self-management and to identify the barriers that can negatively affect the adoption of technologies. MethodsA total of 22 older adults participated in semistructured interviews regarding their experiences of using technologies for health self-management. Interview transcripts were analyzed through an in-depth thematic analysis. ResultsThe interviews revealed that a range of technologies, such as videoconferencing software, fitness trackers, and other devices, were being used by older adults to support their health. Interviews showed that participants were motivated to use technologies to monitor health issues, to stay active and connected, and to record and change their behavior in the light of foreseen risks related to their future health status. Enablers that facilitated the effective use of technologies include social and organizational influence, convenient access to health care and safety provided by the technology, and easy setup and low cost of the technology. Barriers include information overload and a sense of futility about future health decline; telehealth being an inadequate substitute for in-person consultation; concerns about trust related to privacy and accuracy; and technologies being stigmatizing, uncomfortable to use, expensive, and unfamiliar. ConclusionsThis study suggested that older adults were using a variety of technologies to prevent or prepare for future health decline, evidencing a resilient attitude toward health and aging. In addition, older adults were willing to continue using the technology when there was a perceived need. The enabler mentioned by most participants was the social and organizational influence that included health care staff, family, friends, and organizations. This analysis provides a better understanding of how older adults use technologies to support their health and can guide the provision of appropriate health technologies for them.

Abstract Background The gut microbiome is altered in patients with inflammatory bowel disease, yet how these alterations contribute to intestinal inflammation is poorly understood. Murine models have demonstrated the importance of the microbiome in colitis since colitis fails to develop in many genetically susceptible animal models when re-derived into germ-free environments. We have previously shown that Wiskott-Aldrich syndrome protein (WASP)-deficient mice (Was −/− ) develop spontaneous colitis, similar to human patients with loss-of-function mutations in WAS. Furthermore, we showed that the development of colitis in Was −/− mice is Helicobacter dependent. Here, we utilized a reductionist model coupled with multi-omics approaches to study the role of host-microbe interactions in intestinal inflammation. Results Was −/− mice colonized with both altered Schaedler flora (ASF) and Helicobacter developed colitis, while those colonized with either ASF or Helicobacter alone did not. In Was −/− mice, Helicobacter relative abundance was positively correlated with fecal lipocalin-2 (LCN2), a marker of intestinal inflammation. In contrast, WT mice colonized with ASF and Helicobacter were free of inflammation and strikingly, Helicobacter relative abundance was negatively correlated with LCN2. In Was −/− colons, bacteria breach the mucus layer, and the mucosal relative abundance of ASF457 Mucispirillum schaedleri was positively correlated with fecal LCN2. Meta-transcriptomic analyses revealed that ASF457 had higher expression of genes predicted to enhance fitness and immunogenicity in Was −/− compared to WT mice. In contrast, ASF519 Parabacteroides goldsteinii’s relative abundance was negatively correlated with LCN2 in Was −/− mice, and transcriptional analyses showed lower expression of genes predicted to facilitate stress adaptation by ASF519 in Was −/− compared to WT mice. Conclusions These studies indicate that the effect of a microbe on the immune system can be context dependent, with the same bacteria eliciting a tolerogenic response under homeostatic conditions but promoting inflammation in immune-dysregulated hosts. Furthermore, in inflamed environments, some bacteria up-regulate genes that enhance their fitness and immunogenicity, while other bacteria are less able to adapt and decrease in abundance. These findings highlight the importance of studying host-microbe interactions in different contexts and considering how the transcriptional profile and fitness of bacteria may change in different hosts when developing microbiota-based therapeutics. Video abstract

Background: The Centers for Disease Control and Prevention have declared that the United States is amidst a continuing opioid epidemic, with drug overdose–related death tripling between 1999 and 2014. Among the 47,055 overdose-related deaths that occurred in 2014, 28,647 (60.9%) of them involved an opioid. Methods: To determine if there are specific trends in opioid prescribing practices of specific groups of surgeons to better describe any regional or subspecialty trends that exist, the Part D Prescriber Public Use File was used to evaluate all prescription drug orders for Medicare beneficiaries with a Part D prescription drug plan for the 2015 calendar year. Only those providers with the specialty description corresponding to a surgical specialty were included in this study, using the provider's Part B claims. Results: A total of 65,277,932 claims made to Part D by 90,253 surgeons in the 2015 service year were analyzed in this study, demonstrating statistically significant differences in the opioid prescribing practices of surgeons from different states, cities, practice settings, and subspecialties (P

ObjectiveCT-guided, frameless robotic radiosurgery is a novel radiotherapy technique for the treatment of intracranial arteriovenous malformations (AVMs) that serves as an alternative to traditional catheter-angiography targeted, frame-based methods.MethodsPatients diagnosed with AVMs who completed single fraction frameless robotic radiosurgery at Medstar Georgetown University Hospital between July 20, 2006 – March 11, 2013 were included in the present study. All patients received pre-treatment planning with CT angiogram (CTA) and MRI, and were treated using the CyberKnife radiosurgery platform. Patients were followed for at least four years or until radiographic obliteration of the AVM was observed.ResultsTwenty patients were included in the present study. The majority of patients were diagnosed with Spetzler Martin Grade II (35%) or III (35%) AVMs. The AVM median nidus diameter and nidal volume was 1.8 cm and 4.38 cc, respectively. Median stereotactic radiosurgery dose was 1,800 cGy. After a median follow-up of 42 months, the majority of patients (81.3%) had complete obliteration of their AVM. All patients who were treated to a total dose of 1800 cGy demonstrated complete obliteration. One patient treated at a dose of 2,200 cGy developed temporary treatment-related toxicity, and one patient developed post-treatment hemorrhage.ConclusionsFrameless robotic radiosurgery with non-invasive CTA and MRI radiography appears to be a safe and effective radiation modality and serves as a novel alternative to traditional invasive catheter-angiography, frame-based methods for the treatment of intracranial AVMs. Adequate obliteration can be achieved utilizing 1,800 cGy in a single fraction, and minimizes treatment-related side effects.

CD28 plays a critical role in regulating immune responses both by enhancing effector T cell activation and differentiation and controlling the development and function of regulatory T cells. CD28 is expressed at the cell surface as a disulfide linked homodimer that is thought to bind ligand monovalently. How ligand binding triggers CD28 to induce intracellular signaling as well as the proximal signaling pathways that are induced are not well-understood. In addition, recent data suggest inside-out signaling initiated by the T cell antigen receptor can enhance CD28 ligand binding, possibly by inducing a rearrangement of the CD28 dimer interface to allow for bivalent binding. To understand how possible conformational changes during ligand-induced receptor triggering and inside-out signaling are mediated, we examined the CD28 transmembrane domain. We identified an evolutionarily conserved YxxxxT motif that is shared with CTLA-4 and resembles the transmembrane dimerization motif within CD3ζ. We show that the CD28 transmembrane domain can drive protein dimerization in a bacterial expression system at levels equivalent to the well-known glycophorin A transmembrane dimerization motif. In addition, ectopic expression of the CD28 transmembrane domain into monomeric human CD25 can drive dimerization in murine T cells as detected by an increase in FRET by flow cytometry. Mutation of the polar YxxxxT motif to hydrophobic leucine residues (Y145L/T150L) attenuated CD28 transmembrane mediated dimerization in both the bacterial and mammalian assays. Introduction of the Y145L/T150L mutation of the CD28 transmembrane dimerization motif into the endogenous CD28 locus by CRISPR resulted in a dramatic loss in CD28 cell surface expression. These data suggest that under physiological conditions the YxxxxT dimerization motif within the CD28 transmembrane domain plays a critical role in the assembly and/or expression of stable CD28 dimers at the cell surface.

Genome instability is a hallmark of aging and contributes to age-related disorders such as cancer and Alzheimer’s disease. The accumulation of DNA damage during aging has been linked to altered cell cycle dynamics and the failure of cell cycle checkpoints. Here, we use single cell imaging to study the consequences of increased genomic instability during aging in budding yeast and identify striking age-associated genome missegregation events. This breakdown in mitotic fidelity results from the age-related activation of the DNA damage checkpoint and the resulting degradation of histone proteins. Disrupting the ability of cells to degrade histones in response to DNA damage increases replicative lifespan and reduces genomic missegregations. We present several lines of evidence supporting a model of antagonistic pleiotropy in the DNA damage response where histone degradation, and limited histone transcription are beneficial to respond rapidly to damage but reduce lifespan and genomic stability in the long term.

Lithium (Li) is one of the most effective drugs for treating bipolar disorder (BD), however, there is presently no way to predict response to guide treatment. The aim of this study is to identify functional genes and pathways that distinguish BD Li responders (LR) from BD Li non-responders (NR). An initial Pharmacogenomics of Bipolar Disorder study (PGBD) GWAS of lithium response did not provide any significant results. As a result, we then employed network-based integrative analysis of transcriptomic and genomic data. In transcriptomic study of iPSC-derived neurons, 41 significantly differentially expressed (DE) genes were identified in LR vs NR regardless of lithium exposure. In the PGBD, post-GWAS gene prioritization using the GWA-boosting (GWAB) approach identified 1119 candidate genes. Following DE-derived network propagation, there was a highly significant overlap of genes between the top 500- and top 2000-proximal gene networks and the GWAB gene list (Phypergeometric = 1.28E-09 and 4.10E-18, respectively). Functional enrichment analyses of the top 500 proximal network genes identified focal adhesion and the extracellular matrix (ECM) as the most significant functions. Our findings suggest that the difference between LR and NR was a much greater effect than that of lithium. The direct impact of dysregulation of focal adhesion on axon guidance and neuronal circuits could underpin mechanisms of response to lithium, as well as underlying BD. It also highlights the power of integrative multi-omics analysis of transcriptomic and genomic profiling to gain molecular insights into lithium response in BD.

Background. Hospital inpatient readmissions for patients admitted initially with the primary diagnosis of heart failure (HF) can be as high as 20–25% within 30 days of discharge. This, however, does not include admissions for observations or emergency department (ED) visits within the same time frame and does not show a time-dependent hospital encounter following discharge after an index admission. We present data on time-dependent hospital encounter of HF patients discharged after an index admission for a primary diagnosis of HF. Methods. The study recruited patients from 2 hospitals within the same health system. 500 consecutive admissions with the ICD diagnosis of HF were reviewed by inclusion and exclusion screening criteria. The 166 eligible remaining patients were tracked for post hospital discharge encounters consisting of hospital admissions, observation stays, and ED visits. Only those with a primary diagnosis of heart failure were included. Demographics were recorded on all patients. Days until hospital inpatient readmissions or hospital encounters were displayed in Kaplan–Meier plots. Results. A total of 166 patients met inclusion criteria (mean age 79.3 years, males 54%). For the first 90 days following the index admission, there were a total of 287 follow-up visits (1.7 per patient), 1158 total hospitalization days (2.6 per visit, 7.0 per patient, and 8.6 per 100 days at risk), and 21 deaths (12.7%). At 30 days, 25% and 52% of patients had an inpatient readmission or a hospital encounter, respectively. The median time to inpatient readmission was 117 days and to hospital encounter was 27 days. Conclusion. Time-dependent excess days in acute care (unplanned inpatient admission, outpatient observation, and ED visit) rather than 30-day hospital inpatient readmission rate is a more realistic measure of the intensity of care required for HF patients after index admission.

Amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative disease characterized by the degeneration of motor neurons. Though many molecular and genetic causes are thought to serve as predisposing or disease propagating factors, the underlying pathogenesis of the disease is not known. Recent discoveries have demonstrated the presence of inflammation propagating substrates in the central nervous system of patients afflicted with ALS. Over the past decade, this hypothesis has incited an effort to better understand the role of the immune system in ALS and has led to the trial of several potential immune-modulating therapies. Here, we briefly review advances in the role of such therapies. The clinical trials discussed here are currently ongoing or have been concluded at the time of writing.

Wildfire size, frequency, and severity are increasing in the Alaskan boreal forest in response to climate warming. One of the potential impacts of this changing fire regime is the alteration of successional trajectories, from black spruce to mixed stands dominated by aspen, a vegetation composition not experienced since the early Holocene. Such changes in vegetation composition may consequently alter the intensity of fires, influencing fire feedbacks to the ecosystem. Paleorecords document past wildfire-vegetation dynamics and as such, are imperative for our understanding of how these ecosystems will respond to future climate warming. For the first time, we have used reflectance measurements of macroscopic charcoal particles (>180μm) from an Alaskan lake-sediment record to estimate ancient charring temperatures (termed pyrolysis intensity). We demonstrate that pyrolysis intensity increased markedly from an interval of birch tundra 11 ky ago (mean 1.52%Ro; 485°C), to the expansion of trees on the landscape ~10.5 ky ago, remaining high to the present (mean 3.54%Ro; 640°C) irrespective of stand composition. Despite differing flammabilities and adaptations to fire, the highest pyrolysis intensities derive from two intervals with distinct vegetation compositions. 1) the expansion of mixed aspen and spruce woodland at 10 cal. kyr BP, and 2) the establishment of black spruce, and the modern boreal forest at 4 cal. kyr BP. Based on our analysis, we infer that predicted expansion of deciduous trees into the boreal forest in the future could lead to high intensity, but low severity fires, potentially moderating future climate-fire feedbacks.

Receptor tyrosine kinase-like orphan receptors (ROR) 1 and 2 are atypical members of the receptor tyrosine kinase (RTK) family and have been associated with several human diseases. The vertebrate RORs contain an ATP binding domain that deviates from the consensus amino acid sequence, although the impact of this deviation on catalytic activity is not known and the kinase function of these receptors remains controversial. Recently, ROR2 was shown to signal through a Wnt responsive, β-catenin independent pathway and suppress a canonical Wnt/β-catenin signal. In this work we demonstrate that both ROR1 and ROR2 kinase domains are catalytically deficient while CAM-1, the C. elegans homolog of ROR, has an active tyrosine kinase domain, suggesting a divergence in the signaling processes of the ROR family during evolution. In addition, we show that substitution of the non-consensus residues from ROR1 or ROR2 into CAM-1 and MuSK markedly reduce kinase activity, while restoration of the consensus residues in ROR does not restore robust kinase function. We further demonstrate that the membrane-bound extracellular domain alone of either ROR1 or ROR2 is sufficient for suppression of canonical Wnt3a signaling, and that this domain can also enhance Wnt5a suppression of Wnt3a signaling. Based on these data, we conclude that human ROR1 and ROR2 are RTK-like pseudokinases.

Genomic integrity is preserved by checkpoints, which act to delay cell cycle progression in the presence of DNA damage or replication stress. The heterotrimeric Rad9-Rad1-Hus1 (9-1-1) complex is a PCNA-like clamp that is loaded onto DNA at structures resulting from damage and is important for initiating and maintaining the checkpoint response. Rad9 possesses a C-terminal tail that is phosphorylated constitutively and in response to cell cycle position and DNA damage. Previous studies have identified tousled-like kinase 1 (TLK1) as a kinase that may modify Rad9. Here we show that Rad9 is phosphorylated in a TLK-dependent manner in vitro and in vivo, and that T355 within the C-terminal tail is the primary targeted residue. Phosphorylation of Rad9 at T355 is quickly reduced upon exposure to ionizing radiation before returning to baseline later in the damage response. We also show that TLK1 and Rad9 interact constitutively, and that this interaction is enhanced in chromatin-bound Rad9 at later stages of the damage response. Furthermore, we demonstrate via siRNA-mediated depletion that TLK1 is required for progression through S-phase in normally cycling cells, and that cells lacking TLK1 display a prolonged G2/M arrest upon exposure to ionizing radiation, a phenotype that is mimicked by over-expression of a Rad9-T355A mutant. Given that TLK1 has previously been shown to be transiently inactivated upon phosphorylation by Chk1 in response to DNA damage, we propose that TLK1 and Chk1 act in concert to modulate the phosphorylation status of Rad9, which in turn serves to regulate the DNA damage response.

As the permafrost region warms, its large organic carbon pool will be increasingly vulnerable to decomposition, combustion, and hydrologic export. Models predict that some portion of this release will be offset by increased production of Arctic and boreal biomass; however, the lack of robust estimates of net carbon balance increases the risk of further overshooting international emissions targets. Precise empirical or model-based assessments of the critical factors driving carbon balance are unlikely in the near future, so to address this gap, we present estimates from 98 permafrost-region experts of the response of biomass, wildfire, and hydrologic carbon flux to climate change. Results suggest that contrary to model projections, total permafrost-region biomass could decrease due to water stress and disturbance, factors that are not adequately incorporated in current models. Assessments indicate that end-of-the-century organic carbon release from Arctic rivers and collapsing coastlines could increase by 75% while carbon loss via burning could increase four-fold. Experts identified water balance, shifts in vegetation community, and permafrost degradation as the key sources of uncertainty in predicting future system response. In combination with previous findings, results suggest the permafrost region will become a carbon source to the atmosphere by 2100 regardless of warming scenario but that 65%–85% of permafrost carbon release can still be avoided if human emissions are actively reduced.

Abstract The application of genetic breeding programmes to eradicate transmissible spongiform encephalopathies in goats is an important aim for reasons of animal welfare as well as human food safety and food security. Based on the positive impact of Prnp genetics on sheep scrapie in Europe in the past decade, we have established caprine Prnp gene variation in more than 1100 goats from the United Kingdom and studied the association of Prnp alleles with disease phenotypes in 150 scrapie-positive goats. This investigation confirms the association of the Met142 encoding Prnp allele with increased resistance to preclinical and clinical scrapie. It reveals a novel association of the Ser127 encoding allele with a reduced probability to develop clinical signs of scrapie in goats that are already positive for the accumulation of disease-specific prion protein in brain or periphery. A United Kingdom survey of Prnp genotypes in eight common breeds revealed eleven alleles in over thirty genotypes. The Met142 encoding allele had a high overall mean allele frequency of 22.6%, whereas the Ser127 encoding allele frequency was considerably lower with 6.4%. In contrast, a well known resistance associated allele encoding Lys222 was found to be rare (0.9%) in this survey. The analysis of Prnp genotypes in Mexican Criollas goats revealed nine alleles, including a novel Phe to Leu substitution in codon 201, confirming that high genetic variability of Prnp can be found in scrapie-free populations. Our study implies that it should be feasible to lower scrapie prevalence in goat herds in the United Kingdom by genetic selection.

Lithium remains the gold standard for the treatment of bipolar disorder (BD); however, its use has declined over the years mainly due to the side effects and the subjective experience of cognitive numbness reported by patients. In the present study, we aim to methodically test the effects of lithium on neurocognitive functioning in the largest single cohort (n = 262) of BD patients reported to date by harnessing the power of a multi-site, ongoing clinical trial of lithium monotherapy. At the cross-sectional level, multivariate analysis of covariance (MANCOVA) was conducted to examine potential group differences across neurocognitive tests [California Verbal Learning Test (CVLT trials 1-5,CVLT delayed recall), Wechsler Digit Symbol, Trail-making Test parts A and B (TMT-A; TMT-B), and a global cognition index]. At the longitudinal level, on a subset of patients (n = 88) who achieved mood stabilization with lithium monotherapy, we explored the effect of lithium treatment across time on neurocognitive functioning. There were no differences at baseline between BD patients that were taking lithium compared with those that were not. At follow-up a significant neurocognitive improvement in the global cognitive index score [F = 31.69; p

Bipolar disorder (BD) is a serious mood disorder associated with circadian rhythm abnormalities. Risk for BD is genetically encoded and overlaps with systems that maintain circadian rhythms. Lithium is an effective mood stabilizer treatment for BD, but only a minority of patients fully respond to monotherapy. Presently, we hypothesized that lithium-responsive BD patients (Li-R) would show characteristic differences in chronotype and cellular circadian rhythms compared to lithium non-responders (Li-NR). Selecting patients from a prospective, multi-center, clinical trial of lithium monotherapy, we examined morning vs. evening preference (chronotype) as a dimension of circadian rhythm function in 193 Li-R and Li-NR BD patients. From a subset of 59 patient donors, we measured circadian rhythms in skin fibroblasts longitudinally over 5 days using a bioluminescent reporter (Per2-luc). We then estimated circadian rhythm parameters (amplitude, period, phase) and the pharmacological effects of lithium on rhythms in cells from Li-R and Li-NR donors. Compared to Li-NRs, Li-Rs showed a difference in chronotype, with higher levels of morningness. Evening chronotype was associated with increased mood symptoms at baseline, including depression, mania, and insomnia. Cells from Li-Rs were more likely to exhibit a short circadian period, a linear relationship between period and phase, and period shortening effects of lithium. Common genetic variation in the IP3 signaling pathway may account for some of the individual differences in the effects of lithium on cellular rhythms. We conclude that circadian rhythms may influence response to lithium in maintenance treatment of BD.

This article features the College of Education and Professional Studies (CEPS) at Jacksonville State University (JSU) located in Jacksonville, Alabama, which aims to prepare students for successful careers in a variety of professions, including career and technical education (CTE) teacher preparation. The college's uniqueness is reflected by its diversity of programs and services. CEPS programs enable graduates to be creative decision makers who effectively solve problems using concepts and practices appropriate for each discipline. The CEPS programs maintain rigor and relevance through outreach and partnership activities with schools and businesses related to its programs within and surrounding the university's service area. The ultimate goal of the CEPS is to assure that its graduates are effective, highly performing employees. In the College of Educational and Professional Studies, CTE teacher candidates learn the skills necessary to be effective educators through their immersion in schools, in the community, intensive practicum and mentoring that pairs them with established teachers.