Pressure-induced postsynthetic cluster anion substitution in a MIL-53 topology scandium metal-organic framework.

Postsynthetic modification of metal-organic frameworks (MOFs) has proven to be a hugely powerful tool to tune physical properties and introduce functionality, by exploiting reactive sites on both the MOF linkers and their inorganic secondary building units (SBUs), and so has facilitated a wide range of applications. Studies into the reactivity of MOF SBUs have focussed solely on removal of neutral coordinating solvents, or direct exchange of linkers such as carboxylates, despite the prevalence of ancillary charge-balancing oxide and hydroxide ligands found in many SBUs. Herein, we show that the µ2-OH ligands in the MIL-53 topology Sc MOF, GUF-1, are labile, and can be substituted for µ2-OCH3 units through reaction with pore-bound methanol molecules in a very rare example of pressure-induced postsynthetic modification. Using comprehensive solid-state NMR spectroscopic analysis, we show an order of magnitude increase in this cluster anion substitution process after exposing bulk samples suspended in methanol to a pressure of 0.8 GPa in a large volume press. Additionally, single crystals compressed in diamond anvil cells with methanol as the pressure-transmitting medium have enabled full structural characterisation of the process across a range of pressures, leading to a quantitative single-crystal to single-crystal conversion at 4.98 GPa. This unexpected SBU reactivity - in this case chemisorption of methanol - has implications across a range of MOF chemistry, from activation of small molecules for heterogeneous catalysis to chemical stability, and we expect cluster anion substitution to be developed into a highly convenient novel method for modifying the internal pore surface and chemistry of a range of porous materials.

The role of the gut-microbiome-brain axis in metabolic remodeling amongst children with cerebral palsy and epilepsy.

Background: Epilepsy-associated dysbiosis in gut microbiota has been previously described, but the mechanistic roles of the gut microbiome in epileptogenesis among children with cerebral palsy (CP) have yet to be illustrated. Methods: Using shotgun metagenomic sequencing coupled with untargeted metabolomics analysis, this observational study compared the gut microbiome and metabolome of eight children with non-epileptic cerebral palsy (NECP) to those of 13 children with cerebral palsy with epilepsy (CPE). Among children with CPE, 8 had drug-sensitive epilepsy (DSE) and five had drug-resistant epilepsy (DRE). Characteristics at enrollment, medication history, and 7-day dietary intake were compared between groups. Results: At the species level, CPE subjects had significantly lower abundances of Bacteroides fragilis and Dialister invisus but higher abundances of Phascolarctobacterium faecium and Eubacterium limosum. By contrast, DRE subjects had a significantly higher colonization of Veillonella parvula. Regarding microbial functional pathways, CPE subjects had decreased abundances of pathways for serine degradation, quinolinic acid degradation, glutamate degradation I, glycerol degradation, sulfate reduction, and nitrate reduction but increased abundances of pathways related to ethanol production. As for metabolites, CPE subjects had higher concentrations of kynurenic acid, 2-oxindole, dopamine, 2-hydroxyphenyalanine, 3,4-dihydroxyphenylglycol, L-tartaric acid, and D-saccharic acid; DRE subjects had increased concentrations of indole and homovanilic acid. Conclusions: In this study, we found evidence of gut dysbiosis amongst children with cerebral palsy and epilepsy in terms of gut microbiota species, functional pathways, and metabolites. The combined metagenomic and metabolomic analyses have shed insights on the potential roles of B. fragilis and D. invisus in neuroprotection. The combined analyses have also provided evidence for the involvement of GMBA in the epilepsy-related dysbiosis of kynurenine, serotonin, and dopamine pathways and their complex interplay with neuroimmune and neuroendocrinological pathways.

CNS-Sparing Histamine H3 Receptor Antagonist as a Candidate to Prevent the Diabetes-Associated Gastrointestinal Symptoms.

Among the histamine receptors, growing evidence points to the histamine H3 receptor as a pharmacological candidate to counteract the autonomic neuropathy associated with diabetes. The study aimed to evaluate the effect of PF00868087 (also known as ZPL-868), a CNS-sparing histamine H3 receptor antagonist, on the autonomic neuropathy of the intestinal tract associated with diabetes. Diabetes was induced in male BALB/c mice by a single high dose of streptozotocin (150 mg/kg). Colorectal specimens from control and diabetic mice, randomized to vehicle or PF0086087 (10, 30, 100 mg/kg/day by oral gavage for 14 days), were processed for morphological and immunohistochemical analysis. A significant overproduction of mucus in the intestinal mucosa of diabetic mice compared to the controls was observed. PF0086087 at the highest dose prevented mucin overproduction. The immunohistochemistry analysis demonstrated that diabetes causes a decrease in the inhibitory component of enteric motility, measured as the percentage of neuronal nitric oxide synthase-positive neurons (p < 0.05) and a parallel increase in the excitatory component evaluated as substance P-positive fibres (p < 0.01). PF0086087 dose-dependently prevented these pathophysiological events. In conclusion, PF0086087 may be an essential tool in preventing nitrergic dysfunction in the myenteric plexus of the distal colon and diabetes-induced gastrointestinal complications.

Feasibility of modified-TEP technique for large inguinoscrotal and large femoral hernia and its advantages.

PURPOSE: To describe the feasibility of modified-TEP technique in reducing dead space in large inguinoscrotal and large femoral hernia to prevent seroma, reduce recurrence and complications. METHODS: This is a case series of patients who have completed a minimum of 9 months follow-up after undergoing elective endo-laparoscopic inguinal hernia repair with modified-TEP technique for large inguinoscrotal and large femoral hernia in a single institution from June to October 2020. RESULTS: 14 large inguinoscrotal hernia and 4 large femoral hernia were repaired using the modified-TEP technique in 15 patients. These patients reported minimal pain after surgery. There were no reported seroma, complications or recurrences up to 9 months follow-up period. CONCLUSION: Modified-TEP technique for large inguinoscrotal and large femoral hernia has shown good outcomes and patients reported minimum levels of pain. In experienced hands, it is safe, feasible and effective in reducing seroma formation and hernia recurrence.

Oncogenic cooperation between TCF7-SPI1 and NRAS(G12D) requires ß-catenin activity to drive T-cell acute lymphoblastic leukemia.

Spi-1 Proto-Oncogene (SPI1) fusion genes are recurrently found in T-cell acute lymphoblastic leukemia (T-ALL) cases but are insufficient to drive leukemogenesis. Here we show that SPI1 fusions in combination with activating NRAS mutations drive an immature T-ALL in vivo using a conditional bone marrow transplant mouse model. Addition of the oncogenic fusion to the NRAS mutation also results in a higher leukemic stem cell frequency. Mechanistically, genetic deletion of the ß-catenin binding domain within Transcription factor 7 (TCF7)-SPI1 or use of a TCF/ß-catenin interaction antagonist abolishes the oncogenic activity of the fusion. Targeting the TCF7-SPI1 fusion in vivo with a doxycycline-inducible knockdown results in increased differentiation. Moreover, both pharmacological and genetic inhibition lead to down-regulation of SPI1 targets. Together, our results reveal an example where TCF7-SPI1 leukemia is vulnerable to pharmacological targeting of the TCF/ß-catenin interaction.

Using yeast surface display to engineer a soluble and crystallizable construct of hematopoietic progenitor kinase 1 (HPK1).

Hematopoietic progenitor kinase 1 (HPK1) is an intracellular kinase that plays an important role in modulating tumor immune response and thus is an attractive target for drug discovery. Crystallization of the wild-type HPK1 kinase domain has been hampered by poor expression in recombinant systems and poor solubility. In this study, yeast surface display was applied to a library of HPK1 kinase-domain variants in order to select variants with an improved expression level and solubility. The HPK1 variant with the most improved properties contained two mutations, crystallized readily in complex with several small-molecule inhibitors and provided valuable insight to guide structure-based drug design. This work exemplifies the benefit of yeast surface display towards engineering crystallizable proteins and thus enabling structure-based drug discovery.

Rapid Access to Azabicyclo[3.3.1]nonanes by a Tandem Diverted Tsuji-Trost Process.

A three-step synthesis of the 2-azabicyclo[3.3.1]nonane ring system from simple pyrroles, employing a combined photochemical/palladium-catalysed approach is reported. Substrate scope is broad, allowing the incorporation of a wide range of functionality relevant to medicinal chemistry. Mechanistic studies demonstrate that the process occurs by acid-assisted C-N bond cleavage followed by ß-hydride elimination to form a reactive diene, demonstrating that efficient control of what might be considered off-cycle reactions can result in productive tandem catalytic processes. This represents a short and versatile route to the biologically important morphan scaffold.

Optimal timing of hepatitis B virus DNA quantification and clinical predictors for higher viral load during pregnancy.

INTRODUCTION: Authorities publish recommendations on the hepatitis B virus (HBV) viral load threshold to initiate antiviral treatment but the timing of quantification during pregnancy is not well defined. HBV DNA levels in pregnancy women at 28-30 weeks predict the risk of immunoprophylaxis failure. This study compared and evaluated the correlation between HBV DNA levels before 22 and 28-30 weeks' gestation. Clinical predictive factors for HBV DNA >6, 7 and 8 log10  IU/mL were studied. MATERIAL AND METHODS: A retrospective analysis of HBV DNA levels of women <22 and 28-30 weeks of gestation was carried out in 352 pregnant HBV carriers. HBV DNA was examined using the COBAS TaqMan HBV Monitor Test coupled with the COBAS Ampliprep extraction system (Both Roche Diagnostics, Branchburg, NJ, USA). RESULTS: A strong positive correlation was found between the viral loads of women <22 weeks (mean 16.7 weeks) and 28-30 weeks of gestation, which was independent of the viral load level and gestational age of quantification (r = 0.942, P < 0.001). Univariate analysis showed that positive hepatitis B e antigen (HBeAg), maternal age <35 years old and body mass index ≤21 kg/m2 were associated with a higher mean viral load at 28-30 weeks of gestation (P < 0.05). These factors were also associated with a higher chance of viral load >6, 7 and 8 log10  IU/mL at 28-30 weeks (P < 0.05). In multiple regression analysis, only the viral load of <22 weeks and positive HBeAg remained predictive of a higher mean viral load at 28-30 weeks of gestation (P < 0.05). The receiver operating characteristic curve showed that the HBV DNA of <22 weeks was an excellent predictor for different viral load cut-offs at 28-30 weeks. The area under curve was 0.986, 0.998 and 0.994 for viral load 6, 7 and 8 log10  IU/mL, respectively. CONCLUSIONS: HBV DNA quantification should be performed before 22 weeks of gestation. Viral load cut-offs similar to those at 28 weeks can be used to determine immunoprophylaxis failure at earlier gestation. Maternal positive HBeAg status was associated with a higher chance of viral load >6, 7 or 8 log10  IU/mL.

One-Dimensional-Like Titania/4'-Pentyl-4-Biphenylcarbonitrile Composite Synthesized Under Magnetic Field and its Structure-Photocatalytic Activity Relationship.

The demonstration of the structure-properties relationship of shape-dependent photocatalysts remains a challenge today. Herein, one-dimensional (1-D)-like titania (TiO2), as a model photocatalyst, has been synthesized under a strong magnetic field in the presence of a magnetically responsive liquid crystal as the structure-aligning agent to demonstrate the relationship between a well-aligned structure and its photocatalytic properties. The importance of the 1-D-like TiO2 and its relationship with the electronic structures that affect the electron-hole recombination and the photocatalytic activity need to be clarified. The synthesis of 1-D-like TiO2 with liquid crystal as the structure-aligning agent was carried out using the sol-gel method under a magnetic field (0.3 T). The mixture of liquid crystal, 4'-pentyl-4-biphenylcarbonitrile (5CB), tetra-n-butyl orthotitanate (TBOT), 2-propanol, and water, was subjected to slow hydrolysis under a magnetic field. The TiO2-5CB took a well-aligned whiskerlike shape when the reaction mixture was placed under the magnetic field, while irregularly shaped TiO2-5CB particles were formed when no magnetic field was applied. It shows that the strong interaction between 5CB and TBOT during the hydrolysis process under a magnetic field controls the shape of titania. The intensity of the emission peaks in the photoluminescence spectrum of 1-D-like TiO2-5CB was lowered compared with the TiO2-5CB synthesized without the magnetic field, suggesting the occurrence of electron transfer from 5CB to the 1-D-like TiO2-5CB during ultraviolet irradiation. Apart from that, direct current electrical conductivity and Hall effect studies showed that the 1-D-like TiO2 composite enhanced electron mobility. Thus, the recombination of electrons and holes was delayed due to the increase in electron mobility; hence, the photocatalytic activity of the 1-D-like TiO2 composite in the oxidation of styrene in the presence of aqueous hydrogen peroxide under UV irradiation was enhanced. This suggests that the 1-D-like shape of TiO2 composite plays an important role in its photocatalytic activity.

Short, Gram-Scale Syntheses of ß- and γ-Lycorane Using Two Distinct Photochemical Approaches.

The synthesis of two diastereomeric members of the lycorane alkaloid family is reported. Although the routes are quite different in their approach, both involve the use of photochemistry as a key step, enabling the synthesis of gram quantities in the case of ß-lycorane.

Treatment of Rapidly Progressive Glomerulonephritis in the Elderly.

As the population worldwide ages, the epidemic of kidney disease will also increase. Anti-neutrophil cytoplasmic antibodies (ANCA) positive rapidly progressive positive glomerulonephritis (RPGN) is the most common etiology for biopsied patients among the very elderly. Its pathological features and clinical course are well described, though there is still debate about the mechanism of injury involved in individual patients. From very ancient times, the cornerstone of treatment historically has been high-dose cyclophosphamide and a lengthy course of high-dose corticosteroids. Although this regimen has diminished the immediate mortality rate of RPGN, its intermediate and long-term adverse effects are not insignificant. Attempts to minimize toxicity and improve efficacy have been made through the years to allow physicians some options for therapy. Lower cumulative cyclophosphamide regimens, shorter corticosteroid courses, and the introduction of rituximab have modified the armamentarium for treatment of ANCA positive RPGN. As progress is made in understanding the molecular pathogenesis of this disease, new targets will be found for potential therapeutic attack. The complement system is an area of active interest for all glomerular diseases at this time. Indeed, animal studies and preliminary human studies suggest that targeting the complement system can ameliorate the course of ANCA-positive RPGN. Hopefully, as the population ages, we will see more and safer therapeutic options to treat this once rapidly fatal disease.

Limb derived cells as a paradigm for engineering self-assembling skeletal tissues.

Mimicking developmental events has been proposed as a strategy to engineer tissue constructs for regenerative medicine. However, this approach has not yet been investigated for skeletal tissues. Here, it is demonstrated that ectopic implantation of day-14.5 mouse embryonic long bone anlagen, dissociated into single cells and randomly incorporated in a bioengineered construct, gives rise to epiphyseal growth plate-like structures, bone and marrow, which share many morphological and molecular similarities to epiphyseal units that form after transplanting intact long bone anlage, demonstrating substantial robustness and autonomy of complex tissue self-assembly and the overall organogenesis process. In vitro studies confirm the self-aggregation and patterning capacity of anlage cells and demonstrate that the model can be used to evaluate the effects of large and small molecules on biological behaviour. These results reveal the preservation of self-organizing and self-patterning capacity of anlage cells even when disconnected from their developmental niche and subjected to system perturbations such as cellular dissociation. These inherent features make long bone anlage cells attractive as a model system for tissue engineering technologies aimed at creating constructs that have the potential to self-assemble and self-pattern complex architectural structures.

Harvesting Environmental Microalgal Blooms for Remediation and Resource Recovery: A Laboratory Scale Investigation with Economic and Microbial Community Impact Assessment.

A laboratory based microflotation rig termed efficient FLOtation of Algae Technology (eFLOAT) was used to optimise parameters for harvesting microalgal biomass from eutrophic water systems. This was performed for the dual objectives of remediation (nutrient removal) and resource recovery. Preliminary experiments demonstrated that chitosan was more efficient than alum for flocculation of biomass and the presence of bacteria could play a positive role and reduce flocculant application rates under the natural conditions tested. Maximum biomass removal from a hyper-eutrophic water retention pond sample was achieved with 5 mg·L-1 chitosan (90% Chlorophyll a removal). Harvesting at maximum rates showed that after 10 days, the bacterial diversity is significantly increased with reduced cyanobacteria, indicating improved ecosystem functioning. The resource potential within the biomass was characterized by 9.02 µg phosphate, 0.36 mg protein, and 103.7 µg lipid per mg of biomass. Fatty acid methyl ester composition was comparable to pure cultures of microalgae, dominated by C16 and C18 chain lengths with saturated, monounsaturated, and polyunsaturated fatty acids. Finally, the laboratory data was translated into a full-size and modular eFLOAT system, with estimated costs as a novel eco-technology for efficient algal bloom harvesting.

Wortmannin Attenuates Seizure-Induced Hyperactive PI3K/Akt/mTOR Signaling, Impaired Memory, and Spine Dysmorphology in Rats.

Numerous studies have shown epilepsy-associated cognitive deficits, but less is known about the effects of one single generalized seizure. Recent studies demonstrate that a single, self-limited seizure can result in memory deficits and induces hyperactive phosphoinositide 3-kinase/Akt (protein kinase B)/mechanistic target of rapamycin (PI3K/Akt/mTOR) signaling. However, the effect of a single seizure on subcellular structures such as dendritic spines and the role of aberrant PI3K/Akt/mTOR signaling in these seizure-induced changes are unclear. Using the pentylenetetrazole (PTZ) model, we induced a single generalized seizure in rats and: (1) further characterized short- and long-term hippocampal and amygdala-dependent memory deficits, (2) evaluated whether there are changes in dendritic spines, and (3) determined whether inhibiting hyperactive PI3K/Akt/mTOR signaling rescued these alterations. Using the PI3K inhibitor wortmannin (Wort), we partially rescued short- and long-term memory deficits and altered spine morphology. These studies provide evidence that pathological PI3K/Akt/mTOR signaling plays a role in seizure-induced memory deficits as well as aberrant spine morphology.

Corneal Refractive Procedures for the Treatment of Presbyopia.

PURPOSE: Refractive surgery has been in use for a long time and is evolving at a fast pace with several new corneal procedures being used for the correction of presbyopia. The purpose of this article is to give a comprehensive review of the literature to evaluate the outcome and success of different corneal refractive surgical procedures in presbyopic patients. METHODS: We performed a comprehensive search on PubMed to identify published reports of the various procedures utilized in the past and present to correct presbyopia. The outcomes of these procedures were recorded. RESULTS AND CONCLUSION: We found that varying rates of success have been reported with these procedures. The results of our exhaustive search are presented in this report for review.

Crosstalk between astrocytic CXCL12 and microglial CXCR4 contributes to the development of neuropathic pain.

BACKGROUND: Chemokine axis chemokine C-X-C motif ligand 12/C-X-C chemokine receptor type 4 (CXCL12/CXCR4) is an emerging pain modulator, but mechanisms for its involvement in neuropathic pain remain unclear. Here, we aimed to study whether CXCL12/CXCR4 axis modulated the development of neuropathic pain via glial mechanisms. In this study, two mouse models of neuropathic pain, namely partial sciatic nerve ligation (pSNL) model and chronic post-ischemia pain (CPIP) model, were used. RESULTS: In the dorsal horn of L3-L5 segment of spinal cord, CXCL12 and CXCR4 were expressed in both astrocyte and microglia in normal mice. In the pSNL or CPIP model, the expression level of CXCL12 in the ipsilateral L3-L5 segment of mice spinal cord was increased in an astrocyte-dependent manner on post-operative day (POD) 3. Intrathecal administration of CXCL12 with AMD3100 (CXCR4 antagonist) or minocycline (microglia activation inhibitor), but not fluorocitrate (astrocyte activation inhibitor), reversed CXCL12-indued mechanical allodynia in naïve mice. In these models, AMD3100 and AMD3465 (CXCR4 antagonist), administered daily from 1 h before surgery and up to POD 3, attenuated the development of mechanical allodynia. Moreover, AMD3100 administered daily from 1 h before surgery and up to POD 3 downregulated mRNA levels of tumor necrosis factor alpha, interleukin 1ß, and interleukin 6 in the ipsilateral L3-L5 segment of spinal cord in the pSNL and CPIP models on POD 3. CONCLUSION: This study demonstrates the crosstalk between astrocytic CXCL12 and microglial CXCR4 in the pathogenesis of neuropathic pain using pSNL and CPIP models. Our results offer insights for the future research on CXCL12/CXCR4 axis and neuropathic pain therapy.

International Union of Basic and Clinical Pharmacology. XCVIII. Histamine Receptors.

Histamine is a developmentally highly conserved autacoid found in most vertebrate tissues. Its physiological functions are mediated by four 7-transmembrane G protein-coupled receptors (H1R, H2R, H3R, H4R) that are all targets of pharmacological intervention. The receptors display molecular heterogeneity and constitutive activity. H1R antagonists are long known antiallergic and sedating drugs, whereas the H2R was identified in the 1970s and led to the development of H2R-antagonists that revolutionized stomach ulcer treatment. The crystal structure of ligand-bound H1R has rendered it possible to design new ligands with novel properties. The H3R is an autoreceptor and heteroreceptor providing negative feedback on histaminergic and inhibition on other neurons. A block of these actions promotes waking. The H4R occurs on immuncompetent cells and the development of anti-inflammatory drugs is anticipated.

Histamine H4 receptor antagonists for the treatment of inflammatory disorders.

Since its initial discovery by Sir Henry Dale and Patrick Laidlaw in 1910, the biogenic amine histamine has been one of the most widely researched molecules in science. H4R, the newest member of the histamine receptor family, was first identified at the turn of the millennium. Its predominant expression on inflammatory cells and lymphoid tissues, coupled with a key role in processes ranging from chemotaxis to cytokine release, suggests it could command an important role in immune and inflammatory responses.

Rapamycin reverses status epilepticus-induced memory deficits and dendritic damage.

Cognitive impairments are prominent sequelae of prolonged continuous seizures (status epilepticus; SE) in humans and animal models. While often associated with dendritic injury, the underlying mechanisms remain elusive. The mammalian target of rapamycin complex 1 (mTORC1) pathway is hyperactivated following SE. This pathway modulates learning and memory and is associated with regulation of neuronal, dendritic, and glial properties. Thus, in the present study we tested the hypothesis that SE-induced mTORC1 hyperactivation is a candidate mechanism underlying cognitive deficits and dendritic pathology seen following SE. We examined the effects of rapamycin, an mTORC1 inhibitor, on the early hippocampal-dependent spatial learning and memory deficits associated with an episode of pilocarpine-induced SE. Rapamycin-treated SE rats performed significantly better than the vehicle-treated rats in two spatial memory tasks, the Morris water maze and the novel object recognition test. At the molecular level, we found that the SE-induced increase in mTORC1 signaling was localized in neurons and microglia. Rapamycin decreased the SE-induced mTOR activation and attenuated microgliosis which was mostly localized within the CA1 area. These findings paralleled a reversal of the SE-induced decreases in dendritic Map2 and ion channels levels as well as improved dendritic branching and spine density in area CA1 following rapamycin treatment. Taken together, these findings suggest that mTORC1 hyperactivity contributes to early hippocampal-dependent spatial learning and memory deficits and dendritic dysregulation associated with SE.