The effects of the loss of PODPC1 in the regeneration of the zebrafish heart and the characterisation of the PODPC1 null mutant zebrafish

Popeye domain containing 1 (Popdc1) is a member of the POPDC gene family, which code for membrane proteins abundantly expressed in heart and skeletal muscle. They bind cAMP and are thought to function as effector proteins involved in stress signalling. popdc1 null mutant zebrafish have been created using TALENs to cause a premature stop codon resulting in a heavily truncated and non-functional peptide being translated. These mutants survive embryogenesis and larval development and so here I begin to characterise the adults. Popdc1 null mutants displayed abnormal outflow tracts and heart positioning which may cause cardiac stress. It was also observed that cardiomyocyte size is reduced and heart size is increased in mutants, which could result from cardiac remodelling because of stressors such as pressure overload. Moreover, mutants had a thickened cortical layer and reduced trabecular complexity which may lead to improper heart function. Single nuclear RNA sequencing (snRNA-seq) data show a reduction in presumptive trabecular cardiomyocytes and a unique population of hyper-stressed cardiomyocytes which could explain the morphological differences in the mutant. This data also showed popdc1 null mutant cardiomyocytes had abnormalities in genes involved in energy metabolism and cardiac regeneration including fstl1b, tbx5a and runx1. When heart regeneration was tested, mutants displayed reduced regenerative capacity and cardiomyocyte proliferation. Ploidy was also increased in mutant cardiomyocytes, a factor known to hinder cardiomyocyte proliferation. However, this was contrary to the negative regulatory effect that the POPDC proteins have on the proto-oncogene, c-Myc, which would have predicted that the loss of popdc1 would enhance regeneration. Overall, the adult popdc1 null mutant hearts have several morphological phenotypes which are likely caused by or the cause of a hyper-stressed population of cardiomyocytes. High stress along with other factors is also likely to cause the reduced regenerative capacity observed in the mutants.Open Acces

Barriers and facilitators to deprescribing in primary care: a systematic review

Background Managing polypharmacy is a challenge for healthcare systems globally. It is also a health inequality concern as it can expose some of the most vulnerable in society to unnecessary medications and adverse drug-related events. Care for most patients with multimorbidity and polypharmacy occurs in primary care. Safe deprescribing interventions can reduce exposure to inappropriate polypharmacy. However, these are not fully accepted or routinely implemented. Aim To identify barriers and facilitators to safe deprescribing interventions for adults with multimorbidity and polypharmacy in primary care. Design and setting Systematic review of studies published from 2000, examining safe deprescribing interventions for adults with multimorbidity and polypharmacy (PROSPERO: CRD42019121848). Method A search of electronic databases: Medline, Embase, CINHAL, Cochrane and HMIC (26.02.19) using an agreed search strategy; supplemented by handsearching of relevant journals, and screening of reference lists and citations of included studies. Results Forty studies from 14 countries were identified. Cultural and organisational barriers included a culture of diagnosis and prescribing; evidence-based guidance focused on single diseases; a lack of evidence-based guidance for the care of older people with multimorbidities; and a lack of shared communication, decision-making systems, tools and resources. Interpersonal and individual-level barriers included professional etiquette; fragmented care; prescribers’ and patients’ uncertainties; and gaps in tailored support. Facilitators included prudent prescribing; greater availability and acceptability of non-pharmacological alternatives; resources; improved communication, collaboration, knowledge and understanding; patient-centred care; and shared decision-making. Conclusion A whole systems patient-centred approach to safe deprescribing interventions is required, involving key decision-makers, healthcare professionals, patients and carers

Association of Food and Nonalcoholic Beverage Marketing With Children and Adolescents’ Eating Behaviors and Health: A Systematic Review and Meta-analysis

Importance There is widespread interest in the effect of food marketing on children; however, the comprehensive global evidence reviews are now dated. Objective To quantify the association of food and nonalcoholic beverage marketing with behavioral and health outcomes in children and adolescents to inform updated World Health Organization guidelines. Data Sources Twenty-two databases were searched (including MEDLINE, CINAHL, Web of Science, Embase, and The Cochrane Library) with a publication date limit from January 2009 through March 2020. Study Selection Preferred Reporting Items for Systematic Reviews and Meta-Analyses reporting guidelines were followed. Inclusion criteria were primary studies assessing the association of food marketing with specified outcomes in children and adolescents (aged 0-19 years). Exclusion criteria were qualitative studies or those on advertising of infant formula. Of 31 063 articles identified, 96 articles were eligible for inclusion in the systematic review, and 80 articles in the meta-analysis (19 372 participants). Data Extraction and Synthesis Two reviewers independently extracted data. Random-effects models were used for meta-analyses; meta-regressions, sensitivity analyses, and P curve analyses were also performed. Where appropriate, pooling was conducted using combining P values and vote counting by direction of effect. Grading of Recommendations Assessment, Development, and Evaluation was used to judge certainty of evidence. Main Outcomes and Measures Critical outcomes were intake, choice, preference, and purchasing. Important outcomes were purchase requests, dental caries, body weight, and diet-related noncommunicable diseases. Results Participants totaled 19 372 from 80 included articles. Food marketing was associated with significant increases in intake (standardized mean difference [SMD], 0.25; 95% CI, 0.15-0.35; P Output Status: Forthcoming/Available Onlin

Microsatellite Instability Is Associated with the Clinicopathologic Features of Gastric Cancer in Sporadic Gastric Cancer Patients

Purpose: Replication error is an important mechanism in carcinogenesis. The microsatellite instability (MSI-H) of colorectal cancers is associated with the development of multiple cancers. The influence of MSI-H on the development of multiple gastric cancers in sporadic gastric cancer patients has not been defined. This study was performed to reveal the association between the clinicopathologic features and MSI in sporadic gastric cancers. Materials and Methods: Between July 2004 and March 2009, the clinicopathologic characteristics, including MSI status, were evaluated in 128 consecutive patients with sporadic gastric cancers. None of the patients had hereditary non-polyposis colorectal cancer of familial gastric cancer. The markers that were recommended by the NCI to determine the MSI status for colorectal cancers were used. Results: MSI-H cancers were found in 10.9% of the patients (14/128). Synchronous gastric cancers were shown in 4 patients (3.1%). Synchronous cancers were found in 2 of 14 patients with MSI-H gastric cancer (14.3%) and 2 of 114 patients with MSS gastric cancer (1.8%; P=0.059, Fisher's exact test). Among the patients with synchronous cancer 50% (2/4) had MSI-H cancer, but 9.7% of the patients (12/124) without synchronous cancer had MSI-H cancer. MSI-H (RR, 24.7; 95% CI, 1.5~398.9; P=0.024) was related with to synchronous gastric cancer, but age, gender, family history, histologic type, location, gross morphology, size, and stage were not related to synchronous gastric cancer. Conclusions: MSI is associated with the intestinal-type gastric cancer and the presence of multiple gastric cancers in patients with sporadic gastric cancer. Special attention to the presence of synchronous and the development of metachronous multiple cancer in patients with MSI-H gastric cancer is needed. ?? 2010 by The Korean Gastric Cancer Association

Acetyl-leucine slows disease progression in lysosomal storage disorders

Acetyl-DL-leucine is a derivative of the branched chain amino acid leucine. In observational clinical studies acetyl-DL-leucine improved symptoms of ataxia, in particular in patients with the lysosomal storage disorder, Niemann-Pick disease type C1. Here, we investigated acetyl-DL-leucine and its enantiomers acetyl-L-leucine and acetyl-D-leucine in symptomatic Npc1-/- mice and observed improvement in ataxia with both individual enantiomers and acetyl-DL-leucine. When acetyl-DL-leucine and acetyl-L-leucine were administered pre-symptomatically to Npc1-/- mice, both treatments delayed disease progression and extended life span, whereas acetyl-D-leucine did not. These data are consistent with acetyl-L-leucine being the neuroprotective enantiomer. Altered glucose and antioxidant metabolism were implicated as one of the potential mechanisms of action of the L enantiomer in Npc1-/- mice. When the standard of care drug miglustat and acetyl-DL-leucine were used in combination significant synergy resulted. In agreement with these pre-clinical data, when Niemann-Pick disease type C1 patients were evaluated after 12 months of acetyl-DL-leucine treatment, rates of disease progression were slowed, with stabilisation or improvement in multiple neurological domains. A beneficial effect of acetyl-DL-leucine on gait was also observed in this study in a mouse model of GM2 gangliosidosis (Sandhoff disease) and in Tay-Sachs and Sandhoff disease patients in individual cases of off-label-use. Taken together, we have identified an unanticipated neuroprotective effect of acetyl-L-leucine and underlying mechanisms of action in lysosomal storage diseases, supporting its further evaluation in clinical trials in lysosomal disorders

Formation Flying and Change Detection for the UNSW Canberra Space ‘M2’ Low Earth Orbit Formation Flying CubeSat Mission

The University of New South Wales, Canberra (UNSW Canberra) embarked on an ambitious CubeSatellite research, development, and education program in 2017 through funding provided by the Royal Australian Air Force (RAAF). The program consisted of M1 (Mission 1), M2 Pathfinder, and concludes with the formation flying mission M2. M2 is the final mission comprising two 6U CubeSatellites flying in formation using differential aerodynamic drag control. The M2 satellites were launched in a conjoined 12U form factor on RocketLab’s ‘They Go Up So Fast’ launch in March 2021. On 10th September 2021 the spacecraft divided into two 6U CubeSats (M2-A and M2-B) under the action of a small spring force in their near-circular 550km, 45-degree inclination orbit. The formation is controlled by varying the spacecrafts’ attitude, which creates a large variation in the aerodynamic drag force due to the change in the cross-sectional area from the large, double-deployable, solar arrays located on the zenith face of the spacecraft. This paper presents the outcomes of the Formation Flying and Change Detection primary mission objectives for the mission. The results are generated by collecting and analysing optical and RF (Radio Frequency) space domain awareness sensor data from the ground and validating them against GPS (Global Positioning System) and attitude data downlinked from the spacecraft. The outcomes of the broader mission objectives, which include increasing the Technology Readiness Level for a suite of intelligent on-board optical and RF sensor technologies, will be presented in subsequent publications. The results presented here comprise two major campaigns: 1.) The spacecraft separation campaign when the original 12U form factor deployed following launch split in half to form the M2-A and M2-B satellites, and 2) the demonstration of active formation control of the spacecraft via differential aerodynamic drag. M2-A and M2-B underwent several major configuration changes during the spacecraft separation campaign. The results from ground-based sensors detecting the 12U spacecraft separating into two distinct (6U) objects are presented. The effect of the double-deployable solar arrays deployment on the relative orbital motion of the M2-A and M2-B spacecraft is illustrated and compared to data from optical and RF ground-based measurements taken during this window. The formation control campaign involved actively controlling the spacecraft via differential aerodynamic drag in order to significantly alter the separation distance. The mission demonstrated the capability to switch the leading spacecraft’s position between M2-A and M2-B and to actively control separation distance ranging from 130km down to 1km. Formation control is achieved via open-loop, pre-scheduled, commands issued from the UNSW Canberra Space ground station. A two-stage modelling and simulation process is used to derive the scheduled attitude states. Firstly, a batch least squares orbit determination algorithm is applied to GPS data from a steady-state differential drag actuation period (where one spacecraft is in maximum drag and the other in its minimum drag attitude configuration). The batch least squares orbit determination is conducted out using the NASA General Mission Analysis Tool (GMAT), resulting in precise state estimates for each spacecraft and drag coefficient (Cd) estimates for both the maximum and minimum drag configurations. Predictions of trajectory for various attitude profiles can be produced by tailoring the spacecraft’s drag coefficients between the maximum and minimum values generated by the batch least squares state estimation process. Ground-based optical and RF space domain awareness (SDA) sensor measurements collected during the manoeuvre campaign are compared to the spacecraft’s GPS and attitude telemetry data. The SDA sensors are actively seeking to detect changes in the separation distance between the spacecraft. Initial results from an investigation into whether changes observed in photometric light curve signatures can signal the commencement of a differential drag manoeuvre are presented

Nature vs. Nurture: Defining the Effects of Mesenchymal Stromal Cell Isolation and Culture Conditions on Resiliency to Palmitate Challenge

As MSC products move from early development to clinical translation, culture conditions shift from xeno- to xeno-free systems. However, the impact of isolation and culture-expansion methods on the long-term resiliency of MSCs within challenging transplant environments is not fully understood. Recent work in our lab has shown that palmitate, a saturated fatty acid elevated in the serum of patients with obesity, causes MSCs to convert from an immunosuppressive to an immunostimulatory state at moderate to high physiological levels. This demonstrated that metabolically-diseased environments, like obesity, alter the immunomodulatory efficacy of healthy donor MSCs. In addition, it highlighted the need to test MSC efficacy not only in ideal conditions, but within challenging metabolic environments. To determine how the choice of xeno- vs. xeno-free media during isolation and expansion would affect future immunosuppressive function, umbilical cord explants from seven donors were subdivided and cultured within xeno- (fetal bovine serum, FBS) or xeno-free (human platelet lysate, PLT) medias, creating 14 distinct MSC preparations. After isolation and primary expansion, umbilical cord MSCs (ucMSC) were evaluated according to the ISCT minimal criteria for MSCs. Following baseline characterization, ucMSC were exposed to physiological doses of palmitate and analyzed for metabolic health, apoptotic induction, and immunomodulatory potency in co-cultures with stimulated human peripheral blood mononuclear cells. The paired experimental design (each ucMSC donor grown in two distinct culture environments) allowed us to delineate the contribution of inherent (nature) vs. environmentally-driven (nurture) donor characteristics to the phenotypic response of ucMSC during palmitate exposure. Culturing MSCs in PLT-media led to more consistent growth characteristics during the isolation and expansion for all donors, resulting in faster doubling times and higher cell yields compared to FBS. Upon palmitate challenge, PLT-ucMSCs showed a higher susceptibility to palmitate-induced metabolic disturbance, but less susceptibility to palmitate-induced apoptosis. Most striking however, was that the PLT-ucMSCs resisted the conversion to an immunostimulatory phenotype better than their FBS counterparts. Interestingly, examining MSC suppression of PBMC proliferation at physiologic doses of palmitate magnified the differences between donors, highlighting the utility of evaluating MSC products in stress-based assays that reflect the challenges MSCs may encounter post-transplantation

The CXCL16-CXCR6 axis in glioblastoma modulates T-cell activity in a spatiotemporal context

IntroductionGlioblastoma multiforme (GBM) pathobiology is characterized by its significant induction of immunosuppression within the tumor microenvironment, predominantly mediated by immunosuppressive tumor-associated myeloid cells (TAMCs). Myeloid cells play a pivotal role in shaping the GBM microenvironment and influencing immune responses, with direct interactions with effector immune cells critically impacting these processes.MethodsOur study investigates the role of the CXCR6/CXCL16 axis in T-cell myeloid interactions within GBM tissues. We examined the surface expression of CXCL16, revealing its limitation to TAMCs, while microglia release CXCL16 as a cytokine. The study explores how these distinct expression patterns affect T-cell engagement, focusing on the consequences for T-cell function within the tumor environment. Additionally, we assessed the significance of CXCR6 expression in T-cell activation and the initial migration to tumor tissues.ResultsOur data demonstrates that CXCL16 surface expression on TAMCs results in predominant T-cell engagement with these cells, leading to impaired T-cell function within the tumor environment. Conversely, our findings highlight the essential role of CXCR6 expression in facilitating T-cell activation and initial migration to tumor tissues. The CXCL16-CXCR6 axis exhibits dualistic characteristics, facilitating the early stages of the T-cell immune response and promoting T-cell infiltration into tumors. However, once inside the tumor, this axis contributes to immunosuppression.DiscussionThe dual nature of the CXCL16-CXCR6 axis underscores its potential as a therapeutic target in GBM. However, our results emphasize the importance of carefully considering the timing and context of intervention. While targeting this axis holds promise in combating GBM, the complex interplay between TAMCs, microglia, and T cells suggests that intervention strategies need to be tailored to optimize the balance between promoting antitumor immunity and preventing immunosuppression within the dynamic tumor microenvironment

Associations between sleep disturbance, cognitive functioning and work disability in Bipolar Disorder

Bipolar Disorder (BD) is associated with impairment in a number of areas including poor work functioning, often despite the remission of mood symptoms. The present study aimed to examine the role of sleep disturbance and cognitive functioning in occupational impairment in BD. Twenty-four euthymic BD participants and 24 healthy control participants completed a week of prospective assessment of sleep disruption via self-report and actigraphy, a battery of neuropsychological tests of executive functioning, working memory, and verbal learning, and assessments of work functioning. BD participants experienced significantly poorer cognitive functioning as well as greater months of unemployment and greater incidence of being fired than controls. Moderation analyses revealed that both poor sleep and cognitive functioning were associated with poor work performance in BD participants, but not control participants. Sleep and cognitive functioning may be impaired in euthymic BD and are associated with poor work functioning in this population. More research should be conducted to better understand how sleep and cognitive functioning may interact in BD