The roles and regulation of MDM2 and MDMX: it is not just about p53.

Most well studied as proteins that restrain the p53 tumor suppressor protein, MDM2 and MDMX have rich lives outside of their relationship to p53. There is much to learn about how these two proteins are regulated and how they can function in cells that lack p53. Regulation of MDM2 and MDMX, which takes place at the level of transcription, post-transcription, and protein modification, can be very intricate and is context-dependent. Equally complex are the myriad roles that these two proteins play in cells that lack wild-type p53; while many of these independent outcomes are consistent with oncogenic transformation, in some settings their functions could also be tumor suppressive. Since numerous small molecules that affect MDM2 and MDMX have been developed for therapeutic outcomes, most if not all designed to prevent their restraint of p53, it will be essential to understand how these diverse molecules might affect the p53-independent activities of MDM2 and MDMX.

Plasmacytoid Dendritic Cells: Development, Regulation, and Function.

Plasmacytoid dendritic cells (pDCs) are a unique sentinel cell type that can detect pathogen-derived nucleic acids and respond with rapid and massive production of type I interferon. This review summarizes our current understanding of pDC biology, including transcriptional regulation, heterogeneity, role in antiviral immune responses, and involvement in immune pathology, particularly in autoimmune diseases, immunodeficiency, and cancer. We also highlight the remaining gaps in our knowledge and important questions for the field, such as the molecular basis of unique interferon-producing capacity of pDCs. A better understanding of cell type-specific positive and negative control of pDC function should pave the way for translational applications focused on this immune cell type.

B cell clonality in cancer.

Carcinogenesis in the process of long-term co-evolution of tumor cells and immune environment essentially becomes possible due to incorrect decisions made, remembered, and reproduced by the immune system at the level of clonal populations of antigen-specific T- and B-lymphocytes. Tumor-immunity interaction determines the nature of such errors and, consequently, delineates the possible ways of successful immunotherapeutic intervention. It is generally recognized that tumor-infiltrating B cells (TIL-B) can play both pro-tumor and anti-tumor roles. However, the exact mechanisms that determine the contribution of clonal B cell lineages with different specificities and functions remain largely unclear. This is due to the variability of cancer types, the molecular heterogeneity of tumor cells, and, to a large extent, the individual pattern of each immune response. Further progress requires detailed investigation of the functional properties and phenotypes of clonally heterogeneous B cells in relation to their antigenic specificities, which determine the functionality of both effector B lymphocytes and immunoglobulins produced in the tumor environment. Based on a real understanding of the role of clonal antigen-specific populations of B lymphocytes in the tumor microenvironment, we need to learn how to develop new methods of targeted immunotherapy, as well as adapt existing treatment options to the specific needs of different patients and patient subgroups. In this review, we will cover B cells functional diversity and their multifaceted roles in the tumor environment.

Monocyte-Macrophages and T Cells in Atherosclerosis.

Atherosclerosis is an arterial disease process characterized by the focal subendothelial accumulation of apolipoprotein-B-containing lipoproteins, immune and vascular wall cells, and extracellular matrix. The lipoproteins acquire features of damage-associated molecular patterns and trigger first an innate immune response, dominated by monocyte-macrophages, and then an adaptive immune response. These inflammatory responses often become chronic and non-resolving and can lead to arterial damage and thrombosis-induced organ infarction. The innate immune response is regulated at various stages, from hematopoiesis to monocyte changes and macrophage activation. The adaptive immune response is regulated primarily by mechanisms that affect the balance between regulatory and effector T cells. Mechanisms related to cellular cholesterol, phenotypic plasticity, metabolism, and aging play key roles in affecting these responses. Herein, we review select topics that shed light on these processes and suggest new treatment strategies.

Persistence of gender biases in Europe.

Prior work suggests that modern gender bias might have historical roots but has not been able to demonstrate long-term persistence of this bias due to a lack of historical data. We follow archaeological research and employ skeletal records of women's and men's health from 139 archaeological sites in Europe dating back, on average, to about 1200 AD to construct a site-level indicator of historical bias in favor of one gender over the other using dental linear enamel hypoplasias. This historical measure of gender bias significantly predicts contemporary gender attitudes, despite the monumental socioeconomic and political changes that have taken place since. We also show that this persistence is most likely due to the intergenerational transmission of gender norms, which can be disrupted by significant population replacement. Our results demonstrate the resilience of gender norms and highlight the importance of cultural legacies in sustaining and perpetuating gender (in)equality today.

Bringing home the benefits: Do pro-family employee benefits mitigate the risk of depression from competing workplace and domestic labor roles?

Despite significant historical progress toward gender parity in employment status in the US, women remain more likely to provide domestic labor, creating role competition which may increase depression symptoms. Pro-family employee benefits may minimize the stress of competing roles. We tested whether depressive symptoms were higher among women with vs. without competing roles and whether this effect was greater among women without (vs. with) pro-family benefits. Data included employed women surveyed across 4 waves of the National Longitudinal Survey (2010-2019) (N=9884). Depression symptoms were measured with the Mental Health Inventory (MHI-5). The interaction between competing roles and pro-family employee benefits on depressive symptoms was also compared with non-family-related benefits, using marginal structural models to estimate longitudinal effects in the presence of time-varying confounding. MHI-5 scores were 0.56 points higher (95% CI=0.15, 0.97) among women in competing roles (vs. not). Among women without pro-family benefits, competing roles increased MHI-5 scores by 6.1-points (95% CI=1.14, 11.1). In contrast, there was no association between competing roles and MHI-5 scores among women with access to these benefits (MHI-5 difference=0.44; 95% CI=-0.2, 1.0). Results were similar for non-family-related benefits. Dual workplace and domestic labor role competition increases women's depression symptoms, though broad availability of workplace benefits may attenuate that risk.

Employment and workdays lost among spouses of cancer survivors: Intersection with gender across cancer treatment status.

BACKGROUND: Cancer patients and survivors have high care needs, often provided by a spouse or partner. The purpose of this study was to elucidate how employment and work loss patterns differed across cancer history/treatment status and gender. METHODS: Using nationally representative data from the Medical Expenditure Panel Survey (2011, 2016, and 2017), the authors linked data across married participants and categorized them by spouses' cancer treatment status (no cancer history, on treatment for cancer, off treatment for cancer). Multivariable logistic and zero-inflated negative binomial regressions were used to assess the associations among cancer history/treatment status, gender, and employment outcomes (employment status and workdays lost to care for self or others). RESULTS: For men, employment did not differ significantly by cancer history/treatment status (on treatment: odds ratio [OR], 0.58; 95% confidence interval [CI], 0.33-1.02, off treatment: OR, 0.84; 95% CI, 0.62-1.14 vs. no cancer history). For women, employment was not significantly different when the spouse was on treatment for cancer compared to no cancer history (OR, 0.78; 95% CI, 0.33-1.86]) but was significantly increased for women whose spouse was off treatment (OR, 1.39; 95% CI, 1.05-1.84). Among employed participants, women whose spouse was on cancer treatment were nine times more likely to take days off work to provide care (OR, 9.52; 95% CI, 3.94-23.03) and took more than three times as many days off to care for others (OR, 3.21; 95% CI, 2.07-4.97) as men whose spouse had no cancer history. CONCLUSIONS: Wives of cancer survivors are at increased risk of work loss, with implications for their financial and psychological well-being. Employers, policymakers, and clinicians have opportunities to support working caregivers.

Factors influencing the development, recruitment, integration, retention and career development of advanced practice providers in hospital health care teams: a scoping review.

BACKGROUND: Advanced practice providers (APPs), including physician assistants/associates (PAs), nurse practitioners (NPs) and other non-physician roles, have been developed largely to meet changing healthcare demand and increasing workforce shortages. First introduced in primary care in the US, APPs are prevalent in secondary care across different specialty areas in different countries around the world. In this scoping review, we aimed to summarise the factors influencing the development, recruitment, integration, retention and career development of APP roles in hospital health care teams. METHODS: We conducted a scoping review and searched Ovid MEDLINE, Ovid Embase, Ovid Global Health, Ovid PsycINFO and EBSCOhost CINAHL to obtain relevant articles published between Jan 2000 and Apr 2023 that focused on workforce management of APP roles in secondary care. Articles were screened by two reviewers independently. Data from included articles were charted and coded iteratively to summarise factors influencing APP development, recruitment, integration, retention and career development across different health system structural levels (macro-, meso- and micro-level). RESULTS: We identified and analysed 273 articles that originated mostly from high-income countries, e.g. the US (n = 115) and the UK (n = 52), and primarily focused on NP (n = 183) and PA (n = 41). At the macro-level, broader workforce supply, national/regional workforce policies such as work-hour restrictions on physicians, APP scope of practice regulations, and views of external collaborators, stakeholders and public representation of APPs influenced organisations' decisions on developing and managing APP roles. At the meso-level, organisational and departmental characteristics, organisational planning, strategy and policy, availability of resources, local experiences and evidence as well as views and perceptions of local organisational leaders, champions and other departments influenced all stages of APP role management. Lastly at the micro-level, individual APPs' backgrounds and characteristics, clinical team members' perceptions, understanding and relationship with APP roles, and patient perceptions and preferences also influenced how APPs are developed, integrated and retained. CONCLUSIONS: We summarised a wide range of factors influencing APP role development and management in secondary care teams. We highlighted the importance for organisations to develop context-specific workforce solutions and strategies with long-term investment, significant resource input and transparent processes to tackle evolving healthcare challenges.

What Amphibians Can Teach Us About the Evolution of Parental Care.

Parenting is considered a key evolutionary innovation that contributed to the diversification and expansion of vertebrates. However, we know little about how such diversity evolved. Amphibians are an ideal group in which to identify the ecological factors that have facilitated or constrained the evolution of different forms of parental care. Among, but also within, the three amphibian orders-Anura, Caudata, and Gymnophiona-there is a high level of variation in habitat use, fertilization mode, mating systems, and parental sex roles. Recent work using broad phylogenetic, experimental, and physiological approaches has helped to uncover the factors that have selected for the evolution of care and transitions between different forms of parenting. Here, we highlight the exceptional diversity of amphibian parental care, emphasize the unique opportunities this group offers for addressing key questions about the evolution of parenting, and give insights into promising novel directions of research.

Linking the key physiological functions of essential micronutrients to their deficiency symptoms in plants.

In this review, we untangle the physiological key functions of the essential micronutrients and link them to the deficiency responses in plants. Knowledge of these responses at the mechanistic level, and the resulting deficiency symptoms, have improved over the last decade and it appears timely to review recent insights for each of them. A proper understanding of the links between function and symptom is indispensable for an accurate and timely identification of nutritional disorders, thereby informing the design and development of sustainable fertilization strategies. Similarly, improved knowledge of the molecular and physiological functions of micronutrients will be important for breeding programmes aiming to develop new crop genotypes with improved nutrient-use efficiency and resilience in the face of changing soil and climate conditions.

Quantifying co-extinctions and ecosystem service vulnerability in coastal ecosystems experiencing climate warming.

Climate change is negatively impacting ecosystems and their contributions to human well-being, known as ecosystem services. Previous research has mainly focused on the direct effects of climate change on species and ecosystem services, leaving a gap in understanding the indirect impacts resulting from changes in species interactions within complex ecosystems. This knowledge gap is significant because the loss of a species in a food web can lead to additional species losses or "co-extinctions," particularly when the species most impacted by climate change are also the species that play critical roles in food web persistence or provide ecosystem services. Here, we present a framework to investigate the relationships among species vulnerability to climate change, their roles within the food web, their contributions to ecosystem services, and the overall persistence of these systems and services in the face of climate-induced species losses. To do this, we assess the robustness of food webs and their associated ecosystem services to climate-driven species extinctions in eight empirical rocky intertidal food webs. Across food webs, we find that highly connected species are not the most vulnerable to climate change. However, we find species that directly provide ecosystem services are more vulnerable to climate change and more connected than species that do not directly provide services, which results in ecosystem service provision collapsing before food webs. Overall, we find that food webs are more robust to climate change than the ecosystem services they provide and show that combining species roles in food webs and services with their vulnerability to climate change offer predictions about the impacts of co-extinctions for future food web and ecosystem service persistence. However, these conclusions are limited by data availability and quality, underscoring the need for more comprehensive data collection on linking species roles in interaction networks and their vulnerabilities to climate change.

Copper-Catalyzed C-H (Phenylsulfonyl)difluoromethylation of Acrylamides: Scope, Mechanism, and Critical Role of Additives.

Herein, we report the Cu-complex catalyzed, native functional group-assisted, and TFA/NMF additives promoted (phenylsulfonyl)difluoromethylation of vinylic C(sp2 )-H bond of acrylamides. Using our in-home designed reagent, this reaction enables the construction of the C(sp2 )-CF2 SO2 Ph bond from simple C-H bond activation by copper catalysis under mild reaction conditions with total Z-selectivity. The versatility of utilized fluorinated group was illustrated by its conversion into value-added CF2 moieties as well as the remarkable =CHF residue. The performed experimental and computational mechanistic studies enabled to identify the true nature of active catalyst and substrate, as well as establish critical roles of TFA and NMF additives. In this reaction, the TFA acts as a promoter of the much-needed CuII /CuII →CuIII /CuI disproportionation, while the NMF facilitates the following ligand exchange and C-C coupling processes. We ruled out the generation of radical intermediates and established the C-H activation to be irreversible and the rate-determining step of the entire process.

The Evolving Roles and Expectations of Inpatient Palliative Care Through COVID-19: a Systematic Review and Meta-synthesis.

BACKGROUND: Palliative care performed a central role in responding to the systemic suffering incurred by the COVID-19 pandemic. Yet, few studies have elucidated the inpatient palliative care specialists' experiences and perceptions. OBJECTIVE: Systematically review and synthesize the evolving roles and expectations of inpatient palliative care specialists in response to COVID-19. DESIGN: A systematic review and meta-synthesis informed by Thomas and Harden's framework and Pozzar et al.'s approach was conducted in accordance with Preferred Reporting Items for Systematic Reviews and Meta-Analysis (PRISMA) guidelines. DATA SOURCES: MEDLINE, EMBASE, CINAHL, and PubMed were systematically searched for articles published between December 2019 and March 2023. We included all peer-reviewed qualitative and mixed-method literature studying the roles and expectations of inpatient palliative care specialists. A mixed-method appraisal tool was used for quality assessment. RESULTS: Of 3869 unique articles, 52 were included. Studies represented North American (n = 23), European (n = 16), South American (n = 4), Oceanic (n = 2), Asian (n = 2), West African (n = 1), Middle Eastern (n = 1), and inter-continental settings (n = 3). Most were reported in English (n = 50), conducted in 2020 (n = 28), and focused on the perspectives of inpatient palliative care clinicians (n = 28). Three descriptive themes captured the roles and expectations of inpatient palliative care specialists: shifting foundations, reorienting to relationships, and evolving identity. Two analytical themes were synthesized: palliative care propagates compassion through a healing presence, and palliative care enhances the systemic response to suffering through nimble leadership. CONCLUSION: Inpatient palliative care specialists responded to the COVID-19 pandemic by establishing their healing presence and leading with their adaptability. To develop institutionally tailored and collaborative responses to future pandemics, future studies are needed to understand how inpatient palliative care clinicians are recognized and valued within their institutions.

Roles and competencies of the clinical psychologist in adult diabetes care-A consensus report.

AIMS: Psychological care is recognised as an integral part of quality diabetes care. We set out to describe the roles and competencies of the clinical psychologist as a member of the multidisciplinary adult diabetes care team, focused on secondary care. METHODS: The authors are clinically experienced psychologists involved in adult diabetes care, from Australia, Europe and North America, and active members of the international psychosocial aspects of diabetes study group. Consensus was reached as a group on the roles and competencies of the clinical psychologist working in adult diabetes secondary care, building both on expert opinion and a selective review and discussion of the literature on psychological care in diabetes, clinical guidelines and competency frameworks. RESULTS: The clinical psychologist fulfils multiple roles: (1) as a clinician (psychological assessment and therapy), (2) as advisor to the healthcare team (training, consulting), (3) as a communicator and promotor of person-centred care initiatives and (4) as a researcher. Four competencies that are key to successfully fulfilling the above-mentioned roles in a diabetes setting are as follows: (a) specialised knowledge, (b) teamwork and advice, (c) assessment, (d) psychotherapy (referred to as STAP framework). CONCLUSIONS: The roles and competencies of clinical psychologists working in diabetes extend beyond the requirements of most university and post-graduate curricula. There is a need for a comprehensive, accredited specialist post-graduate training for clinical psychologists working in diabetes care, building on the proposed STAP framework. This calls for a collaborative effort involving diabetes organisations, clinical psychology societies and diabetes psychology interest groups.

17ß-estradiol in colorectal cancer: friend or foe?

Colorectal cancer (CRC) is a common gastrointestinal malignancy with higher incidence and mortality rates in men compared to women, potentially due to the effects of estrogen signaling. There is substantial evidence supporting the significant role of 17ß-Estradiol (E2) in reducing CRC risk in females, although this perspective remains debated. E2 has been demonstrated to inhibit CRC cell proliferation and migration at the cellular level by enhancing DNA mismatch repair, modulating key gene expression, triggering cell cycle arrest, and reducing activity of migration factors. Furthermore, E2 contributes to promote a tumor microenvironment unfavorable for CRC growth by stimulating ERß expression, reducing inflammatory responses, reversing immunosuppression, and altering the gut microbiome composition. Conversely, under conditions of high oxidative stress, hypoxia, and nutritional deficiencies, E2 may facilitate CRC development through GPER-mediated non-genomic signaling. E2's influence on CRC involves the genomic and non-genomic signals mediated by ERß and GPER, respectively, leading to its dual roles in anticancer activity and carcinogenesis. This review aims to summarize the potential mechanisms by which E2 directly or indirectly impacts CRC development, providing insights into the phenomenon of sexual dimorphism in CRC and suggesting potential strategies for prevention and treatment.

Uromodulin biology.

Uromodulin is a kidney-specific glycoprotein which is exclusively produced by the epithelial cells lining the thick ascending limb and early distal convoluted tubule. It is currently recognized as a multifaceted player in kidney physiology and disease, with discrete roles for intracellular, urinary, interstitial and serum uromodulin. Among these, uromodulin modulates renal sodium handling through the regulation of tubular sodium transporters that reabsorb sodium and are targeted by diuretics, such as the loop diuretic-sensitive Na+-K+-2Cl- cotransporter type 2 (NKCC2) and the thiazide-sensitive Na+/Cl- cotransporter (NCC). Given these roles, the contribution of uromodulin to sodium-sensitive hypertension has been proposed. However, recent studies in humans suggest a more complex interaction between dietary sodium intake, uromodulin and blood pressure. This review presents an updated overview of the uromodulin's biology and its various roles, and focuses on the interaction between uromodulin and sodium-sensitive hypertension.

Comprehensive analysis of phospholipid in milk and their biological roles as nutrients and biomarkers.

Phospholipids (PL) have garnered significant attention due to their physiological activities. Milk and other dairy products are important dietary sources for humans and have been extensively used to analyze the presence of PL by various analytical techniques. In this paper, the analysis techniques of PL were reviewed with the eight trigrams of phospholipidomics and a comprehensive fingerprint of 1295 PLs covering 8 subclasses in milk and other dairy products, especially. Technology is the primary productive force. Based on phospholipidomics technology, we further review the relationship between the composition of PL and factors that may be involved in processing and experimental operation, and emphasized the significance of the biological role played by PL in dietary supplements and biomarkers (production, processing and clinical research), and providing the future research directions.

Expanding the roles of community health workers to sustain programmes during malaria elimination: a meeting report on operational research in Southeast Asia.

In Southeast Asia malaria elimination is targeted by 2030. Cambodia aims to achieve this by 2025, driven in large part by the urgent need to control the spread of artemisinin-resistant falciparum malaria infections. Rapid elimination depends on sustaining early access to diagnosis and effective treatment. In much of Cambodia, rapid elimination will rely on a village malaria worker (VMW) network. Yet as malaria declines and is no longer a common cause of febrile illness, VMWs may become less popular with febrile patients, as VMWs do not diagnose or treat other conditions at present. There is a risk that VMWs become inactive and malaria rebounds before the complete interruption of transmission is achieved.During 2021-23 a large-scale operational research study was conducted in western Cambodia to explore how a VMW network could be sustained by including health activities that cover non-malarial illnesses to encourage febrile patients to continue to attend. 105 VMWs received new rapid diagnostic tests (including dengue antigen-antibody and combined malaria/C-reactive protein tests), were trained in electronic data collection, and attended health education packages on hygiene and sanitation, disease surveillance and first aid, management of mild illness, and vaccination and antenatal care.In August 2023 the National Malaria Control Programme of Cambodia convened a stakeholder meeting in Battambang, Cambodia. Findings from the study were reviewed in the context of current malaria elimination strategies. The discussions informed policy options to sustain the relevance of the VMW network in Cambodia, and the potential for its integration with other health worker networks. This expansion could ensure VMWs remain active and relevant until malaria elimination is accomplished.

Glowing wonders: exploring the diversity and ecological significance of bioluminescent organisms in Brazil.

Bioluminescence, the emission of light by living organisms, is a captivating and widespread phenomenon with diverse ecological functions. This comprehensive review explores the biodiversity, mechanisms, ecological roles, and conservation challenges of bioluminescent organisms in Brazil, a country known for its vast and diverse ecosystems. From the enchanting glow of fireflies and glow-in-the-dark mushrooms to the mesmerizing displays of marine dinoflagellates and cnidarians, Brazil showcases a remarkable array of bioluminescent species. Understanding the biochemical mechanisms and enzymes involved in bioluminescence enhances our knowledge of their evolutionary adaptations and ecological functions. However, habitat loss, climate change, and photopollution pose significant threats to these bioluminescent organisms. Conservation measures, interdisciplinary collaborations, and responsible lighting practices are crucial for their survival. Future research should focus on identifying endemic species, studying environmental factors influencing bioluminescence, and developing effective conservation strategies. Through interdisciplinary collaborations, advanced technologies, and increased funding, Brazil can unravel the mysteries of its bioluminescent biodiversity, drive scientific advancements, and ensure the long-term preservation of these captivating organisms.

Gender Roles and Mobile Dating Applications: Exploring Links Between User Characteristics and Traditional Gender Expressions in Self-Presentations.

This linkage study examined the prevalence of traditional gender expressions in the textual and visual profile cues on mobile dating applications (MDA) (nbiographies = 396, npictures = 1352) of 396 young adults' (Mage = 22.39 years, SD = 2.86, 73% women) with attention to users' gender, sexual orientation, and platform type. For 184 users (Mage = 22.10 years, SD = 2.91, 75% women) media content data were linked to self-report survey data. Results showed that individuals aligned their self-presentations with traditional gender roles and expectations, and this link depended on their gender. No significant differences according to individuals' sexual orientation or platform type were found. Individuals' (hyper-) gender orientation also related to engagement in traditional gender expressions. Specifically, women with a stronger feminine gender orientation expressed more traditional femininity in their MDA profiles. For men, no significant associations between (aspects of) a masculine gender orientation and expressing traditional masculinity in their MDA profiles were found. Future research should further disentangle selective gendered self-presentations.