Latent regulatory potential of human-specific repetitive elements

At least half of the human genome is derived from repetitive elements, which are often lineage specific and silenced by a variety of genetic and epigenetic mechanisms. Using a transchromosomic mouse strain that transmits an almost complete single copy of human chromosome 21 via the female germline, we show that a heterologous regulatory environment can transcriptionally activate transposon-derived human regulatory regions. In the mouse nucleus, hundreds of locations on human chromosome 21 newly associate with activating histone modifications in both somatic and germline tissues, and influence the gene expression of nearby transcripts. These regions are enriched with primate and human lineage-specific transposable elements, and their activation corresponds to changes in DNA methylation at CpG dinucleotides. This study reveals the latent regulatory potential of the repetitive human genome and illustrates the species specificity of mechanisms that control it

The potential of wildflower strips to enhance pollination services in sweet cherry orchards grown under polytunnels

Sweet cherry production benefits from insect pollination, but the extent to which wildflower strips can boost pollinator visitation under polytunnels is unknown. Wildflowers were established in alleyways between tree rows under polytunnels in 10 commercial cherry orchards. Their management involved either a single cut in September (Standard Wildflower Strips (SWS)) or being actively maintained to 20 cm with regular cutting (Actively Managed Wildflower Strips (AMWS)), compared with unsown Control Strips (CS). Flower visitors of cherry and wildflowers were recorded by visual observations for 3 years (2017–2019), while cherry production (quantity and quality) was assessed in 2019. In total, 67 visitor species were identified; managed commercial species (Apis mellifera and Bombus terrestris) made up ~74% of all records. During the cherry blossom period (anthesis), AMWS had the highest visitor density to cherry blossoms compared with CS and SWS but no significant difference in harvestable fruit was recorded. After anthesis, greater visitor density, diversity and richness were observed in both wildflower treatments compared with CS, being greatest in SWS, which was consistent with differences in floral communities between treatments. Although visitor density was not correlated with fruit set, pollinating insects were key for fruit yields and quality. Fruit set was ~17% from blossoms exposed to visitors compared with <1% when excluded. Furthermore, hand pollination resulted in ~32% fruit set, indicating greatest pollination deficits in CS (~50%) compared with AMWS (~28%) and SWS (~35%). Synthesis and applications. Sweet cherry is highly dependent on pollinators to underpin commercial yields, and pollination deficits exist under polytunnels. Growers should, therefore, reconsider their pollination strategies and look to combine effective pollinator management with polytunnel use to mitigate deficits; establishing and actively managing wildflowers in alleyways could enhance wild visitors and pollination

An experimental assessment of social tolerance and den ecology in a high-density octopus population

Long held notions of the universally asocial octopus are being challenged due to the identification of high-density and interacting octopus populations in Australia, Indonesia, Japan and the deep sea. This study experimentally assessed the social tolerance and presence of potential prey items of Caribbean reef octopus, Octopus briareus, in a tropical marine lake (25°21′40″N, 76°30′40″W) on the island of Eleuthera, The Bahamas, by deploying artificial dens in multi-den groups or ‘units’ in the months of May and June 2019. Fifteen octopus were observed occupying dens (n = 100), resulting in 13 den units being occupied (n = 40). Two examples of adjacent occupation within a single den unit were identified but with zero examples of cohabitation/den sharing. Ecological models showed den and den unit occupation was predicted to increase with depth and differ between sites. Octopus also displayed no preference for isolated or communal units but preferred isolated dens over dens adjacent to others. Additionally, 47 % of occupied dens contained bivalve or crustacean items with no epifauna on their interior surface. The lack of epifauna suggests that these items have been recently ‘cleaned’ by occupying octopus and so represent likely prey. This study presents evidence of possible antisocial den use by O. briareus, a modification of the default ‘asocial’ ignoring of conspecifics typically attributed to octopus. This is likely in response to the high population density and may imply behavioural plasticity, making this system appropriate for further scrutiny as a research location on the influence of large, insular environments on marine species

Drivers of octopus abundance and density in an anchialine lake: a 30 year comparison

Anchialine systems are isolated from the sea and often support species’ populations distinct from their marine counterparts. Sweetings Pond, an anchialine lake on the island of Eleuthera in The Bahamas was identified as a site of high Caribbean reef octopus, Octopus briareus (Robson, 1929) density, relative to coastal populations. However, observed deterioration in local benthic habitat and increased anthropogenic influence over the last 30 years imply that this octopus population may have undergone density and distribution shifts in response to these changing conditions. Here, we assess the system wide octopus density to provide an updated estimate. We hypothesize that despite depressed habitat availability in the 1980s, it will now support octopus densities less than historical estimates because of increasing human impact on the system. Drivers of abundance were also modelled, testing ecological hypotheses of the relationship between octopus count and prey, habitat coverage, and human disturbance. Octopus briareus were found in 7 of 27 of surveys with a mean survey count of 0.630 ± 1.25 per 900 m2. Octopus density did not vary significantly between sites. Octopus count was predicted to increase with increasing cover of calcareous rubble and the density of a preferred prey species, and intriguingly, counts decreased as a function of natural den abundance. System wide octopus density was comparable to earlier studies from the 1980s (1982 = 717.38 per km2; 1983 = 282.59 per km2; 2019 = 643.81 per km2) with no significant difference between years. Given the ecosystem’s unique and closed ecological community and the population dynamics and distribution drivers we present, Sweetings Pond has the potential to act as a ‘natural laboratory’ to explore further questions about marine insular systems and their influence on species populations in terms of ecological and behavioural change

Characterization of a New Chlorovirus Type with Permissive and Non-permissive Features on Phylogenetically Related Algal Strains

A previous report indicated that prototype chlorovirus PBCV-1 replicated in two Chlorella variabilis algal strains, NC64A and Syngen 2-3, that are ex-endosymbionts isolated from the protozoan Paramecium bursaria. Surprisingly, plaque-forming viruses on Syngen 2-3 lawns were often higher than on NC64A lawns from indigenous water samples. These differences led to the discovery of viruses that exclusively replicate in Syngen 2-3 cells, named Only Syngen (OSy) viruses. OSy-NE5, the prototype virus for the proposed new species, had a linear dsDNA genome of 327 kb with 44-nucleotide-long, incompletely base-paired, covalently closed hairpin ends. Each hairpin structure was followed by an identical 2,612 base-paired inverted sequence after which the DNA sequence diverged. OSy-NE5 encoded 357 predicted CDSs and 13 tRNAs. Interestingly, OSy-NE5 attached to and initiated infection in NC64A cells but infectious progeny viruses were not produced; thus OSy-NE5 replication in NC64A is blocked at some later stage of replication

Longitudinal Synaptic Loss in Primary Tauopathies: An In Vivo [11 C]UCB-J Positron Emission Tomography Study

BACKGROUND: Synaptic loss is characteristic of many neurodegenerative diseases; it occurs early and is strongly related to functional deficits. OBJECTIVE: In this longitudinal observational study, we determine the rate at which synaptic density is reduced in the primary tauopathies of progressive supranuclear palsy (PSP) and corticobasal degeneration (CBD), and we test the relationship with disease progression. METHODS: Our cross-sectional cohort included 32 participants with probable PSP and 16 with probable CBD (all amyloid-negative corticobasal syndrome), recruited from tertiary care centers in the United Kingdom, and 33 sex- and age-matched healthy control subjects. Synaptic density was estimated by positron emission tomography imaging with the radioligand [11 C]UCB-J that binds synaptic vesicle 2A. Clinical severity and cognition were assessed by the PSP Rating Scale and the Addenbrooke's cognitive examination. Regional [11 C]UCB-J nondisplaceable binding potential was estimated in Hammersmith Atlas regions of interest. Twenty-two participants with PSP/CBD had a follow-up [11 C]UCB-J positron emission tomography scan after 1 year. We calculated the annualized change in [11 C]UCB-J nondisplaceable binding potential and correlated this with the change in clinical severity. RESULTS: We found significant annual synaptic loss within the frontal lobe (-3.5%, P = 0.03) and the right caudate (-3.9%, P = 0.046). The degree of longitudinal synaptic loss within the frontal lobe correlated with the rate of change in the PSP Rating Scale (R = 0.47, P = 0.03) and cognition (Addenbrooke's Cognitive Examination-Revised, R = -0.62, P = 0.003). CONCLUSIONS: We provide in vivo evidence for rapid progressive synaptic loss, correlating with clinical progression in primary tauopathies. Synaptic loss may be an important therapeutic target and outcome variable for early-phase clinical trials of disease-modifying treatments. © 2023 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society

Technology-assisted stroke rehabilitation in Mexico: a pilot randomized trial comparing traditional therapy to circuit training in a Robot/technology-assisted therapy gym

Background Stroke rehabilitation in low- and middle-income countries, such as Mexico, is often hampered by lack of clinical resources and funding. To provide a cost-effective solution for comprehensive post-stroke rehabilitation that can alleviate the need for one-on-one physical or occupational therapy, in lower and upper extremities, we proposed and implemented a technology-assisted rehabilitation gymnasium in Chihuahua, Mexico. The Gymnasium for Robotic Rehabilitation (Robot Gym) consisted of low- and high-tech systems for upper and lower limb rehabilitation. Our hypothesis is that the Robot Gym can provide a cost- and labor-efficient alternative for post-stroke rehabilitation, while being more or as effective as traditional physical and occupational therapy approaches. Methods A typical group of stroke patients was randomly allocated to an intervention (n = 10) or a control group (n = 10). The intervention group received rehabilitation using the devices in the Robot Gym, whereas the control group (n = 10) received time-matched standard care. All of the study subjects were subjected to 24 two-hour therapy sessions over a period of 6 to 8 weeks. Several clinical assessments tests for upper and lower extremities were used to evaluate motor function pre- and post-intervention. A cost analysis was done to compare the cost effectiveness for both therapies. Results No significant differences were observed when comparing the results of the pre-intervention Mini-mental, Brunnstrom Test, and Geriatric Depression Scale Test, showing that both groups were functionally similar prior to the intervention. Although, both training groups were functionally equivalent, they had a significant age difference. The results of all of the upper extremity tests showed an improvement in function in both groups with no statistically significant differences between the groups. The Fugl-Meyer and the 10 Meters Walk lower extremity tests showed greater improvement in the intervention group compared to the control group. On the Time Up and Go Test, no statistically significant differences were observed pre- and post-intervention when comparing the control and the intervention groups. For the 6 Minute Walk Test, both groups presented a statistically significant difference pre- and post-intervention, showing progress in their performance. The robot gym therapy was more cost-effective than the traditional one-to-one therapy used during this study in that it enabled therapist to train up to 1.5 to 6 times more patients for the approximately same cost in the long term. Conclusions The results of this study showed that the patients that received therapy using the Robot Gym had enhanced functionality in the upper extremity tests similar to patients in the control group. In the lower extremity tests, the intervention patients showed more improvement than those subjected to traditional therapy. These results support that the Robot Gym can be as effective as traditional therapy for stroke patients, presenting a more cost- and labor-efficient option for countries with scarce clinical resources and funding. Trial registration ISRCTN98578807

A phase I trial of the γ-secretase inhibitor MK-0752 in combination with gemcitabine in patients with pancreatic ductal adenocarcinoma.

BACKGROUND: The Notch pathway is frequently activated in cancer. Pathway inhibition by γ-secretase inhibitors has been shown to be effective in pre-clinical models of pancreatic cancer, in combination with gemcitabine. METHODS: A multi-centre, non-randomised Bayesian adaptive design study of MK-0752, administered per os weekly, in combination with gemcitabine administered intravenously on days 1, 8 and 15 (28 day cycle) at 800 or 1000 mg m-2, was performed to determine the safety of combination treatment and the recommended phase 2 dose (RP2D). Secondary and tertiary objectives included tumour response, plasma and tumour MK-0752 concentration, and inhibition of the Notch pathway in hair follicles and tumour. RESULTS: Overall, 44 eligible patients (performance status 0 or 1 with adequate organ function) received gemcitabine and MK-0752 as first or second line treatment for pancreatic cancer. RP2Ds of MK-0752 and gemcitabine as single agents could be combined safely. The Bayesian algorithm allowed further dose escalation, but pharmacokinetic analysis showed no increase in MK-0752 AUC (area under the curve) beyond 1800 mg once weekly. Tumour response evaluation was available in 19 patients; 13 achieved stable disease and 1 patient achieved a confirmed partial response. CONCLUSIONS: Gemcitabine and a γ-secretase inhibitor (MK-0752) can be combined at their full, single-agent RP2Ds

Mutant Mice With Calcium-Sensing Receptor Activation Have Hyperglycemia That Is Rectified by Calcilytic Therapy

The calcium-sensing receptor (CaSR) is a family C G-protein-coupled receptor (GPCR) that plays a pivotal role in extracellular calcium homeostasis. The CaSR is also highly expressed in pancreatic islet α- and β-cells that secrete glucagon and insulin, respectively. To determine whether the CaSR may influence systemic glucose homeostasis, we characterized a mouse model with a germline gain-of-function CaSR mutation, Leu723Gln, referred to as Nuclear flecks (Nuf). Heterozygous- (CasrNuf/+) and homozygous-affected (CasrNuf/Nuf) mice were shown to have hypocalcemia in association with impaired glucose tolerance and insulin secretion. Oral administration of a CaSR antagonist compound, known as a calcilytic, rectified the glucose intolerance and hypoinsulinemia of CasrNuf/+ mice, and ameliorated glucose intolerance in CasrNuf/Nuf mice. Ex vivo studies showed CasrNuf/+ and CasrNuf/Nuf mice to have reduced pancreatic islet mass and β-cell proliferation. Electrophysiological analysis of isolated CasrNuf/Nuf islets showed CaSR activation to increase the basal electrical activity of β-cells independently of effects on the activity of the ATP-sensitive K+ (KATP) channel. CasrNuf/Nuf mice also had impaired glucose-mediated suppression of glucagon secretion, which was associated with increased numbers of α-cells and a higher α-cell proliferation rate. Moreover, CasrNuf/Nuf islet electrophysiology demonstrated an impairment of α-cell membrane depolarization in association with attenuated α-cell basal KATP channel activity. These studies indicate that the CaSR activation impairs glucose tolerance by a combination of α- and β-cell defects and also influences pancreatic islet mass. Moreover, our findings highlight a potential application of targeted CaSR compounds for modulating glucose metabolism

International meta-analysis of PTSD genome-wide association studies identifies sex- and ancestry-specific genetic risk loci.

The risk of posttraumatic stress disorder (PTSD) following trauma is heritable, but robust common variants have yet to be identified. In a multi-ethnic cohort including over 30,000 PTSD cases and 170,000 controls we conduct a genome-wide association study of PTSD. We demonstrate SNP-based heritability estimates of 5-20%, varying by sex. Three genome-wide significant loci are identified, 2 in European and 1 in African-ancestry analyses. Analyses stratified by sex implicate 3 additional loci in men. Along with other novel genes and non-coding RNAs, a Parkinson's disease gene involved in dopamine regulation, PARK2, is associated with PTSD. Finally, we demonstrate that polygenic risk for PTSD is significantly predictive of re-experiencing symptoms in the Million Veteran Program dataset, although specific loci did not replicate. These results demonstrate the role of genetic variation in the biology of risk for PTSD and highlight the necessity of conducting sex-stratified analyses and expanding GWAS beyond European ancestry populations