Liver Characterization of a Cohort of Alpha-1 Antitrypsin Deficiency Patients with and without Lung Disease.

Background And Aims: Alpha-1 antitrypsin deficiency (AATD) is a genetic disorder characterized by the misfolding and accumulation of the mutant variant of alpha-1 antitrypsin (AAT) within hepatocytes, which limits its access to the circulation and exposes the lungs to protease-mediated tissue damage. This results in progressive liver disease secondary to AAT polymerization and accumulation, and chronic obstructive pulmonary disease (COPD) due to deficient levels of AAT within the lungs. Our goal was to characterize the unique effects of COPD secondary to AATD on liver disease and gene expression.

Improving hydrological modeling to close the gap between elevated CO concentration and crop response: Implications for water resources.

Rising atmospheric carbon dioxide concentrations ([CO]) affect crop growth and the associated hydrological cycle through physiological forcing, which is mainly regulated by reducing stomatal conductance (g) and increasing leaf area index (LAI). However, reduced g and increased LAI can affect crop water consumption, and the overall effects need to be quantified under elevated [CO]. Here we develop a SWAT-g-LAI model by incorporating a nonlinear g-CO equation and a missing LAI-CO relationship to investigate the responses of water consumption of grain maize, maize yield, and losses of water and soil to elevated [CO] in the Upper Mississippi River Basin (UMRB; 492,000 km).

MetALD: Does it require a different therapeutic option?

New guidelines for the definitions of steatotic liver disease have named the entity of metabolic dysfunction and alcohol-associated liver disease (MetALD) as an overlap condition of metabolic dysfunction-associated steatotic liver disease (MASLD) and alcohol-associated liver disease. There is a broad range of therapeutics in all stages of development for MASLD, but these therapeutics, in general, have not been studied in patients with significant ongoing alcohol use. In this review, we discuss the current understanding of the endogenous and exogenous risks for MASLD and MetALD.

Macrophage RAGE activation is proinflammatory in NASH.

Intrahepatic macrophages in nonalcoholic steatohepatitis (NASH) are heterogenous and include proinflammatory recruited monocyte-derived macrophages. The receptor for advanced glycation endproducts (RAGE) is expressed on macrophages and can be activated by damage associated molecular patterns (DAMPs) upregulated in NASH, yet the role of macrophage-specific RAGE signaling in NASH is unclear. Therefore, we hypothesized that RAGE-expressing macrophages are proinflammatory and mediate liver inflammation in NASH.

Assessment of the sustainability of groundwater utilization and crop production under optimized irrigation strategies in the North China Plain under future climate change.

Over-exploitation of groundwater due to intensive irrigation and anticipated climate change pose severe threats to the water and food security worldwide, particularly in the North China Plain (NCP). Limited irrigation has been recognized as an effective way to improve crop water productivity and slow the rapid decline of groundwater levels. Whether optimized limited irrigation strategies could achieve a balance between groundwater pumping and grain production in the NCP under future climate change deserves further study.

A phase 1 randomized, placebo-controlled study to investigate potential interactions between ASP8062, a positive allosteric modulator of the GABA receptor, and morphine in recreational opioid users.

Background: Recent increases in opioid use and subsequent opioid use disorder are a major public health crisis in the United States.

Aims: This phase 1 randomized, placebo-controlled study investigated the safety, tolerability, and pharmacokinetics (PKs) of ASP8062, a γ-aminobutyric acid B receptor-positive allosteric modulator, with and without administration of morphine in participants who used opioids recreationally.

Methods: Participants were randomly assigned (2:1) to daily dosing with ASP8062 25 mg or placebo on days 1-10.

Polytrimethylenimines: Highly Potent Antibacterial Agents with Activity and Toxicity Modulated by the Polymer Molecular Weight.

Cationic polymers have been extensively investigated as a potential replacement for traditional antibiotics. Here, we examined the effect of molecular weight (MW) on the antimicrobial, cytotoxic, and hemolytic activity of linear polytrimethylenimine (L-PTMI). The results indicate that the biological activity of the polymer sharply increases as MW increases.

The Cause and Effect Relationship of Diabetes after Acute Pancreatitis.

Acute pancreatitis (AP) is an acute inflammation of the pancreas associated with high morbidity and mortality. Endocrine pancreatic insufficiency secondary to AP has drawn increasing attention in recent years. The aim of this paper is to analyze the available clinical and experimental literature to determine the cause and effect relationship of diabetes type 3c (T3cDM; pancreatogenic diabetes) after acute pancreatitis.

A phase 1b study to investigate the potential interactions between ASP8062 and buprenorphine/naloxone in patients with opioid use disorder.

Background: There is an unmet need for therapeutics with greater efficacy and tolerability for the treatment of opioid use disorder (OUD). ASP8062 is a novel compound with positive allosteric modulator activity on the γ-aminobutyric acid type B receptor under development for use with standard-of-care treatment for patients with OUD.

Aims: To investigate the safety, tolerability, interaction potential, and pharmacokinetics (PK) of ASP8062 in combination with buprenorphine/naloxone (B/N; Suboxone).

Assessing impacts of global climate change on water and food security in the black soil region of Northeast China using an improved SWAT-CO model.

Future climate change may have substantial impacts on both water resources and food security in China's black soil region. The Liao River Basin (LRB; 220,000 km) is representative of the main black soil area, making it ideal for studying climate change effects on black soil. In this study, the Soil and Water Assessment Tool (SWAT) model was first initialized for the LRB.

Association of Genetic Variants in Gene (rs1800795) with the Concentration of Inflammatory Markers (IL-6, hs-CRP) and Superoxide Dismutase in the Blood of Patients with Acute Pancreatitis-Preliminary Findings.

In the course of acute pancreatitis, interleukin-6 plays an important role as a mediator in the inflammatory response. The course of inflammatory disease is associated with intensive oxidative stress, which may activate transcription factors leading to gene-expression changes. Isoenzymes of superoxide dismutase are involved in the defense against free radicals.

A phase 1 study to assess potential interaction between ASP8062 and alcohol in healthy adult subjects.

Background: ASP8062 is a novel orally active GABA receptor positive allosteric modulator in clinical development for the treatment of alcohol use disorder (AUD) and opioid use disorder (OUD).

Aims: This study assessed the potential pharmacokinetic/pharmacodynamic interaction between ASP8062 and alcohol under single-dose conditions in healthy adults.

Methods: A double-blind, placebo-controlled, crossover phase 1 study was conducted in which 20 subjects were randomly assigned to four treatment sequences (ASP8062 + alcohol; ASP8062 + placebo alcohol; placebo + alcohol; placebo + placebo alcohol) each consisting of four treatment periods, separated by washout periods of at least 14 days.

Single- and multiple-dose safety, tolerability, pharmacokinetic, and pharmacodynamic profiles of ASP0367, or bocidelpar sulfate, a novel modulator of peroxisome proliferator-activated receptor delta in healthy adults: Results from a phase 1 study.

Introduction/aims: ASP0367, or bocidelpar sulfate, is an orally administered small molecule that potently and selectively modulates peroxisome proliferator-activated receptor δ (PPARδ) to address mitochondrial dysfunction occurring in diseases including primary mitochondrial myopathy and Duchenne muscular dystrophy. The objectives of this first-in-human trial were to evaluate the safety/tolerability, pharmacokinetics, and pharmacodynamics of ASP0367 in healthy participants.

Methods: In this double-blind phase 1 study, adult participants were randomized to single or multiple ascending oral doses of ASP0367 or placebo.

Quantitative measurement of the histological features of alpha-1 antitrypsin deficiency-associated liver disease in biopsy specimens.

Background: Pathological mutations in Alpha-1 Antitrypsin (AAT) protein cause retention of toxic polymers in the hepatocyte endoplasmic reticulum. The risk for cirrhosis in AAT deficiency is likely directly related to retention of these polymers within the liver. Polymers are classically identified on liver biopsy as inclusion bodies by periodic acid schiff staining after diastase treatment and immunohistochemistry.

Sinus bradycardia with haemodynamic compromise following lithium intoxication.

Lithium is a well-established treatment for mood disorders and considered first-line pharmacological therapy for bipolar disorder as per the American Psychiatric Association guidelines. However, lithium is associated with significant toxicity. Cardiotoxicity including sinus node dysfunction is a rare but clinically significant presentation of lithium intoxication.

Cortical influences of serotonin and glutamate on layer V pyramidal neurons.

Layer V pyramidal neurons constitute principle output neurons of the medial prefrontal cortex (mPFC)/neocortex to subcortical regions including the intralaminar/midline thalamic nuclei, amygdala, basal ganglia, brainstem nuclei and the spinal cord. The effects of 5-hydroxytryptamine (5-HT) on layer V pyramidal cells primarily reflect a range of excitatory influences through 5-HT receptors and inhibitory influences through non-5-HT receptors, including 5-HT receptors. While the 5-HT receptor is primarily a postsynaptic receptor on throughout the apical dendritic field of 5-HT receptors, activation of a minority of 5-HT receptors also appears to increase spontaneous excitatory postsynaptic currents/potentials (EPSCs/EPSPs) via a presynaptic effect on thalamocortical terminals arising from the midline and intralaminar thalamic nuclei.

A randomized phase 1 single-dose polysomnography study of ASP8062, a GABA receptor positive allosteric modulator.

Rationale: Previous research suggests that sleep polysomnography and EEG endpoints can be used to assess GABAergic activity; however, the impact of GABA receptor positive allosteric modulators on sleep endpoints remains unclear.

Objectives: This phase 1 study compared a single dose of ASP8062 (35 mg or 70 mg), a GABA receptor positive allosteric modulator, with placebo and paroxetine (40 mg).

Methods: Healthy adult volunteers were randomized to four treatments (35 mg ASP8062, 70 mg ASP8062, paroxetine 40 mg, or matching placebo), each separated by a 14-day washout.

Efficacy and Safety of ASP0819 in Patients with Fibromyalgia: Results of a Proof-of-Concept, Randomized, Double-Blind, Placebo-Controlled Trial.

Purpose: ASP0819 is a novel, non-opioid K3.1 channel opener that reverses abnormal nerve firing of primary sensory afferent nerves. Currently available treatments for fibromyalgia provide only modest relief and are accompanied by a host of adverse side effects.

Phase 1 randomized study on the safety, tolerability, and pharmacodynamic cognitive and electrophysiological effects of a dopamine D receptor positive allosteric modulator in patients with schizophrenia.

ASP4345, a novel dopamine D receptor positive allosteric modulator, is being evaluated for the treatment of cognitive impairment associated with schizophrenia (CIAS). This phase 1 multiple ascending-dose study (NCT02720263) assessed the safety, tolerability, and pharmacodynamics of ASP4345 in patients with schizophrenia/schizoaffective disorder. Pharmacodynamic assessments were Cogstate cognitive tests and electrophysiological biomarkers, including gamma-band power and phase synchronization in response to 40-Hz auditory steady-state stimulation, as well as mismatch negativity (MMN) and P3a event-related potentials.

Alpha-1 antitrypsin deficient individuals have circulating extracellular vesicles with profibrogenic cargo.

Background: Alpha-1 antitrypsin deficiency (AATD)-mediated liver disease is a toxic "gain-of-function" inflammation in the liver associated with intracellular retention of mutant alpha-1 antitrypsin. The clinical presentation of the disease includes fibrosis, cirrhosis and liver failure. However, the pathogenic mechanism of AATD-mediated liver disease is not well understood.

Pharmacokinetics of ASP4345 from Single Ascending-Dose and Multiple Ascending-Dose Phase I Studies.

Background: Cognitive impairment is a core feature of schizophrenia. While first- and second-generation antipsychotic drugs treat psychotic exacerbations, no treatment is approved for the cognitive dysfunction. We have identified ASP4345, a positive allosteric modulator of the dopamine type 1 (D) receptor that selectively binds to, and enhances the activity of, D receptors.