Developmental dysfunction in a preclinical model of Kcnq2 developmental and epileptic encephalopathy.

Background: Developmental and epileptic encephalopathies (DEE) are rare but severe neurodevelopmental disorders characterised by early-onset seizures often combined with developmental delay, behavioural and cognitive deficits. Treatment for DEEs is currently limited to seizure control and provides no benefits to the patients' developmental and cognitive outcomes. Genetic variants are the most common cause of DEE with KCNQ2 being one of the most frequently identified disease-causing genes.

Time-resolved single-cell transcriptomics defines immune trajectories in glioblastoma.

Deciphering the cell-state transitions underlying immune adaptation across time is fundamental for advancing biology. Empirical in vivo genomic technologies that capture cellular dynamics are currently lacking. We present Zman-seq, a single-cell technology recording transcriptomic dynamics across time by introducing time stamps into circulating immune cells, tracking them in tissues for days.

Non-canonical BIM-regulated energy metabolism determines drug-induced liver necrosis.

Paracetamol (acetaminophen, APAP) overdose severely damages mitochondria and triggers several apoptotic processes in hepatocytes, but the final outcome is fulminant necrotic cell death, resulting in acute liver failure and mortality. Here, we studied this switch of cell death modes and demonstrate a non-canonical role of the apoptosis-regulating BCL-2 homolog BIM/Bcl2l11 in promoting necrosis by regulating cellular bioenergetics. BIM deficiency enhanced total ATP production and shifted the bioenergetic profile towards glycolysis, resulting in persistent protection from APAP-induced liver injury.

Spatial and Temporal Mapping of Breast Cancer Lung Metastases Identify TREM2 Macrophages as Regulators of the Metastatic Boundary.

Unlabelled: Cancer mortality primarily stems from metastatic recurrence, emphasizing the urgent need for developing effective metastasis-targeted immunotherapies. To better understand the cellular and molecular events shaping metastatic niches, we used a spontaneous breast cancer lung metastasis model to create a single-cell atlas spanning different metastatic stages and regions. We found that premetastatic lungs are infiltrated by inflammatory neutrophils and monocytes, followed by the accumulation of suppressive macrophages with the emergence of metastases.

Alterations in iron content, iron-regulatory proteins and behaviour without tau pathology at one year following repetitive mild traumatic brain injury.

Repetitive mild traumatic brain injury (r-mTBI) has increasingly become recognised as a risk factor for the development of neurodegenerative diseases, many of which are characterised by tau pathology, metal dyshomeostasis and behavioural impairments. We aimed to characterise the status of tau and the involvement of iron dyshomeostasis in repetitive controlled cortical impact injury (5 impacts, 48 h apart) in 3-month-old C57Bl6 mice at the chronic (12-month) time point. We performed a battery of behavioural tests, characterised the status of neurodegeneration-associated proteins (tau and tau-regulatory proteins, amyloid precursor protein and iron-regulatory proteins) via western blot; and metal levels using bulk inductively coupled plasma-mass spectrometry (ICP-MS).

The transcriptional and regulatory identity of erythropoietin producing cells.

Erythropoietin (Epo) is the master regulator of erythropoiesis and oxygen homeostasis. Despite its physiological importance, the molecular and genomic contexts of the cells responsible for renal Epo production remain unclear, limiting more-effective therapies for anemia. Here, we performed single-cell RNA and transposase-accessible chromatin (ATAC) sequencing of an Epo reporter mouse to molecularly identify Epo-producing cells under hypoxic conditions.

Immune escape of colorectal tumours via local LRH-1/Cyp11b1-mediated synthesis of immunosuppressive glucocorticoids.

Control of tumour development and growth by the immune system critically defines patient fate and survival. What regulates the escape of colorectal tumours from destruction by the immune system remains currently unclear. Here, we investigated the role of intestinal synthesis of glucocorticoids in the tumour development during an inflammation-induced mouse model of colorectal cancer.

Management of Sternal Wound Infection-Determinants of Length of Stay and Recurrence of Infection after Muscle Flap Coverage.

Aim: The aim of this study was to define determinants of length of hospital stay (LOS) longer than mean and recurrence of infection (ROI) after complete healing of patients with deep sternal wound infections (DSWI).

Patients And Methods: In this observational study, we included 303 patients (155 females and 148 males, with mean age of 68 years) treated from 2016 to 2020 at the Department of Plastic Surgery of the HELIOS Klinik Krefeld, Germany. All patients received extensive necrosectomy, repetitive negative pressure therapy periods, and final transplantation of a pectoral musculocutaneous flap.

Deferiprone attenuates neuropathology and improves outcome following traumatic brain injury.

Background And Purpose: Traumatic brain injury (TBI) remains a leading cause of mortality and morbidity in young adults. The role of iron in potentiating neurodegeneration following TBI has gained recent interest as iron deposition has been detected in the injured brain in the weeks to months post-TBI, in both the preclinical and clinical setting. A failure in iron homeostasis can lead to oxidative stress, inflammation and excitotoxicity; and whether this is a cause or consequence of the long-term effects of TBI remains unknown.

IL-12 regulates type 3 immunity through interfollicular keratinocytes in psoriasiform inflammation.

Psoriasis is a chronic inflammatory skin disorder underpinned by dysregulated cytokine signaling. Drugs neutralizing the common p40 subunit of interleukin-12 (IL-12) and IL-23 represented a therapeutic breakthrough; however, new drugs that block the IL-23p19 subunit and spare IL-12 are more effective, suggesting a regulatory function of IL-12. To pinpoint the cell type and underlying mechanism of IL-12–mediated immune regulation in psoriasis, we generated a conditional -knockout (KO)/reporter mouse strain.

Sex-dependent effects of amyloid precursor-like protein 2 in the SOD1-G37R transgenic mouse model of MND.

Motor neurone disease (MND) is a neurodegenerative disorder characterised by progressive destruction of motor neurons, muscle paralysis and death. The amyloid precursor protein (APP) is highly expressed in the central nervous system and has been shown to modulate disease outcomes in MND. APP is part of a gene family that includes the amyloid precursor-like protein 1 (APLP1) and 2 (APLP2) genes.

Large Isotope Effects in Organometallic Chemistry.

The kinetic isotope effect (KIE) is key to understanding reaction mechanisms in many areas of chemistry and chemical biology, including organometallic chemistry. This ratio of rate constants, k /k , typically falls between 1-7. However, KIEs up to 105 have been reported, and can even be so large that reactivity with deuterium is unobserved.

Regulation of Tissue Immune Responses by Local Glucocorticoids at Epithelial Barriers and Their Impact on Interorgan Crosstalk.

The anti-inflammatory role of extra-adrenal glucocorticoid (GC) synthesis at epithelial barriers is of increasing interest with regard to the search for alternatives to synthetic corticosteroids in the therapy of inflammatory disorders. Despite being very effective in many situations the use of synthetic corticosteroids is often controversial, as exemplified in the treatment of influenza patients and only recently in the current COVID-19 pandemic. Exploring the regulatory capacity of locally produced GCs in balancing immune responses in barrier tissues and in pathogenic disorders that lead to symptoms in multiple organs, could provide new perspectives for drug development.

Keratinocytes control skin immune homeostasis through de novo-synthesized glucocorticoids.

Glucocorticoids (GC), synthesized by the 11β-hydroxylase (Cyp11b1), control excessive inflammation through immunosuppressive actions. The skin was proposed to regulate homeostasis by autonomous GC production in keratinocytes. However, their immunosuppressive capacity and clinical relevance remain unexplored.

The versatility of liver X receptors in T cell homeostasis: Location, location, location!

Nuclear receptors control the transcriptional program of target cells and thereby their phenotype and activities. Two complementary studies by Micheals et al. (https://doi.

Pharmacological LRH-1/Nr5a2 inhibition limits pro-inflammatory cytokine production in macrophages and associated experimental hepatitis.

Liver receptor homolog-1 (LRH-1, Nr5a2) is an orphan nuclear receptor mainly expressed in tissues of endodermal origin, where its physiological role has been extensively studied. LRH-1 has been implicated in liver cell differentiation and proliferation, as well as glucose, lipid, and bile acid metabolism. In addition, increasing evidence highlights its role in immunoregulatory processes via glucocorticoid synthesis in the intestinal epithelium.

Geological and geochemical characterizations of sediments in six borehole cores from the arsenic-contaminated aquifer of the Mekong Delta, Vietnam.

The Mekong Delta, situated between Cambodia and Vietnam, is one of the most productive aquifer systems in the region. In recent years, however, several studies have shown that groundwater in several areas of the delta is highly contaminated with arsenic (As). Although more than 80% of the total area of the Mekong Delta is situated in Vietnam, most of the studies have been conducted on the Cambodian-side of the delta.

The orphan nuclear receptor LRH-1/NR5a2 critically regulates T cell functions.

LRH-1 (liver receptor homolog-1/NR5a2) is an orphan nuclear receptor, which regulates glucose and lipid metabolism, as well as intestinal inflammation via the transcriptional control of intestinal glucocorticoid synthesis. Predominantly expressed in epithelial cells, its expression and role in immune cells are presently enigmatic. LRH-1 was found to be induced in immature and mature T lymphocytes upon stimulation.

The solid-phase partitioning of arsenic in unconsolidated sediments of the Mekong Delta, Vietnam and its modes of release under various conditions.

Arsenic (As) contamination of the groundwater in the Mekong Delta is a serious problem affecting millions of people who rely on this important resource for drinking and agriculture. In this study, borehole cores up to a depth of 40 m were collected in the Vietnamese-side of the delta, and the solid-phase partitioning of As with depth was investigated to understand the factors and processes controlling the release of this toxic element under oxic, acidic and reducing conditions. The results showed that in most of the sediments, substantial amounts of As are partitioned with exchangeable phases that are easily released into solution.

Extra-adrenal glucocorticoid synthesis at epithelial barriers.

Epithelial barriers play an important role in the exchange of nutrients, gases, and other signals between our body and the outside world. However, they protect it also from invasion by potential pathogens. Defective epithelial barriers and associated overshooting immune responses are the basis of many different inflammatory disorders of the skin, the lung, and the intestinal mucosa.

Simultaneous nitrosylation and N-nitrosation of a Ni-thiolate model complex of Ni-containing SOD.

Nitric oxide (NO) is used as a substrate analogue/spectroscopic probe of metal sites that bind and activate oxygen and its derivatives. To assess the interaction of superoxide with the Ni center in Ni-containing superoxide dismutase (NiSOD), we studied the reaction of NO and NO with the model complex, EtN[Ni(nmp)(SPh--NH--CF)] (; nmp = dianion of -(2-mercaptoethyl)picolinamide; SPh--NH--CF = 2-amino-4-(trifluoromethyl)benzenethiolate) and its oxidized analogue , respectively. The ultimate products of these reactions are the disulfide of SPh--NH--CF and the ,-bridged tetrameric complex [Ni(nmp)], a result of S-based redox activity.

Molecular Mechanism of the Cell Membrane Pore Formation Induced by Bubble Stable Cavitation.

Microbubbles in combination with ultrasound provide a new and promising way to deliver drugs into living cells. It is believed that the stable vibration or the collapse of the bubbles under ultrasound are the two main mechanisms that induce the formation of pores in the cell membranes, through which drugs may get inside the cell cytoplasm. The bubble collapse hypothesis is not only intuitive since released shock waves can easily penetrate and create pores in the membrane, but it is also confirmed by both experiment and theory.

Amyloid precursor protein and amyloid precursor-like protein 2 have distinct roles in modulating myelination, demyelination, and remyelination of axons.

The identification of factors that regulate myelination provides important insight into the molecular mechanisms that coordinate nervous system development and myelin regeneration after injury. In this study, we investigated the role of amyloid precursor protein (APP) and its paralogue amyloid precursor-like protein 2 (APLP2) in myelination using APP and APLP2 knockout (KO) mice. Given that BACE1 regulates myelination and myelin sheath thickness in both the peripheral and central nervous systems, we sought to determine if APP and APLP2, as alternate BACE1 substrates, also modulate myelination, and therefore provide a better understanding of the events regulating axonal myelination.

Analysis of Motor Function in Amyloid Precursor-Like Protein 2 Knockout Mice: The Effects of Ageing and Sex.

The amyloid precursor protein (APP) is a member of a conserved gene family that includes the amyloid precursor-like proteins 1 (APLP1) and 2 (APLP2). APP and APLP2 share a high degree of similarity, and have overlapping patterns of spatial and temporal expression in the central and peripheral tissues, in particular at the neuromuscular junction. APP-family knockout (KO) studies have helped elucidate aspects of function and functional redundancy amongst the APP-family members.