Unraveling a Stable 16-Ring Aluminophosphate DNL-11 through Three-Dimensional Electron Diffraction for Atmospheric Water Harvesting.

Sorption-based atmospheric water harvesting (AWH) is a promising solution for addressing water scarcity. Developing cost-effective and stable water adsorbents with high water uptake capacity and a low-temperature regeneration requirement is a crucially important procedure. In this Communication, we present a novel and stable aluminophosphate (AlPO) molecular sieve (MS) named DNL-11 with 16-ring channels synthesized by using an affordable and commercialized organic structure directing agent (OSDA), whose crystallographic structure is elucidated by three-dimensional electron diffraction (3D ED). DNL-11 exhibits a significant water uptake capacity (189 mg/g) at a very low vapor pressure (5% relative humidity at 30 °C). In addition, most of the adsorbed water can be effortlessly removed by purging N2 at 25 °C under ambient pressure conditions. This may expand the possibility of AWH under extreme drought conditions.

New Alkalescent Electrolyte Chemistry for Zinc-Ferricyanide Flow Battery.

Alkaline zinc-ferricyanide flow batteries are efficiency and economical as energy storage solutions. However, they suffer from low energy density and short calendar life. The strongly alkaline conditions (3 mol L-1 OH-) reduce the solubility of ferri/ferro-cyanide (normally only 0.4 mol L-1 at 25 °C) and induce the formation of zinc dendrites at the anode. Here, we report a new zinc-ferricyanide flow battery based on a mild alkalescent (pH 12) electrolyte. Using a chelating agent to rearrange ferri/ferro-cyanide ion-solvent interactions and improve salt dissociation, we increased the solubility of ferri/ferro-cyanide to 1.7 mol L-1 and prevented zinc dendrites. Our battery has an energy density of ~74 Wh L-1 catholyte at 60 °C and remains stable for 1800 cycles (1800 hours) at 0 °C and for >1400 cycles (2300 hours) at 25 °C. An alkalescent zinc-ferricyanide cell stack built using this alkalescent electrolyte stably delivers 608 W of power for ~40 days.

Selective modulation of alkali metal ions on acetylcholinesterase.

Acetylcholinesterase (AChE) is an important hydrolase in cholinergic synapses and a candidate target in the treatment of Alzheimer's disease. The lithium treatment widely used in neurological disorders can alter the AChE activity, yet the underlying mechanism of how the ion species regulate the enzymatic activity remains unclear. In this work, we performed combined quantum mechanics/molecular mechanics (QM/MM) and molecular dynamics (MD) simulations and well-tempered metadynamics to understand the modulation of human AChE (hAChE) activity using three alkali metal ions (Li+, Na+, and K+) in different concentrations. Our simulations show that the binding affinity and catalytic activity are affected by different ion species through allosteric ion coordination geometries on the hAChE complex and distant electrostatic screening effect. A Li+ cluster involving D330, E393, and D397 residues and three Li+ ions was found to be highly conserved and can be critical to the enzyme activity. Binding energy calculations indicate that the electrostatic screening from allosterically bound cations can affect the key residues at the catalytic site and active-site gorge, including E199. Furthermore, an increase in ion concentration can lead to lower reactivity, especially for Li+ ions, which exhibit more cation-hAChE contacts than Na+ and K+. The selective ion binding and their preferred modulation on hAChE are highly related to ion species. This work provides a molecular perspective on selective modulation by different ion species of the enzyme catalytic processes.

The indication and treatment outcome predictors of mifepristone treating ectopic pregnancy.

OBJECTIVE: Ectopic pregnancy is a life-threatening disease and is an important cause of pregnancy-related mortality. MTX is the primary conservative treatment medicine of ectopic pregnancy, and mifepristone is also a promising medicine. Through studying the ectopic cases at the third affiliated hospital of Sun Yat-Sen University, the study aims to analyze the indication and treatment outcome predictors of mifepristone. METHODS: The data of 269 ectopic pregnancy cases treated with mifepristone during the year 2011-2019 were retrospectively collected. Logistic-regression analysis was used to analyze the factors affiliated with the treatment outcome of mifepristone. Then ROC curve was used to analyze the indication and predictors. RESULTS: Through logistic-regression analysis, HCG is the only factor related to the treatment outcome of mifepristone. The AUC of ROC curve predicting treatment outcome with pre-treatment HCG is 0.715, and the cutoff value of ROC curve is 372.66 (sensitivity 0.752, specificity 0.619). The AUC of 0/4 ratio predicting the treatment outcome is 0.886, and the cutoff value is 0.3283 (sensitivity 0.967, specificity 0.683). The AUC of 0/7 ratio is 0.947, and the cutoff value is 0.3609 (sensitivity 1, specificity 0.828). CONCLUSIONS: Mifepristone can be used to treat ectopic pregnancy. HCG is the only factor related to the treatment outcome of mifepristone. Patients with HCG less than 372.66 U/L can be treated by mifepristone. If HCG descends more than 67.18% on the 4th day or 63.91% on the 7th day, it is more likely to have a successful treatment outcome. It is more precise to retest on the 7th day.

GRHL2 Regulation of Growth/Motility Balance in Luminal versus Basal Breast Cancer.

The transcription factor Grainyhead-like 2 (GRHL2) is a critical transcription factor for epithelial tissues that has been reported to promote cancer growth in some and suppress aspects of cancer progression in other studies. We investigated its role in different breast cancer subtypes. In breast cancer patients, GRHL2 expression was increased in all subtypes and inversely correlated with overall survival in basal-like breast cancer patients. In a large cell line panel, GRHL2 was expressed in luminal and basal A cells, but low or absent in basal B cells. The intersection of ChIP-Seq analysis in 3 luminal and 3 basal A cell lines identified conserved GRHL2 binding sites for both subtypes. A pathway analysis of ChIP-seq data revealed cell-cell junction regulation and epithelial migration as well as epithelial proliferation, as candidate GRHL2-regulated processes and further analysis of hub genes in these pathways showed similar regulatory networks in both subtypes. However, GRHL2 deletion in a luminal cell line caused cell cycle arrest while this was less prominent in a basal A cell line. Conversely, GRHL2 loss triggered enhanced migration in the basal A cells but failed to do so in the luminal cell line. ChIP-Seq and ChIP-qPCR demonstrated GRHL2 binding to CLDN4 and OVOL2 in both subtypes but not to other GRHL2 targets controlling cell-cell adhesion that were previously identified in other cell types, including CDH1 and ZEB1. Nevertheless, E-cadherin protein expression was decreased upon GRHL2 deletion especially in the luminal line and, in agreement with its selectively enhanced migration, only the basal A cell line showed concomitant induction of vimentin and N-cadherin. To address how the balance between growth reduction and aspects of EMT upon loss of GRHL2 affected in vivo behavior, we used a mouse basal A orthotopic transplantation model in which the GRHL2 gene was silenced. This resulted in reduced primary tumor growth and a reduction in number and size of lung colonies, indicating that growth suppression was the predominant consequence of GRHL2 loss. Altogether, these findings point to largely common but also distinct roles for GRHL2 in luminal and basal breast cancers with respect to growth and motility and indicate that, in agreement with its negative association with patient survival, growth suppression is the dominant response to GRHL2 loss.

Stiffening Effect of Ceramide on Lipid Membranes Provides Non-Sacrificial Protection against Potent Chemical Damage.

Ceramide is a sphingolipid that constitutes only a small fraction of membrane biomolecules but plays a central role in regulating many biological processes. The ceramide level in cell membranes can drastically increase in response to external damage, which has been hypothesized to involve ceramide's biophysical role that increases the membrane packing density and lowers the membrane permeability. However, direct observation of the consequent influence on membrane chemistry resulting from these ceramide-induced physical properties has been absent. Using our unique field-induced droplet ionization mass spectrometry technique combined with molecular dynamics simulations, here we report that the addition of ceramide to POPC monolayer membranes at the air-water interface greatly reduces the chemical damage from potent chemicals, •OH radicals, and HCl vapor, by stiffening the membrane packing and lowering the permeability. These results shed new light on the underlying chemoprotective role of ceramide in lipid membranes, which might serve as a previously unknown protection mechanism in response to external stimuli that cause cell stress or death.

Carbon Monoxide Poisoning and Chronic Kidney Disease Risk: A Nationwide, Population-Based Study.

INTRODUCTION: Patients with carbon monoxide poisoning (COP) commonly have long-term morbidities. However, it is not known whether patients with COP exhibit an increased risk of developing chronic kidney disease (CKD) and whether hyperbaric oxygen therapy (HBOT) alters this risk. METHODS: This study identified 8,618 patients who survived COP and 34,464 propensity score-matched non-COP patients from 2000 to 2013 in a nationwide administrative registry. The primary outcome was the development of CKD. The association between COP and the risk of developing CKD was estimated using a Cox proportional hazards regression model; the cumulated incidence of CKD among patients stratified by HBOT was evaluated using a Kaplan-Meier analysis. RESULTS: After adjusting for covariates, the risk of CKD was 6.15-fold higher in COP patients than in non-COP controls. Based on the subgroup analyses, regardless of demographic characteristics, environmental factors, and comorbidities, the COP cohort exhibited an increased risk of developing CKD compared with the controls. The cumulative incidence of CKD in COP patients did not differ between the HBOT and non-HBOT groups (p = 0.188). CONCLUSIONS: COP might be an independent risk factor for developing CKD. Thus, clinicians should enhance the postdischarge follow-up of kidney function among COP patients.

A double bilayer to study the nonequilibrium environmental response of GIRK2 in complex states.

G protein-gated inwardly rectifying potassium (GIRK) channels play essential roles in electrical signaling in neurons and muscle cells. Nonequilibrium environments provide crucial driving forces behind many cellular events. Here, we apply the antiparallel alignment double bilayer model to study GIRK2 in response to the time-dependent membrane potential. Using molecular dynamics and umbrella sampling, we examined the time-dependent environmental impact on the ion conduction, energy basis, and primary motions of GIRK2 in different complex states with phosphatidylinositol-4,5-bisphosphate (PIP2) and G-protein ßγ subunits (Gßγ). The antiparallel alignment double bilayer model enables us to study the transport performance in inward and outward K+ and mixed K+ and Na+. We obtained the recoverable discharge process of GIRK2 complexed with both PIP2 and Gßγ, compared with occasional conduction under PIP2-only regulation. Calculations of potential of mean force suggest different regulation by the helix bundle crossing (HBC) gate and G-loop gate regarding different complex states and under a membrane potential. In a nonequilibrium environment, distinct functional rocking motions of GIRK2 were identified under strengthened correlations between the transmembrane helices and downstream cytoplasmic domains with binding of PIP2, cations, and Gßγ. The findings suggest the potential domain motions and dynamics associated with a nonequilibrium environment and highlight the application of the antiparallel alignment double bilayer model to investigate factors in an asymmetric environment.

H-NS uses an autoinhibitory conformational switch for environment-controlled gene silencing.

As an environment-dependent pleiotropic gene regulator in Gram-negative bacteria, the H-NS protein is crucial for adaptation and toxicity control of human pathogens such as Salmonella, Vibrio cholerae or enterohaemorrhagic Escherichia coli. Changes in temperature affect the capacity of H-NS to form multimers that condense DNA and restrict gene expression. However, the molecular mechanism through which H-NS senses temperature and other physiochemical parameters remains unclear and controversial. Combining structural, biophysical and computational analyses, we show that human body temperature promotes unfolding of the central dimerization domain, breaking up H-NS multimers. This unfolding event enables an autoinhibitory compact H-NS conformation that blocks DNA binding. Our integrative approach provides the molecular basis for H-NS-mediated environment-sensing and may open new avenues for the control of pathogenic multi-drug resistant bacteria.

Effects of NAC and Gallic Acid on the Proliferation Inhibition and Induced Death of Lung Cancer Cells with Different Antioxidant Capacities.

N-acetylcysteine (NAC) is a recognized antioxidant in culture studies and treatments for oxidative stress-related diseases, but in some cases, NAC is a pro-oxidant. To study the effect of NAC on cell proliferation in the presence or absence of ROS stress, we used the stable ROS generator gallic acid (GA) to treat CL1-0 lung cancer cell models with different antioxidant activities. Different antioxidant activities were achieved through the ectopic expression of different PERP-428 single nucleotide polymorphisms. GA increased ROS levels in CL1-0/PERP-428C cells and caused cell death but had no effect on CL1-0/PERP-428G cells within 24 h. We found that 0.1 mM NAC eliminated GA-induced growth inhibition, but 0.5 mM NAC enhanced GA-induced CL1-0/PERP-428C cell death. However, in the absence of GA, NAC exceeding 2 mM inhibited the growth of CL1-0/PERP-428G cells more significantly than that of CL1-0/PERP-428C cells. Without GA, NAC has an antioxidant effect. Under GA-induced ROS stress, NAC may have pro-oxidant effects. Each cell type has a unique range of ROS levels for survival. The levels of ROS in the cell determines the sensitivity of the cell to an antioxidant or pro-oxidant. Cells with different antioxidant capacities were used to show that the intracellular ROS level affects NAC function and provides valuable information for the adjuvant clinical application of NAC.

BH3-in-groove dimerization initiates and helix 9 dimerization expands Bax pore assembly in membranes.

Pro-apoptotic Bax induces mitochondrial outer membrane permeabilization (MOMP) by forming oligomers through a largely undefined process. Using site-specific disulfide crosslinking, compartment-specific chemical labeling, and mutational analysis, we found that activated integral membrane Bax proteins form a BH3-in-groove dimer interface on the MOM surface similar to that observed in crystals. However, after the α5 helix was released into the MOM, the remaining interface with α2, α3, and α4 helices was rearranged. Another dimer interface was formed inside the MOM by two intersected or parallel α9 helices. Combinations of these interfaces generated oligomers in the MOM. Oligomerization was initiated by BH3-in-groove dimerization, without which neither the other dimerizations nor MOMP occurred. In contrast, α9 dimerization occurred downstream and was required for release of large but not small proteins from mitochondria. Moreover, the release of large proteins was facilitated by α9 insertion into the MOM and localization to the pore rim. Therefore, the BH3-in-groove dimerization on the MOM nucleates the assembly of an oligomeric Bax pore that is enlarged by α9 dimerization at the rim.

Higher Accuracy Achieved for Protein-Ligand Binding Pose Prediction by Elastic Network Model-Based Ensemble Docking.

Molecular docking plays an indispensable role in predicting the receptor-ligand interactions in which the protein receptor is usually kept rigid, whereas the ligand is treated as being flexible. Because of the inherent flexibility of proteins, the binding pocket of apo receptors might undergo significant conformational rearrangement upon ligand binding, which limits the prediction accuracy of docking. Here, we present an iterative anisotropic network model (iterANM)-based ensemble docking approach, which generates multiple holo-like receptor structures starting from the apo receptor and incorporates protein flexibility into docking. In a validation data set consisting of 233 chemically diverse cyclin-dependent kinase 2 (CDK2) inhibitors, the iterANM-based ensemble docking achieves higher capacity to reproduce native-like binding poses compared with those using single apo receptor conformation or conformational ensemble from molecular dynamics simulations. The prediction success rate within the top5-ranked binding poses produced by the iterANM can further be improved through reranking with the molecular mechanics-Poisson-Boltzmann surface area method. In a smaller data set with 58 CDK2 inhibitors, the iterANM-based ensemble shows a higher success rate compared with the flexible receptor-based docking procedure AutoDockFR and other receptor conformation generation approaches. Further, an additional docking test consisting of 10 diverse receptor-ligand combinations shows that the iterANM is robustly applicable for different receptor structures. These results suggest the iterANM-based ensemble docking as an accurate, efficient, and practical framework to predict the binding mode of a ligand for receptors with flexibility.

Life-threatening acute water intoxication in a woman undergoing hysteroscopic myomectomy: a case report and review of the literature.

BACKGROUND: Acute water intoxication after hysteroscopy is a rare, life-threatening condition, often accompanied with delayed diagnosis owing to masked symptoms because of general anesthesia. CASE PRESENTATION: Herein we presented a 39-year-old female who presented with cardiac arrest after hysteroscopic myomectomy because of acute water intoxication and survived after extracorporeal membrane oxygenation, continuous venous-venous hemofiltration, and aggressive high sodium fluid resuscitation. CONCLUSION: Failure to recognize and treat this condition appropriately may lead to potentially lethal cardiopulmonary complications.

"Printing" DNA Strand Patterns on Small Molecules with Control of Valency, Directionality, and Sequence.

The incorporation of synthetic molecules as corner units in DNA structures has been of interest over the last two decades. In this work, we present a facile method for generating branched small molecule-DNA hybrids with controllable valency, different sequences, and directionalities (5'-3') using a "printing" process from a simple 3-way junction structure. We also show that the DNA-imprinted small molecule can be extended asymmetrically using polymerase chain reaction (PCR) and can be replicated chemically. This strategy provides opportunities to achieve new structural motifs in DNA nanotechnology and introduce new functionalities to DNA nanostructures.

Capturing the multiscale dynamics of membrane protein complexes with all-atom, mixed-resolution, and coarse-grained models.

The structures and dynamics of protein complexes are often challenging to model in heterogeneous environments such as biological membranes. Herein, we meet this fundamental challenge at attainable cost with all-atom, mixed-resolution, and coarse-grained models of vital membrane proteins. We systematically simulated five complex models formed by two distinct G protein-coupled receptors (GPCRs) in the lipid-bilayer membrane on the ns-to-µs timescales. These models, which suggest the swinging motion of an intracellular loop, for the first time, provide the molecular details for the regulatory role of such a loop. For the models at different resolutions, we observed consistent structural stability but various levels of speed-ups in protein dynamics. The mixed-resolution and coarse-grained models show two and four times faster protein diffusion than the all-atom models, in addition to a 4- and 400-fold speed-up in the simulation performance. Furthermore, by elucidating the strengths and challenges of combining all-atom models with reduced resolution models, this study can serve as a guide to simulating other complex systems in heterogeneous environments efficiently.

Emphysematous cholecystitis presenting as gas-forming liver abscess and pneumoperitoneum in a dialysis patient: a case report and review of the literature.

BACKGROUND: Emphysematous cholecystitis is a rare variant of acute cholecystitis with a high mortality rate. The combination of emphysematous cholecystitis, liver abscess and pneumoperitoneum are even rarer. Herein we present a case of emphysematous cholecystitis in a senile diabetic lady who had worsening hemodynamics while undergoing hemodialysis. CASE PRESENTATION: A 64-year-old woman with history of type 2 diabetes mellitus and end stage renal disease with regular hemodialysis presented to the emergency department with a 1-day history of sudden onset of lassitude and hypotension during hemodialysis. The result of a computed tomography (CT)-scan revealed air encircling the gallbladder, liver parenchymal and minimal pneumoperitoneal and liver abscess with no cholelithiasis. The patient had received empirical antibiotics with piperacillin-tazobactam 2.25 g intravenous route every 6 h for 14 days and cholecystectomy with surgical debridement and lead an uneventful postoperative hospital course. Escherichia coli was demonstrated as well as blood culture and peritoneal fluid culture. CONCLUSION: In a senile diabetic and dialysis patient, we should take emphysematous cholecystitis into consideration once vague abdominal pain occurrs. Empirical antibiotic therapy and adequate surgical intervention should take place as soon as possible.

Plantar Purpura as the Initial Presentation of Viridians Streptococcal Shock Syndrome Secondary to Streptococcus gordonii Bacteremia.

Viridians streptococcal shock syndrome is a subtype of toxic shock syndrome. Frequently, the diagnosis is missed initially because the clinical features are nonspecific. However, it is a rapidly progressive disease, manifested by hypotension, rash, palmar desquamation, and acute respiratory distress syndrome within a short period. The disease course is generally fulminant and rarely presents initially as a purpura over the plantar region. We present a case of a 54-year-old female hospital worker diagnosed with viridians streptococcal shock syndrome caused by Streptococcus gordonii. Despite aggressive antibiotic treatment, fluid hydration, and use of inotropes and extracorporeal membrane oxygenation, the patient succumbed to the disease. Early diagnosis of the potentially fatal disease followed by a prompt antibiotic regimen and appropriate use of steroids are cornerstones in the management of this disease to reduce the risk of high morbidity and mortality.

The differential roles of Slit2-exon 15 splicing variants in angiogenesis and HUVEC permeability.

Slit2, a secreted glycoprotein, is down-regulated in many cancers. Slit2/Robo signaling pathway plays an important, but controversial, role in angiogenesis. We identified splicing variants of Slit2 at exon 15, Slit2-WT and Slit2-ΔE15, with differential effects on proliferation and invasive capability of lung cancer cells. The aim of this study was to elucidate the differential roles of these exon 15 splicing variants in angiogenesis. Our results revealed that both Slit2-WT and Slit2-ΔE15 inhibit motility of human umbilical vein endothelial cells (HUVECs). The conditioned medium (CM) collected from CL1-5/VC or CL1-5/Slit2-WT lung adenocarcinoma cells blocked HUVEC tube formation and angiogenesis on chorioallantoic membrane (CAM) assay when compared with untreated HUVECs and CAM, respectively. However, CM of CL1-5/Slit2-ΔE15 restored the quality of tubes and the size of vessels. Although both Slit2-WT and Slit2-ΔE15 inhibited permeability induced by CM of cancer cells, Slit2-ΔE15 exhibited stronger effect. These results suggested that Slit2-ΔE15 plays important roles in normalization of blood vessels by enhancing tube quality and tightening endothelial cells, while Slit2-WT only enhances tightening of endothelial cells. It appears that Robo4 is responsible for Slit2 isoform-mediated inhibition of permeability, while neither Robo1 nor Robo4 is required for Slit2-ΔE15-enhanced tube quality. The results of this study suggest that Slit2-ΔE15 splicing form is a promising molecule for normalizing blood vessels around a tumor, which, in turn, may increase efficacy of chemotherapy and radiotherapy.

Dysphagia aortica: a fatal delay in diagnosis.

Extrinsic esophageal compression leading to dysphagia is an uncommon and late presentation of large thoracic aortic aneurysm named dysphagia aortica. Herein, we report an 86-year-old man who presented with 1-week duration of chest pain, backache, and dysphagia and was eventually diagnosed as dysphagia aortica. Our patient developed progressive dyspnea due to tracheal compression and failed surgery. The case illustrates the importance of early identification of the rare entity of dysphagia especially in elderly cases with cardiovascular disease with complaint of undetermined dysphagia accompanied with chest pain and backache.

Regulating Molecular Recognition with C-Shaped Strips Attained by Chirality-Assisted Synthesis.

Chirality-assisted synthesis (CAS) is a general approach to control the shapes of large molecular strips. CAS is based on enantiomerically pure building blocks that are designed to strictly couple in a single geometric orientation. Fully shape-persistent structures can thus be created, even in the form of linear chains. With CAS, selective recognition between large host and guest molecules can reliably be designed de novo. To demonstrate this concept, three C-shaped strips that can embrace a pillar[5]arene macrocycle were synthesized. The pillar[5]arene bound to the strips was a better host for electron-deficient guests than the free macrocycle. Experimental and computational evidence is provided for these unique cooperative interactions to illustrate how CAS could open the door towards the precise positioning of functional groups for regulated supramolecular recognition and catalysis.