Enzymatic synthesis of reactive RNA probes containing squaramate-linked cytidine or adenosine for bioconjugations and cross-linking with lysine-containing peptides and proteins.

Protein-RNA interactions play important biological roles and hence reactive RNA probes for cross-linking with proteins are important tools in their identification and study. To this end, we designed and synthesized 5'-O-triphosphates bearing a reactive squaramate group attached to position 5 of cytidine or position 7 of 7-deazaadenosine and used them as substrates for polymerase synthesis of modified RNA. In vitro transcription with T7 RNA polymerase or primer extension using TGK polymerase was used for synthesis of squaramate-modified RNA probes which underwent covalent bioconjugations with amine-linked fluorophore and lysine-containing peptides and proteins including several viral RNA polymerases or HIV reverse transcriptase.

The Evaluation of Glyceryl C3-Azolyl-Thiogalactosides as Galectin-1 and Galectin-3 Ligands.

Galectins are a family of galactoside-binding proteins involved in various pathophysiological processes, which makes them attractive targets for drug discovery. The derivatization of d-galactose at C3 and C1 positions has been shown to increase the affinity of synthetic galectin antagonists. In this study, two small libraries of d-galactose derivatives have been designed and synthesized.

Phytochemical -methyl-L-cysteine sulfoxide from Brassicaceae: a key to health or a poison for bees?

Intensive agricultural practices impact the health and nutrition of pollinators like honey bees (). Rapeseed ( L.) is widely cultivated, providing diverse nutrients and phytochemicals, including -methyl-L-cysteine sulfoxide (SMCSO).

Bacteriophage-related epigenetic natural and non-natural pyrimidine nucleotides and their influence on transcription with T7 RNA polymerase.

DNA modifications on pyrimidine nucleobases play diverse roles in biology such as protection of bacteriophage DNA from enzymatic cleavage, however, their role in the regulation of transcription is underexplored. We have designed and synthesized a series of uracil 2'-deoxyribonucleosides and 5'-O-triphosphates (dNTPs) bearing diverse modifications at position 5 of nucleobase, including natural nucleotides occurring in bacteriophages, α-putrescinylthymine, α-glutaminylthymine, 5-dihydroxypentyluracil, and methylated or non-methylated 5-aminomethyluracil, and non-natural 5-sulfanylmethyl- and 5-cyanomethyluracil. The dNTPs bearing basic substituents were moderate to poor substrates for DNA polymerases, but still useful in primer extension synthesis of modified DNA.

Naphthylated LEGO-lipophosphonoxin antibiotics used as a fluorescent tool for the observation of target membrane perturbations preceding its disruption.

Linker-Evolved-Group-Optimized-Lipophosphonoxins (LEGO-LPPO) are small synthetic modular peptidomimetics with promising antimicrobial activity. The LEGO-LPPO mechanism of antibacterial action has been determined to be the depolarization and disruption of bacterial membranes. Their modular nature is advantageous for fine tuning their biological properties.

Influence of Selective Deoxyfluorination on the Molecular Structure of Type-2 -Acetyllactosamine.

-Acetyllactosamine is a common saccharide motif found in various biologically active glycans. This motif usually works as a backbone for additional modifications and thus significantly influences glycan conformational behavior and biological activity. In this work, we have investigated the type-2 -acetyllactosamine scaffold using the complete series of its monodeoxyfluorinated analogs.

Overcommitment, Work-Related Behavior, and Cognitive and Emotional Irritation in Veterinarians: A Comparison of Different Veterinary Working Fields.

Mental health is a serious problem among veterinarians. The aim of this study was to analyze work-related behaviors and experience (AVEM), overcommitment (OC), and cognitive and emotional irritation (IS) in different veterinary working fields. The survey included 724 German veterinarians (average age 41.

Sociodemographic influences on private and professional contact behaviour during the COVID-19 pandemic in Germany: cross-sectional analysis based on a Regional Blood Donor Cohort.

Objective: The COVID-19 pandemic has had significant health and socioeconomic impacts worldwide. Extensive measures, including contact restrictions, were implemented to control the spread of the virus. This study aims to examine the factors that influenced private and professional contact behaviour during the COVID-19 pandemic.

Determining the optimal frequency of SARS-CoV-2 regular asymptomatic testing: A randomized feasibility trial in a home care setting.

Background: The SARS-CoV-2 pandemic presented a challenge for caregiving relatives in the home care setting. Caregivers can transmit SARS-CoV-2 to their relatives who are often at high risk for a severe course of COVID-19. Regular testing of asymptomatic caregivers for SARS-CoV-2 may reduce the risk of transmission.

ABNOH-Linked Nucleotides and DNA for Bioconjugation and Cross-linking with Tryptophan-Containing Peptides and Proteins.

Reactive N-hydroxy-9-azabicyclo[3.3.1]nonane (ABNOH) linked 2'-deoxyuridine 5'-O-mono- and triphosphates were synthesized through a CuAAC reaction of ABNOH-PEG-N with 5-ethynyl-dUMP or -dUTP.

Development of Prolinol Containing Inhibitors of Hypoxanthine-Guanine-Xanthine Phosphoribosyltransferase: Rational Structure-Based Drug Design.

Inhibition of hypoxanthine-guanine-xanthine phosphoribosyltransferase activity decreases the pool of 6-oxo and 6-amino purine nucleoside monophosphates required for DNA and RNA synthesis, resulting in a reduction in cell growth. Therefore, inhibitors of this enzyme have potential to control infections, caused by and , , , and . Five compounds synthesized here that contain a purine base covalently linked by a prolinol group to one or two phosphonate groups have values ranging from 3 nM to >10 μM, depending on the structure of the inhibitor and the biological origin of the enzyme.

Expedient production of site specifically nucleobase-labelled or hypermodified RNA with engineered thermophilic DNA polymerases.

Innovative approaches to controlled nucleobase-modified RNA synthesis are urgently needed to support RNA biology exploration and to synthesize potential RNA therapeutics. Here we present a strategy for enzymatic construction of nucleobase-modified RNA based on primer-dependent engineered thermophilic DNA polymerases - SFM4-3 and TGK. We demonstrate introduction of one or several different base-modified nucleotides in one strand including hypermodified RNA containing all four modified nucleotides bearing four different substituents, as well as strategy for primer segment removal.

Multiple environmental antigens may trigger autoimmunity in psoriasis through T-cell receptor polyspecificity.

Introduction: Psoriasis is a T-cell mediated autoimmune skin disease. is the main psoriasis-specific risk gene. Using a Vα3S1/Vβ13S1 T-cell receptor (TCR) from a lesional psoriatic CD8 T-cell clone we had discovered that, as an underlying pathomechanism, HLA-C*06:02 mediates an autoimmune response against melanocytes in psoriasis, and we had identified an epitope from ADAMTS-like protein 5 (ADAMTSL5) as a melanocyte autoantigen.

The Medicare Care Choices Model was associated with reductions in disparities in the use of hospice care for Medicare beneficiaries with terminal illness.

Objective: To assess the effects of the Medicare Care Choices Model (MCCM) on disparities in hospice use and quality of end-of-life care for Medicare beneficiaries from underserved groups-those from racial and ethnic minority groups, dually eligible for Medicare and Medicaid, or living in rural areas.

Data Sources And Study Setting: Medicare enrollment and claims data from 2013 to 2021 for terminally ill Medicare fee-for-service beneficiaries nationwide.

Study Design: Through MCCM, terminally ill enrolled Medicare beneficiaries received supportive and palliative care services from hospice providers concurrently with curative treatments.

Stereoselective Reduction of Steroidal 4-Ene-3-ketones in the Presence of Biomass-Derived Ionic Liquids Leading to Biologically Important 5β-Steroids.

The stereoselective reduction of the steroidal 4-ene-3-ketone moiety (enone) affords the 5β-steroid backbone that is a key structural element of biologically important neuroactive steroids. Neurosteroids have been currently studied as novel and potent central nervous system drug-like compounds for the treatment of, e.g.

Compact 20-pass thin-disk multipass amplifier stable against thermal lensing effects and delivering 330 mJ pulses with M2 < 1.17.

We report on an Yb:YAG thin-disk multipass amplifier delivering 100 ns long pulses at a central wavelength of 1030 nm with an energy of 330 mJ at a repetition rate of 100 Hz. The beam quality factor at the maximum energy was measured to be M < 1.17.

The synthesis and characterization of electron-poor glycosylamines and derived glycosylamides.

This paper describes a unified approach toward diglycosylamines using methanolic ammonia. All the glycosylamines prepared have been fully characterized, and their anomeric configuration has been determined. The article presents a novel method for the N-acylation of diglycosylamines and other electron-poor glycosylamines, which employs nitromethane as a solvent in carboxylic anhydride acylation under acidic conditions.

On the origin of the electronic and magnetic circular dichroism of naphthyl C-glycosides: Anomeric configuration.

Aryl C-glycosides, in which the glycosidic bond is changed to a carbon-carbon bond, are an important family of biologically-active compounds. They often serve as secondary metabolites or exhibit antibiotic and cytostatic activities. Their stability to hydrolysis has made them attractive targets for new drugs.

Well-being of veterinarians in rural and urban areas.

Introduction: The field of veterinary medicine is characterized by a variety of challenging working conditions. The alarmingly low mental well-being of veterinarians has been examined from various perspectives. However, the influence of work location on the well-being of veterinary professionals has scarcely been investigated.

Physical stress and musculoskeletal complaints of veterinarians - A narrative review.

Introduction: Veterinarians have high physical workloads. The aim of this narrative review is to evaluate the literature on typical physical workloads, such as lifting/carrying and forced position (during surgery) and predictors of injuries. The health complaints of veterinarians were also examined.

Selection of Galectin-Binding Ligands from Synthetic Glycopeptide Libraries.

Galectins, a class of carbohydrate-binding proteins, play a crucial role in various physiological and disease processes. Therefore, the identification of ligands that efficiently bind these proteins could potentially lead to the development of new therapeutic compounds. In this study, we present a method that involves screening synthetic click glycopeptide libraries to identify lectin-binding ligands with low micromolar affinity.

Medicare Care Choices Model Improved End-Of-Life Care, Lowered Medicare Expenditures, And Increased Hospice Use.

The Medicare Care Choices Model (MCCM) tested a new option for eligible Medicare beneficiaries to receive conventional treatment for terminal conditions along with supportive and palliative care from participating hospice providers. Using claims data, we estimated differences in average outcomes from enrollment to death between deceased MCCM enrollees and matched comparison beneficiaries who received usual services covered by original Medicare. Enrollees were 15 percentage points less likely to receive an aggressive life-prolonging treatment at the end of life and spent more than five more days at home.

Discovery of a Druggable, Cryptic Pocket in SARS-CoV-2 nsp16 Using Allosteric Inhibitors.

A collaborative, open-science team undertook discovery of novel small molecule inhibitors of the SARS-CoV-2 nsp16-nsp10 2'--methyltransferase using a high throughput screening approach with the potential to reveal new inhibition strategies. This screen yielded compound , a ligand possessing an electron-deficient double bond, as an inhibitor of SARS-CoV-2 nsp16 activity. Surprisingly, X-ray crystal structures revealed that covalently binds within a previously unrecognized cryptic pocket near the -adenosylmethionine binding cleft in a manner that prevents occupation by -adenosylmethionine.