Acute high-altitude hypoxia (AHH) disrupts systemic homeostasis and alters the pharmacokinetic (PK) profiles of drugs, yet the role of the organic anion transport network in mediating altered drug disposition and the link to regulation by the Remote Sensing and Signaling Theory remain unclear. Moreover, the underlying mechanisms governing the PK of acetazolamide (ACZ), an FDA-approved therapeutic agent for high-altitude illness, remain unelucidated. This study aimed to clarify the effects of AHH on the PK of ACZ, identify the organic anion transport network involved, and characterize perturbations in renal metabolism. Results demonstrated that AHH markedly altered ACZ PK: with a 3.27-fold increase in AUC0-∞ and a 2.62-fold prolongation in t1/2. For the first time, ACZ was confirmed as a specific substrate of organic anion transporter 1, multidrug resistance-related protein (MRP4), and breast cancer resistance protein. Mechanistically, AHH dysregulated these transporters, including upregulating breast cancer resistance protein, downregulating organic anion transporters, organic anion transporting polypeptides, MRPs, and P-glycoprotein via transcriptional regulation of nuclear receptors (hypoxia-inducible factor-1α, Pregnane X receptor, constitutive androstane receptor, and hepatocyte nuclear factor-4α), a finding validated in acute hypoxic Caco-2 cells and AHH rat models. Renal metabolomics further revealed profound perturbations in organic anion metabolism, notably, indoxyl sulfate, hippuric acid, and kynurenic acid were decreased by 56.84%, 88.53%, and 69.77%, respectively, whereas estrone glucuronide was elevated 4.78-fold, and these 4 metabolites were identified as novel renal tissue-specific biomarkers of AHH-induced renal organic anion transport network dysfunction. Collectively, this study elucidates organic anionic drug disposition mechanisms under AHH, validates Remote Sensing and Signaling Theory by linking organic anion transport network to drug metabolism crosstalk, and provides evidence for personalized pharmacotherapy of high-altitude sickness. SIGNIFICANCE STATEMENT: This study uncovers how acute high-altitude hypoxia dysregulates the organic anion transport network to disrupt acetazolamide (ACZ) disposition and renal metabolic homeostasis. It first identifies ACZ as an organic anion transporter 1/multidrug resistance-related protein 4/breast cancer resistance protein substrate and defines indoxyl sulfate, hippuric acid, kynurenic acid, and estrone glucuronide as endogenous renal tissue-specific biomarkers for organic anion transport network dysfunction. Filling the gap in understanding acute high-altitude hypoxia-mediated organic anion transport network regulation, this work validates the Remote Sensing and Signaling Theory and provides critical insights for optimizing ACZ pharmacotherapy and exploring metabolic homeostasis in high-altitude environments.

Two mixed-anion chalcohalides, Pb4Sb4S9Cl2 and Pb4Sb4Se9Cl2, which crystallize in the orthorhombic space group Pbam (No. 55), were synthesized by a solid-state reaction. Their structures consist of puckered two-dimensional 2∞[Pb4Sb4Q9Cl][+] layers (Q = S, Se) constructed from NaCl-type ribbon motifs of Pb- and Sb-centered polyhedra, with Cl[-] ions located between the layers. Single-crystal X-ray diffraction and synchrotron powder X-ray diffraction confirm the structural models and support the presence of mixed chalcogen/halogen occupancies at selected anion sites. X-ray photoelectron spectroscopy confirms the presence of Pb[2+], Sb[3+], Q[2-] (Q = S, Se), and Cl[-]. Diffuse-reflectance measurements indicate indirect optical band gaps of 1.55 eV for the sulfide and 1.01 eV for the selenide, in agreement with density functional theory calculations that reproduce the indirect-gap character and the band-gap narrowing upon S to Se substitution. Both compounds exhibit low thermal conductivity at 300 K, with values of 1.1 W m[-1] K[-1] for Pb4Sb4S9Cl2 and 0.7 W m[-1] K[-1] for Pb4Sb4Se9Cl2, and the thermal conductivity decreases slightly with increasing temperature. This behavior is attributed to structural complexity, bonding heterogeneity associated with the mixed-anion framework, stereochemically active lone-pair cations, and partial halogen occupancy. These results clarify the structure-property relationships in Pb4Sb4Q9Cl2 and highlight mixed-anion design as a useful strategy for developing layered semiconducting chalcohalides with low thermal conductivity.

The structure-property relationship investigations constitute a fundamental paradigm for the rational design and synthesis of high-performance functional materials. Herein, four guanidinopropionates (C4H10N3O2)X (X = Cl- (GPC), Br[-] (GPB), [HSeO3][-] (GPSe), and [NH2SO3][-] (GPMS)) were reported. Anion-size-dependent modulation of the C2─C3 single bond rotation (linking guanidino and carboxylic π-conjugated groups) induces a reduction of the dihedral angle between the two π-conjugated planes (α) from 175° to 65°. With such a coplanarity reduction, the optical anisotropy property (birefringence, Δn) decreases from an excessive 0.20 in GPC to a favorable 0.11 in GPMS. Remarkably, GPMS also exhibits a large band gap (5.63 eV) and an enhanced second-harmonic generation (SHG) response (3.3 × KH2PO4). DFT reveals these four conformations are nearly degenerated, and the HOMO-LUMO gap, polarizability anisotropy, and hyperpolarizability across these four conformers are broadly tunable. This work first demonstrates how conformational folding control of flexible π-conjugated units effectively modulates and optimally balances three critical yet mutually restrictive parameters essential for high-performance SHG materials.

Volume-activated chloride current (VACC), the most common and abundant anion current in organisms, is involved in various physiological and pathological processes. However, its expression and characteristics in preadipocytes remain unclear. Whole-cell patch clamp technique was used to investigate the presence and properties of VACC in 3T3-L1 preadipocytes, as well as the effects of chloride channel blockers (NPPB, DIDS, and tamoxifen) on this current under different osmotic conditions. Additionally, 3T3-L1 preadipocytes were treated with the chloride channel blocker TMEM16A to observe its effect on cell differentiation. Hypotonic stimulation significantly induced whole-cell currents in 3T3-L1 preadipocytes, which exhibited obviously outward-rectifying and volume-activated characteristics. Under hypotonic stimulation, NPPB, DIDS, and tamoxifen all inhibited the current, with NPPB showing a significantly stronger inhibitory effect than DIDS and tamoxifen. Moreover, growth-arrested 3T3-L1 preadipocytes at 2 days post-confluence were successfully induced, with mRNA levels of C/EBPα, C/EBPβ, PPARγ and FABP4 peaking on day 3 and decreasing by day 14. Protein levels of PPARγ, perilipin 1 and LRRC8A were significantly upregulated during differentiation. Treatment with TMEM16A significantly reduced adipocyte lipid droplet formation and FABP4 mRNA/protein levels, but increased C/EBPα and PPARγ mRNA levels, as well as LRRC8A protein levels after 3 days. Collectively, our results clarify the characteristics of VACC in 3T3-L1 preadipocytes, confirm the inhibitory effect of chloride channel blockers on 3T3-L1 preadipocyte differentiation, fill the gap in the understanding of VACC in preadipocytes, and lay a preliminary experimental foundation for further exploring the role of VACC in adipocyte differentiation.

The Lewis pairing between existing dopant molecules offers great potential for developing new organic dopants with exceptional doping strength and stability. However, the high reactivity of Lewis-paired dopants complicates doping-level control, while the use of non-orthogonal solvents can damage organic semiconductor (OSC) films, hindering device applications. Here, the dopant reactivity is controlled by regulating the association-dissociation kinetics among pairing dopants and solvent molecules, which are strongly influenced by solvent polarity. In highly polar solvents, Lewis acid-solvent adducts predominantly form, suppressing the generation of Lewis-paired dopants. As solvent polarity decreases, the dissociation rate of the Lewis acid-solvent adduct increases, establishing a dynamic equilibrium between the Lewis acid and the solvent and thereby optimizing reactivity. Consequently, the optimally processed Lewis-paired dopant enables efficient doping of various OSCs with finely tunable doping levels, simultaneously achieving a high thermoelectric power factor (170 µW m[-1] K[-2]) and Seebeck coefficient (227 µV K[-1]). These performances surpass those of the conventional salt-type FeCl3 dopant and exhibit markedly improved doping stability under ambient and elevated-temperature conditions. This study provides a practical strategy for utilizing Lewis-paired dopants by elucidating their doping mechanisms, paving the way to overcome long-standing limitations in OSC doping.

Background: Valproic acid (VPA) poisoning has a dynamic clinical course and may require extracorporeal toxin removal (ECTR) in severe cases. Intermittent hemodialysis is the preferred ECTR technique; however, clinical experience with expanded hemodialysis (HDx) using medium cut-off (MCO) membranes in acute VPA intoxication is scarce. We describe a case of severe VPA poisoning managed with intermittent HDx and outline the clinical rationale and kinetic response. Case Report: A 54-year-old woman presented to the emergency department after accidental presumably ingesting approximately 4 g of VPA, with depressed consciousness (Glasgow Coma Scale 7) and metabolic acidosis (pH 7.10, HCO3[-] 13 mmol/L, PCO2 50 mmHg, lactate 2.8 mmol/L, ionized calcium 0.8 mmol/L, elevated anion gap). Initial plasma VPA was 262.99 µg/mL, ammonia was 14 µmol/L, and cranial computed tomography showed no acute abnormalities. ECTR was initiated in the intensive care unit as intermittent HDx using an MCO dialyzer for 4 h. Serial VPA concentrations were obtained before treatment, at 2 h, and at the end of the session to guide real-time prescription adjustment, with an increase in blood flow from 200 to 230 mL/min. Results: VPA decreased from 262.99 µg/mL pre-HD to 141.48 µg/mL at 2 h (46.2% reduction) and 97.81 µg/mL at 4 h (62.8% reduction), with clear improvement in the level of consciousness. A mild post-dialysis rebound was observed (100.07 µg/mL at 14 h). The patient recovered without additional ECTR and was discharged with normalized VPA levels on follow-up. Conclusions: In this patient, intermittent HDx with an MCO membrane was feasible, well tolerated, and associated with rapid VPA clearance and neurological recovery. Serial drug monitoring enabled bedside optimization of the dialysis prescription and post-treatment evaluation. A single HDx session was sufficient, and VPA therapy was safely reintroduced under close monitoring.

Understanding laboratory variables in animals undergoing haemodialysis is essential for optimizing therapeutic strategies. This study investigated the laboratory variables of uraemic crisis dogs undergoing intermittent haemodialysis (IHD). Medical records of dogs with chronic kidney disease (CKD) in uraemic crisis and those with acute kidney injury (AKI) undergoing IHD between 2017 and 2024 were reviewed. Fifty-eight dogs and 149 sessions were included. A high prevalence of anaemia and hypoalbuminaemia was observed at admission to the IHD, with the prevalence increasing as the number of sessions increased. Among the dogs with AKI and CKD, 84.6% and 78.1%, respectively, had anaemia. Acidaemia, metabolic acidosis and secondary respiratory alkalosis were common and were corrected after the sessions. Among dogs whose pH was within the reference range at admission to IHD, 43.5% exhibited reductions in bicarbonate and PCO2. The prevalence of metabolic acidosis was 40.6% in CKD and 34.6% in AKI. After the sessions, there were decreases (p ≤ 0.001) in RBC, haematocrit, MCHC, platelets, creatinine, urea, phosphorus, plasma proteins and potassium, and increases (p ≤ 0.043) in MCV, pH, HCO3, the anion gap, chloride, sodium and ionized calcium. There was an average decrease in haematocrit of 3.42-5% per session (p < 0.0001). The documented laboratory changes support early therapeutic planning. Acid-base correction and toxin removal highlight the efficacy of IHD, while the progression of anaemia and hypoalbuminaemia requires continued monitoring. Estimating the average decrease in haematocrit per session allows for the prediction of haematocrit decline, enabling more precise planning of priming fluid selection and blood product replacement.

Methanol-induced optic neuropathy (MON) is a serious and potentially blinding condition with significant public health concerns. Despite advancements in treatment, predicting long-term visual outcomes of MON remain challenging. The current study aimed to assess the potential association between arterial blood gas parameters and long-term changes of retinal nerve fiber layer (RNFL) in survivors of acute methanol poisoning. This prospective study was conducted on patients hospitalized with diagnosis of acute methanol poisoning at Ali Asghar Hospital, Shiraz, Iran, between 27 June 2020 and 12 August 2021 in COVID-19 era. The treatment included acid-base correction, hemodialysis, ethanol administration, erythropoietin, corticosteroids, and vitamin supplementation. Clinical and laboratory as well as comprehensive ophthalmologic examinations and high-definition optical coherence tomography (OCT) were performed at admission and after a 12-month follow-up to evaluate RNFL thickness and visual acuity (VA) alternations. A total of 61 patients (mean age: 30.08 ± 5.20 years; 91.8% male) with methanol poisoning were included in the study. Optic disc swelling was noted in 29 patients (47.54%), while 32 (52.46%) had normal optic discs. Most patients presented on Day 2 (34.43%) and Day 1 (32.79%) post-poisoning. Arterial blood gas analysis revealed a median pH of 7.0 (IQR: 6.85-7.28), bicarbonate levels of 17.0 mmol/L (IQR: 13.0-23.0), and an anion gap of 12.0 mmol/L (IQR: 9.0-15.0). Initially, 67.2% of patients had a VA ≥ 5/10, increasing to 87.7% after one year, with none of the patients having VA worse than 1/10 at follow-up. The VA improvement was observed during the follow-up in both eyes (p < .001). Also, significant RNFL thinning was observed across superior, nasal, inferior, and temporal quadrants (p < .001). Lower arterial pH, decreased bicarbonate levels, and higher anion gap were significantly associated with RNFL thinning and worse visual outcomes (p < .001). This study revealed the crucial role of arterial pH, bicarbonate levels, and anion gap in predicting long-term visual impairment in patients with MON. Early erythropoietin and corticosteroids therapy showed promising neuroprotective effects, supporting their use in improving visual outcomes. OCT remains an essential tool for monitoring optic nerve damages in patients with MON.

"Hypocapnia" and "hypocarbia" both refer to reduced levels of carbon dioxide (CO2) in the blood, typically below 35 mm Hg, although the terms are not entirely synonymous. Normal arterial CO2 partial pressure (PaCO2) ranges from 35 to 45 mm Hg. "Hypocarbia" denotes a reduction in the overall CO2 content of blood, which may result from a decrease in PaCO2, termed "hypocapnia," or a reduction in dissolved CO2. This change reflects the balance between CO2 production from cellular metabolism and removal through pulmonary and renal regulation, with additional modulation by the carbonic acid-bicarbonate buffering system, comprising carbonic acid formed from CO2 and the bicarbonate (HCO3-) ion. Disturbances that produce hypocarbia are frequently associated with respiratory alkalosis. Acid-base disorders are categorized according to the nature of the primary disturbance. Metabolic acidosis is characterized by decreased serum HCO3- and reduced pH, whereas metabolic alkalosis is marked by elevated HCO3- and increased pH. Respiratory acidosis arises from elevated arterial CO2, producing a lower pH, while respiratory alkalosis results from decreased arterial CO2, causing elevated pH. Simple acid-base disorders involve a single primary disturbance accompanied by the expected compensatory response from the respiratory or renal system. Mixed acid-base disorders involve 2 or more concurrent primary disturbances, which may be suspected based on patient history, abnormal compensatory responses, or serum electrolytes and the anion gap.