Miracle-dz/UniFAR-FTUs huggingface dataset:
Optimized partitioning in perturbation theory: Comparison to related approaches

A generalized Epstein–Nesbet type perturbation theory is introduced by a unique, “optimal” determination of level shift parameters. As a result, a new partitioning emerges in which third order energies are identically zero, most fifth order terms also vanish, and low (2nd, 4th) order corrections are quite accurate. Moreover, the results are invariant to unitary transformations within the zero order excited states. Applying the new partitioning to many-body perturbation theory, the perturbed energies exhibit appealing features: (i) they become orbital invariant if all level shifts are optimized in an excitation subspace; and (ii) meet the size-consistency requirement if no artificial truncations in the excitation space is used. As to the numerical results, low order corrections do better than those of Mo/ller–Plesset partitioning. At the second order, if the single determinantal Hartree–Fock reference state is used, the CEPA-0 (=LCCD) energies are recovered. Higher order corrections provide a systematic wa.
Inclusive Practices toward LGBT Older Adults in Healthcare and Social Services: A Scoping Review of Quantitative and Qualitative Evidence

ABSTRACT Objectives: To determine what constitutes inclusive practices toward LGBT older adults in healthcare and social services and the supportive competencies of these practices. Methods: A comprehensive scoping review of the existing literature was conducted. Results: To be competent when addressing LGBT elder needs, personnel must have knowledge on LGBT realities, openness and be able to put certain skills into practice. Conclusions: Given the limited powers conferred on them by their respective positions, institutions must also play a role in encouraging the inclusion of LGBT older adults. Beyond the importance of taking into account the three dimensions of competence in staff training, changes must be made at all levels of the organizational structures. Clinical implications: Inclusive practices require 1) Educating personnel on the diversity of the life journeys of LGBT older adults; 2) Promoting relational and communication skills and open, friendly attitudes toward the diversity of LGBT identities; 3) Developing policies and procedures to create and maintain inclusive and safe environments for LGBT older adults.
Preferential Evolution of Prussian Blue's Morphology from Cube to Hexapod

Prussian blue (PB), [Fe2+(CN)6]3·xH2O, has been used as a pigment for three centuries. It has a prototypical haxacyanometallic face centered cubic structure, with the Fe coordinating the nitrogen atoms and the Fe to the carbon, resulting in Fe−NC−Fe−CN−Fe linkage. The separation between the Fe ions corresponds to an a = 1.031 nm. A similar compound, soluble Prussian blue, (KFe [Fe2+(CN)6]) contains potassium ions in alternate interstitial sites (Scheme 1). PB analogues have unique and potentially useful magnetic, optical, and structural properties. Photoinduced magnetization has been observed in K0.2Co1. 4[Fe(CN)6]·9H2O, a PB analogue. Incident light can induce electrons to transfer from Fe (S=0) to Co (S=0) in the Fe−CN−Co linkage, yielding a long-lived metastable Fe−CN−Co linkage with Fe (S=1/2) to Co (S=3/2), resulting in photo-induced magnetization. Therefore, PB analogues have been studied as photoinduced magnets and molecular magnets and photomagnetic switches. They have porous frameworks and contain water molecules at the incomplete coordination sites at the surfaces of their frameworks. The coordinated water molecules can be removed by moderate heating and hydrogen gas can be stored in the resulting spaces, making PB analogues potential useful for hydrogen storage. They can also act as electrocatalysts for both the reduction and oxidation of hydrogen peroxide and as sensors of hydrogen peroxide and biological glucose. Controlling PB analogues' morphology during their synthesis is important as it affect their properties. PB analogues have face centered cubic structures, leading to most PB analogues showing cubic morphologies. Most synthetic methods have aimed to prepare a single final morphology and relatively little is known about the morphology evolution of PB analogues with respect to the synthetic conditions. To the best of authors’ knowledge, this is the first report of the evolution of PB's morphology from cube to hexapod. Figure 1 shows X-ray diffraction (XRD) patterns of PB products prepared by microwave-assisted reactions from aqueous K4[Fe2+(CN)6] using different concentrations of HNO3. When 8.0 × 10 M HNO3 was used, XRD patterns resulted in peaks attributable to only KFe3+[Fe2+(CN)6], Fe4 3+
Identification of potential non-nucleoside MraY inhibitors for tuberculosis chemotherapy using structure-based virtual screening

Abstract The efforts to limit the spread of the tuberculosis epidemic have been challenged by the rise of drug-resistant strains of Mycobacterium tuberculosis (Mtb), the causative agent of tuberculosis. It is critical to discover new chemical scaffolds acting on novel or unexploited targets to beat this drug-resistant pathogen. MraY (phospho-MurNAc-pentapeptide translocase or translocase I) is an in vivo validated target for antibacterials-discovery. MraY is inhibited by nucleoside-based natural products that suffer from poor in vivo efficacy. The current study is focused on discovering novel chemical entities, particularly, non-nucleoside small molecules, as MraY Mtb inhibitors possessing antituberculosis activity. In the absence of any reported X-ray crystal structures of MraY Mtb , we used a homology model-based virtual screening approach combined with the ligand-based e-pharmacophore screening. We screened ∼12 million commercially available compounds from the ZINC15 database using GOLD software. The resulting hits were filtered using a 2-pronged screening method comprising e-pharmacophore hypotheses and docking against the MraY Mtb homology model using Glide. Further clustering based on Glide scores and optimal binding interactions resulted in 15 in silico hits. We performed molecular dynamics (MD) simulations for the three best-ranking compounds and one other poorer-ranking compound, out of the 15 in silico hits, to analyze the interaction modes in detail. The MD simulations indicated stable interactions between the compounds and key residues in the MraY active site that are crucial for maintaining the enzymatic activity. These in silico hits could advance the antibacterial drug discovery campaign to find new MraY inhibitors for tuberculosis treatment. Communicated by Ramaswamy H. Sarma
Strut remodeling with hypercompliant balloon: A new approach to Y stent-assisted coil embolization in the treatment of complex wide-neck bifurcation aneurysms

Background The objective of this study was to present the long-term safety and effectiveness of strand remodelling with a hypercompliant balloon. Methods Patients with complex wide-neck bifurcation aneurysms (WNBAs) who underwent strand remodelling with a hypercompliant balloon via Y-stent-assisted coil embolization (Y-SACE) between September 2016 and January 2020 were included in the study. The feasibility, safety, effectiveness, and complication rates of the strand remodelling technique were investigated. Results A total of 12 patients (6 females, 6 males) were included in this study. Significant expansion was obtained in the intersection zone after remodelling. No regression was observed in the expansion rates during follow-up. There was no additional morbidity or mortality. No delayed thromboembolic complications occurred in our patients during long-term follow-up. Conclusions Performing strand remodelling to reduce thromboembolic complications triggered by structural faults caused by the Y-stent configuration is feasible, safe, and effective. This new approach can aid in the prevention of thromboembolic complications in Y-SACE.
Selective Excitation of Branched Vibrational Ladder in Uranium Hexafluoride Laser Isotope Separation

Theoretical investigation was made on the dynamics of initial excitation process in molecular laser isotope separation for uranium hexafluoride (UF6) based on the generalized N-level density-matrix equation derived by Goodman et al. Branched vibrational model due to anharmonic-splitting components for the ν3 mode of UF6 molecule were formalized and phase interferences of density-matrix elements were considered to analyze the selective excitation. Because of a power-broadening effect, no more than 0.05 J/cm2 fluence of a laser pulse completely masks high enrichment peaks in broadband (Δν=2 GHz) pumping case. Even when matching the laser frequency with ν3 band (n=0→4) of 238UFG6 the enrichment factor (α≡Rproduct/Rfeed, R≡[238UF6]/ [238UF6] ; R is the abundance ratio and [ ] means the mole fraction.) does not decrease. A narrow spectral linewidth (Δν=-400 MHz) is shown to be essential to achieve a high concentra-tion ratio in the system with a branched N-level ladder as expected from a general two-level system. The exciting frequency, which does not necessarily accord with the ν3 band of 235UF6, gives the maximum enrichment peak. Both the detuning of the optimum frequency and the sharp enrichment peak suggest a direct excitation due to multiphoton resonance. Spectral stability of the laser pulse is also required to excite only the desired isotope for the system with complicated anharmonic-splittings.
Age-associated deficient recruitment of 53BP1 in G1 cells directs DNA double-strand break repair to BRCA1/CtIP-mediated DNA-end resection

DNA repair mechanisms play a crucial role in maintaining genome integrity. However, the increased frequency of DNA double-strand breaks (DSBs) and genome rearrangements in aged individuals suggests an age-associated DNA repair deficiency. Previous work from our group revealed a delayed firing of the DNA damage response in human mammary epithelial cells (HMECs) from aged donors. We now report a decreased activity of the main DSB repair pathways, the canonical non-homologous end-joining (c-NHEJ) and the homologous recombination (HR) in these HMECs from older individuals. We describe here a deficient recruitment of 53BP1 to DSB sites in G1 cells, probably influenced by an altered epigenetic regulation. 53BP1 absence at some DSBs is responsible for the age-associated DNA repair defect, as it permits the ectopic formation of BRCA1 foci while still in the G1 phase. CtIP and RPA foci are also formed in G1 cells from aged donors, but RAD51 is not recruited, thus indicating that extensive DNA-end resection occurs in these breaks although HR is not triggered. These results suggest an age-associated switch of DSB repair from canonical to highly mutagenic alternative mechanisms that promote the formation of genome rearrangements, a source of genome instability that might contribute to the aging process.
Computational approach to explore the inhibitory potential of biologically derived compounds against Spodoptera litura vitellogenin receptor (VgR) using structure based virtual screening and molecular dynamics

Abstract In the everlasting combat against the pests of agricultural importance, it is essential to come up with a novel strategy for pest control. This can be achieved through understanding the insect pest at cellular and molecular levels. Vitellogenin (Vg) and vitellogenin receptor (VgR) are essential for successful reproduction in insect. The N-terminal Ligand Binding Domain (LBD) of VgR is responsible for the transportation of vital protein (Vg) to the developing oocyte through receptor mediated endocytosis pathway. This can be implemented to various predicaments and betterments for exploitation in pest management, in a target specific and eco-friendly manner. For this, natural metabolites isolated from various biological sources were used as ligand. The purpose of this study was to analyze the inhibitory potential of 14 biologically derived compounds against N-terminal (Ligand Binding Repeats) LBRs of S. litura by computational docking. 3 D structure of LBRs of S. litura was generated by Raptor X software and the structure was refined and validated. The validated structure was docked using autodock vina. Docking results revealed that spinosyn A and milbemycin A4 have inhibitory activity against VgR. Molecular dynamics (MD) simulation confirms the stable binding of the ligand. From the above results, spinosyn A and milbemycin A4 may be exploited for the pest management. Communicated by Ramaswamy H. Sarma
PHYSICOCHEMICAL PROPERTIES OF RITUXIMAB

In order to demonstrate physicochemical comparability of a recombinant protein medicament as a drug substance (Active Pharmaceutical Ingredient or API), such as Rituximab, one must first choose suitable orthogonal analytical methods that selectively provide information regarding the identity and heterogeneity of the molecule. The application of these methods in the investigation of process-derived variability of the reference molecule can yield valuable information to establish comparability criteria. This could become the basis to determine the critical physicochemical attributes that should be verified by relevant in-process controls and batch release criteria. In this paper we show the determination and analysis of relevant attributes from two different proposed biosimilars. We show differences in Reditux proposed Rituximab biosimilar, mainly in charge heterogeneity patterns, whereas no major differences were found for Kikuzubam as related to the Mabthera reference batches. The detected differences are an indication of the capability of several analytical methods to show relevant physicochemical attributes during comparability exercises.
Phase I Study of MK-4166, an Anti-human Glucocorticoid-Induced TNF Receptor Antibody, Alone or with Pembrolizumab in Advanced Solid Tumors

Purpose: In this first-in-human phase I study (NCT02132754), we explored MK-4166 [humanized IgG1 agonist mAb targeting glucocorticoid-induced TNF receptor (GITR)] with and without pembrolizumab in advanced solid tumors. Patients and Methods: MK-4166 was tested alone (0.0015–900 mg i.v. every 3 weeks for four doses) or with pembrolizumab (200 mg i.v. every 3 weeks for ≤35 doses) in patients with metastatic solid tumors (dose escalation/confirmation) and advanced melanoma (expansion). Primary objectives were to evaluate the safety and tolerability and establish the MTD of MK-4166. Exploratory endpoints were objective response rate (ORR) and T cell–inflamed gene expression profile (GEP) analysis using RNA from baseline tumor samples. Results: A total of 113 patients were enrolled [monotherapy, n = 48; combination therapy, n = 65 (20 in the expansion)]. Forty-six patients (40.7%) had grade ≥3 adverse events, 9 (8.0%) of which were treatment related. No treatment-related deaths were observed. One dose-limiting toxicity event with monotherapy (bladder perforation in patient with neobladder) was considered related to study drug. MTD was not reached. MK-4166 pharmacodynamics showed decreased GITR availability on circulating T cells with increasing doses. One objective response (ORR, 2.2%) was achieved with combination therapy in the dose escalation/confirmation (n = 45). In the expansion, 8 of 13 patients with immune checkpoint inhibitor (ICI)-naïve melanoma achieved a response (ORR, 62%; 95% confidence interval, 32–86; 5 complete responses and 3 partial responses). None of the ICI-pretreated patients (n = 7) responded. High response rates were observed in ICI-naïve patients irrespective of GEP status. Conclusions: MK-4166 900 mg i.v. every 3 weeks as monotherapy and with pembrolizumab was tolerable. Responses were observed with combination therapy, mostly in patients with ICI-naïve melanoma.
The effects of caregiver characteristics on behavioral and psychological symptoms of dementia of patients with dementia

Abstract Objective To determine the association between caregiver characteristics and behavioral and psychological symptoms of dementia (BPSD) in patients with dementia (PWD) in a Taiwanese community-dwelling population. Methods This cross-sectional study was conducted using the data of 190 patients with Alzheimer’s disease/dementia and 190 informal matched caregivers in Taiwan. BPSD were examined using the Neuropsychiatric Inventory-Questionnaire (NPI-Q). Correlation and regression analyses were used to explore associations between caregiver characteristics and the presence, severity, and distress of NPI-Q items. Results Only spouse primary caregiver was positively associated with presence of delusions in PWD. Caregiver education was positively correlated to severity of hallucinations, agitation/aggression, and apathy/indifference in PWD, while child primary caregiver was positively related to severity of disinhibition in PWD but negatively related to severity of anxiety in PWD. Spouse primary caregiver was positively related to severity of anxiety and appetite/eating in PWD while sole primary caregiver was positively related to severity of anxiety and nighttime behaviors in PWD. Caregiver education was positively correlated to distress of agitation/aggression in caregivers while child primary caregiver was positively related to distress of disinhibition in caregivers. Spouse primary caregiver was positively related to distress of anxiety and appetite/eating in caregivers while spouse caregiver was positively related to distress of nighttime behaviors in caregivers. Conclusions Caregiver education, child and spouse primary caregiver were relevant to severity of PWD and distress of caregivers of BPSD. It is suggested that healthcare professionals provide caregivers with proper individualized interventions based on these results to enhance caring quality. Key points Caregiver education was positively correlated to severity of hallucinations, agitation/aggression, and apathy/indifference, and distress of agitation/aggression. Child primary caregiver was positively related to severity and distress of disinhibition but negatively related to severity of anxiety. Spouse primary caregiver was positively related to severity and distress of anxiety and appetite/eating, and distress of nighttime behaviors
Detecting fecal egg count (FEC) for gastrointestinal nematodes of adult Turkish sheep with different scrapie related PRNP haplotypes

Abstract Scrapie is a transmissible spongiform encephalopathy caused by prions and leads to neurodegeneration in the Central Nervous System (CNS) of sheep and goats. Genetic resistance/susceptibility to scrapie is well studied and it is known that the variations of 136th, 154th and 171st codons at the ovine PRNP gene have a major effect on the development of the disease. Many studies demonstrated that selection for PRNP genotypes has not influenced other performance traits, nevertheless, there is a knowledge gap about the possible link between the PRNP gene and the status of the other important diseases that affect the sheep population worldwide. In the present study, we tested whether there is an association between scrapie-related PRNP genotypes and fecal egg count (FEC) of gastrointestinal nematodes in seven adult Turkish sheep breeds. For this purpose, FEC scores of studied sheep (n = 253) were determined and the same animals were genotyped for the PRNP gene. Finally, an association analysis was performed for scrapie resistant (ARR), susceptible (VRQ), and wild-type (ARQ) haplotypes. Based on our statistical analysis, it is concluded that PRNP genotypes have no positive or negative effect on the FEC scores of adult sheep.
l-Arabinose Induces the Formation of Viable Nonproliferating Spheroplasts in Vibrio cholerae

Vibrios spp. among other bacteria form transient cell wall-deficient forms as a response to different stresses and revert to proliferating rods when permissive conditions have been restored. Such cellular forms have been associated with antimicrobial tolerance, chronic infections, and environmental dispersion. ABSTRACT Vibrio cholerae, the agent of the deadly human disease cholera, propagates as a curved rod-shaped bacterium in warm waters. It is sensitive to cold but persists in cold waters in the form of viable but nondividing coccoidal-shaped cells. Additionally, V. cholerae is able to form nonproliferating spherical cells in response to cell wall damage. It was recently reported that l-arabinose, a component of the hemicellulose and pectin of terrestrial plants, stops the growth of V. cholerae. Here, we show that l-arabinose induces the formation of spheroplasts that lose the ability to divide and stop growing in volume over time. However, they remain viable, and upon removal of l-arabinose, they start expanding in volume, form branched structures, and give rise to cells with a normal morphology after a few divisions. We further show that WigKR, a histidine kinase/response regulator pair implicated in the induction of high-level expression of cell wall synthetic genes, prevents the lysis of the spheroplasts during growth restart. Finally, we show that the physiological perturbations result from the import and catabolic processing of l-arabinose by the V. cholerae homolog of the Escherichia coli galactose transport and catabolic system. Taken together, our results suggest that the formation of nongrowing spherical cells is a common response of vibrios exposed to detrimental conditions. They also permit us to define conditions preventing any physiological perturbation of V. cholerae when using l-arabinose to induce gene expression from the tightly regulated promoter of the Escherichia coli araBAD operon. IMPORTANCE Vibrio spp. , among other bacteria, form transient cell wall-deficient forms as a response to different stresses and revert to proliferating rods when permissive conditions have been restored. Such cellular forms have been associated with antimicrobial tolerance, chronic infections, and environmental dispersion. The effect of l-Ara on V. cholerae could provide an easily tractable model to study the ability of vibrios to form viable reversible spheroplasts. Indeed, the quick transition to spheroplasts and reversion to proliferating rods by addition or removal of l-Ara are ideal to understand the genetic program governing this physiological state and the spatial rearrangements of the cellular machineries during cell shape transitions.
The latest automated docking technologies for novel drug discovery

ABSTRACT Introduction Molecular docking has been consolidated as one of the most important methods in the molecular modeling field. It has been recognized as a prominent tool in the study of protein-ligand complexes, to describe intermolecular interactions, to accurately predict poses of multiple ligands, to discover novel promising bioactive compounds. Molecular docking methods have evolved in terms of their accuracy and reliability; but there are pending issues to solve for improving the connection between the docking results and the experimental evidence Areas covered In this article, the author reviews very recent innovative molecular docking applications with special emphasis on reverse docking, treatment of protein flexibility, the use of experimental data to guide the selection of docking poses, the application of Quantum mechanics(QM) in docking, and covalent docking. Expert opinion There are several issues being worked on in recent years that will lead to important breakthroughs in molecular docking methods in the near future These developments are related to more efficient exploration of large datasets and receptor conformations, advances in electronic description, and the use of structural information for guiding the selection of results.