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Abstract: We report measurements of the transverse diffusion of electrons in P-10 gas (90% Ar, 10% CH4) in a laboratory-scale time projection chamber (TPC) utilizing a novel pixelated signal capture and digitization technique known as Q-Pix. The Q-Pix method incorporates a precision switched integrating transimpedance amplifier whose output is compared to a threshold voltage. Upon reaching the threshold, a comparator sends a 'reset' signal, initiating a discharge of the integrating capacitor. The time difference between successive resets is inversely proportional to the average current at the pixel in that time interval, and the number of resets is directly proportional to the total collected charge. We developed a 16-channel Q-Pix prototype fabricated from commercial off-the-shelf components and coupled them to 16 concentric annular anode electrodes to measure the spatial extent of the electron swarm that reaches the anode after drifting through the uniform field of the TPC. The swarm is produced at a gold photocathode using pulsed UV light. The measured transverse diffusion agrees with simulations in PyBoltz across a range of operating pressures (200–1500 Torr). These results demonstrate that a Q-Pix readout can successfully reconstruct the ionization topology in a TPC.

Introduction: As climate change advances, the looming threat of dengue fever, intricately tied to rising temperatures, intensifies, posing a substantial and enduring public health challenge in the Philippines. This study aims to investigate the historical and projected excess dengue disease burden attributable to temperature to help inform climate change policies, and guide resource allocation for strategic climate change and dengue disease interventions., Methods: The study utilized established temperature-dengue risk functions to estimate the historical dengue burden attributable to increased temperatures. Future projections were derived using Coupled Model Intercomparison Project Phase 6 (CMIP6) Shared Socioeconomic Pathway (SSP) scenarios to estimate the excess dengue burden on a national scale. Current health burden estimates were calculated by charting the attributable fraction per epidemiological week against the exponential risk function., Results: Projections indicate a substantial increase in temperature-related dengue incidence across all SSP climate scenarios by 2100. Between 2010-2019, 72.1% of reported dengue cases in the Philippines were attributable to temperature, demonstrating that temperature is a significant driver in dengue transmission. The highest attributable fractions were observed between the warm-dry season to early rainy season (Epi Weeks 15-25). Southern, periequatorial areas, particularly those undergoing rapid urbanization, had the highest temperature-related dengue incidence., Discussion: The findings emphasize the critical interplay between climate change and socioeconomic factors in shaping future dengue risk. By incorporating future climate scenarios and provincial-level projections, this study provides valuable insights for policy planning, early warning systems, and public health programming. Strengthening health infrastructure, promoting sustainable urban development, and implementing effective vector control measures are crucial to mitigating the future dengue burden in the Philippines., Competing Interests: 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 Seposo, Valenzuela, Apostol, Wangkay, Lao and Enriquez.)

A 59-year-old man who under surveillance for abdominal aortic aneurysm and peripheral artery disease, was investigated with a CT Angiogram aorta. The CT scan showed an abdominal aortic aneurysm reaching 6.2cm with significant thrombus burden, occluded coeliac artery, occluded left iliac artery, calcified stenosis of the right renal artery and features of chronic renal infarct in the right upper pole. Technetium-99m dimercaptosuccinic acid (Tc-99m DMSA) renal scan was done to document the extent of the infarction and for differential function of the kidneys.

Pediatric malignancies frequently harbor chromosomal translocations that induce expression of fusion oncoproteins. The EWSR1-FLI1 fusion oncoprotein acts as a neomorphic transcription factor and is the dominant genetic driver of Ewing's sarcoma. Interrogation of the mechanisms by which EWSR1-FLI1 drives tumorigenesis has been limited by a lack of model systems to precisely and selectively control its expression in patient-derived cell lines and xenografts. Here, we report the generation of a panel of patient-derived EWS cell lines in which inducible protein degrons were engineered into the endogenous EWSR1-FLI1 locus. These alleles enabled rapid and efficient depletion of EWSR1-FLI1. Complete suppression of EWSR1-FLI1 induced a reversible cell cycle arrest at the G 1 -S checkpoint, and we identified a core set of transcripts downstream of EWSR1-FLI1 across multiple cell lines and degron systems. Additionally, depletion of EWSR1-FLI1 potently suppressed tumor growth in xenograft models validating efforts to directly target EWSR1-FLI1 in Ewing's sarcoma., Competing Interests: DECLARATION OF INTERESTS: The authors declare no competing interests

A subset of people living with HIV (PLWH) can produce broadly neutralizing antibodies (bNAbs) against HIV, but the lymph node (LN) dynamics that promote the generation of these antibodies are poorly understood. Here, we explored LN-associated histological, immunological, and virological mechanisms of bNAb generation in a cohort of anti-retroviral therapy (ART)-naïve PLWH. We found that participants who produce bNAbs, termed neutralizers, have a superior LN-associated B cell follicle architecture compared with PLWH who do not. The latter was associated with a significantly higher in situ prevalence of Bcl-6 hi follicular helper CD4 T cells (TFH), expressing a molecular program that favors their differentiation and stemness, and significantly reduced IL-10 follicular suppressor CD4 T cells. Furthermore, our data reveal possible molecular targets mediating TFH- B cell interactions in neutralizers. Together, we identify cellular and molecular mechanisms that contribute to the development of bNAbs in PLWH., Competing Interests: Disclosure of Conflicts of Interest The authors declare no competing conflicts of interest.

Early Th 17 responses are necessary to provide protection against Mycobacterium tuberculosis (Mtb). Mtb impedes Th 17 polarization by restricting CD40 co-stimulatory pathway on dendritic cells (DCs). We previously demonstrated that engaging CD40 on DCs increased Th 17 responses. However, the molecular mechanisms that contributed to Th 17 polarization were unknown. Here, we identify the Notch ligand DLL4 as necessary for Th 17 polarization and demonstrate that Mtb limits DLL4 on DCs to prevent optimal Th 17 responses. Although Mtb infection induced only low levels of DLL4, engaging CD40 on DCs increased DLL4 expression. Antibody blockade of DLL4 on DCs reduced Th 17 polarization in vitro and in vivo . In addition, we show that the Mtb Hip1 protease attenuates DLL4 expression on lung DCs by impeding CD40 signaling. Overall, our results demonstrate that Mtb impedes CD40-dependent DLL4 expression to restrict Th 17 responses and identify the CD40-DLL4 pathways as targets for developing new Th 17 -inducing vaccines and adjuvants for tuberculosis., Competing Interests: The authors declare no competing interests., (© 2022 The Author(s).)

Tuberculosis (TB) remains one of the leading causes of death worldwide due to a single infectious disease agent. BCG, the only licensed vaccine against TB, offers limited protection against pulmonary disease in children and adults. TB vaccine research has recently been reinvigorated by new data suggesting alternative administration of BCG induces protection and a subunit/adjuvant vaccine that provides close to 50% protection. These results demonstrate the need for generating adjuvants in order to develop the next generation of TB vaccines. However, development of TB-targeted adjuvants is lacking. To help meet this need, NIAID convened a workshop in 2020 titled "Advancing Vaccine Adjuvants for Mycobacterium tuberculosis Therapeutics". In this review, we present the four areas identified in the workshop as necessary for advancing TB adjuvants: 1) correlates of protective immunity, 2) targeting specific immune cells, 3) immune evasion mechanisms, and 4) animal models. We will discuss each of these four areas in detail and summarize what is known and what we can advance on in order to help develop more efficacious TB vaccines., Competing Interests: Author RNM was employed by company Columbus Technologies & Services Inc. JE and SM are employees of and own shares in Inimmune Corporation. The remaining 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 © 2021 Enriquez, Izzo, Miller, Stewart, Mahon, Frank, Evans, Rengarajan and Triccas.)

Disorders of sex development (DSDs) are congenital anomalies that affect sexual differentiation of genitourinary organs and secondary sex characters. A common cause of female genital virilization is congenital adrenal hyperplasia (CAH), in which excess androgen production during development of 46XX females can result in vaginal atresia, masculinization of the urethra, a single urogenital sinus, and clitoral hypertrophy or ambiguous external genitalia. Development of the vagina depends on sexual differentiation of the urogenital sinus ridge, an epithelial thickening that forms where the sex ducts attach to the anterior urethra. In females, the sinus ridge descends posteriorly to allow the vaginal opening to form in the vulva, whereas in males and in females with CAH, androgens inhibit descent of the sinus ridge. The mechanisms that regulate development of the female urethra and vagina are largely unknown. Here we show that the timing and duration of, and the cell population targeted by, androgen signaling determine the position of vaginal attachment to the urethra. Manipulations of androgen signaling in utero reveal a temporal window of development when sinus ridge fate is determined. Cell type-specific genetic deletions of androgen receptor (Ar) identify a subpopulation of mesenchymal cells that regulate sinus ridge morphogenesis. These results reveal a common mechanism that coordinates development of the vagina and feminization of the urethra, which may account for development of a single urogenital sinus in females exposed to excessive androgen during a critical period of prenatal development., Competing Interests: The authors declare no conflict of interest.