Global cellular proteo-lipidomic profiling of diverse lysosomal storage disease mutants using nMOST.

Lysosomal storage diseases (LSDs) comprise ~50 monogenic disorders marked by the buildup of cellular material in lysosomes, yet systematic global molecular phenotyping of proteins and lipids is lacking. We present a nanoflow-based multiomic single-shot technology (nMOST) workflow that quantifies HeLa cell proteomes and lipidomes from over two dozen LSD mutants. Global cross-correlation analysis between lipids and proteins identified autophagy defects, notably the accumulation of ferritinophagy substrates and receptors, especially in and mutants, where lysosomes accumulate cholesterol.

Global cellular proteo-lipidomic profiling of diverse lysosomal storage disease mutants using nMOST.

Lysosomal storage diseases (LSDs) comprise ~50 monogenic disorders marked by the buildup of cellular material in lysosomes, yet systematic global molecular phenotyping of proteins and lipids is lacking. We present a nanoflow-based multi-omic single-shot technology (nMOST) workflow that quantifies HeLa cell proteomes and lipidomes from over two dozen LSD mutants. Global cross-correlation analysis between lipids and proteins identified autophagy defects, notably the accumulation of ferritinophagy substrates and receptors, especially in and mutants, where lysosomes accumulate cholesterol.

PKA regulatory subunit Bcy1 couples growth, lipid metabolism, and fermentation during anaerobic xylose growth in Saccharomyces cerevisiae.

Organisms have evolved elaborate physiological pathways that regulate growth, proliferation, metabolism, and stress response. These pathways must be properly coordinated to elicit the appropriate response to an ever-changing environment. While individual pathways have been well studied in a variety of model systems, there remains much to uncover about how pathways are integrated to produce systemic changes in a cell, especially in dynamic conditions.

Comparison of tumor-agnostic and tumor-specific clinical oncology trial designs: a systematic review and meta-analysis.

To examine whether tumor-specific and tumor-agnostic oncology trials produce comparable estimates of objective response rate (ORR) in -altered cancers. Electronic database searches were performed to identify phase I-III clinical trials testing tyrosine kinase inhibitors from 2000 to 2021. A random-effects model was used to pool ORRs.

An analysis of published trials found that current use of pragmatic trial labels is uninformative.

Objectives: Randomized trials labelled as "pragmatic" are attractive to funders, patients, and clinicians as the label implies that the results are directly applicable to clinical care. We examined how authors justify use of the label (e.g.

Real-World Utilization Patterns of Long-Acting Injectable Antipsychotics in Canada: A Retrospective Study.

The objective of this study was to analyze the real-world prevalence of long-acting injectable (LAI) antipsychotic use and determine when LAIs are being used in sequencing of antipsychotic medications among Canadian patients with schizophrenia. This was a retrospective, longitudinal cohort study using Canadian pharmacy prescription data between August 2005 and June 2017. Patients with inferred schizophrenia spectrum disorder were indexed on the date of their first antipsychotic prescription and analyzed for minimum 12 months to track lines of antipsychotic therapy and LAI utilization.

Persistence of GLP-1 RA in combination with basal insulin among adults with type 2 diabetes in Canada.

Aims: The purpose of this study is to assess the persistence of Canadians with Type 2 diabetes mellitus (T2D) on loose-dose combination treatment (i.e., administered by separate devices) with a glucagon-like peptide 1 receptor agonist (GLP-1 RA) and basal insulin over 12 months.

Linking muscarinic receptor activation to UPS-mediated object memory destabilization: Implications for long-term memory modification and storage.

Consolidated memories can become destabilized during reactivation, resulting in a transient state of instability, a process that has been hypothesized to underlie long-term memory updating. Consistent with this notion, relatively remote memories, which are resistant to standard destabilization procedures, are reliably destabilized when novel information (i.e.

US Spending on Personal Health Care and Public Health, 1996-2013.

Importance: US health care spending has continued to increase, and now accounts for more than 17% of the US economy. Despite the size and growth of this spending, little is known about how spending on each condition varies by age and across time.

Objective: To systematically and comprehensively estimate US spending on personal health care and public health, according to condition, age and sex group, and type of care.

Promiscuous indolyl vinyl isonitrile synthases in the biogenesis and diversification of hapalindole-type alkaloids.

The hapalindole-type alkaloids naturally show striking late stage diversification of what was believed to be a conserved intermediate, -indolyl vinyl isonitrile (). Here we demonstrate enzymatically, as well as through applying a synthetic biology approach, that the pathway generating (itself, a potent natural broad-spectrum antibiotic) is also dramatically flexible. We harness this to enable early stage diversification of the natural product and generation of a wide range of halo-analogues of .

Psychological markers in the detection of autism in infancy in a large population.

Background: Investigation to see if there are key psychological risk indicators for autism in a random population study of children at 18 months of age; and to assess how well these discriminate children who receive a diagnosis of autism from other forms of developmental delay.

Method: Sixteen thousand children in the southeast of England were screened for autism by their health visitor or GP, during their routine 18-month-old developmental check-up, using the CHAT (Checklist for Autism in Toddlers). From a previous high-risk study we predicted that children at 18 months of age who failed three items ('protodeclarative pointing', 'gaze-monitoring', and 'pretend play') would be at risk for receiving a diagnosis of autism.

The nonorthogonal nature of risk factors: Implications for research on the causes of maladjustment.

High-risk research on the determinants of psychopathology has attempted to identify markers of vulnerability for specific disorders. This task is made more difficult by the fact that risk factors are correlated in the general population. Correlated risk factors present a challenge that is not amenable to the univariate, main effects models that are typically used by researchers in the field.

Dielectric behavior of water in biological solutions: studies on myoglobin, human low-density lipoprotein, and polyvinylpyrrolidone.

The dielectric behavior of the aqueous solutions of three widely differing macromolecules has been investigated: myoglobin, polyvinylpyrrolidone (PVP), and human serum low-density lipoprotein (LDL). It was not possible to interpret unambiguously the dielectric properties of the PVP solution in terms of water structure. The best interpretation of the dielectric data on the myoglobin and LDL solutions was that, in both cases, the macromolecule attracts a layer of water of hydration one or two water molecules in width.

Identification and reporting of child maltreatment by Head Start personnel: attitudes and experiences.

A two-part questionnaire was administered to 143 Head Start personnel in order to determine how personal characteristics of the Head Start workers and the characteristics of the families they serve, affect the identification and reporting of child maltreatment. Of additional interest was whether some forms of maltreatment, once identified, would be more likely to be reported than other forms of maltreatment. The results support the efficacy of educational programs in child maltreatment for increasing the identification and reporting of maltreatment by workers.

The dielectric properties of the cerebellum, cerebrum and brain stem of mouse brain at radiowave and microwave frequencies.

The relative permittivity and conductivity of the cerebellum, cerebrum and brain stem of mouse brain were measured at a temperature of 37 degrees C over a frequency range of 72 MHz to over 5 GHz using time-domain spectroscopy. An analysis of the data suggests that the water exists in various forms of binding with an average relaxation frequency less than free water.

The role of water in microwave absorption by biological material with particular reference to microwave hazards.

The problem of the absorption of the energy of plane electromagnetic radiation by an aqueous solution of macromolecules is considered. A simplified model for the hydrated molecule is employed, consisting of a spherical shell of bound water surrounding a spherical core. The power deposition per unit volume of the shell is calculated in the frequency range 100 MHz-100 GHz for several bound water relaxation frequencies.