Understanding the Directed Evolution of a Natural-like Efficient Artificial Metalloenzyme.

The artificial metalloenzyme containing iridium in place of iron along with four directed evolution mutations C317G, T213G, L69V, and V254L in a natural cytochrome P450 presents an important milestone in merging the extraordinary efficiency of biocatalysts with the versatility of small molecule chemical catalysts in catalyzing a new-to-nature carbene insertion reaction. This is a show-stopper enzyme, as it exhibits a catalytic efficiency similar to that of natural enzymes. Despite this remarkable discovery, there is no mechanistic and structural understanding as to why it displays extraordinary efficiency after the incorporation of the four active site mutations by directed evolution methods, which so far has been intractable to any experimental methods.

Human papillomavirus (HPV) vaccine introduction in Sikkim state: Best practices from the first statewide multiple-age cohort HPV vaccine introduction in India-2018-2019.

Background: Cervical cancer is a leading cause of cancer-associated mortality among women in India, with 96,922 new cases and 60,078 deaths each year, almost one-fifth of the global burden. In 2018, Sikkim state in India introduced human papillomavirus (HPV) vaccine for 9-13-year-old girls, primarily through school-based vaccination, targeting approximately 25,000 girls. We documented the program's decision-making and implementation processes.

Explaining regional variations in mother-child health: Additional identified determinants in India and Bangladesh.

This paper explores the sources of spatial variation in child wasting and maternal anemia in three Indian states and six Bangladeshi divisions.  Our initial probability models incorporate traditionally-cited variables from Demographic and Health Surveys such as mother's education, mother's age and household wealth, along with seasonal fluctuations and regional fixed effects. The regional fixed effects are highly significant, even after controlling for the traditionally-cited determinants.

Sensitivity and Specificity of Gene Xpert in the Diagnosis of Spinal Tuberculosis: A Prospective Controlled Clinical Study.

Study Design: Prospective matched cohort study.

Objective: To evaluate the sensitivity and specificity of Gene Xpert in the diagnosis of spinal tuberculosis.

Methods: From January 2016 to August 2018, Gene Xpert results were prospectively studied in 68 patients of clinicoradiologically suspected spinal tuberculosis (STB) and a control group (CG) of 92 patients, all of whom underwent computed tomography-guided/C-arm-guided/open surgical biopsy.

Whole genome sequence analysis of NDM-1, CMY-4, and SHV-12 coproducing serovar Typhimurium isolated from a case of fatal burn wound infection.

species are frequently associated with gastrointestinal infections such as diarrhea. However, extraintestinal infections, including burn infections, have been described. Here, we report the first case of a carbapenem-resistant and metallo-β-lactamase (New Delhi metallo-β-lactamase), extended-spectrum β-lactamase (SHV-12), and AmpC β-lactamase (CMY-4) coproducing Typhimurium isolated from a fatal case of burn wound infection.

Origin of the Non-Arrhenius Behavior of the Rates of Enzymatic Reactions.

The origin of the non-Arrhenius behavior of the rate constant for hydride transfer enzymatic reactions has been a puzzling problem since its initial observation. This effect has been used originally to support the idea that enzymes work by dynamical effects and more recently to suggest an entropy funnel model. Our analysis, however, has advanced the idea that the reason for the non-Arrhenius trend reflects the temperature dependence of the rearrangements of the protein polar groups in response to the change in the charge distribution of the reacting system during the transition from the ground state (GS) to the transition state (TS).

Catalytic Mechanism of Salicylate Dioxygenase: QM/MM Simulations Reveal the Origin of Unexpected Regioselectivity of the Ring Cleavage.

Salicylate 1,2-dioxygenase (SDO) was the first enzyme discovered, in the family of iron dioxygenases, to catalyze the ring cleavage of a monohydroxylated aromatic compound, salicylate, without a proton donor. Salicylate is not electron-rich like the familiar dihydroxy or aromatic substrates with an electron-donating group that are utilized in the well-known dioxygenases. SDO carries out the intramolecular C-C bond cleavage in salicylate bearing the OH and COOH groups with high regioselectivity in comparison with the extradiol and intradiol dioxygenases.

Epigenetic drift towards histone modifications regulates CAV1 gene expression in colon cancer.

Background: Caveolin-1 (CAV1) is an important structural component of cellular caveolae involved in cell signaling. CAV1 gene on/off regulatory mechanism in multiple diseases, including cancer is not clearly understood. The tumor suppressor versus oncogene paradox of CAV1 during tumor development tempted us to investigate the role for the epigenetic drift of CAV1 gene regulation.

Synergistic Substrate and Oxygen Activation in Salicylate Dioxygenase Revealed by QM/MM Simulations.

Salicylate 1,2-dioxygenase (SDO) is the first enzyme to be discovered to catalyze the oxidative cleavage of a monohydroxylated aromatic compound, namely salicylate, instead of the well-known electron-rich substrates. We have investigated the mechanism of dioxygen activation in SDO by QM/MM calculations. Our study reveals that the non-heme Fe(II) center in SDO activates salicylate and O2 synergistically through a strong covalent interaction to facilitate the reductive cleavage of O2.

Clusterin gene is predominantly regulated by histone modifications in human colon cancer and ectopic expression of the nuclear isoform induces cell death.

Clusterin (CLU) is an important glycoprotein involved in various cellular functions. Different reports have mentioned that the two isoforms of CLU; secretary (sCLU) and nuclear (nCLU) have opposite (paradoxical) roles in cancer development. sCLU provides pro-survival signal, whereas nCLU is involved in pro-apoptotic signaling.

Elucidation of caveolin 1 both as a tumor suppressor and metastasis promoter in light of epigenetic modulators.

Caveolin-1 (CAV1) is an integral part of plasma membrane protein playing a vital role in breast cancer initiation and progression. CAV1 acts both as a tumor suppressor as well as an oncogene, and its activity is thus highly dependent on cellular environment. Keeping this fact in mind, the recent work is designed to reveal the role of CAV1 in inhibiting cancer cell progression in presence of epigenetic modulators like 5-aza-2'-deoxycytidine (AZA), trichostatin A (TSA), S-adenosyl methionine (SAM) and sulforaphane (SFN).

Metallacyclocumulenes: a theoretical perspective on the structure, bonding, and reactivity.

Conspectus Transition metals help to stabilize highly strained organic fragments. Metallacycles, especially unsaturated ones, provide much variety in this area. We had a sustained interest in understanding new C-C bond formation reactions affected by binuclear transition metal fragments Cp2M.

Ovarian haemangioma: A rare case report.

Introduction: Haemangioma of ovary is a rare tumour.

Presentation Of Case: We report an ovarian haemangioma which presented as an acute abdomen due to an adnexal mass.

Discussion: We report an ovarian haemangioma which presented as an acute abdomen due to an adnexal mass.

Extranodal Rosai-Dorfman Disease presenting as spinal extradural lesion: a case report with a review of the literature.

Sinus histiocytosis with massive lymphadenopathy (SHML) or Rosai-Dorfman disease (RDD) is a rare, but well-documented entity. We report a male patient who presented with progressive paraparesis, with thoracolumbar extradural lesion (from D11 to L2 level) on magnetic resonance imaging (MRI). He underwent D12-L2 laminectomy followed by total removal of extradural spinal space-occupying lesion (SOL).

Reactions of titanocene bis(trimethylsilyl)acetylene complexes with carbodiimides: an experimental and theoretical study of complexation versus C-N bond activation.

The reaction of the low valent metallocene(II) sources Cp'(2)Ti(η(2)-Me(3)SiC(2)SiMe(3)) (Cp' = η(5)-cyclopentadienyl, 1a or η(5)-pentamethylcyclopentadienyl, 1b) with different carbodiimide substrates RN═C═NR' 2-R-R' (R = t-Bu; R' = Et; R = R' = i-Pr; t-Bu; SiMe(3); 2,4,6-Me-C(6)H(2) and 2,6-i-Pr-C(6)H(3)) was investigated to explore the frontiers of ring strained, unusual four-membered heterometallacycles 5-R. The product complexes show dismantlement, isomerization, or C-C coupling of the applied carbodiimide substrates, respectively, to form unusual mono-, di-, and tetranuclear titanium(III) complexes. A detailed theoretical study revealed that the formation of the unusual complexes can be attributed to the biradicaloid nature of the unusual four-membered heterometallacycles 5-R, which presents an intriguing situation of M-C bonding.

Reactions of group 4 metallocene alkyne complexes with carbodiimides: experimental and theoretical studies of the structure and bonding of five-membered hetero-metallacycloallenes.

The reaction of the low-valent metallocene(II) sources Cp(2)Ti(η(2)-Me(3)SiC(2)SiMe(3)) (7) and Cp(2)Zr(py)(η(2)-Me(3)SiC(2)SiMe(3)) (11, Cp = η(5)-cyclopentadienyl, py = pyridine) with carbodiimides RN═C═NR (R = Cy, i-Pr, p-Tol) leads to the formation of five membered hetero-metallacycloallenes Cp(2)M{Me(3)SiC═C═C[N(SiMe(3))(R)]-N(R)} (9M-R) (M = Ti, R = i-Pr; M = Zr, R = Cy, i-Pr, p-Tol). Elimination of the alkyne (as the hitherto known reactivity of titanocene and zirconocene alkyne complexes would suggest) was not observed. The molecular structures of the obtained complexes were confirmed by X-ray studies.

Cobalt(II) complexes of terpyridine bases as photochemotherapeutic agents showing cellular uptake and photocytotoxicity in visible light.

Cobalt(II) complexes of terpyridine bases [Co(L)₂](ClO₄)₂ (1-3), where L is 4'-phenyl-2,2':6',2''-terpyridine (ph-tpy in 1), 4'-(9-anthracenyl)-2,2':6',2''-terpyridine (an-tpy in 2) and 4'-(1- pyrenyl)-2,2':6',2''-terpyridine (py-tpy in 3), are prepared and their photo-induced DNA and protein cleavage activity and photocytotoxic property in HeLa cells studied. The 1 : 2 electrolytic and three-electron paramagnetic complexes show a visible band near 550 nm in DMF-Tris-HCl buffer. The complexes 1-3 show emission spectral bands at 355, 421 and 454 nm, respectively, when excited at 287, 368 and 335 nm.