The topology of the lymphotoxin ß receptor that accumulates upon endolysosomal dysfunction dictates the NF-κB signaling outcome.

Cytokine receptors, such as tumor necrosis factor receptor I (TNFRI, also known as TNFRSF1A) and lymphotoxin ß receptor (LTßR), activate inflammatory nuclear factor (NF)-κB signaling upon stimulation. We have previously demonstrated that depletion of ESCRT components leads to endosomal accumulation of TNFRI and LTßR, and their ligand-independent signaling to NF-κB. Here, we studied whether other perturbations of the endolysosomal system could trigger intracellular accumulation and signaling of ligand-free LTßR. While depletion of the CORVET components had no effect, knockdown of Rab7a or HOPS components, or pharmacological inhibition of lysosomal degradation, caused endosomal accumulation of LTßR and increased its interaction with the TRAF2 and TRAF3 signaling adaptors. However, the NF-κB pathway was not activated under these conditions. We found that knockdown of Rab7a or HOPS components led to sequestration of LTßR in intraluminal vesicles of endosomes, thus precluding NF-κB signaling. This was in contrast to the LTßR localization on the outer endosomal membrane that was seen after ESCRT depletion and was permissive for signaling. We propose that the inflammatory response induced by intracellular accumulation of endocytosed cytokine receptors critically depends on the precise receptor topology within endosomal compartments.

ChatGPT-3.5 passes Poland's medical final examination-Is it possible for ChatGPT to become a doctor in Poland?

Objectives: ChatGPT is an advanced chatbot based on Large Language Model that has the ability to answer questions. Undoubtedly, ChatGPT is capable of transforming communication, education, and customer support; however, can it play the role of a doctor? In Poland, prior to obtaining a medical diploma, candidates must successfully pass the Medical Final Examination. Methods: The purpose of this research was to determine how well ChatGPT performed on the Polish Medical Final Examination, which passing is required to become a doctor in Poland (an exam is considered passed if at least 56% of the tasks are answered correctly). A total of 2138 categorized Medical Final Examination questions (from 11 examination sessions held between 2013-2015 and 2021-2023) were presented to ChatGPT-3.5 from 19 to 26 May 2023. For further analysis, the questions were divided into quintiles based on difficulty and duration, as well as question types (simple A-type or complex K-type). The answers provided by ChatGPT were compared to the official answer key, reviewed for any changes resulting from the advancement of medical knowledge. Results: ChatGPT correctly answered 53.4%-64.9% of questions. In 8 out of 11 exam sessions, ChatGPT achieved the scores required to successfully pass the examination (60%). The correlation between the efficacy of artificial intelligence and the level of complexity, difficulty, and length of a question was found to be negative. AI outperformed humans in one category: psychiatry (77.18% vs. 70.25%, p = 0.081). Conclusions: The performance of artificial intelligence is deemed satisfactory; however, it is observed to be markedly inferior to that of human graduates in the majority of instances. Despite its potential utility in many medical areas, ChatGPT is constrained by its inherent limitations that prevent it from entirely supplanting human expertise and knowledge.

Tollip-deficient zebrafish display no abnormalities in development, organ morphology or gene expression in response to lipopolysaccharide.

Tollip is a multifunctional adaptor protein implicated in innate immunity, lysosomal trafficking/autophagy of protein aggregates and various signaling processes in mammalian models. To verify evolutionary conservation of these functions, we used CRISPR/Cas9 editing to construct a zebrafish line bearing a stable tollip knockout. In contrast to previously reported tollip morphants, Tollip-deficient fish display normal development until adulthood, are fertile, and have no apparent physiological defects. When challenged with lipopolysaccharide (LPS), inflammatory gene expression is unaffected. Moreover, Tollip deficiency does not aggravate swimming deficiency resulting from lysosomal dysfunction and proteotoxicity in a fish model of Gaucher disease. Thus, individual functions of Tollip may be organism-specific or manifest only upon certain conditions/challenges or disease backgrounds.

18F-choline positron emission tomography/computed tomography for the detection of prostate cancer relapse: assessment of maximum standardized uptake value correlation with prostate-specific antigen levels.

OBJECTIVE: Patients with prostate cancer are monitored by prostate-specific antigen (PSA) evaluation and PET [PET/computed tomography (CT)]. The aim of our study was to evaluate correlations between PSA levels and standardized uptake values (SUV) in patients with recurrent prostate cancer. METHODS: We analyzed 282 prostate cancer patients undergoing PET-CT due to suspicion of recurrence. Levels of PSA and PSA change per month were analyzed, together with maximum standardized uptake value (SUVmax). RESULTS: PET/CT results were positive in 175 patients (62.1%) and negative in 107 patients (37.9%). In the positive group, PSA levels were significantly higher. The ROC curve analysis indicated PSA level of 1.70 ng/ml and PSA level change in time of 0.12 ng/ml are the optimal cut-off values. Patients were divided into subgroups: with metastases (M), local relapse (L), and local relapse and metastases (M + L). The latest PSA levels, were similar in subgroups L and M: 5.00 (2.98-10.30) ng/ml and 3.90 (1.27-14.08) ng/ml, but lower than in subgroup M + L: 12.43 (6.08-49.36) ng/ml. PSA level change in time was similar in the subgroups L and M: 0.63 (0.09-1.00) ng/ml/month and 0.33 (0.02-1.73) ng/ml/month, but lower in subgroup M + L: 2.21 (0.22-10.34) ng/ml/month, P < 0.05. SUVmax was significantly (P < 0.05) lower in subgroup L than in M and L + M: 3.00 (2.30-4.00), 4.60 (2.70-7.40), and 4.90 (3.80-8.00), respectively. PSA level significantly correlated with SUVmax in patients from subgroups L (R = 0.424; P < 0.05) and M (R = 0.314; P < 0.01). Positive correlation between PSA change and SUVmax was observed in subgroup M + L (R = 0.561; P < 0.01) and M (R = 0.270; P < 0.05). CONCLUSION: The study confirmed that patients with high PSA level and fast PSA increase are likely to be diagnosed with both, local relapse and metastases. Moreover, SUVmax values in metastatic lesions are usually higher.

The frequency of mitochondrial polymerase gamma related disorders in a large Polish population cohort.

Diseases related to DNA polymerase gamma dysfunction comprise of heterogeneous clinical presentations with variable severity and age of onset. Molecular screening for the common POLG variants: p.Ala467Thr, p.Trp748Ser, p.Gly848Ser, and p.Tre251Ile has been conducted in a large population cohort (n = 3123) and in a clinically heterogeneous group of 1289 patients. Recessive pathogenic variants, including six novel ones were revealed in 22/26 patients. Infantile Alpers-Huttenlocher syndrome and adulthood ataxia spectrum were the most common found in our group. Distinct molecular profile identified in the Polish patients with significant predominance of p.Trp748Ser variant (50% of mutant alleles) reflected strikingly low population frequency of the three remaining variants and slightly higher p.Trp748Ser allele frequency in the general Polish population as compared to the non-Finish European population.

Endothelial Notch signalling limits angiogenesis via control of artery formation.

Angiogenic sprouting needs to be tightly controlled. It has been suggested that the Notch ligand dll4 expressed in leading tip cells restricts angiogenesis by activating Notch signalling in trailing stalk cells. Here, we show using live imaging in zebrafish that activation of Notch signalling is rather required in tip cells. Notch activation initially triggers expression of the chemokine receptor cxcr4a. This allows for proper tip cell migration and connection to the pre-existing arterial circulation, ultimately establishing functional arterial-venous blood flow patterns. Subsequently, Notch signalling reduces cxcr4a expression, thereby preventing excessive blood vessel growth. Finally, we find that Notch signalling is dispensable for limiting blood vessel growth during venous plexus formation that does not generate arteries. Together, these findings link the role of Notch signalling in limiting angiogenesis to its role during artery formation and provide a framework for our understanding of the mechanisms underlying blood vessel network expansion and maturation.