A Systematic Review and Meta-Analysis of the Management of Gallstone Cholecystitis and Common Biliary Duct Stones to Reduce the Incidence of Complications in Elderly Patients.

As the age increases particularly above the age of 50 years, there is a significantly higher risk of developing gallstone-related complications especially cholecystitis and common bile duct stones with its associated consequences. Complications that arise after surgical operations for cholecystitis have been reported to have negative impacts on senior patients. These effects include a higher rate of complications, a longer hospital stay, higher expenditures, and decreased patient satisfaction. Therefore, finding the most effective treatment for cholecystitis in older patients is still a challenge. The aim of the study was carried out in order to identify many approaches that can be taken in the treatment of cholecystitis and stones in the common bile duct in older patients. A search was conducted through Medline (PubMed), EMBASE, ProQuest, and Cochrane using relevant Medical Subject Heading (MeSH) terms and keywords (elderly, age over 50, cholecystitis, bile duct stones, cholecystectomy, ERCP, surgical, conservative management, and open). The searches were limited to studies on elderly individuals over 50 who had cholecystectomy and endoscopic retrograde cholangiopancreatography between January 2000 and December 2022. The meta-analysis used the Mantel-Haenszel odds ratio (MHOR) and 95% confidence interval (CI). Aries Systems Corporation's Editorial Manager® (Aries Systems Corporation, North Andover, USA) and ProduXion Manager® (Aries Systems Corporation, North Andover, USA) facilitated the study. Out of 102 citations, 39 studies were selected for further study. After that, 18 studies were eliminated, leaving 21 for meta-analysis. The study found a protective risk of cholecystitis in cholecystectomy patients (MHOR = 0.16; 95%, CI = 0.10 to 0.25; p 0.001). Developing cholecystitis was substantially lower in early cholecystectomy patients (MHOR = 0.16; 95%, CI = 0.10 to 0.25; p 0.001). There was no significant difference in cholecystitis risk between open and laparoscopic surgery (MHOR = 0.65; 95%, CI = 0.41 to 1.04; p 0.07). Cholecystectomy performed at an earlier stage protects elderly patients from developing recurrent cholecystitis. In contrast to late cholecystitis, in which the patient would experience several attacks of cholecystitis, early cholecystectomy protects against the recurrence of the condition.

Monitoring of Curing Process of Epoxy Resin by Long-Period Fiber Gratings.

The curing of epoxy resin is a complex thermo-chemical process that is difficult to monitor using existing sensing systems. We monitored the curing process of an epoxy resin by using long-period fiber gratings. The refractive index of the epoxy resin increases during the curing process and can be measured to determine the degree of curing. We employed long-period fiber gratings that are sensitive to the refractive index of an external medium for the measurement of refractive index changes in the resin. We observed that the resonances of long-period fiber gratings increased their depth with the increased refractive index of the resin, which was well described by our simulation taking the coupling to radiation modes into account. We demonstrated that the degree of cure can be estimated from the depth of the grating resonances using a phenomenological model. At the same time, long-period fiber gratings are sensitive to temperature variations and internal strains that are induced during curing. These factors may affect the measurements of curing degree and should also be addressed.

SIK1 Downregulates Synaptic AMPA Receptors and Contributes to Cognitive Defects in Alzheimer's Disease.

A reduction in AMPA receptor (AMPAR) expression and weakened synaptic activity is early cellular phenotypes in Alzheimer's disease (AD). However, the molecular processes leading to AMPAR downregulation are complex and remain less clear. Here, we report that the salt inducible kinase SIK1 interacts with AMPARs, leading to a reduced accumulation of AMPARs at synapses. SIK1 protein level is sensitive to amyloid beta (Aß) and shows a marked increase in the presence of Aß and in AD brains. In neurons, Aß incubation causes redistribution of SIK1 to synaptic sites and enhances SIK1-GluA1 association. SIK1 function is required for Aß-induced AMPAR reduction. Importantly, in 3xTG AD mice, knockdown of SIK1 in the brain leads to restoration of AMPAR expression and a rescue of the cognitive deficits. These findings indicate an important role for SIK1 in meditating the cellular and functional pathology in AD.

Impact of a diabetes-designed meal delivery service on changes in hemoglobin A1c and quality of life in patients with diabetes.

BACKGROUND: Over 34 million Americans have diabetes, and nutrition therapy is essential in self-management. AIMS: The primary aim of the study was to evaluate the impact of meals designed for patients with type 2 diabetes (T2D) through a meal delivery program. The primary outcome was a 3-month change in hemoglobin A1c (HbA1c). Secondary outcomes included a 3-month change in weight, blood pressure, high-density lipoprotein, low-density lipoprotein, and triglycerides. Furthermore, the study aimed to evaluate the impact of the meal delivery program on the participants' quality of life. METHODS: In this randomized crossover clinical trial, patients were allocated in a 1:1 fashion to treatment sequence AB or treatment sequence BA. In Phase 1, participants allocated to sequence AB received 10 meals per week for 3 months, followed by a 3-month washout period and a 3-month standard intervention period with no meals. Participants allocated to sequence BA received 3 months of standard intervention with no meals followed by a 3-month washout period and a 3-month period with 10 meals per week. A quality-of-life survey was obtained during weeks 0, 12, 24, and 36. RESULTS: The mean 3-month change in HbA1c (primary outcome) was nearly a half point lower with meal delivery (-0.44% [95% CI: -0.85%, -0.03%]; P = 0.037). The estimated mean 3-month change in quality of life was approximately 2 points lower (better) with meal delivery (-2.2 points [95% CI: -4.2, -0.3]; P = .027). There were no statistically significant differences in secondary outcomes with meal delivery (all P ≥ 0.15). CONCLUSIONS: A meal delivery system for patients with T2D improves glycemic control and quality of life.

Naked mole-rats have distinctive cardiometabolic and genetic adaptations to their underground low-oxygen lifestyles.

The naked mole-rat Heterocephalus glaber is a eusocial mammal exhibiting extreme longevity (37-year lifespan), extraordinary resistance to hypoxia and absence of cardiovascular disease. To identify the mechanisms behind these exceptional traits, metabolomics and RNAseq of cardiac tissue from naked mole-rats was compared to other African mole-rat genera (Cape, Cape dune, Common, Natal, Mahali, Highveld and Damaraland mole-rats) and evolutionarily divergent mammals (Hottentot golden mole and C57/BL6 mouse). We identify metabolic and genetic adaptations unique to naked mole-rats including elevated glycogen, thus enabling glycolytic ATP generation during cardiac ischemia. Elevated normoxic expression of HIF-1α is observed while downstream hypoxia responsive-genes are down-regulated, suggesting adaptation to low oxygen environments. Naked mole-rat hearts show reduced succinate levels during ischemia compared to C57/BL6 mouse and negligible tissue damage following ischemia-reperfusion injury. These evolutionary traits reflect adaptation to a unique hypoxic and eusocial lifestyle that collectively may contribute to their longevity and health span.

Health-Analytics Data to Evidence Suite (HADES): Open-Source Software for Observational Research.

The Health-Analytics Data to Evidence Suite (HADES) is an open-source software collection developed by Observational Health Data Sciences and Informatics (OHDSI). It executes directly against healthcare data such as electronic health records and administrative claims, that have been converted to the Observational Medical Outcomes Partnership (OMOP) Common Data Model. Using advanced analytics, HADES performs characterization, population-level causal effect estimation, and patient-level prediction, potentially across a federated data network, allowing patient-level data to remain locally while only aggregated statistics are shared. Designed to run across a wide array of technical environments, including different operating systems and database platforms, HADES uses continuous integration with a large set of unit tests to maintain reliability. HADES implements OHDSI best practices, and is used in almost all published OHDSI studies, including some that have directly informed regulatory decisions.

A comprehensive clinically informed map of dependencies in cancer cells and framework for target prioritization.

Genetic screens in cancer cell lines inform gene function and drug discovery. More comprehensive screen datasets with multi-omics data are needed to enhance opportunities to functionally map genetic vulnerabilities. Here, we construct a second-generation map of cancer dependencies by annotating 930 cancer cell lines with multi-omic data and analyze relationships between molecular markers and cancer dependencies derived from CRISPR-Cas9 screens. We identify dependency-associated gene expression markers beyond driver genes, and observe many gene addiction relationships driven by gain of function rather than synthetic lethal effects. By combining clinically informed dependency-marker associations with protein-protein interaction networks, we identify 370 anti-cancer priority targets for 27 cancer types, many of which have network-based evidence of a functional link with a marker in a cancer type. Mapping these targets to sequenced tumor cohorts identifies tractable targets in different cancer types. This target prioritization map enhances understanding of gene dependencies and identifies candidate anti-cancer targets for drug development.

Vulnerability to climate change of United States marine mammal stocks in the western North Atlantic, Gulf of Mexico, and Caribbean.

Climate change and climate variability are affecting marine mammal species and these impacts are projected to continue in the coming decades. Vulnerability assessments provide a framework for evaluating climate impacts over a broad range of species using currently available information. We conducted a trait-based climate vulnerability assessment using expert elicitation for 108 marine mammal stocks and stock groups in the western North Atlantic, Gulf of Mexico, and Caribbean Sea. Our approach combined the exposure (projected change in environmental conditions) and sensitivity (ability to tolerate and adapt to changing conditions) of marine mammal stocks to estimate vulnerability to climate change, and categorize stocks with a vulnerability index. The climate vulnerability score was very high for 44% (n = 47) of these stocks, high for 29% (n = 31), moderate for 20% (n = 22), and low for 7% (n = 8). The majority of stocks (n = 78; 72%) scored very high exposure, whereas 24% (n = 26) scored high, and 4% (n = 4) scored moderate. The sensitivity score was very high for 33% (n = 36) of these stocks, high for 18% (n = 19), moderate for 34% (n = 37), and low for 15% (n = 16). Vulnerability results were summarized for stocks in five taxonomic groups: pinnipeds (n = 4; 25% high, 75% moderate), mysticetes (n = 7; 29% very high, 57% high, 14% moderate), ziphiids (n = 8; 13% very high, 50% high, 38% moderate), delphinids (n = 84; 52% very high, 23% high, 15% moderate, 10% low), and other odontocetes (n = 5; 60% high, 40% moderate). Factors including temperature, ocean pH, and dissolved oxygen were the primary drivers of high climate exposure, with effects mediated through prey and habitat parameters. We quantified sources of uncertainty by bootstrapping vulnerability scores, conducting leave-one-out analyses of individual attributes and individual scorers, and through scoring data quality for each attribute. These results provide information for researchers, managers, and the public on marine mammal responses to climate change to enhance the development of more effective marine mammal management, restoration, and conservation activities that address current and future environmental variation and biological responses due to climate change.

Reproducible variability: assessing investigator discordance across 9 research teams attempting to reproduce the same observational study.

OBJECTIVE: Observational studies can impact patient care but must be robust and reproducible. Nonreproducibility is primarily caused by unclear reporting of design choices and analytic procedures. This study aimed to: (1) assess how the study logic described in an observational study could be interpreted by independent researchers and (2) quantify the impact of interpretations' variability on patient characteristics. MATERIALS AND METHODS: Nine teams of highly qualified researchers reproduced a cohort from a study by Albogami et al. The teams were provided the clinical codes and access to the tools to create cohort definitions such that the only variable part was their logic choices. We executed teams' cohort definitions against the database and compared the number of subjects, patient overlap, and patient characteristics. RESULTS: On average, the teams' interpretations fully aligned with the master implementation in 4 out of 10 inclusion criteria with at least 4 deviations per team. Cohorts' size varied from one-third of the master cohort size to 10 times the cohort size (2159-63 619 subjects compared to 6196 subjects). Median agreement was 9.4% (interquartile range 15.3-16.2%). The teams' cohorts significantly differed from the master implementation by at least 2 baseline characteristics, and most of the teams differed by at least 5. CONCLUSIONS: Independent research teams attempting to reproduce the study based on its free-text description alone produce different implementations that vary in the population size and composition. Sharing analytical code supported by a common data model and open-source tools allows reproducing a study unambiguously thereby preserving initial design choices.

The von Willebrand factor-binding aptamer rondaptivon pegol as a treatment for severe and nonsevere hemophilia A.

Factor VIII (FVIII) circulates in a noncovalent complex with von Willebrand Factor (VWF), the latter determining FVIII half-life. The VWF-binding aptamer rondaptivon pegol (BT200) increases plasma levels of VWF/FVIII in healthy volunteers. This trial assessed its safety, pharmacokinetics, and pharmacodynamics in hemophilia A. Nineteen adult patients (ages 20-62 years, 4 women) with hemophilia A (8 mild, 2 moderate, and 9 severe) received subcutaneous injections of rondaptivon pegol. After an initial fixed dose of 3 mg on days 0 and 4, patients received weekly doses of 2 to 9 mg until day 28. Severe hemophilia A patients underwent sparse-sampling population pharmacokinetics individual profiling after the final dose of rondaptivon pegol. Adverse events, pharmacokinetics, and pharmacodynamics were assessed. FVIII activity and VWF levels were measured. All patients tolerated rondaptivon pegol well. The geometric mean half-life of rondaptivon pegol was 5.4 days and rondaptivon pegol significantly increased VWF levels. In severe hemophilia A, 6 doses of rondaptivon pegol increased the half-lives of 5 different FVIII products from a median of 10.4 hours to 31.1 hours (range, 20.8-56.0 hours). Median FVIII increased from 22% to 48% in mild hemophilia A and from 3% to 7.5% in moderate hemophilia A. Rondaptivon pegol is a first-in-class prohemostatic molecule that extended the half-life of substituted FVIII approximately 3-fold and increased endogenous FVIII levels approximately 2-fold in hemophilia patients. This trial was registered at www.clinicaltrials.gov as #NCT04677803.

Exploring the Promise of Multifunctional "Zintl-Phase-Forming" Electrolytes for Si-Based Full Cells.

Li-M-Si ternary Zintl phases have gained attention recently due to their high structural stability, which can improve the cycling stability compared to a bulk Si electrode. Adding multivalent cation salts (such as Mg2+ and Ca2+) in the electrolyte was proven to be a simple way to form Li-M-Si ternary phases in situ in Si-based Li-ion cells. To explore the promise of Zintl-phase-forming electrolytes, we systematically investigated their application in pouch cells via electrochemical and multiscale postmortem analysis. The introduction of multivalent cations, such as Mg2+, during charging can form LixMySi ternary phases. They can stabilize Si anions and reduce side reactions with electrolyte, improving the bulk stability. More importantly, Mg2+ and Ca2+ incorporate into interfacial side reactions and generate inorganic-rich solid-electrolyte interphase, thus enhancing the interfacial stability. Therefore, the full cells with Zintl-phase-forming electrolytes achieve higher capacity retentions at the C/3 rate after 100 cycles, compared to a baseline electrolyte. Additionally, strategies for mitigating the electrode-level fractures of Si were evaluated to make the best use of Zintl-phase-forming electrolytes. This work highlights the significance of synergistic impact of multifunctional additives to stabilize both bulk and interface chemistry in high-energy Si anode materials for Li-ion batteries.

Island Hopping through Urban Filters: Anthropogenic Habitats and Colonized Landscapes Alter Morphological and Performance Traits of an Invasive Amphibian.

A prominent feature of the modern era is the increasing spread of invasive species, particularly within island and urban ecosystems, and these occurrences provide valuable natural experiments by which evolutionary and invasion hypotheses can be tested. In this study, we used the invasion route of guttural toads (Sclerophrys gutturalis) from natural-native and urban-native populations (Durban, South Africa) to their urban-invasive and natural-invasive populations (Mauritius and Réunion) to determine whether phenotypic changes that arose once the toads became urbanized in their native range have increased their invasive potential before they were transported (i.e., prior adaptation) or whether the observed changes are unique to the invasive populations. This urban/natural by native/invasive gradient allowed us to examine differences in guttural toad morphology (i.e., body size, hindlimb, and hindfoot length) and performance capacity (i.e., escape speed, endurance, and climbing ability) along their invasion route. Our findings indicate that invasive island populations have reduced body sizes, shorter limbs in relation to snout-vent length, decreased escape speeds, and decreased endurance capacities that are distinct from the native mainland populations (i.e., invasion-derived change). Thus, these characteristics did not likely arise directly from a pre-transport anthropogenic "filter" (i.e., urban-derived change). Climbing ability, however, did appear to originate within the urban-native range and was maintained within the invasive populations, thereby suggesting it may have been a prior adaptation that provided this species with an advantage during its establishment in urban areas and spread into natural forests. We discuss how this shift in climbing performance may be ecologically related to the success of urban and invasive guttural toad populations, as well as how it may have impacted other island-derived morphological and performance phenotypes.

Revealing Unknown Benefits of Existing Medications to Aid the Discovery of New Treatments for Post-Traumatic Stress Disorder.

Objective: To systematically identify novel pharmacological strategies for preventing or treating post-traumatic stress disorder (PTSD) by leveraging large-scale analysis of real-world observational data. Methods: Using a self-controlled study design, the association between 1399 medications and the incidence of PTSD across four US insurance claims databases covering commercially insured, Medicare eligible, and Medicaid patients was examined. A validated algorithm for identifying PTSD in claims data was used, and medications were identified by their RxNorm ingredient. Medications used to treat PTSD or its symptoms (e.g., antidepressants, antipsychotics) were excluded. Medications associated with ≥30% reduction in risk of PTSD in ≥2 databases were identified. Results: A total of 137,182,179 individuals were included in the analysis. Fifteen medications met the threshold criteria for a potential protective effect on PTSD; six were categorized as "primary signals" while the remaining nine were considered "potential signals". The primary signals include a beta blocker that has been previously studied for PTSD, and five medications used to treat attention-deficit/hyperactivity disorder. The potential signals include four medications used to treat substance use disorders and five medications used to treat sleep disorders. Discussion: The medications identified in this analysis provide targets for further research in studies that are designed to examine specific hypotheses regarding these medications and the incidence of PTSD. This work may aid in discovering novel therapeutic approaches to treat PTSD, wherein new and effective treatments are badly needed.

PK-modifying anchors significantly alter clearance kinetics, tissue distribution, and efficacy of therapeutics siRNAs.

Effective systemic delivery of small interfering RNAs (siRNAs) to tissues other than liver remains a challenge. siRNAs are small (∼15 kDa) and therefore rapidly cleared by the kidneys, resulting in limited blood residence times and tissue exposure. Current strategies to improve the unfavorable pharmacokinetic (PK) properties of siRNAs rely on enhancing binding to serum proteins through extensive phosphorothioate modifications or by conjugation of targeting ligands. Here, we describe an alternative strategy for enhancing blood and tissue PK based on dynamic modulation of the overall size of the siRNA. We engineered a high-affinity universal oligonucleotide anchor conjugated to a high-molecular-weight moiety, which binds to the 3' end of the guide strand of an asymmetric siRNA. Data showed a strong correlation between the size of the PK-modifying anchor and clearance kinetics. Large 40-kDa PK-modifying anchors reduced renal clearance by ∼23-fold and improved tissue exposure area under the curve (AUC) by ∼26-fold, resulting in increased extrahepatic tissue retention (∼3- to 5-fold). Furthermore, PK-modifying oligonucleotide anchors allowed for straightforward and versatile modulation of blood residence times and biodistribution of a panel of chemically distinct ligands. The effects were more pronounced for conjugates with low lipophilicity (e.g., N-Acetylgalactosamine [GalNAc]), where significant improvement in uptake by hepatocytes and dose-dependent silencing in the liver was observed.

Impact of substance use disorders on employment for veterans.

Approximately 1.1 million veterans meet criteria for substance use disorders (SUDs) with 1 in 4 struggling with illicit drugs, 4 in 5 struggling with alcohol use, and 1 in 13 struggling with both. The purpose of this study was to examine the impact of SUDs on closure status (exiting with employment, did not exit with employment) for veterans served in a Department of Veterans Affairs' Veterans Health Administration (VHA) vocational rehabilitation (VR) program. Data (N = 2,620) from a VHA VR program in the Veterans Integrated Service Network 12 network were obtained for the purpose of the present study and consisted of veterans enrolled from 2012 to 2018. Findings showed that veterans without SUDs were more likely to exit with employment, and veterans enrolled in transitional work and community-based employment were more likely to exit with employment compared to those within supported employment (SE). Given that SE helps to serve veterans with the most severe psychological or medical conditions (e.g., active psychosis, schizophrenia, bipolar disorder, spinal cord injury, traumatic brain injury), findings suggest veterans are more successful with less serious mental health conditions. (PsycInfo Database Record (c) 2023 APA, all rights reserved).

The VWF binding aptamer rondoraptivon pegol increases platelet counts and VWF/FVIII in type 2B von Willebrand disease.

Type 2B von Willebrand disease (VWD) is characterized by an increased binding affinity of von Willebrand factor (VWF) to platelet glycoprotein Ib. This can lead to clearance of high-molecular-weight (HMW) multimers and thrombocytopenia with a resulting moderate-severe bleeding phenotype. Rondoraptivon pegol (BT200) is a pegylated aptamer binding to the A1 domain of VWF with a novel mechanism of action: it enhances VWF/factor VIII (FVIII) levels by decreasing their clearance. To study the potential benefit of rondoraptivon pegol in patients with type 2B VWD, we conducted a prospective phase 2 trial. Patients with type 2B VWD received 3 mg rondoraptivon pegol subcutaneously on study days 1, 4, and 7, followed by 6 to 9 mg every week until day 28. Five patients (male:female ratio = 3:2) were included. Rondoraptivon pegol rapidly tripled platelet counts from a median of 60 to 179 × 10E9/L (P < .001). Circulating VWF antigen increased from a median of 64% to 143%, which doubled FVIII activity levels from 67% to 134%. In all thrombocytopenic patients, plasma levels of VWF:GPIbM normalized, VWF ristocetin cofactor and VWF collagen-binding activity increased, and HMW multimers appeared. These pronounced improvements reversed during washout of the drug, thus demonstrating causality. The A1 domain binding aptamer directly corrects the underlying defect of type 2B VWD, thus providing a novel potential option for prophylaxis and treatment of patients with this VWD type. These data provide the basis for a phase 2b/3 trial in such patients. This trial was registered at www.clinicaltrials.gov as #NCT04677803.

Longitudinal EEG model detects antisense oligonucleotide treatment effect and increased UBE3A in Angelman syndrome.

Angelman syndrome is a neurodevelopmental disorder caused by deficiency of the maternally inherited UBE3A gene in neurons. Antisense oligonucleotide therapies are under development to reinstate UBE3A protein production. Non-invasive biomarkers to detect target engagement and treatment response are needed to support clinical trials. Delta power measured in the scalp EEG is a reliable biomarker for Angelman syndrome but varies widely across individuals and throughout development, making detection of a treatment effect using single measurements challenging. We utilized a longitudinal dataset of 204 EEG recordings from 56 subjects with Angelman syndrome to develop a natural history model of delta (2-4 Hz) power, with predictors of age, elapsed time, and relative delta power at an initial recording. Using this model, we computed the sample and effect sizes needed to detect a treatment effect in a human clinical trial with 80% power. We applied the same model structure to a mouse model of Angelman syndrome (n = 41) to detect antisense oligonucleotide-mediated treatment effects on absolute delta activity and Ube3a expression. In humans, delta power at a second time point can be reliably predicted using the natural history model. In mice, a treatment effect can be detected after antisense oligonucleotide treatment targeting the Ube3a-antisense transcript through at least 8 weeks post-treatment (P < 1e-15). Deviations in delta power from the expected natural history correlated with Ube3a expression in the mouse model (P < 0.001). Deviations in delta power from a human natural history model in Angelman syndrome can detect antisense oligonucleotide-mediated improvement in Ube3a expression in Angelman syndrome mice and may be relevant for human clinical trials.

A genome-scale metabolic model of Cupriavidus necator H16 integrated with TraDIS and transcriptomic data reveals metabolic insights for biotechnological applications.

Exploiting biological processes to recycle renewable carbon into high value platform chemicals provides a sustainable and greener alternative to current reliance on petrochemicals. In this regard Cupriavidus necator H16 represents a particularly promising microbial chassis due to its ability to grow on a wide range of low-cost feedstocks, including the waste gas carbon dioxide, whilst also naturally producing large quantities of polyhydroxybutyrate (PHB) during nutrient-limited conditions. Understanding the complex metabolic behaviour of this bacterium is a prerequisite for the design of successful engineering strategies for optimising product yields. We present a genome-scale metabolic model (GSM) of C. necator H16 (denoted iCN1361), which is directly constructed from the BioCyc database to improve the readability and reusability of the model. After the initial automated construction, we have performed extensive curation and both theoretical and experimental validation. By carrying out a genome-wide essentiality screening using a Transposon-directed Insertion site Sequencing (TraDIS) approach, we showed that the model could predict gene knockout phenotypes with a high level of accuracy. Importantly, we indicate how experimental and computational predictions can be used to improve model structure and, thus, model accuracy as well as to evaluate potential false positives identified in the experiments. Finally, by integrating transcriptomics data with iCN1361 we create a condition-specific model, which, importantly, better reflects PHB production in C. necator H16. Observed changes in the omics data and in-silico-estimated alterations in fluxes were then used to predict the regulatory control of key cellular processes. The results presented demonstrate that iCN1361 is a valuable tool for unravelling the system-level metabolic behaviour of C. necator H16 and can provide useful insights for designing metabolic engineering strategies.

The elusive role of prolactin in the sociality of the naked mole-rat.

Despite decades of research into the evolutionary drivers of sociality, we know relatively little about the underlying proximate mechanisms. Here we investigate the potential role of prolactin in the highly social naked mole-rat. Naked mole-rats live in large social groups but, only a small number of individuals reproduce. The remaining non-breeders are reproductively suppressed and contribute to burrow maintenance, foraging, and allo-parental care. Prolactin has well-documented links with reproductive timing and parental behaviour, and the discovery that non-breeding naked mole-rats have unusually high prolactin levels has led to the suggestion that prolactin may help maintain naked mole-rat sociality. To test this idea, we investigated whether urinary prolactin was correlated with cooperative behaviour and aggression. We then administered the prolactin-suppressing drug Cabergoline to eight female non-breeders for eight weeks and assessed the physiology and behaviour of the animals relative to controls. Contrary to the mammalian norm, and supporting previous findings for plasma, we found non-breeders had elevated urinary prolactin concentrations that were similar to breeding females. Further, prolactin levels were higher in heavier, socially dominant non-breeders. Urinary prolactin concentrations did not explain variation in working behaviour or patterns of aggression. Furthermore, females receiving Cabergoline did not show any behavioural or hormonal (progesterone) differences, and urinary prolactin did not appear to be suppressed in individuals receiving Cabergoline. While the results add to the relatively limited literature experimentally manipulating prolactin to investigate its role in reproduction and behaviour, they fail to explain why prolactin levels are high in non-breeding naked mole-rats, or how female non-breeding phenotypes are maintained.

Intrathecal Delivery of Therapeutic Oligonucleotides for Potent Modulation of Gene Expression in the Central Nervous System.

Therapeutic oligonucleotides hold tremendous potential for treating central nervous system (CNS) disorders. The route of administration of oligonucleotides significantly impacts both distribution and silencing efficiency. Here, we describe a technically simple, clinically relevant method to administer oligonucleotide compounds into the CNS via direct intrathecal injections. This method achieves distribution throughout the CNS rapidly and permits high-throughput testing of oligonucleotide efficacy and potency in mammals.