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ABSTRACT Knowledge about sex‐specific difference in life‐history traits—like growth, mortality, or behavior—is of key importance for management and conservation as these parameters are essential for predictive modeling of population sustainability. We applied a newly developed molecular sex identification method, in combination with a SNP (single nucleotide polymorphism) panel for inferring the population of origin, for more than 300 large Atlantic bluefin tuna (ABFT) collected over several years from newly reclaimed feeding grounds in the Northeast Atlantic. The vast majority (95%) of individuals were genetically assigned to the eastern Atlantic population, which migrates between spawning grounds in the Mediterranean and feeding grounds in the Northeast Atlantic. We found a consistent pattern of a male bias among the eastern Atlantic individuals, with a 4‐year mean of 63% males (59%–65%). Males were most prominent within the smallest ( 250 cm) length classes, while the sex ratio was close to 1:1 for intermediate sizes (230–250 cm). The results from this new, widely applicable, and noninvasive approach suggests differential occupancy or migration timing of ABFT males and females, which cannot be explained alone by sex‐specific differences in growth. Our findings are corroborated by previous traditional studies of sex ratios in dead ABFT from the Atlantic, the Mediterranean, and the Gulf of Mexico. In concert with observed differences in growth and mortality rates between the sexes, these findings should be recognized in order to sustainably manage the resource, maintain productivity, and conserve diversity within the species.

Abstract Comorbid proteinopathies are observed in many neurodegenerative disorders including Alzheimer’s disease (AD), increase with age, and influence clinical outcomes, yet the mechanisms remain ill-defined. Here, we show that reduction of progranulin (PGRN), a lysosomal protein associated with TDP-43 proteinopathy, also increases tau inclusions, causes concomitant accumulation of α-synuclein and worsens mortality and disinhibited behaviors in tauopathy mice. The increased inclusions paradoxically protect against spatial memory deficit and hippocampal neurodegeneration. PGRN reduction in male tauopathy attenuates activity of β-glucocerebrosidase (GCase), a protein previously associated with synucleinopathy, while increasing glucosylceramide (GlcCer)-positive tau inclusions. In neuronal culture, GCase inhibition enhances tau aggregation induced by AD-tau. Furthermore, purified GlcCer directly promotes tau aggregation in vitro. Neurofibrillary tangles in human tauopathies are also GlcCer-immunoreactive. Thus, in addition to TDP-43, PGRN regulates tau- and synucleinopathies via GCase and GlcCer. A lysosomal PGRN–GCase pathway may be a common therapeutic target for age-related comorbid proteinopathies.

Abstract Tauopathies encompass a group of neurodegenerative disorders characterised by diverse tau amyloid fibril structures. The persistence of polymorphism across tauopathies suggests that distinct pathological conditions dictate the adopted polymorph for each disease. However, the extent to which intrinsic structural tendencies of tau amyloid cores contribute to fibril polymorphism remains uncertain. Using a combination of experimental approaches, we here identify a new amyloidogenic motif, PAM4 (Polymorphic Amyloid Motif of Repeat 4), as a significant contributor to tau polymorphism. Calculation of per-residue contributions to the stability of the fibril cores of different pathologic tau structures suggests that PAM4 plays a central role in preserving structural integrity across amyloid polymorphs. Consistent with this, cryo-EM structural analysis of fibrils formed from a synthetic PAM4 peptide shows that the sequence adopts alternative structures that closely correspond to distinct disease-associated tau strains. Furthermore, in-cell experiments revealed that PAM4 deletion hampers the cellular seeding efficiency of tau aggregates extracted from Alzheimer’s disease, corticobasal degeneration, and progressive supranuclear palsy patients, underscoring PAM4’s pivotal role in these tauopathies. Together, our results highlight the importance of the intrinsic structural propensity of amyloid core segments to determine the structure of tau in cells, and in propagating amyloid structures in disease.

BackgroundFrontotemporal lobar degeneration (FTLD) is a leading cause of dementia in individuals aged

Key Clinical Message Recurrent depression with psychotic features is an atypical presentation of neurosyphilis. This case emphasizes the polymorphic clinical presentation of neurosyphilis and how it mimics affective disorders with psychotic symptoms.

Cytochrome P450 enzymes (P450s) play a critical role in drug metabolism, with the CYP3A subfamily being responsible for the biotransformation of over 50% of marked drugs. While CYP3A enzymes are known for their extensive catalytic versatility, one intriguing and less understood function is the ability to mediate carbon–carbon (C–C) bond cleavage. These uncommon reactions can lead to unusual metabolites and potentially influence drug safety and efficacy. This review focuses on examining examples of C–C bond cleavage catalyzed by CYP3A, exploring the mechanisms, physiological significance, and implications for drug metabolism. Additionally, examples of CYP3A-mediated ring expansion via C–C bond cleavages are included in this review. This work will enhance our understanding of CYP3A-catalyzed C–C bond cleavages and their mechanisms by carefully examining and analyzing these case studies. It may also guide future research in drug metabolism and drug design, improving drug safety and efficacy in clinical practice.

Abstract Background Anal sac adenocarcinoma (ASACA) in dogs is a malignant perianal tumour that often metastasizes to the iliosacral lymph nodes. Additionally, this tumour can be associated with hypercalcemia of malignancy. To date, no study has looked at the association between increased blood calcium levels and suspected or confirmed lymph node metastasis as a primary objective. Objective The objective of this study was to determine if increased total serum calcium level is associated with iliosacral lymph node metastasis in dogs diagnosed with ASACA. Methods Medical records of a single referral hospital were searched to identify dogs examined between 2011 and 2021 that had a diagnosis of ASACA via cytology or histopathology. Only dogs that had serum total calcium recorded and abdominal ultrasound were included in the study. All images were reviewed by a board‐certified radiologist blinded to any patient identifiers. Results Of the 58 dogs, 33% (19/58) had total hypercalcaemia, and of these, 68% had confirmed or suspected iliosacral lymph node metastasis. Total hypercalcaemia was significantly associated with confirmed or suspected iliosacral lymph node metastasis (p < 0.01). However, 46% (11/24) of dogs with confirmed or suspected iliosacral lymph node metastasis were normocalcaemic. Conclusions Based on these results, it is suggested that while the presence of total hypercalcaemia may increase the likelihood of concurrent lymph node metastasis, total hypercalcaemia alone cannot be used as a screening tool for lymph node metastasis. Dogs diagnosed with ASACA should undergo full staging regardless of total serum calcium values.

Background: Anal sac adenocarcinoma (ASACA) in dogs is a malignant perianal tumour that often metastasizes to the iliosacral lymph nodes. Additionally, this tumour can be associated with hypercalcemia of malignancy. To date, no study has looked at the association between increased blood calcium levels and suspected or confirmed lymph node metastasis as a primary objective. Objective: The objective of this study was to determine if increased total serum calcium level is associated with iliosacral lymph node metastasis in dogs diagnosed with ASACA. Methods: Medical records of a single referral hospital were searched to identify dogs examined between 2011 and 2021 that had a diagnosis of ASACA via cytology or histopathology. Only dogs that had serum total calcium recorded and abdominal ultrasound were included in the study. All images were reviewed by a board‐certified radiologist blinded to any patient identifiers. Results: Of the 58 dogs, 33% (19/58) had total hypercalcaemia, and of these, 68% had confirmed or suspected iliosacral lymph node metastasis. Total hypercalcaemia was significantly associated with confirmed or suspected iliosacral lymph node metastasis (p < 0.01). However, 46% (11/24) of dogs with confirmed or suspected iliosacral lymph node metastasis were normocalcaemic. Conclusions: Based on these results, it is suggested that while the presence of total hypercalcaemia may increase the likelihood of concurrent lymph node metastasis, total hypercalcaemia alone cannot be used as a screening tool for lymph node metastasis. Dogs diagnosed with ASACA should undergo full staging regardless of total serum calcium values. [ABSTRACT FROM AUTHOR]