The "Click-tail approach" for the design and synthesis of novel carbonic anhydrase inhibitors

The Carbonic Anhydrases (CAs) are a family of zinc enzymes deputed to the interconversion of carbonic dioxide to hydrogen carbonate. Herein, we report on a sustainable modular strategy, also called "clicktail approach", used to obtain two series of 4-(4-substituted-lH-l,2,3-triazol-lyl) benzenesulfonamides. Design and synthesis strategies, x-ray derived CA-ligand binding mode and enzyme-based inhibition results will be presented

Analysing long-term opportunities for offshore energy system integration in the Danish North Sea

Acknowledgment The authors gratefully acknowledge the financial support of the Danish Hydrocarbon Research and Technology centre (DHRTC) for funding this research in the context of the “Alternative use of offshore infrastructures and reservoirs” program. Any remaining errors are the authors’ responsibility.Peer reviewedPublisher PD

An examination of entrance criteria for international medical graduates (IMGs) into Canadian psychiatry residency programs

Background: Although international medical graduates (IMGs) are essential in health care service delivery, a gap exists in the literature about how IMGs are selected into psychiatry residency programs in Canada. The purpose of this study was to identify the relative weight or importance that Canadian program directors (PDs) of psychiatry place on certain selection criteria when matching IMGs into residency programs.Methods: We electronically distributed a web-based questionnaire to 16 university residency program directors of psychiatry in Canada. Program Directors were asked to rate the importance of 43 selection criteria using 5-point Likert Scales. Criteria were grouped into six domains: academic criteria, extracurricular activities, supporting information, behavioural issues of concern, medical school country, and other education. Mean total values for each set of criteria were calculated and used to create rank orders within each domain.Results: Eight out of 16 program directors responded. Our analysis indicated that academics and behavioral issues of concern were the most important selection criteria.Conclusion: Our findings provide valuable insight about the perspectives of Program Directors toward IMGs who apply for psychiatry residency programs in Canada. Further studies are needed to better understand which criteria contribute to IMGs’ performances as psychiatric residents

Lysosomes in acute myeloid leukemia: potential therapeutic targets?

Lysosomes, since their discovery, have been primarily known for degrading cellular macromolecules. However, in recent studies, they have begun to emerge as crucial regulators of cell homeostasis. They are at the crossroads of catabolic and anabolic pathways and are intricately involved in cellular trafficking, nutrient signaling, energy metabolism, and immune regulation. Their involvement in such essential cellular functions has renewed clinical interest in targeting the lysosome as a novel way to treat disease, particularly cancer. Acute myeloid leukemia (AML) is an aggressive blood cancer with a low survival probability, particularly in older patients. The genomic landscape of AML has been extensively characterized but few targeted therapies (with the exception of differentiation therapy) can achieve a long-term cure. Therefore, there is an unmet need for less intensive and more tolerable therapeutic interventions. In this review, we will give an overview on the myriad of functions performed by lysosomes and their importance in malignant disease. Furthermore, we will discuss their relevance in hematopoietic cells and different ways to potentially target them in AML

Un análisis preliminar de la estructura de la kata Goju-ryu

Miyagi Chojun (1888-1953) fue el fundador del Goju-ryu, un estilo de kárate-do que supuestamente tenía lazos con una escuela de boxeo chino establecida en Okinawa en 1828. Miyagi se basó en las enseñanzas de su primer instructor, Higaonna Kanryo (1850-1915). Hasta ahora, la transmisión del actual Goju-ryu en lo que se refiere a sus katas (formas) y estas fuentes históricas nunca ha sido establecida. Por ello, hemos utilizado una técnica estadística para analizar la relación entre las katas clásicas del Goju-ryu moderno. Se ha concluido que podría existir esta continuidad a través de todas las katas del Goju-ryu moderno si en verdad éstas vinieron de una fuente similar. Los resultados obtenidos son esclarecedores y sugieren los posibles orígenes de las katas de Goju-ryu

pH-Induced conformational changes of human bocavirus capsids

Human bocavirus 1 (HBoV1) and HBoV2 to-4 infect children and immunocompromised individuals, resulting in respiratory and gastrointestinal infections, respectively. Using cryo-electron microscopy and image reconstruction, the HBoV2 capsid structure was determined to 2.7-angstrom resolution at pH 7.4 and compared to the previously determined HBoV1, HBoV3, and HBoV4 structures. Consistent with previous findings, surface variable region III (VR-III) of the capsid protein VP3, proposed as a host tissue tropism determinant, was structurally similar among the gastrointestinal strains HBoV2 to-4, but differed from that of HBoV1 with its tropism for the respiratory tract. Toward understanding the entry and trafficking properties of these viruses, HBoV1 and HBoV2 were further analyzed as species representatives of the two HBoV tropisms. Their cell surface glycan-binding characteristics were analyzed, and capsid structures determined to 2.5-to 2.7-angstrom resolution at pHs 5.5 and 2.6, conditions normally encountered during infection. The data showed that glycans with terminal sialic acid, galactose, GlcNAc, or heparan sulfate moieties do not facilitate HBoV1 or HBoV2 cellular attachment. With respect to trafficking, conformational changes common to both viruses were observed under low-pH conditions localized to the VP N terminus under the 5-fold channel, in the surface loops VR-I and VR-V and specific side chain residues such as cysteines and histidines. The 5-fold conformational movements provide insight into the potential mechanism of VP N-terminal dynamics during HBoV infection, and side chain modifications highlight pH-sensitive regions of the capsid. IMPORTANCE Human bocaviruses (HBoVs) are associated with disease in humans. However, the lack of an animal model and a versatile cell culture system to study their life cycle limits the ability to develop specific treatments or vaccines. This study presents the structure of HBoV2, at 2.7-A resolution, determined for comparison to the existing HBoV1, HBoV3, and HBoV4 structures, to enable the molecular characterization of strain and genus-specific capsid features contributing to tissue tropism and antigenicity. Furthermore, HBoV1 and HBoV2 structures determined under acidic conditions provide insight into capsid changes associated with endosomal and gastrointestinal acidification. Structural rearrangements of the capsid VP N terminus, at the base of the 5-fold channel, demonstrate a disordering of a "basket" motif as pH decreases. These observations begin to unravel the molecular mechanism of HBoV infection and provide information for control strategies.Peer reviewe

Atomic Resolution Structures of Human Bufaviruses Determined by Cryo-Electron Microscopy

Bufavirus strain 1 (BuV1), a member of the Protoparvovirus genus of the Parvoviridae, was first isolated from fecal samples of children with acute diarrhea in Burkina Faso. Since this initial discovery, BuVs have been isolated in several countries, including Finland, the Netherlands, and Bhutan, in pediatric patients exhibiting similar symptoms. Towards their characterization, the structures of virus-like particles of BuV1, BuV2, and BuV3, the current known genotypes, have been determined by cryo-electron microscopy and image reconstruction to 2.84, 3.79, and 3.25 angstrom, respectively. The BuVs, 65-73% identical in amino acid sequence, conserve the major viral protein, VP2, structure and general capsid surface features of parvoviruses. These include a core -barrel (B-I), -helix A, and large surface loops inserted between these elements in VP2. The capsid contains depressions at the icosahedral 2-fold and around the 5-fold axes, and has three separated protrusions surrounding the 3-fold axes. Structure comparison among the BuVs and to available parvovirus structures revealed capsid surface variations and capsid 3-fold protrusions that depart from the single pinwheel arrangement of the animal protoparvoviruses. These structures provide a platform to begin the molecular characterization of these potentially pathogenic viruses.Peer reviewe

On the Importance of Nanoparticle Necks and Carbon Impurities for Charge Trapping in TiO2

Particle attachment and neck formation inside TiO2 nanoparticle networks determine materials performance in sensing, photo-electrochemistry, and catalysis. Nanoparticle necks can feature point defects with potential impact on the separation and recombination of photogenerated charges. Here, we investigated with electron paramagnetic resonance a point defect that traps electrons and predominantly forms in aggregated TiO2 nanoparticle systems. The associated paramagnetic center resonates in the g factor range between g = 2.0018 and 2.0028. Structure characterization and electron paramagnetic resonance data suggest that during materials processing, the paramagnetic electron center accumulates in the region of nanoparticle necks, where O2 adsorption and condensation can occur at cryogenic temperatures. Complementary density functional theory calculations reveal that residual carbon atoms, which potentially originate from synthesis, can substitute oxygen ions in the anionic sublattice, where they trap one or two electrons that mainly localize at the carbon. Their emergence upon particle neck formation is explained by the synthesis- and/or processing-induced particle attachment and aggregation facilitating carbon atom incorporation into the lattice. This study represents a substantial advance in linking dopants, point defects, and their spectroscopic fingerprints to microstructural features of oxide nanomaterials

Capsid Structure of Aleutian Mink Disease Virus and Human Parvovirus 4: New Faces in the Parvovirus Family Portrait

Parvoviruses are small, single-stranded DNA viruses with non-enveloped capsids. Determining the capsid structures provides a framework for annotating regions important to the viral life cycle. Aleutian mink disease virus (AMDV), a pathogen in minks, and human parvovirus 4 (PARV4), infecting humans, are parvoviruses belonging to the genera Amdoparvovirus and Tetraparvovirus, respectively. While Aleutian mink disease caused by AMDV is a major threat to mink farming, no clear clinical manifestations have been established following infection with PARV4 in humans. Here, the capsid structures of AMDV and PARV4 were determined via cryo-electron microscopy at 2.37 and 3.12 Å resolutions, respectively. Despite low amino acid sequence identities (10–30%) both viruses share the icosahedral nature of parvovirus capsids, with 60 viral proteins (VPs) assembling the capsid via two-, three-, and five-fold symmetry VP-related interactions, but display major structural variabilities in the surface loops when the capsid structures are superposed onto other parvoviruses. The capsid structures of AMDV and PARV4 will add to current knowledge of the structural platform for parvoviruses and permit future functional annotation of these viruses, which will help in understanding their infection mechanisms at a molecular level for the development of diagnostics and therapeutics

Capsid Structure of Aleutian Mink Disease Virus and Human Parvovirus 4: New Faces in the Parvovirus Family Portrait

Parvoviruses are small, single-stranded DNA viruses with non-enveloped capsids. Determining the capsid structures provides a framework for annotating regions important to the viral life cycle. Aleutian mink disease virus (AMDV), a pathogen in minks, and human parvovirus 4 (PARV4), infecting humans, are parvoviruses belonging to the genera Amdoparvovirus and Tetraparvovirus, respectively. While Aleutian mink disease caused by AMDV is a major threat to mink farming, no clear clinical manifestations have been established following infection with PARV4 in humans. Here, the capsid structures of AMDV and PARV4 were determined via cryo-electron microscopy at 2.37 and 3.12 Å resolutions, respectively. Despite low amino acid sequence identities (10–30%) both viruses share the icosahedral nature of parvovirus capsids, with 60 viral proteins (VPs) assembling the capsid via two-, three-, and five-fold symmetry VP-related interactions, but display major structural variabilities in the surface loops when the capsid structures are superposed onto other parvoviruses. The capsid structures of AMDV and PARV4 will add to current knowledge of the structural platform for parvoviruses and permit future functional annotation of these viruses, which will help in understanding their infection mechanisms at a molecular level for the development of diagnostics and therapeutics