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At many vertebrate synapses, presynaptic functions are tuned by expression of different Ca v 2 channels. Most invertebrate genomes contain only one Ca v 2 gene. The Drosophila Ca v 2 homolog, cacophony (cac), induces synaptic vesicle release at presynaptic active zones (AZs). We hypothesize that Drosophila cac functional diversity is enhanced by two mutually exclusive exon pairs that are not conserved in vertebrates, one in the voltage sensor and one in the loop binding Ca β and G βγ subunits. We find that alternative splicing in the voltage sensor affects channel activation voltage. Only the isoform with the higher activation voltage localizes to AZs at the glutamatergic Drosophila larval neuromuscular junction and is imperative for normal synapse function. By contrast, alternative splicing at the other alternative exon pair tunes multiple aspects of presynaptic function. While expression of one exon yields normal transmission, expression of the other reduces channel number in the AZ and thus release probability. This also abolishes presynaptic homeostatic plasticity. Moreover, reduced channel number affects short-term plasticity, which is rescued by increasing the external calcium concentration to match release probability to control. In sum, in Drosophila alternative splicing provides a mechanism to regulate different aspects of presynaptic functions with only one Ca v 2 gene., Competing Interests: CB, LK, DG, JA, LD, HK, CR, OK, JS, MH, CD, SR No competing interests declared, (© 2024, Bell, Kilo et al.)

Germline loss of function (LoF) DDX41 variants predispose to late-onset hematopoietic malignancies (HMs), predominantly of myeloid lineage. Among 43 families with germline DDX41 LoF variants, bone marrow (BM) biopsies in those without (n=8) or with malignancies (n=21) revealed mild dysplasia in peripheral blood (57%) and BM (88%), long before the average age of DDX41-related HM onset. Therefore, we recommend baseline bone marrow biopsies in people with germline DDX41LoF alleles to avoid over-diagnosis of myelodysplastic syndromes. A variety of solid tumors were also observed in our cohort, with 24% penetrance by age 75. Although acquired DDX41 mutations are common in HMs, we failed to identify such alleles in solid tumors arising in those with germline DDX41LoF variants (n=15), suggesting an alternative mechanism driving solid tumor development. Furthermore, 33% of pedigrees in which >15% of first-degree relatives including the proband were diagnosed with a solid tumor had second germline deleterious variants in other cancerpredisposition genes, likely serving as primary cancer drivers. Finally, both lymphoblastoid cell lines and primary peripheral blood from individuals with germline DDX41LoF variants exhibited differential levels of inflammation-associated proteins. These data provide evidence of inflammatory dysfunction mediated by germline DDX41LoF alleles that may contribute to solid tumor growth in the context of additional germline cancer-associated variants. For those with HMs and personal/family histories of solid tumors, we recommend broad germline testing. DDX41 may be an indirect modifier of solid tumor pathogenesis compared to its tumor suppressor function within hematopoietic tissues, a hypothesis that can be addressed in future work.

Purpose: To compare the impact of proton versus photon postmastectomy radiation (PMRT) on implant related complications., Materials: The records of breast cancer patients treated with mastectomy and expander and/or implant reconstruction followed by PMRT at our institution between 2011-2022 were reviewed. Patients were divided into two groups by treatment modality: proton and photon. All identified proton patients were treated using conventional fractionation and radiobiological effectiveness (RBE) was set to 1.1 compared to photons x-rays. Recorded complications included infection/skin necrosis (I/N) requiring operative debridement, capsular contracture (CC) necessitating capsulotomy, absolute reconstruction failure (ARF) implying complete loss of reconstruction, and overall reconstruction failure (ORF) defined as multiple revisions leading to replacement of the implant or salvage autologous reconstruction. Subgroup analysis for proton patients explored correlation between dosimetric parameters and complications using logistic regression and Cox proportional hazards regression models., Results: 203 patients with an overall median follow-up of 4.7 years were identified. Among those 203 patients, 50 patients (25%) received protons while 153 patients (75%) received photons. The complication rates for protons vs photons were: Infection/necrosis (20% vs 13%, OR:1.6, p=0.2), capsular contracture (30% vs 10%, OR:3.9, p<0.001), Absolute Reconstruction Failure (16% vs 12%, OR:1.4, p=0.4) and Overall Reconstruction Failure (56% vs 36%, OR: 2.2, p=0.01). Sensitivity analyses and time-to-event models yielded similar results. The median (Dmean) for CTV, implant and skin was 50.6, 50.8, and 6.7 Gy (RBE), respectively. The median hot spot (D1cc) for CTV (clinical-target-volume), implant and skin was 52.8, 52.7, and 49.8 Gy (RBE) respectively. None of these parameters were significantly correlated with complications. The 5-year local failure cumulative incidence was 0% vs 4% (p=0.13) for protons and photons, respectively., Conclusions: Proton PMRT was associated with higher rates of implant capsular contracture and reconstruction failures compared to photons with equivalent local-control. No dosimetric parameter correlated with reconstruction complications., Competing Interests: Declaration of competing interest None of the Authors have a relevant Conflict of interest to disclose., (Copyright © 2025. Published by Elsevier Inc.)

Objective: Optimizing sexual history intake is crucial for effective STI screening and diagnosis. This study, conducted at a university health center, investigated whether implementing a self-administered electronic questionnaire focused on organ contact, compared to the conventional verbal intake method used previously, would increase the number and diversity of screening tests, and subsequently improve detection rates for chlamydia (CT) and gonorrhea (GC)., Methods: The number and types of CT and GC tests ordered, along with diagnosis rates, were analyzed during the implementation of the electronic questionnaire and compared with data from the preceding four years., Results: There was a significant increase in both testing frequency and CT and GC diagnoses after initiation of the new sexual history intake compared to previous years., Conclusion: Implementing a self-administered electronic questionnaire for sexual history intake focusing on organ contact may enhance STI screening strategies and improve diagnostic yield for CT and GC infections.

Organisms are repeatedly exposed to fluctuating environmental and nutritional conditions. Transcriptional memory has been shown to be a mechanism to cope with these fluctuations because it increases the speed and the magnitude of the cellular response to a certain re-occurring condition and therefore optimizes adaptation and fitness in a given environment. We found that genes coding for sterigmatocystin (ST) production in Aspergillus nidulans are activated stronger when cells are repeatedly exposed to nutrient starvation, compared to cells that experience this condition for the first time. We studied possible underlying mechanisms and found that persistence of the transcription factor AflR, which can undergo activation-inactivation cycles, accounts for a large part of the memory. In addition, a chromatin-based mechanism through histone H3 lysine 4 dimethylation (H3K4me2) and extracellular metabolites produced during the first activation phase contribute to the memory process. Genome-wide transcriptome and chromatin analyses showed that only a few genes within the ST and other starvation-induced biosynthetic gene clusters gain the H3K4me2 mark during the 1st activation, but the majority of those which receive the mark also maintain it during the subsequent repression and re-activation phase. Combined with previous findings on chromatin-level regulation of biosynthetic gene clusters (BGCs) our recent data suggest that the H3K4me2 mark may contribute to the correct 3D organization of BGCs and that this is a prerequisite for activation and transcriptional memory., Competing Interests: Conflict of Interest The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2024. Published by Elsevier GmbH.)