SH3-domain mutations selectively disrupt Csk homodimerization or PTPN22 binding

The kinase Csk is the primary negative regulator of the Src-family kinases (SFKs, i.e., Lck, Fyn, Lyn, Hck, Fgr, Blk, Src, Yes), phosphorylating a tyrosine on the SFK C-terminal tail that nucleates an autoinhibitory complex. Csk also binds phosphatases, including PTPN12 (PTP-PEST) and immune-cell PTPN22 (Pep/LYP), which dephosphorylate the SFK activation loop to promote autoinhibition. High local concentrations of Csk are required to promote its negative-regulatory function, and Csk-binding proteins (e.g., CBP/PAG1) oligomerize within membrane microdomains. Purified Csk also homodimerizes in solution through an interface that overlaps the phosphatase binding site. Here we demonstrate that Csk can homodimerize in Jurkat T cells, in competition with PTPN22 binding. We designed SH3-domain mutations in Csk that selectively impair homodimerization (H21I) or PTPN22 binding (K43D) and verified their kinase activity in solution. Csk W47A, an SH3-domain mutant commonly used to block PTPN22 binding, also impairs homodimerization. Csk H21I and K43D will be useful tools for dissecting the protein-specific drivers of autoimmunity mediated by the human polymorphism PTPN22 R620W, which impairs interaction with both Csk and with the E3 ubiquitin ligase TRAF3. Future investigations of Csk homodimer activity and phosphatase interactions may reveal new facets of SFK regulation in hematopoietic and non-hematopoietic cells.

Have (R)-[11C]PK11195 challengers fulfilled the promise? A scoping review of clinical TSPO PET studies

Purpose The prototypical TSPO radiotracer (R)-[11C]PK11195 has been used in humans for more than thirty years to visualize neuroinflammation in several pathologies. Alternative radiotracers have been developed to improve signal-to-noise ratio and started to be tested clinically in 2008. Here we examined the scientific value of these “(R)-[11C]PK11195 challengers” in clinical research to determine if they could supersede (R)-[11C]PK11195. Methods A systematic MEDLINE (PubMed) search was performed (up to end of year 2020) to extract publications reporting TSPO PET in patients with identified pathologies, excluding studies in healthy subjects and methodological studies. Results Of the 288 publications selected, 152 used 13 challengers, and 142 used (R)-[11C]PK11195. Over the last 20 years, the number of (R)-[11C]PK11195 studies remained stable (6 ± 3 per year), but was surpassed by the total number of challenger studies for the last 6 years. In total, 3914 patients underwent a TSPO PET scan, and 47% (1851 patients) received (R)-[11C]PK11195. The 2 main challengers were [11C]PBR28 (24%—938 patients) and [18F]FEPPA (11%—429 patients). Only one-in-ten patients (11%—447) underwent 2 TSPO scans, among whom 40 (1%) were scanned with 2 different TSPO radiotracers. Conclusions Generally, challengers confirmed disease-specific initial (R)-[11C]PK11195 findings. However, while their better signal-to-noise ratio seems particularly useful in diseases with moderate and widespread neuroinflammation, most challengers present an allelic-dependent (Ala147Thr polymorphism) TSPO binding and genetic stratification is hindering their clinical implementation. As new challengers, insensitive to TSPO human polymorphism, are about to enter clinical evaluation, we propose this systematic review to be regularly updated (living review).

Polish army soldier and scientist – Stanisław Ossowski

The article reminds Stanisław Ossowski, an outstanding sociologist and political scientist, a representative of the Lviv-Warsaw school, and a brave soldier. The author focuses her attention on two problems selected from his work: on man as an ethical subject and on opportunities and threats in shaping individual and collective social personalities. Stanisław Ossowski regarded disobedience in thinking, faithfulness to the truth, and intellectual honesty as the professional duty of a scientist, especially a humanist, who studies ideas and value systems. He justified the theory of mutual conditioning of the social structure-personality. He studied the impact of decisions of senior government officials on the dynamics of human behaviour and the development of human polymorphism.

General and particular issues of etiopathogenesis of peptic ulcer and gastric cancer: current status of the problem

The development of peptic ulcer (PU) and gastric cancer (GC) is the result of the interaction of various internal and external factors. Moreover, if the role ofHelicobacter pylori(H. pylori) in the development of diseases of the stomach is fully established, the significance of many other factors continues to be discussed. Serious controversy is caused by the participation of various strains ofH. pyloriin the development of PU and GC. First of all, these are Vac- and Cag-positive strains ofH. pylori. The role of genetic human polymorphism in the development of this pathology is debatable. Especially the interleukin genes and necrotizing tumor factor alpha. The role of environmental factors in the formation of PU and GC is not fully understood. So, the role of alcohol, occupational hazards and drugs in the development of these diseases continues to be discussed. Further study of risk factors for various diseases of the stomach will optimize their prevention and treatment. The review presents a modern view of individual issues in the pathogenesis of PU and GC.

Endocannabinoid genetic variation enhances vulnerability to THC reward in adolescent female mice

Adolescence represents a developmental period with the highest risk for initiating cannabis use. Little is known about whether genetic variation in the endocannabinoid system alters mesolimbic reward circuitry to produce vulnerability to the rewarding properties of the exogenous cannabinoid Δ9-tetrahydrocannabinol (THC). Using a genetic knock-in mouse model (FAAHC/A) that biologically recapitulates the human polymorphism associated with problematic drug use, we find that in adolescent female mice, but not male mice, this FAAH polymorphism enhances the mesolimbic dopamine circuitry projecting from the ventral tegmental area (VTA) to the nucleus accumbens (NAc) and alters cannabinoid receptor 1 (CB1R) levels at inhibitory and excitatory terminals in the VTA. These developmental changes collectively increase vulnerability of adolescent female FAAHC/A mice to THC preference that persists into adulthood. Together, these findings suggest that this endocannabinoid genetic variant is a contributing factor for increased susceptibility to cannabis dependence in adolescent females.

A Single-Nucleotide Polymorphism of αVβ3 Integrin Is Associated with the Andes Virus Infection Susceptibility

The Andes Orthohantavirus (ANDV), which causes the hantavirus cardiopulmonary syndrome, enters cells via integrins, and a change from leucine to proline at residue 33 in the PSI domain (L33P), impairs ANDV recognition. We assessed the association between this human polymorphism and ANDV infection. We defined susceptible and protective genotypes as “TT” (coding leucine) and “CC” (coding proline), respectively. TT was present at a rate of 89.2% (66/74) among the first cohort of ANDV cases and at 60% (63/105) among exposed close-household contacts, who remained uninfected (p < 0.05). The protective genotype (CC) was absent in all 85 ANDV cases, in both cohorts, and was present at 11.4% of the exposed close-household contacts who remained uninfected. Logistic regression modeling for risk of infection had an OR of 6.2–12.6 (p < 0.05) in the presence of TT and well-known ANDV risk activities. Moreover, an OR of 7.3 was obtained when the TT condition was analyzed for two groups exposed to the same environmental risk. Host genetic background was found to have an important role in ANDV infection susceptibility, in the studied population.