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Lesbian, Gay, Bisexual, Transgender, Queer, and other sexual and gender minority (LGBTQ+) youth and young adults (YYAs) have poorer mental health outcomes than their cisgender, heterosexual peers in large part due to multilevel stigmatization and minority stress. This was exacerbated by psychological stressors stemming from the COVID-19 pandemic; these experiences intersected with YYA unique developmental stage. Here we explored LGBTQ+ YYA's pandemic-related experiences, focusing on intersections between stigma and belonging, developmental processes, and their relationship to mental health. We conducted qualitative interviews from August to November 2021 with 34 LGBTQ+ YYA ages 14 to 24; interviews were nested within a quantitative study on YYA experiences during COVID-19. Interviews were transcribed and coded using thematic analysis. YYA described how pandemic impacts like quarantine and isolation directly impacted their mental health; these coalesced around four types of thematic shifts: shifts in (1) time; (2) living situations; (3) community supports; and (4) social and political climate. Multilevel stigmatization also created new mechanisms of norm enforcement for LGBTQ+ YYA. Interviews demonstrated how the pandemic also impacted key developmental processes including identity formation and autonomy seeking. The potential consequences of these pandemic-related shifts largely depended on YYA's experiences of stigma and/or belonging throughout the pandemic. Findings suggested that isolation from the COVID-19 pandemic intersected with existing socio-ecological structures in LGBTQ+ young people's lives. Efforts to investigate longitudinal impacts of the pandemic, as well as to intervene to reduce the stigmatization experienced by LGBTQ+ YYA, remain urgent.

Macrophages must respond appropriately to pathogens and other pro-inflammatory stimuli in order to perform their roles in fighting infection. One way in which inflammatory stimuli can vary is in their dynamics-that is, the amplitude and duration of stimulus experienced by the cell. In this study, we performed long-term live cell imaging in a microfluidic device to investigate how the pro-inflammatory genes IRF1, CXCL10, and CXCL9 respond to dynamic interferon-gamma (IFNγ) stimulation. We found that IRF1 responds to low concentration or short duration IFNγ stimulation, whereas CXCL10 and CXCL9 require longer or higherconcentration stimulation to be expressed. We also investigated the heterogeneity in the expression of each gene and found that CXCL10 and CXCL9 have substantial cell-to-cell variability. In particular, the expression of CXCL10 appears to be largely stochastic with a subpopulation of nonresponding cells across all the stimulation conditions tested. We developed both deterministic and stochastic models for the expression of each gene. Our modeling analysis revealed that the heterogeneity in CXCL10 can be attributed to a slow chromatin-opening step that is on a similar timescale to that of adaptation of the upstream signal. In this way, CXCL10 expression in individual cells can remain stochastic in response to each pulse of repeated stimulation, which we also validated by experiments. Together, we conclude that pro-inflammatory genes in the same signaling pathway can respond to dynamic IFNγ stimulus with very different response features and that upstream signal adaptation can contribute to shaping heterogeneous gene expression.

Lysine succinylation (Ksu) has recently emerged as a protein modification that regulates diverse functions in various biological processes. However, the systemically and precise role of lysine succinylation in erythropoiesis remains to be fully elucidated. In this study, we noted a prominent increase of succinyl-CoA and lysine succinylation during human erythroid differentiation. To explore the functional significance of succinylation, we inhibited succinylation by either knock downing key succinyltransferases or overexpressing desuccinylases. Succinylation inhibition led to suppressed cell proliferation, increased apoptosis, and disrupted erythroid differentiation. In vivo overexpression of the desuccinylases SIRT5 delayed erythroid differentiation. Furthermore, integrative proteome and succinylome analysis identifies 939 succinylated proteins with 3,562 Ksu sites, distributed across various cellular compartments and involved in multiple cellular processes. Significantly, inconsistencies between protein expression levels and succinylation levels were observed, indicating that the succinylation of certain proteins may function independently of expression. Mechanistically, we implicated KAT2A-mediated succinylation of histone H3 K79, leading to chromatin remodeling and subsequently erythropoiesis regulation. Specially, we identified CYCS as a key regulator of erythropoiesis, which depends on its succinylation sites K28/K40. Taken together, our comprehensive investigation of the succinylation landscape during erythropoiesis provides valuable insights into its regulatory role and offer potential implications for erythroid-related diseases.

Metabolic cross-feeding plays vital roles in promoting ecological diversity. While some microbes depend on exchanges of essential nutrients for growth, the forces driving the extensive cross-feeding needed to support the coexistence of free-living microbes are poorly understood. Here we characterize bacterial physiology under self-acidification and establish that extensive excretion of key metabolites following growth arrest provides a collaborative, inter-species mechanism of stress resistance. This collaboration occurs not only between species isolated from the same community, but also between unrelated species with complementary (glycolytic vs. gluconeogenic) modes of metabolism. Cultures of such communities progress through distinct phases of growth-dilution cycles, comprising of exponential growth, acidification-triggered growth arrest, collaborative deacidification, and growth recovery, with each phase involving different combinations of physiological states of individual species. Our findings challenge the steady-state view of ecosystems commonly portrayed in ecological models, offering an alternative dynamical view based on growth advantages of complementary species in different phases.

ABSTRACTCluster of differentiation 47 (CD47) is a transmembrane protein highly expressed in tumor cells that interacts with signal regulatory protein alpha (SIRPα) and triggers a “don’t eat me” signal to the macrophage, inhibiting phagocytosis and enabling tumor escape from immunosurveillance. The CD47-SIRPα axis has become an important target for cancer immunotherapy. To date, the advancement of CD47-targeted modalities is hindered by the ubiquitous expression of the target, often leading to rapid drug elimination and hematologic toxicity including anemia. To overcome those challenges a bispecific approach was taken. CC-96673, a humanized IgG1 bispecific antibody co-targeting CD47 and CD20, is designed to bind CD20 with high affinity and CD47 with optimally lowered affinity. As a result of the detuned CD47 affinity, CC-96673 selectively binds to CD20-expressing cells, blocking the interaction of CD47 with SIRPα. This increased selectivity of CC-96673 over monospecific anti-CD47 approaches allows for the use of wild-type IgG1 Fc, which engages activating crystallizable fragment gamma receptors (FcγRs) to fully potentiate macrophages to engulf and destroy CD20+ cells, while sparing CD47+CD20− normal cells. The combined targeting of anti-CD20 and anti-CD47 results in enhanced anti- tumor activity compared to anti-CD20 targeting antibodies alone. Furthermore, preclinical studies have demonstrated that CC-96673 exhibits acceptable pharmacokinetic properties with a favorable toxicity profile in non-human primates. Collectively, these findings define CC-96673 as a promising CD47 × CD20 bispecific antibody that selectively destroys CD20+ cancer cells via enhanced phagocytosis and other effector functions.

While magnetic random-access memories (MRAMs) are promising because of their nonvolatility, relatively fast speeds, and high endurance, there are major challenges in adopting them for the advanced technology nodes. One of the major challenges in scaling MRAM devices is caused by the ever-increasing resistances of interconnects. In this article, we first study the impact of shrunk interconnect dimensions on MRAM performance at various technology nodes. Then, we investigate the impact of various potential back-end-of-the-line (BEOL) technology solutions at the 7 nm node. Based on interconnect resistance values from technology computer-aided design (TCAD) simulations and MRAM device characteristics from experimentally validated/calibrated physical models, we quantify the potential array-level performance of MRAM using SPICE simulations. We project that some potential BEOL technology solutions can reduce the write energy by up to 34.6% with spin–orbit torque (SOT) MRAM and 29.0% with spin-transfer torque (STT) MRAM. We also observe up to 21.4% reduction in the read energy of the SOT-MRAM arrays.

The efforts to adopt a new Civil Code, initiated in the period 1999-2004 and finalized in 2011, aimed to expand the scope of representation in succession cases, including cases involving unworthy heirs and renunciants. However, legislative stagnation partially prevailed, as the Law no. 287 of 2009 on the Civil Code, with amendments introduced by Law no. 71/2011 for its implementation, only regulated the possibility of representation for unworthy heirs and not for renunciants. The partial modernization of the rules on representation in succession raises new questions and the need for answers. In the current context of the regulation of representation in succession, we aim to address the legitimate question of whether an unworthy heir can renounce inheritance and, if so, whether a renunciant unworthy heir can be represented by their descendants. We note that in the legal doctrine associated with the Civil Code of 1864, no speculation was made regarding this legal situation, as an unworthy heir could not be represented in succession, and such a discussion would have been pointless. Therefore, we will present the historical and evolutionary journey of the institution of representation in succession, from Roman law to modern times, as well as the winding path of adopting a new Civil Code in this area. By doing so, we can reach a valid conclusion regarding the issues addressed in this material.

The Amazonian region covers a significant part of the South American continent and harbors outstanding biodiversity. However, much of its history is still unknown. This situation has begun to change with paleontological field efforts over the last decades, which have been proving that fossils can be common in this region. Despite their great current species richness and abundance in the area today, marsupials have a sparse fossil record, restricted to a few specimens from handful Cenozoic Amazonian localities. Here we present new records of fossil marsupial teeth from the Solimões Formation (lower Eocene–Pliocene), on the Juruá and Envira riverbanks (Acre, Northwestern Brazil). The localities investigated yield at least four distinct didelphid didelphimorphians at PRE 06 (Ponto Rio Envira: Marmosini ?Marmosa sp., Didelphis cf. D. solimoensis, Thylamys? colombianus, plus unidentified didelphids), and two paucituberculatans from the Juruá River localities (Ponto Rio Juruá: the palaeothentid Palaeothentinae indet. at PRJ 25 and PRJ 33’, and Abderitidae indet. from PRJ 33). In agreement with the associated mammalian faunas, most of the didelphids, except for Thylamys? colombianus from PRE 06, indicate a (?early) Late Miocene age for this locality. Conversely, the abderitid specimens found in situ at PRJ 33 would match a Middle Miocene age. The palaeothentids found at PRJ 25 and PRJ 33’ localities cannot be considered for biostratigraphic inferences, since they were found outside a stratigraphic context. Nevertheless, these paucituberculatans considerably add to our knowledge, as they are the first ever recorded in Brazilian Amazonia.

Bacterial cells navigate their environment by directing their movement along chemical gradients. This process, known as chemotaxis, can promote the rapid expansion of bacterial populations into previously unoccupied territories. However, despite numerous experimental and theoretical studies on this classical topic, chemotaxis-driven population expansion is not understood in quantitative terms. Building on recent experimental progress, we here present a detailed analytical study that provides a quantitative understanding of how chemotaxis and cell growth lead to rapid and stable expansion of bacterial populations. We provide analytical relations that accurately describe the dependence of the expansion speed and density profile of the expanding population on important molecular, cellular, and environmental parameters. In particular, expansion speeds can be boosted by orders of magnitude when the environmental availability of chemicals relative to the cellular limits of chemical sensing is high. Analytical understanding of such complex spatiotemporal dynamic processes is rare. Our analytical results and the methods employed to attain them provide a mathematical framework for investigations of the roles of taxis in diverse ecological contexts across broad parameter regimes.

Abstract Loss of the tumor suppressive activity of the protein phosphatase 2A (PP2A) is associated with cancer, but the underlying molecular mechanisms are unclear. PP2A holoenzyme comprises a heterodimeric core, a scaffolding A subunit and a catalytic C subunit, and one of over 20 distinct substrate-directing regulatory B subunits. Methylation of the C subunit regulates PP2A heterotrimerization, affecting B subunit binding and substrate specificity. Here, we report that the leucine carboxy methyltransferase (LCMT1), which methylates the L309 residue of the C subunit, acts as a suppressor of androgen receptor (AR) addicted prostate cancer (PCa). Decreased methyl-PP2A-C levels in prostate tumors is associated with biochemical recurrence and metastasis. Silencing LCMT1 increases AR activity and promotes castration-resistant prostate cancer growth. LCMT1-dependent methyl-sensitive AB56αCme heterotrimers target AR and its critical coactivator MED1 for dephosphorylation, resulting in the eviction of the AR-MED1 complex from chromatin and loss of target gene expression. Mechanistically, LCMT1 is regulated by S6K1-mediated phosphorylation-induced degradation requiring the β-TRCP, leading to acquired resistance to anti-androgens. Finally, feedforward stabilization of LCMT1 by small molecule activator of phosphatase (SMAP) results in attenuation of AR-signaling and tumor growth inhibition in anti-androgen refractory PCa. These findings highlight methyl-PP2A-C as a prognostic marker and that the loss of LCMT1 is a major determinant in AR-addicted PCa, suggesting therapeutic potential for AR degraders or PP2A modulators in prostate cancer treatment.

Using solar energy and waste heat for medium-temperature thermal applications depends on efficient and economical heat storage development. Developing a compact thermal energy storage system is essential to use excess thermal energy from a source in a process or to shift the utilisation time of solar thermal energy or recovered waste heat. Phase change materials are commonly used for energy storage applications globally. In this work, a latent heat thermal energy storage (LHTES) system with 2.37 kg of Erythritol as the phase change material (PCM) has been studied. A shell and tube heat storage system is selected due to its effectiveness in heat transfer. Synthetic silicone oil Hi-Tech Therm-60 was used as heat transfer fluid. Thermal stability tests in a differential scanning calorimeter (DSC) for a small sample mass and a specifically designed experiment for a larger sample mass were performed to assess the stability of the PCM. The time-dependent temperature distribution inside the storage system and the effect of heat transfer fluid (HTF) inlet temperature on the charging behaviour were studied during the charging process. Charging time and melt fraction have been calculated. No significant change in melting temperature and a 10% reduction in latent heat of PCM was observed in the thermal stability test for a small sample mass in DSC. The charging time of the storage device was observed to be 91–97 min and 195 min for 140 °C and 130 °C HTF inlet temperatures, respectively. The total stored energy in the system was 922 kJ with a Stefan number of 0.59. Temperature variation during the charging process inside the storage also suggests a buoyancy effect, leading to increased natural convection during the melting process.

Abstract Metabolic cross-feeding plays vital roles in promoting ecological diversity. While some microbes depend on exchanges of essential nutrients for growth, the forces driving the extensive cross-feeding needed to support the coexistence of free-living microbes are poorly understood. Here we characterize bacterial physiology under self-acidification and establish that extensive excretion of key metabolites following growth arrest provides a collaborative, inter-species mechanism of stress resistance. This collaboration occurs not only between species isolated from the same community, but also between unrelated species with complementary (glycolytic vs. gluconeogenic) modes of metabolism. Cultures of such communities progress through distinct phases of growth-dilution cycles, comprising of exponential growth, acidification-triggered growth arrest, collaborative deacidification, and growth recovery, with each phase involving different combinations of physiological states of individual species. Our findings challenge the steady-state view of ecosystems commonly portrayed in ecological models, offering an alternative dynamical view based on growth advantages of complementary species in different phases.

Abstract Background Small‐cell lung cancer (SCLC) is the deadliest form of lung cancer but lacks targeted therapies. Methods We studied the effect of the natural product mistletoe lectin (ML) in pre‐clinical models of SCLC, focusing on cell lines with amplification of the myc family oncogenes C‐myc and N‐myc. Results We found that ML treatment inhibits growth of SCLC cell lines in culture and induces apoptosis. ML treatment also decreases the expression of the amplified myc proteins. Over‐expression of either C‐myc or N‐myc results in enhanced SCLC cell sensitivity to ML. In a mouse xenograft model of SCLC, treatment with ML results in decreased tumor growth over 4 weeks with evidence of increased apoptosis in tumors from treated animals. Conclusion Overall, our results demonstrate that ML exhibits therapeutic potential in SCLC, that is at least partially dependent on myc protein expression.