The changing role of operational meteorology towards a transdisciplinary approach to future weather and climate services.

This paper describes the role of operational meteorology from a single disciplinary standpoint through to multidisciplinary, interdisciplinary and, more recently, transdisciplinary approaches and what this means for future forecasting systems. We start from the foundation of a single meteorological discipline: in this case, the forecasting of wind speed and direction that led to the creation of the first gale warning service in the wake of the 'Royal Charter Storm' in 1859. We build on this, giving further examples of where multidisciplinary and interdisciplinary methods have enhanced our understanding of observed meteorological and hydrometeorological phenomena from multiple perspectives, to produce a more holistic understanding of the effect of weather and climate on the 'whole of society'.

NOTCH1 S2513 is critical for the regulation of NICD levels impacting the segmentation clock in hiPSC-derived PSM cells and somitoids.

The segmentation clock is a molecular oscillator that regulates the timing of somite formation in the developing vertebrate embryo. NOTCH signaling is one of the key pathways required for proper functioning of the segmentation clock. Aberrant NOTCH signaling results in developmental abnormalities such as congenital scoliosis as well as diseases such as T-cell acute lymphoblastic lymphoma (T-ALL).

Neuroactive steroids activate membrane progesterone receptors to induce sex specific effects on protein kinase activity.

Neuroactive steroids (NAS), which are synthesized in the brain from progesterone, exert potent effects on behavior and are used to treat postpartum depression, yet how these compounds induce sustained modifications in neuronal activity are ill-defined. Here, we examined the efficacy of NAS for membrane progesterone receptors (mPRs) δ and ε, members of a family of GPCRs for progestins that are expressed in the CNS. NAS increase PKC activity via the G activation of mPRδ with EC50s between 3 and 11nM.

Activation of KCC2 during development alleviates cognitive, behavioral, and neural excitability in adult CDKL5-deficient mice.

Cyclin-dependent kinase-like 5 (CDKL5) deficiency disorder (CDD) is a developmental and epileptic encephalopathy (DEE) characterized by severe drug-resistant epileptic disorders beginning in early childhood, along with cognitive and social impairments in later childhood and adulthood. Existing pharmacological therapies for CDD primarily focus on anti-seizure medications, which often have associated sedative side effects. In addition, there are currently no effective treatments for cognitive or behavioral impairments associated with this disorder.

Neuroactive steroids activate membrane progesterone receptors to induce sex specific effects on protein kinase activity.

Neuroactive steroids (NAS), which are synthesized in the brain from progesterone, exert potent effects on behavior and are used to treat postpartum depression, yet how these compounds induce sustained modifications in neuronal activity are ill-defined. Here, we examined the efficacy of NAS for membrane progesterone receptors (mPRs) δ and ε, members of a family of GPCRs for progestins that are expressed in the CNS. NAS increase PKC activity via G activation of mPRδ with EC50s between 3-11nM.

Tuning the Electronic Properties of Azophosphines as Ligands and Their Application in Base-Free Transfer Hydrogenation Catalysis.

The design and tuning of new ligands is crucial for unlocking new reactivity at transition metal centers. Azophosphines have recently emerged as a new class of 1,3-P,N ligands in ruthenium piano-stool complexes. This work shows that the azophosphine synthesis can tolerate -aryl substituents with strongly electron-donating and electron-withdrawing -R groups and that the nature of this R group can affect the spectroscopic and structural properties of the azophosphines, as measured by NMR spectroscopy, UV-vis spectroscopy, single-crystal X-ray diffraction, and DFT studies.

Assessment of the efficacy of field and laboratory methods for the detection of Tropilaelaps spp.

Tropilaelaps spp. are invasive mites that cause severe disease in Apis mellifera colonies. The UK has deployed an elaborate surveillance system that seeks to detect these mites early in any invasion to allow the best opportunity to eradicate any incursion.

Transfusion sample mislabelling and wrong blood in tube in the UK: Insights from the national comparative audits of blood transfusion in 2012 and 2022.

Background: Samples for transfusion rejected due to mislabelling can lead to harm when a patient has to be re-bled or has a transfusion or procedure delayed. Electronic labelling systems which scan the patient's identification band and generate a label at their side aim to reduce mislabelling and misidentification leading to wrong blood in tube (WBIT) errors. The 2022 National Comparative audit of sample collection aimed to compare national rates of sample mislabelling and WBIT to the 2012 audit and to examine the impact of electronic systems.

Sustained Inhibition of GABA-AT by OV329 Enhances Neuronal Inhibition and Prevents Development of Benzodiazepine Refractory Seizures.

γ-Aminobutyric acid (GABA) is the principal inhibitory neurotransmitter in the adult brain which mediates its rapid effects on neuronal excitability via ionotropic GABA receptors. GABA levels in the brain are critically dependent upon GABA-aminotransferase (GABA-AT) which promotes its degradation. Vigabatrin, a low-affinity GABA-AT inhibitor, exhibits anticonvulsant efficacy, but its use is limited due to cumulative ocular toxicity.

Regiodivergent Synthesis of 4- and 5-Sulfenyl Oxazoles from Alkynyl Thioethers.

The regiodivergent synthesis of 4- and 5-sulfenyl oxazoles from 1,4,2-dioxazoles and alkynyl thioethers has been achieved. Gold-catalysed conditions are used to favour the formation of 5-sulfenyl oxazoles via β-selective attack of the nitrenoid relative to the sulfenyl group. In contrast, 4-sulfenyl oxazoles are formed by α-selective reaction under Brønsted acid conditions from the same substrates.

The brain-specific kinase LMTK3 regulates neuronal excitability by decreasing KCC2-dependent neuronal Cl extrusion.

LMTK3 is a brain-specific transmembrane serine/threonine protein kinase that acts as a scaffold for protein phosphatase-1 (PP1). Although LMKT3 has been identified as a risk factor for autism and epilepsy, its physiological significance is unknown. Here, we demonstrate that LMTK3 copurifies and binds to KCC2, a neuron-specific K/Cl transporter.

Correction: Biochemical characterization of protease activity of Nsp3 from SARS-CoV-2 and its inhibition by nanobodies.

[This corrects the article DOI: 10.1371/journal.pone.

A laterally-fused N-heterocyclic carbene framework from polysubstituted aminoimidazo[5,1-]oxazol-6-ium salts.

A polysubstituted 3-aminoimidazo[5,1-]oxazol-6-ium framework has been accessed from a new nitrenoid reagent by a two-step ynamide annulation and imidazolium ring-formation sequence. Metalation with Au(I), Cu(I) and Ir(I) at the C2 position provides an L-shaped NHC ligand scaffold that has been validated in gold-catalysed alkyne hydration and arylative cyclisation reactions.

Design and high-throughput implementation of MALDI-TOF/MS-based assays for Parkin E3 ligase activity.

Parkinson's disease (PD) is a progressive neurological disorder that manifests clinically as alterations in movement as well as multiple non-motor symptoms including but not limited to cognitive and autonomic abnormalities. Loss-of-function mutations in the gene encoding the ubiquitin E3 ligase Parkin are causal for familial and juvenile PD. Among several therapeutic approaches being explored to treat or improve the prognosis of patients with PD, the use of small molecules able to reinstate or boost Parkin activity represents a potential pharmacological treatment strategy.

Digital adaptation of the Standing up for Myself intervention in young people and adults with intellectual disabilities: the STORM feasibility study.

Background: Stigma contributes to the negative social conditions persons with intellectual disabilities are exposed to, and it needs tackling at multiple levels. Standing Up for Myself is a psychosocial group intervention designed to enable individuals with intellectual disabilities to discuss stigmatising encounters in a safe and supportive setting and to increase their self-efficacy in managing and resisting stigma.

Objectives: To adapt Standing Up for Myself to make it suitable as a digital intervention; to evaluate the feasibility and acceptability of Digital Standing Up for Myself and online administration of outcome measures in a pilot; to describe usual practice in the context of the coronavirus disease 2019 pandemic to inform future evaluation.

The Concise Guide to PHARMACOLOGY 2023/24: Ion channels.

The Concise Guide to PHARMACOLOGY 2023/24 is the sixth in this series of biennial publications. The Concise Guide provides concise overviews, mostly in tabular format, of the key properties of approximately 1800 drug targets, and over 6000 interactions with about 3900 ligands. There is an emphasis on selective pharmacology (where available), plus links to the open access knowledgebase source of drug targets and their ligands (https://www.

Windows of opportunity for predicting seasonal climate extremes highlighted by the Pakistan floods of 2022.

Skilful predictions of near-term climate extremes are key to a resilient society. However, standard methods of analysing seasonal forecasts are not optimised to identify the rarer and most impactful extremes. For example, standard tercile probability maps, used in real-time regional climate outlooks, failed to convey the extreme magnitude of summer 2022 Pakistan rainfall that was, in fact, widely predicted by seasonal forecasts.

Evaluation of Structural and Compositional Changes of a Model Monoaromatic Hydrocarbon in a Benchtop Hydrocracker Using GC, FTIR, and NMR Spectroscopy.

Hydrogenation is a catalytic process that has the potential to facilitate sustainable chemical production. In this work, a model monoaromatic hydrocarbon, phenyldodecane (PDD), comprising an aromatic ring with a long aliphatic side chain has been chosen as representative of a typical species involved in hydrogenation and hydrocracked at a high pressure and temperature over a platinum catalyst in a bespoke benchtop mini-reactor. Gas chromatography-mass spectrometry (GC-MS), Fourier transform infrared (FTIR) spectroscopy, UV-vis spectroscopy, and nuclear magnetic resonance (NMR) spectroscopy were employed to analyze the changes that took place after hydrocracking for different time periods.

One for all-human kidney Caki-1 cells are highly susceptible to infection with corona- and other respiratory viruses.

investigations of host-virus interactions are reliant on suitable cell and tissue culture models. Results are only as good as the model they are generated in. However, choosing cell models for work often depends on availability and previous use alone.

Development of a highly potent and selective degrader of LRRK2.

The discovery of disease-modifying therapies for Parkinson's Disease (PD) represents a critical need in neurodegenerative medicine. Genetic mutations in leucine-rich repeat kinase 2 (LRRK2) are risk factors for the development of PD, and some of these mutations have been linked to increased LRRK2 kinase activity and neuronal toxicity in cellular and animal models. Furthermore, LRRK2 function as a scaffolding protein in several pathways has been implicated as a plausible mechanism underlying neurodegeneration caused by LRRK2 mutations.

S-acylation stabilizes ligand-induced receptor kinase complex formation during plant pattern-triggered immune signaling.

Plant receptor kinases are key transducers of extracellular stimuli, such as the presence of beneficial or pathogenic microbes or secreted signaling molecules. Receptor kinases are regulated by numerous post-translational modifications. Here, using the immune receptor kinases FLS2 and EFR, we show that S-acylation at a cysteine conserved in all plant receptor kinases is crucial for function.

Spectrin-beta 2 facilitates the selective accumulation of GABA receptors at somatodendritic synapses.

Fast synaptic inhibition is dependent on targeting specific GABAR subtypes to dendritic and axon initial segment (AIS) synapses. Synaptic GABARs are typically assembled from α1-3, β and γ subunits. Here, we isolate distinct GABARs from the brain and interrogate their composition using quantitative proteomics.