Development of Peptide-Based Probes for Molecular Imaging of the Postsynaptic Density in the Brain.

The postsynaptic density (PSD) comprises numerous scaffolding proteins, receptors, and signaling molecules that coordinate synaptic transmission in the brain. Postsynaptic density protein 95 (PSD-95) is a master scaffold protein within the PSD and one of its most abundant proteins and therefore constitutes a very attractive biomarker of PSD function and its pathological changes. Here, we exploit a high-affinity inhibitor of PSD-95, AVLX-144, as a template for developing probes for molecular imaging of the PSD.

Sulfur(VI) Fluoride Exchange Chemistry in Solid-Phase Synthesis of Compound Arrays: Discovery of Histone Deacetylase Inhibitors.

Multistep synthesis performed on solid support is a powerful means to generate small-molecule libraries for the discovery of chemical probes to dissect biological mechanisms as well as for drug discovery. Therefore, expansion of the collection of robust chemical transformations amenable to solid-phase synthesis is desirable for achieving chemically diverse libraries for biological testing. Here, we show that sulfur(VI) fluoride exchange (SuFEx) chemistry, exemplified by pairing phenols with aryl fluorosulfates, can be used for the solid-phase synthesis of biologically active compounds.

First in Class Dual Non-ATP-Competitive Glycogen Synthase Kinase 3β/Histone Deacetylase Inhibitors as a Potential Therapeutic to Treat Alzheimer's Disease.

Despite recent FDA approvals, Alzheimer's disease (AD) still represents an unmet medical need. Among the different available therapeutic approaches, the development of multitarget molecules represents one of the most widely pursued. In this work, we present a second generation of dual ligands directed toward highly networked targets that are deeply involved in the development of the disease, namely, Histone Deacetylases (HDACs) and Glycogen Synthase Kinase 3β (GSK-3β).

Correction to "Rational Chemical Design of Molecular Glue Degraders".

[This corrects the article DOI: 10.1021/acscentsci.2c01317.

Rational Chemical Design of Molecular Glue Degraders.

Targeted protein degradation with molecular glue degraders has arisen as a powerful therapeutic modality for eliminating classically undruggable disease-causing proteins through proteasome-mediated degradation. However, we currently lack rational chemical design principles for converting protein-targeting ligands into molecular glue degraders. To overcome this challenge, we sought to identify a transposable chemical handle that would convert protein-targeting ligands into molecular degraders of their corresponding targets.

Class I histone deacetylases (HDAC1-3) are histone lysine delactylases.

Lysine L-lactylation [K(L-la)] is a newly discovered histone mark stimulated under conditions of high glycolysis, such as the Warburg effect. K(L-la) is associated with functions that are different from the widely studied histone acetylation. While K(L-la) can be introduced by the acetyltransferase p300, histone delactylases enzymes remained unknown.

The 3F Library: Fluorinated Fsp -Rich Fragments for Expeditious F NMR Based Screening.

Fragment-based drug discovery (FBDD) is a popular method in academia and the pharmaceutical industry for the discovery of early lead candidates. Despite its wide-spread use, the approach still suffers from laborious screening workflows and a limited diversity in the fragments applied. Presented here is the design, synthesis, and biological evaluation of the first fragment library specifically tailored to tackle both these challenges.

[Tuberculosis in the Czech Republic in the year 2000].

Background: Incidence of tuberculosis (TB) in the Czech Republic (CR) during the year 2000 was evaluated on the basis of newly detected cases as well the restriction of known TB sources by antituberculosis treatment. Data from compulsory reported TB cases in the TB register for the year 2000 were used as well as data from the analysis of treatment in cohorts of patients reported quarterly in 1999 and evaluated 12 months later.

Methods And Results: 1442 cases of new diseases and TB relapses were reported in 2000 (14.

[Multiresistant tuberculosis in the Czech Republic in 1998 and causes of its occurrence].

Multidrug resistant tuberculosis (MDR-TB) belongs to the most serious forms of TB. The number of MDR-TB patients represents an indicator of the effectiveness of TB regimentation. The aim of the study was to determine the number of registered MDR-TB patients in CR in 1998 and to identify causes of the resistance.

Is quarterly cohort analysis useful for assessing treatment outcomes in a low incidence country?

Setting: In the Czech Republic, a country regarded as having a low incidence of tuberculosis (TB), short-course chemotherapy (SCC) of TB has been implemented in routine practice country-wide.

Objective: To assess the outcome of SCC by quarterly cohort analysis of patients using the methodology recommended by the World Health Organization (WHO).

Design: Patients with newly detected bacteriologically confirmed pulmonary TB notified in 1998 were treated according to local recommendations (SCC) or with the WHO-recommended DOTS strategy.

Screening of TB contacts by tuberculin skin tests in a low-incidence community by BCG vaccination.

A 36-year-old man, an unemployed waiter, a regular patron of two bars living in a Czech city suffered for about a year from disorders caused probably by tuberculosis (TB). When hospitalised, diabetes mellitus and extensive lung TB were diagnosed. TB was found also at the post mortem examination when the patient died one week later.

[Tuberculosis in the Czech Republic in 1999].

Report is given on the tuberculosis (TB) prevalence and the new diseases monitoring in Czech Republic (CR) in 1999 using the register of notifiable TB diseases. 1631 new TB cases and relapse were notified (15.9/100,000 citizens).

[Tuberculosis in the Czech Republic in 1998].

In Czech Republic (CR) the epidemiological situation in tuberculosis (TB) was evaluated in 1998 using the notification TB into the TB register. 1805 new TB cases and relapses were notified (17.5/100,000 citizens).

Survey of BCG vaccination policy in Europe: 1994-96.

A retrospective survey, based on a standardized questionnaire sent to qualified public health experts in tuberculosis in 50 European countries, was carried out to evaluate the following: concordance between national vaccination programmes and WHO recommendations on BCG vaccination for prevention of tuberculosis; relation between BCG vaccination and revaccination policy and the tuberculosis epidemiological situation; and differences in BCG vaccination policy between Western and Central-Eastern European countries. The results obtained (from 41 (82%) of the 50 countries) revealed that BCG vaccination programmes met WHO recommendations in 44% of European countries. Mass primary vaccination and general revaccination were extremely common in countries where the prevalence of tuberculosis was high.

[Tuberculosis in Central Europe. Comparison of the present situation and development of tuberculosis in the Czech Republic and in Germany 1991-1993].

Comparison of the position as regards tuberculosis in the Czech Republic (CR) and in the Federal German Republic (FRG), two neighbouring countries of the Central European region was made possible by an approximation of systems of health services in the two countries and by the common effort to standardize definitions of indicators of the epidemiological situation as regards tuberculosis according to international recommendations. The relative number of newly assessed diseases of all forms and at all sites was equal in the two countries in 1993 and did not differ significantly during the past three years. No significant differences were found on comparison of indicators of incidence classified by bacteriological confirmation, site and age distribution.

Six years' experience with the discontinuation of BCG vaccination. 4. Protective effect of BCG vaccination against the Mycobacterium avium intracellulare complex.

Setting: In 1986, mass BCG vaccination of newborns was discontinued in an extensive territorial sample of neonates in the Czech Republic (30,000 infants annually). The non-vaccinated children have since been tuberculin tested at two-year intervals; those with continual or repeated intensive contact with animals in households or on farms were also tested with Mycobacterium avium intracellulare complex sensitin in addition to tuberculin.

Objective: Within the frame work of the surveillance programme the incidence of infection and disease caused by M.

Six years' experience with the discontinuation of BCG vaccination. 3. Transmission of tubercle bacilli in an unvaccinated population.

Setting: Mass BCG vaccination of newborns has been discontinued since 1986 in one third of the Czech Republic (30,000 newborns annually) except for babies with a high risk of tuberculosis.

Objective: The transmission and risk of tuberculosis infection were evaluated in non-BCG-vaccinated children representing a population living in satisfactory socio-economic conditions.

Design: In 1986-92, of 184,648 children tuberculin tested at 2-year intervals, 283 were infected.

Six years' experience with the discontinuation of BCG vaccination. 2. Cost and benefit of mass BCG vaccination.

In 1986 the compulsory mass BCG vaccination of infants born in a selected area of the Czech Republic was abolished. The observed annual risk of tuberculous infection in children aged 0-6 years was below 0.1% and the annual risk of tuberculous disease 7/100,000.

Six years' experience with the discontinuation of BCG vaccination. 1. Risk of tuberculosis infection and disease.

BCG vaccination programmes were introduced into Czechoslovakia 40 years ago under a quite different epidemiological situation than that of today. Compulsory mass BCG vaccination of infants born in a selected area was discounted in 1986, except for those having a high risk of contracting tuberculosis or those whose parents expressly asked for it. The aim of this study was to ascertain the risk of tuberculosis infection and breakdown rate from infection to disease in 165,854 newborns following a period of 6 years.

[Tuberculosis prevention needs adaptation to conditions of Central European countries].

Recommendations to stop mandatory BCG vaccination were issued for countries with a favourable epidemiological situation by tuberculosis. In three regions of Czechia nonvaccinated children made up 160,000. By tuberculin test, annual risk to develop tuberculous infection in children aged 0-6 years amounted to 0.

[Tuberculosis surveillance in the Czech Republic in 1990].

The authors evaluated data on the extent of the problem of tuberculosis and the effectiveness of control measures in the surveillance of TB in the Czech Republic (CR) in 1990. The data are assembled and monitored by the same method for a period of 10 years. The incidence of respiratory TB confirmed bacteriologically was 11.

Epidemiological and clinical study of tuberculosis in the Kolin district, Czechoslovakia.

A research study was in progress in a Czech district (100,000 inhabitants) in the years 1961-1972 with the aim to analyze the epidemiological situation of tuberculosis and the impact and effectiveness of control measures. Most of the conclusions are still valid and have their role in present tuberculosis programmes in Czechoslovakia or in other countries, too. There were recommended sensitive epidemiological indices and methods by which the actual situation should be characterized, changed or monitored: direct smear-positive cases and their importance, reevaluation of BCG vaccination and revaccination, as well as of case-finding and economic aspects of chemotherapy.

Tuberculosis surveillance in the Czech Republic in 1989.

The authors report on tuberculosis situation in the Czech Republic (CR) in 1989 and compare the data with 1988. The incidence of all cases of respiratory TB was 15.5 and that of bacteriologically confirmed cases 11.

[Surveillance of tuberculosis in the Czech Republic in 1989].

The authors report on the tuberculosis situation in the Czech Republic (CR) in 1989 and compare the data with 1988. The incidence of all cases of TB was 18.4/100,000, the incidence of all cases of respiratory TB 15.