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SLC13A5 citrate transporter disorder is a rare epileptic encephalopathy caused by loss of function pathogenic variants in the SLC13A5 gene. Loss of sodium/citrate cotransporter (NaCT) function causes a severe early life epilepsy resulting in life-long developmental disabilities and increased extracellular citrate. Current antiseizure medications may reduce seizure frequency, yet more targeted treatments are needed to address the epileptic and neurodevelopmental SLC13A5 phenotype. We performed preclinical studies in SLC13A5 deficient mice evaluating phenotype rescue with adeno-associated virus (AAV) vector carrying a functional copy of the human SLC13A5 gene (AAV9/SLC13A5). Cerebrospinal fluid-delivery of AAV9/SLC13A5 decreased extracellular citrate levels, normalized electrophysiologic and sleep architecture abnormalities, and restored resistance to chemically induced seizures and death. Treatment benefits were achieved with administration during early brain development and in young adult mice, indicating therapeutic efficacy across developmental and post-developmental stages. Comparison of delivery routes in young adult KO mice showed that higher brain targeting achieved with intra-cisterna magna delivery resulted in greater treatment benefit as compared to intrathecal lumbar puncture delivery. Together, these results support further development of AAV9/SLC13A5 for treating SLC13A5 citrate transporter disorder.

Introduction Increasing access to multi‐month dispensing (MMD) of antiretroviral therapy (ART) supports treatment continuity and viral load suppression for people living with HIV (PLHIV) and reduces burden on health facilities. During the COVID‐19 response, PEPFAR worked with ministries of health to scale up MMD and expand eligibility to new groups of PLHIV, including children and pregnant/breastfeeding women. We analysed PEPFAR program data to understand the impact of the policy changes on actual practice. Methods We conducted a desk review in 21 PEPFAR‐supported countries to identify and collect official documentation released between March and June 2020 addressing changes to MMD guidance during the COVID‐19 response. MMD coverage, the proportion of all ART clients on MMD, was assessed in the calendar quarters preceding the COVID‐19 response (Q4 2019, October–December 2019; and Q1, January–March 2020) and the quarters following the start of the response (Q2 2020, April–June 2020; Q3 2020, July–September, 2020; Q4 2020, October–December 2020). We used the two‐proportion Z‐test to test for differences in MMD coverage pre‐COVID‐19 (Q4 2019) and during implementation of COVID‐19 policy adaptations (Q2 2020). Results and discussion As of June 2020, 16 of the 21 PEPFAR‐supported countries analysed adapted MMD policy or promoted intensified scale‐up of MMD in response to COVID‐19. MMD coverage for all clients on ART grew from 49% in Q4 2019 pre‐COVID‐19 to 72% in Q2 2020 during COVID‐19; among paediatric clients (< 15), MMD coverage increased from 27% to 51% in the same period. Adaptations to MMD policy were associated with a significantly accelerated growth in the proportion of clients on MMD (p < 0.001) for all populations, irrespective of age and dispensing interval. Conclusions Access to MMD markedly expanded during the COVID‐19 pandemic, supporting treatment continuity while mitigating exposure to COVID‐19 at health facilities. This model is beneficial in public health emergencies and during disruptions to the healthcare system. Outside emergency contexts, expanded MMD eligibility extends client‐centred care to previously excluded populations. The success in expanding MMD access during COVID‐19 should motivate countries to recommend broader MMD access as a new standard of care.

Changes in behaviour and physiology are the primary responses of fishes to anthropogenic impacts such as climate change and over-fishing. Behavioural changes (such as a shift in distribution or changes in phenology) can ensure that a species remains in an environment suited for its optimal physiological performance. However, if fishes are unable to shift their distribution, they are reliant on physiological acclimatization (either by broadening their metabolic curves to tolerate a range of stressors, or by shifting their metabolic curves to maximize their performance at extreme stressors). However, since there are links between fish physiology and behaviour, changes to either of these trait groups may have reciprocal interactions. This paper reviews the current knowledge of the links between the behaviour and aerobic metabolic physiology of fishes, discusses these in the context of exploitation and climate change and makes recommendations for future research needs. The review revealed that our understanding of the links between fish behaviour and metabolic physiology is rudimentary. However, both are hypothesized to be linked to stress responses along the hypothalamic pituitary axis. The link between metabolic physiological capacity and behaviour is particularly important as both determine the response of an individual to a changing climate and are under selection by fisheries. While, it appears that all types of capture fisheries are likely to reduce the adaptive potential of fished populations to climate stressors, angling, which is primarily associated with recreational fishing, may induce the separation of natural populations by removing individuals with bold behavioural traits and potentially the physiological traits required to facilitate behavioural change. Future research should focus on assessing how the links between metabolic physiological capacity and behaviour influence catchability, the response to climate change drivers and post-release recovery. The plasticity of phenotypic traits should be examined under a range of stressors of differing intensity, in several species and life history stages. Future studies should also assess plasticity (fission or fusion) in the phenotypic structuring of social hierarchy and how this influences habitat selection. Ultimately, to fully understand how physiology is influenced by the selective processes driven by fisheries, long-term monitoring of the physiological and behavioural structure of fished populations, their fitness and catch rates are required. This will provide information that can be used by managers to retain behavioural and physiological trait diversity, which will be necessary to improve the resilience of fished populations to the impacts of climate change and safeguard the provision of resources for future generations.

Rationale Cocaine use disorder (CUD) is a highly heritable form of substance use disorder, with genetic variation accounting for a substantial proportion of the risk for transitioning from recreational use to a clinically impairing addiction. With repeated exposures to cocaine, psychomotor and incentive sensitization are observed in rodents. These phenomena are thought to model behavioral changes elicited by the drug that contribute to the progression into addiction, but little is known about how genetic variation may moderate these consequences. Objectives Here, we describe the use of two Collaborative Cross (CC) recombinant inbred mouse strains that either exhibit high (CC018/UncJ) or no (CC027/GeniUncJ) psychomotor sensitization in response to cocaine to measure phenotypes related to incentive sensitization after repeated cocaine exposures; given the relationship of incentive motivation to nucleus accumbens core (NAc) dopamine release and reuptake, we also assessed these neurochemical mechanisms. Methods Adult male and female CC018/UncJ and CC027/GeniUncJ mice underwent Pavlovian conditioning to associate a visual cue with presentation of a palatable food reward, then received five, every-other-day injections of cocaine or vehicle. Following Pavlovian re-training, they underwent testing acquisition of a new operant response for the visual cue, now serving as a conditioned reinforcer. Subsequently, electrically evoked dopamine release was assessed using fast-scan cyclic voltammetry from acute brain slices containing the NAc. Results While both strains acquired the Pavlovian association, only CC018/UncJ mice showed conditioned reinforcement and incentive sensitization in response to cocaine, while CC027/GeniUncJ mice did not. Voltammetry data revealed that CC018/UncJ, compared to CC027/GeniUnc, mice exhibited higher baseline dopamine release and uptake. Moreover, chronic cocaine exposure blunted tonic and phasic dopamine release in CC018/UncJ, but not CC027/GeniUncJ, mice. Conclusions Genetic background is a moderator of cocaine-induced neuroadaptations in mesolimbic dopamine signaling, which may contribute to both psychomotor and incentive sensitization and indicate a shared biological mechanism of variation.

While a bidirectional positive link between palatable food intake and alcohol drinking has been suggested, several rodents studies report reduced alcohol drinking following palatable diets exposure. These studies utilized purified rodents’ diets high in sugar/fat; however, the effects of hyper-palatable food (HPF) rich in fat and sugar on alcohol drinking remain unclear. Furthermore, neural substrates involved in HPF-mediated changes in alcohol consumption are poorly understood. Therefore, the present study evaluated the effects of patterned feeding of a hyper-palatable food (Oreo cookies) on alcohol drinking as well as dopamine (DA) and serotonin (5-HT) content in rat’s mesocorticolimbic (medial-prefrontal cortex, orbitofrontal cortex, amygdala, and nucleus accumbens) circuitry. Male Long Evans rats received 8-weeks of intermittent (Mon, Tue, Wed) Oreo cookies access, which induced a patterned feeding, in which rats in the Oreo group overconsumed calories on HPF days whereas underconsumption was observed on chow only (Thu, Fri) days. Following HPF exposure, alcohol consumption was evaluated while patterned feeding continued. Alcohol intake in the Oreo group was significantly lower as compared to the chow controls. However, alcohol intake in the Oreo group increased to the levels seen in the group receiving chow following the suspension of patterned HPF feeding. Finally, DA levels in the nucleus accumbens were significantly greater, whereas its metabolite (DOPAC) levels were lower in the Oreo group compared to the chow controls. Surprisingly, 5-HT levels remained unaltered in all tested brain areas. Together, these data suggest that HPF-associated increased DA availability and reduced DA turnover within mesocorticolimbic circuitry may regulate alcohol drinking following patterned HPF feeding.

Background The World Health Organization (WHO) and the Uganda Ministry of Health recommend differentiated service delivery models (DSDMs) as patient-centered antiretroviral therapy (ART) mechanisms for people living with HIV/AIDS (PLHIV) with undetectable viral loads. We studied patient satisfaction with ART services, and its associated factors amongst PLHIV enrolled in DSDMs in Uganda. Methods This cross-sectional study involved a random sample of PLHIV accessing DSDM-related ART at nine facilities in East Central Uganda. Eligible patients were adult PLHIV (≥18 years), on ART, and enrolled for at least 12 months in one of three DSDMs: Community Client-Led ART Delivery (CCLAD), Community Drug Distribution Points (CDDP), or Fast-Track Drug Refill (FTDR). We collected data from June to July 2019. A validated tool measured satisfaction. General Estimating Equations with modified Poisson regression and exchangeable correlation structures accounted for clustering at health facilities and identified DSDM-related satisfaction factors. Results Of 842 participants enrolled, 530 (63.5%) accessed HIV care through CDDP, 166 (20.1%) through CCLAD, and 146 (16.3%) through FTDR; 541 (64.2%) were satisfied with DSDM services: 78.7% in CDDP, 42.8% in CCLAD, and 36.3% in FTDR. The delivery and treatment factors positively associated with satisfaction included: being enrolled on CDDP [adjusted prevalence ratio (aPR) = 1.51, 95% CI:1.47–1.56] or FTDR [aPR = 1.47, 95% CI:1.26–1.71] relative to CCLAD and being enrolled in a DSDM for more than 3 years [aPR = 1.28, 95% CI:1.11–1.48]. Poor ART adherence [aPR = 0.33, 95% CI:0.19–0.56] and having a baseline WHO HIV stage of 3 or 4 [aPR = 0.36, 95% CI:0.20–0.64] relative to stages 1 and 2 were negatively associated. Among socioeconomic factors, having lower transport costs (< $1.35) per clinic visit [aPR = 1.34, 95% CI:1.17–1.53], being employed [aPR = 1.61, 95% CI:1.38–1.87], and being single [aPR = 1.10, 95% CI:1.08–1.13] were positively associated with satisfaction; drinking alcohol at least once a week [aPR = 0.77, 95% CI:0.63–0.93] was negatively associated with patient satisfaction. Conclusions Results showed that 64.2% of patients were satisfied with DSDM services. HIV service delivery and treatment factors (DSDM type, time in DSDM, WHO stage, ART adherence), plus social factors (employment and marital status, transport costs, alcohol consumption), were associated with patient satisfaction. DSDM implementers should tailor services to address these factors to improve patient satisfaction.

Artificial lights may be altering interactions between bats and moth prey. According to the allotonic frequency hypothesis (AFH), eared moths are generally unavailable as prey for syntonic bats (i.e., bats that use echolocation frequencies between 20 and 50 kHz within the hearing range of eared moths) due to the moths’ ability to detect syntonic bat echolocation. Syntonic bats therefore feed mainly on beetles, flies, true bugs, and non-eared moths. The AFH is expected to be violated around lights where eared moths are susceptible to exploitation by syntonic bats because moths’ evasive strategies become less effective. The hypothesis has been tested to date almost exclusively in areas with permanent lighting, where the effects of lights on bat diets are confounded with other aspects of human habitat alteration. We undertook diet analysis in areas with short-term, localized artificial lighting to isolate the effects of artificial lighting and determine if syntonic and allotonic bats (i.e., bats that use echolocation frequencies outside the hearing range of eared moths) consumed more moths under conditions of artificial lights than in natural darkness. We found that syntonic bats increased their consumption of moth prey under experimentally lit conditions, likely owing to a reduction in the ability of eared moths to evade the bats. Eared moths may increase in diets of generalist syntonic bats foraging around artificial light sources, as opposed to allotonic species and syntonic species with a more specialized diet.

Background: SLC13A5 Citrate Transporter Disorder is a rare pediatric neurodevelopmental disorder. Patients have epilepsy, developmental disability, and impaired mobility. While sleep disorders are common in children with neurodevelopmental disorders, sleep abnormalities have not been reported in SLC13A5 patients. Methods: Here, we assessed sleep disturbances in patients through caregiver reported surveys and in a transgenic mouse model of SLC13A5 deficiency. A total of 26 patients were evaluated with the Sleep Disturbance Scale for Children three times over a one-year span. Sleep and wake activities were assessed in the SLC13A5 knock-out (KO) mice using wireless telemetry devices. Results: A high burden of clinically significant sleep disturbances were reported in the patients, with heterogeneous symptoms that remained stable across time. While sleep disturbances were common, less than 30% of patients were prescribed medications for sleep. Comparatively, in SLC13A5 KO mice using EEG recordings, significant alterations were found during light cycles, when rodents typically sleep. During the sleep period, SLC13A5 mice had increased activity, decreased paradoxical sleep, and changes in absolute power spectral density, indicating altered sleep architecture in the mouse model. Conclusions: Our results demonstrate a significant component of sleep disturbances in SLC13A5 patients and mice, highlighting a potential gap in patient care. Further investigation of sleep dysfunction and the underlying etiologies of sleep disturbances in SLC13A5 citrate transporter disorder is warranted.

Swi1 and Swi3 form the replication fork protection complex and play critical roles in proper activation of the replication checkpoint and stabilization of replication forks in the fission yeast Schizosaccharomyces pombe. However, the mechanisms by which the Swi1-Swi3 complex regulates these processes are not well understood. Here, we report functional analyses of the Swi1-Swi3 complex in fission yeast. Swi1 possesses the DDT domain, a putative DNA binding domain found in a variety of chromatin remodeling factors. Consistently, the DDT domain-containing region of Swi1 interacts with DNA in vitro, and mutations in the DDT domain eliminate the association of Swi1 with chromatin in S. pombe cells. DDT domain mutations also render cells highly sensitive to S-phase stressing agents and induce strong accumulation of Rad22-DNA repair foci, indicating that the DDT domain is involved in the activity of the Swi1-Swi3 complex. Interestingly, DDT domain mutations also abolish Swi1's ability to interact with Swi3 in cells. Furthermore, we show that Swi1 is required for efficient chromatin association of Swi3 and that the Swi1 C-terminal domain directly interacts with Swi3. These results indicate that Swi1 associates with chromatin through its DDT domain and recruits Swi3 to function together as the replication fork protection complex.

Abstract Changes in ocean temperature are expected to have a considerable effect on fishes through the impact of temperature on physiological performance, vital energetic processes (i.e. metabolism, foraging and swimming style) and reproductive fitness. To understand the sensitivity of an exploited population of Chrysoblephus laticeps in to temperature variability, intermittent-flow respirometry was used to quantify and compare changes in metabolic rate and aerobic scope under different temperatures (10, 16, 21 and 24°C) mimicking thermal variations experienced in the home range of this species. A total performance score was developed to represent aerobic performance across the range of test temperatures. This score was calculated for each temperature from the lower (25%), mid (50%) and upper (75%) percentiles of the aerobic scope range available for the species. The results of this study identified heterogeneity in physiological performance phenotypes amongst individuals of the exploited population. There was significant variation in the aerobic performance of high, intermediate and low performers at higher temperatures. However, differences in performance were not significant at low temperatures, where several intermediate performers maintained high performance. High performers maintained high rates of physiological performance across a broad range of temperatures, whereas low performers were physiologically limited outside of their optimal thermal range. These results suggest that individuals with a broad aerobic scope (i.e. high aerobic scope (AS) values across a range of temperatures) may likely be the most resilient to short-term thermal variability caused by marine heat waves and upwelling events in temperate coastal environments. Since the shape of thermal performance curves differs between individuals and reflects the range at which individuals can function above specified performance thresholds, individual thermal performance must be measured repeatedly in the same individual over a thermal gradient. An understanding of physiological phenotypic diversity amongst individuals is critical to understand the impacts of thermal variability on fished populations. Lay Summary Metabolic rate was used to quantify and compare thermal performance under temperature variations experienced in the home range of an exploited coastal fishery species. Individuals that had high aerobic scope values across a range of temperatures performed significantly better in a thermally variable environment.