Clinical diagnosis of viral hepatitis: Current status and future strategies.

Viral hepatitis (VH) is a significant public health issue with tremendous potential to aggravate into chronic hepatitis, liver cirrhosis, and hepatocellular carcinoma. Recent decade has witnessed remarkable uprising in the drug development and effective treatment of VH. An upsurge is seen in identification of antiviral therapies with low rates of viral resistance, the improvement of Hepatitis B Virus (HBV) vaccination and the development of direct-acting antivirals for Hepatitis C Virus (HCV). But unfortunately, the "2030 worldwide eradication" objective of World Health Organization (WHO) is still unmet. It can be largely attributed to the deficit faced by the healthcare system concerning screening and diagnosis. A timely, accurate and comprehensive screening; encompassing maximum population coverage is essential to combat this disease. However, advancements in VH diagnostics remain inadequate and with a marginal use in routine practice. This paper deliberates upon the lacunae in traditional and prevailing diagnostic methodology of viral hepatitis, especially their inadequacy in meeting the unique situations prevailing low- and middle-income countries (LMIC).

Intracranial Interdural and Extradural Cerebellar Convexity Dermoid Cyst: A Case Report of Rare Tumor at the Rarest Location.

Intracranial dermoid cysts are rare dysembryonic tumors of benign nature. These are uncommon in adults. If present, they are usually located in the midline or along the lines of embryonic fusion. The posterior fossa region is an infrequent site. Extradural or interdural locations are even more rare. In this case report, the authors report a laterally located large posterior fossa right cerebellar convexity interdural and extradural dermoid cyst over the sigmoid sinus. It was managed by totally extradural maximum possible safe decompression with microneurosurgical technique. The authors share their experience of addressing this rare pathology at the rarest location with unusual imaging findings.

Recent Advances in Nanomechanical Measurements and Their Application for Pharmaceutical Crystals.

Mechanical behavior of pharmaceutical crystals directly impacts the formulation development and manufacturing of drug products. The understanding of crystal structure-mechanical behavior of pharmaceutical and molecular crystals has recently gained substantial attention among pharmaceutical and materials scientists with the advent of advanced nanomechanical testing instruments like nanoindentation. For the past few decades, instrumented nanoindentation was a popular technique for measuring the mechanical properties of thin films and small-length scale materials. More recently it is being implemented to investigate the mechanical properties of pharmaceutical crystals. Integration of correlative microscopy techniques and environmental control opened the door for advanced structure-property correlation under processing conditions. Preventing the degradation of active pharmaceutical ingredients from external factors such as humidity, temperature, or pressure is important during processing. This review deals with the recent developments in the synchronized nanomechanical measurements of pharmaceutical crystals toward the fast and effective development of high-quality pharmaceutical drug products. This review also summarizes some recent reports to intensify how one can design and control the nanomechanical properties of pharmaceutical solids. Measurement challenges and the scope for studying nanomechanical properties of pharmaceutical crystals using nanoindentation as a function of crystal structure and in turn to develop fundamental knowledge in the structure-property relationship with the implications for drug manufacturing and development are discussed in this review. This review further highlights recently developed capabilities in nanoindentation, for example, variable temperature nanoindentation testing, in situ imaging of the indented volume, and nanoindentation coupled Raman spectroscopy that can offer new quantitative details on nanomechanical behavior of crystals and will play a decisive role in the development of coherent theories for nanomechanical study of pharmaceutical crystal.

The repertoire of mutational signatures in tobacco- and non-tobacco-induced oral cancer.

The use of tobacco products is one of the established contributors toward the development and spread of oral cancer. Additionally, recent research has indicated oral microbiome, infections with Human papilloma virus (HPV), Epstein-Barr virus (EBV), Candida as significant contributing factors to this disease along with lifestyle habits. Deregulation of cellular pathways envisaging metabolism, transcription, translation, and epigenetics caused by these risk factors either individually or in unison is manifold, resulting in the increased risk of oral cancer. Globally, this cancer continues to exist as one of the major causes of cancer-related mortalities; the numbers in the developing South Asian countries clearly indicate yearly escalation. This review encompasses the variety of genetic modifications, including adduct formation, mutation (duplication, deletion, and translocation), and epigenetic changes evident in oral squamous cell carcinoma (OSCC). In addition, it highlights the interference caused by tobacco products in Wnt signaling, PI3K/Akt/mTOR, JAK-STAT, and other important pathways. The information provided also ensures a comprehensive and critical revisit to non-tobacco-induced OSCC. Extensive literature survey and analysis has been conducted to generate the chromosome maps specifically highlighting OSCC-related mutations with the potential to act as spectacles for the early diagnosis and targeted treatment of this disease cancer.

Genic-intergenic polymorphisms of CYP1A genes and their clinical impact.

The humancytochrome P450 1A (CYP1A) subfamily genes, CYP1A1 and CYP1A2, encoding monooxygenases are critically involved in biotransformation of key endogenous substrates (estradiol, arachidonic acid, cholesterol) and exogenous compounds (smoke constituents, carcinogens, caffeine, therapeutic drugs). This suggests their significant involvement in multiple biological pathways with a primary role of maintaining endogenous homeostasis and xenobiotic detoxification. Large interindividual variability exist in CYP1A gene expression and/or catalytic activity of the enzyme, which is primarily due to the existence of polymorphic alleles which encode them. These polymorphisms (mainly single nucleotide polymorphisms, SNPs) have been extensively studied as susceptibility factors in a spectrum of clinical phenotypes. An in-depth understanding of the effects of polymorphic CYP1A genes on the differential metabolic activity and the resulting biological pathways is needed to explain the clinical implications of CYP1A polymorphisms. The present review is intended to provide an integrated understanding of CYP1A metabolic activity with unique substrate specificity and their involvement in physiological and pathophysiological roles. The article further emphasizes on the impact of widely studied CYP1A1 and CYP1A2 SNPs and their complex interaction with non-genetic factors like smoking and caffeine intake on multiple clinical phenotypes. Finally, we attempted to discuss the alterations in metabolism/physiology concerning the polymorphic CYP1A genes, which may underlie the reported clinical associations. This knowledge may provide insights into the disease pathogenesis, risk stratification, response to therapy and potential drug targets for individuals with certain CYP1A genotypes.

CO2 capture from ambient air via crystallization with tetraalkylammonium hydroxides.

Aqueous solutions of a series of short carbon chain tetra(n-alkyl)ammonium hydroxides, [Nnnnn][OH] with n = 2: n-ethyl, 3: n-propyl, 4: n-butyl, have been serendipitously found to be potential candidates for direct air carbon capture (DAC) when being used as reagents in more complicated reactions. Aqueous solutions of [N3333][OH], [N2222][OH], or [N3333][OH] with UO2SO4·3H2O and 1,4-diamidoximylbenzene, and [N4444][OH] with cytosine (HCyt) directly absorb CO2 from the atmosphere upon mild heating in the open atmosphere crystallizing in complexes reaching up to 2 : 1 CO2/[Nnnnn]OH ratio. [N2222][HCO3]·3H2O (1), [N2222]2[H(HCO3)3]·5H2O (2), [N3333][HCO3]·0.5H2O (3), [N3333][H(HCO3)2] (4), [N3333]2[(tpa)(H2CO3)2] (5; tpa = terephthalate), [N4444][H(Cyt)(HCO3)]·H2O (6) and [N4444][H2(Cyt)2(HCO3)]·H2O (7) have been isolated in crystalline form and structurally characterized by single crystal X-ray diffraction. The compounds are characterized by complex polyanionic formations from bicarbonate dimers ([(HCO3)2·(H2O)]24-) or chains ([H(HCO3)2]nn- or [H2(tpa)(HCO3)2]n2n-) to water-bicarbonate associates ([(HCO3)2·6H2O]2- and [(H2CO3·(HCO3)2)2·6H2O·2H2O]2-) and three-component anionic layers ([H(Cyt)(HCO3)·H2O]nn- and [H2(Cyt)2(HCO3)·H2O]nn-) frequently showing proton sharing. While some hydroxides themselves can maintain a high CO2/[Nnnnn][OH] ratio, particularly 2 and 4, the presence of secondary hydrogen bond donors/acceptors may increase the sorption efficiency through decreased solubility and enhanced crystallization.

Assessing Long Non-coding RNAs in Tobacco-associated Oral Cancer.

Cancer is one of the compelling and pegged diseases battled by clinicians and researchers worldwide. Among different types of cancer, oral cancer holds the sixth position globally. With an escalating prevalence in Asian countries, India, China, and Pakistan constitute a large proportion of total incidents of oral cancer patients in terms of new cases or deaths. This mounting prevalence is ascribed to poor oral hygiene and rampant use of substances earmarked as potential risk factors for the disease. Risk factors (dietary/lifestyle habits/occupational/environmental) trigger the activation of oncogenes, dysregulation of lncRNA and miRNA, and silence the tumor suppressor genes, which robustly contributes to the onset and progression of tumorigenesis in oral squamous cell carcinoma. Evidence suggests that specific carcinogens identified in tobacco and related products alter many cellular pathways predisposing to advanced stages of oral cancer. Long non-coding RNAs represent a broad group of heterogenous transcripts longer than 200 nucleotides which do not translate to form functional proteins. They regulate various cellular pathways by specifically interacting with other RNAs, DNA, and proteins. Their role in the pathogenesis of OSCC and other cancer is still being debated. In this review, we discuss the molecular insights of significant lncRNAs involved in some crucial deregulated pathways of tobacco-associated OSCC. The implications and challenges to harnessing the potential of lncRNAs as biomarkers in early diagnosis and targeted treatment have also been analyzed.

Probing time dependent phase transformation in a flexible metal-organic framework with nanoindentation.

Phase transformation in a flexible metal-organic framework, {[Zn4(1,4-NDC)4(1,2-BPE)2]·xSolvent}n, which loses guest molecules rapidly at room temperature, leading to several phase transitions, is examined using the nanoindentation technique. Nanoindentation results revealed that the time dependent transformation of an open to a closed phase happens gradually, through multiple intermediate phases, with the mechanical properties (elastic modulus and hardness) increasing as the transformation progresses from an open to a closed phase.

Multidrug efflux transporter ABCG2: expression and regulation.

The adenosine triphosphate (ATP)-binding cassette efflux transporter G2 (ABCG2) was originally discovered in a multidrug-resistant breast cancer cell line. Studies in the past have expanded the understanding of its role in physiology, disease pathology and drug resistance. With a widely distributed expression across different cell types, ABCG2 plays a central role in ATP-dependent efflux of a vast range of endogenous and exogenous molecules, thereby maintaining cellular homeostasis and providing tissue protection against xenobiotic insults. However, ABCG2 expression is subjected to alterations under various pathophysiological conditions such as inflammation, infection, tissue injury, disease pathology and in response to xenobiotics and endobiotics. These changes may interfere with the bioavailability of therapeutic substrate drugs conferring drug resistance and in certain cases worsen the pathophysiological state aggravating its severity. Considering the crucial role of ABCG2 in normal physiology, therapeutic interventions directly targeting the transporter function may produce serious side effects. Therefore, modulation of transporter regulation instead of inhibiting the transporter itself will allow subtle changes in ABCG2 activity. This requires a thorough comprehension of diverse factors and complex signaling pathways (Kinases, Wnt/ß-catenin, Sonic hedgehog) operating at multiple regulatory levels dictating ABCG2 expression and activity. This review features a background on the physiological role of transporter, factors that modulate ABCG2 levels and highlights various signaling pathways, molecular mechanisms and genetic polymorphisms in ABCG2 regulation. This understanding will aid in identifying potential molecular targets for therapeutic interventions to overcome ABCG2-mediated multidrug resistance (MDR) and to manage ABCG2-related pathophysiology.

Catalytic Enantioselective Synthesis of Aryl-Methyl Organophosphorus Compounds.

A catalytic enantioselective protocol for the synthesis of aryl-methyl organophosphorus compounds is reported. Utilizing a chiral phosphoric acid as a catalyst, a wide range of indole derivatives reacted with phosphorylated quinomethanes in high yield with excellent enantioselectivity. This is the first report on the application of phosphorylated quinomethanes in asymmetric synthesis.

Insights into Structural Modifications of Valproic Acid and Their Pharmacological Profile.

Valproic acid (VPA) is a well-established anticonvulsant drug discovered serendipitously and marketed for the treatment of epilepsy, migraine, bipolar disorder and neuropathic pain. Apart from this, VPA has potential therapeutic applications in other central nervous system (CNS) disorders and in various cancer types. Since the discovery of its anticonvulsant activity, substantial efforts have been made to develop structural analogues and derivatives in an attempt to increase potency and decrease adverse side effects, the most significant being teratogenicity and hepatotoxicity. Most of these compounds have shown reduced toxicity with improved potency. The simple structure of VPA offers a great advantage to its modification. This review briefly discusses the pharmacology and molecular targets of VPA. The article then elaborates on the structural modifications in VPA including amide-derivatives, acid and cyclic analogues, urea derivatives and pro-drugs, and compares their pharmacological profile with that of the parent molecule. The current challenges for the clinical use of these derivatives are also discussed. The review is expected to provide necessary knowledgebase for the further development of VPA-derived compounds.

Crystallographic evidence of Watson-Crick connectivity in the base pair of anionic adenine with thymine.

Utilizing an ionic liquid strategy, we report crystal structures of salts of free anionic nucleobases and base pairs previously studied only computationally and in the gas phase. Reaction of tetrabutylammonium ([N4444]+) or tetrabutylphosphonium ([P4444]+) hydroxide with adenine (HAd) and thymine (HThy) led to hydrated salts of deprotonated adenine, [N4444][Ad]·2H2O, and thymine, [P4444][Thy]·2H2O, as well as the double salt cocrystal, [P4444]2[Ad][Thy]·3H2O·2HThy. The cocrystal includes the anionic [Ad-(HThy)] base pair which is a stable formation in the solid state that has previously not even been suggested. It exhibits Watson-Crick connectivity as found in DNA but which is unusual for the free neutral base pairs. The stability of the observed anionic bases and their supramolecular formations and hydrates has also been examined by electronic structure calculations, contributing to more insight into how base pairs can bind when a proton is removed and highlighting mechanisms of stabilization or chemical transformation in the DNA chains.

Forcing Dicyanamide Coordination to f-Elements by Dissolution in Dicyanamide-Based Ionic Liquids.

A robust general route to lanthanide dicyanamide (DCA-) complexes has been developed where f-element salts are dissolved in DCA--based ionic liquids (ILs) directly or formed in situ, forcing coordination of these normally weakly coordinating soft N-donor anions, even in an ambient, non-moisture-excluding environment. A series of lanthanide complexes [C2mim][Ln(DCA)4(H2O)4] (C2mim = 1-ethyl-3-methylimidazolium; Ln = La, Nd, Eu, Tb, Dy, and Yb) and [C2mim]3n[La(OH2)4(µ2-DCA)4]n[La(OH2)2(µ3-DCA)3(µ2-DCA)4]2n(Cl)4n were crystallized under a variety of conditions using this methodology and structurally characterized using single crystal X-ray diffraction. Although not all examples were isostructural, the dominant feature across the series was the presence of [Ln(DCA)4(H2O)4]- anionic nodes with all terminal DCA- ligands accepting hydrogen bonds from the coordinated water molecules forming a 3D metal organic framework. To determine if any structural clues might aid in the further development of the synthetic methodology, the metal-free IL [C1mim][DCA] (C1mim = 1,3-dimethylimidazolium), a room-temperature solid, crystalline analogue of the reaction IL, which is liquid at room temperature, was also prepared and structurally characterized. The ready isolation of these compounds allowed us to begin an investigation of the physical properties such as the luminescence at room and low temperatures for the Eu, Tb, and Dy representatives.

Thermoluminescence Studies of ß and γ-Irradiated Geological Materials for Environment Monitoring.

In the present report, thermally stimulated luminescence (TSL) of quartz and limestone samples irradiated with ß and γ-rays has been investigated. Herein the formation of trap depths and calculation of kinetic parameters of ß and γ - irradiated quartz and limestone samples were studied through thermoluminescence (TL) glow curve analyses. The quartz and limestone samples were collected from various sites of Chhattisgarh (Patharia and Dalli-Rajhara mines). The collected raw samples were annealed at 400 °C. The phase formation of collected samples is confirmed by X-ray diffraction studies. The grain sizes of the samples are determined by using Debye-Scherrer formula. TL glow curves of the collected samples were recorded for various doses of ß and γ-rays. Kinetic parameters such as order of kinetics frequency factor and trap depth were calculated by employing CGCD methods. A comparative study on the TL properties of the geological materials under ß and γ-irradiation was done. The trap model analysis was executed to determine the nature of traps responsible for dominant TL peaks of ß and γ-irradiated limestone and quartz samples.

Are ionic liquids and liquid coordination complexes really different? - Synthesis, characterization, and catalytic activity of AlCl3/base catalysts.

Lewis acid/base catalysts of AlCl3/N-methyl-2-pyrrolidone (O-NMP) and AlCl3/1-methylimidazole (N-Mim) were prepared and found to have higher catalytic activity in the Friedel-Crafts alkylation of benzene than the known super acidic ionic liquid chloroaluminate [HN222][Al2Cl7] ([HN222]+ = triethylammonium). Crystals structures were obtained for AlCl3(N-Mim), [AlCl2(O-NMP)2][AlCl4], and [Al(O-NMP)6][AlCl4]3·(C6H6)3 supporting the assignments of neutral and charged catalytic species.

Crystallographic and Energetic Insights into Reduced Dissolution and Physical Stability of a Drug-Surfactant Salt: The Case of Norfloxacin Lauryl Sulfate.

A commonly used pharmaceutical surfactant, sodium lauryl sulfate (SLS), has been reported to reduce the dissolution rate of drugs due to the formation of a less soluble drug-lauryl sulfate salt. In this study, we provide direct crystallographic evidence of the formation of salt between SLS and norfloxacin (NOR), [NORH+][LS-]·1.5 H2O. The available crystal structure also enables the use of the energy framework to gain an understanding of the structure-property relationship. Results show that the hydrophobic methyl groups in SLS dominate the surfaces of the [NORH+][LS-]·1.5 H2O crystals, resulting in the increased hydrophobicity and reduced wettability by aqueous media. Moreover, an analysis of molecular environments and energy calculations of water molecules provides insight into the stability of [NORH+][LS-]·1.5 H2O with variations in the relative humidity and temperature. In summary, important pharmaceutical properties, such as solubility, dissolution, and thermal stability, of the drug-surfactant salt [NORH+][LS-]·1.5 H2O have been characterized and understood based on crystallographic and energetic analyses of the crystal structure.

Solubility Studies of Cyclosporine Using Ionic Liquids.

Six ionic liquids (ILs) were selected based on their chemical and physical properties to study the solubility of cyclosporine A. Of these, cyclosporine exhibited higher room temperature solubility in 1-ethyl-3-methylimidazolium acetate ([C2mim][OAc]) than in acetone, an effective molecular solvent used to solubilize and purify cyclosporine. The solubility of cyclosporine in the ILs dramatically increased at higher temperatures, a critical factor that cannot be varied in a wide range with low boiling molecular solvents. The differences in solubility were explored for cyclosporine purification. Cyclosporine was purified up to ∼93% with n-butylammonium acetate ([C4NH3][OAc]) and could be further purified to 95% using an IL/organic solvent biphasic system. After purification, cyclosporine was recovered as an amorphous solid using the ILs.

Probing stress induced phase transformation in aspirin polymorphs using Raman spectroscopy enabled nanoindentation.

Nanoindentation has extensively been used to measure the mechanical properties of molecular crystals. However, the possibilities of stress induced polymorphic transformation during indentation are still unexplored. Here, we have adopted a spatially synchronized Raman spectroscopy and nanoindentation technique to probe indentation induced polymorphic transformation in aspirin polymorphs. Spatial hardness maps, generated using an accelerated property mapping technique, showed micro-domain formation in aspirin form II crystals.

Crystallographic Insights into the Behavior of Highly Acidic Metal Cations in Ionic Liquids from Reactions of Titanium Tetrachloride with [1-Butyl-3-Methylimidazolium][X] Ionic Liquids (X = Chloride, Bromide, Tetrafluoroborate).

Highly charged metal ions are difficult to investigate in weakly coordinating ionic liquids (ILs) because of the insolubility of their solid forms, but the molecular liquid TiCl4 offers a way to react tetravalent metal ions in an IL. Reactions of TiCl4 with 1-butyl-3-methylimidazolium ([C4mim]+)-based ILs containing chloride or bromide lead to mixtures of highly metastable amorphous solids and small amounts of crystalline chlorotitanate salts including [C4mim]2[TiCl6] and two polymorphs of [C4mim]2[Ti2Cl10] in a manner not well correlated with stoichiometry or anion identity. The reaction of TiCl4 with [C4mim][BF4] yields crystals of the mixed fluoro-chloro complex [C4mim]2[Ti4F6Cl12], indicating spontaneous reaction of the IL ions to generate HF in situ. These unusual behaviors are explained in terms of the exceptionally high acidity of Ti4+ and the unusual behavior of TiCl4 among metal halides as a nonpolar molecular compound.

From Molecules to Interactions to Crystal Engineering: Mechanical Properties of Organic Solids.

Mechanical properties of organic molecular crystals have been noted and studied over the years but the complexity of the subject and its relationship with diverse fields such as mechanochemistry, phase transformations, polymorphism, and chemical, mechanical, and materials engineering have slowed understanding. Any such understanding also needs conceptual advances-sophisticated instrumentation, computational modeling, and chemical insight-lack of such synergy has surely hindered progress in this important field. This Account describes our efforts at focusing down into this interesting subject from the viewpoint of crystal engineering, which is the synthesis and design of functional molecular solids. Mechanical properties of soft molecular crystals imply molecular movement within the solid; the type of property depends on the likelihood of such movement in relation to the applied stress, including the ability of molecules to restore themselves to their original positions when the stress is removed. Therefore, one is interested in properties such as elasticity, plasticity, and brittleness, which are linked to structural anisotropy and the degree to which a structure veers toward isotropic character. However, these matters are still by no means settled and are system dependent. While elasticity and brittleness are probably displayed by all molecular solids, the window of plasticity is perhaps the one that is most amenable to crystal engineering strategies and methods. In all this, one needs to note that mechanical properties have a kinetic component: a crystal that is elastic under slow stress application may become plastic or brittle if the same stress is applied quickly. In this context, nanoindentation studies have shown themselves to be of invaluable importance in understanding structural anisotropy. Several problems in solid state chemistry, including classical ones, such as the melting point alternation in aliphatic straight chain dicarboxylic acids and hardness modulation in solid solutions, have been understood more clearly with this technique. The way may even be open to picoindentation studies and the observation of molecular level movements. As in all types of crystal engineering, an understanding of the intermolecular interactions can lead to property oriented crystal design, and we present examples where complex properties may be deliberately turned on or off in organic crystals: one essentially fine-tunes the degree of isotropy/anisotropy by modulating interactions such as hydrogen bonding, halogen bonding, π···π interactions, and C-H···π interactions. The field is now wide open as is attested by the activities of several research groups working in the area. It is set to take off into the domains of smart materials, soft crystals, and superelasticity and a full understanding of solid state reactivity.