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Gene-expression noise can influence cell-fate choices across pathology and physiology. However, a crucial question persists: do regulatory proteins or pathways exist that control noise independently of mean expression levels? Our integrative approach, combining single-cell RNA sequencing with proteomics and regulator enrichment analysis, identifies 32 putative noise regulators. SON, a nuclear speckle-associated protein, alters transcriptional noise without changing mean expression levels. Furthermore, SON's noise control can propagate to the protein level. Long-read and total RNA sequencing shows that SON's noise control does not significantly change isoform usage or splicing efficiency. Moreover, SON depletion reduces state switching in pluripotent mouse embryonic stem cells and impacts their fate choice during differentiation. Collectively, we demonstrate a class of proteins that control noise orthogonally to mean expression levels. This work serves as a proof of concept that can identify other functional noise regulators throughout development and disease progression.
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Glaucoma is a leading cause of blindness worldwide and glaucoma patients exhibit an early diffuse loss of retinal sensitivity followed by focal loss of RGCs. Combining some previous published results and some new data, this paper provides our current view on how high IOP (H-IOP) affects the light response sensitivity of a subset of RGCs, the alpha-ganglion cells (αGCs), as well as their presynaptic bipolar cells (DBCs and HBCs) and A2 amacrine cells (AIIACs) in dark-adapted mouse retinas. Our data demonstrate that H-IOP in experimental glaucoma mice significantly decreases light-evoked spike response sensitivity of sONαGCs and sOFFαGCs (i.e., raises thresholds by 1.5-2.5 log units), but not that of the tONαGCs and tOFFαGCs. The sensitivity loss in sONαGCs and sOFFαGCs is mediated by a H-IOP induced suppression of AIIAC response which is caused by a decrease of transmission efficacy of the DBCRâAIIAC synapse. We also provide evidence supporting the hypothesis that BK channels in the A17ACâDBCR feedback synapse are the H-IOP sensor that regulates the DBCRâAIIAC synaptic efficacy, as BK channel blocker IBTX mimics the action of H-IOP. Our results provide useful information for designing strategies for early detection and possible treatments of glaucoma as physiological changes occur before irreversible structural damage.
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Modelos Animais de Doenças , Glaucoma , Pressão Intraocular , Camundongos Endogâmicos C57BL , Células Ganglionares da Retina , Animais , Camundongos , Pressão Intraocular/fisiologia , Células Ganglionares da Retina/fisiologia , Células Ganglionares da Retina/patologia , Glaucoma/fisiopatologia , Células Amácrinas/fisiologia , Adaptação à Escuridão/fisiologia , Células Bipolares da Retina/fisiologiaRESUMO
This concurrent qualitative study was carried out with the main objective to determine wildlife beliefs, taboos, usages, health perceptions, and practices among ten ethnic groups in four communities in Tak and Mae Hong Son provinces of Thailand from November 2020 to January 2021. We also gathered comprehensive information on study respondents' knowledge related to potential risk behaviors that could lead to zoonotic disease transmission and infection. Furthermore, we intended to use the study's findings to develop communication strategies and health literacy improvement interventions for mitigating risky behaviors, with a focus on ethnic groups and particular individuals who live in close proximity to forests and wildlife, to prevent future pandemics. Sixty-five respondents were purposively selected based on their extensive knowledge, active participation in local cultural contexts, beliefs, and exposure to wildlife contact or consuming game animals. Twenty (30.8%) participated in in-depth interviews (IDIs), while 45 (69.2%) participated in eight focused group discussions (FGDs). The results revealed that the characteristics of wildlife contact are similar and distinct based on their beliefs and taboos among various ethnic groups and study locations, which are influenced by cultural backgrounds and traditions. Although some ethnic groups do not have explicit restrictions on the consumption of wildlife, others adhere to specific beliefs and taboos that forbid the consumption or killing of specific wild animals. These beliefs frequently correspond with conservation initiatives, thereby facilitating the preservation of threatened species. The study also revealed a lack of appropriate health knowledge, perceptions, and practices regarding wildlife contact and consumption. As a result, it is recommended that public health officials and local governments develop and execute communication and education initiatives. These campaigns should aim to increase health literacy and promote safe handling, preparation, and cooking practices to reduce the risk of zoonotic disease transmission and infection effectively. Moreover, it is necessary to design and implement wildlife conservation education and outreach activities. The programs should promote environmental stewardship while considering the cultural contexts, beliefs, and practices of various ethnic groups. The activities should involve diverse stakeholders, including local leaders, religious influencers, community members, schoolteachers, students, health professionals, village health volunteers, and civil society organizations.
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Animais Selvagens , Etnicidade , Conhecimentos, Atitudes e Prática em Saúde , Pesquisa Qualitativa , Tabu , Humanos , Tailândia/etnologia , Animais , Masculino , Etnicidade/estatística & dados numéricos , Etnicidade/psicologia , Feminino , Adulto , Pessoa de Meia-Idade , Zoonoses/prevenção & controle , Grupos Focais , Adulto JovemRESUMO
OBJECTIVES: Informal care provided by adult children is of great importance for older adults' well-being in China. This paper investigates and compares the functional transitions among older adults living in rural areas who receive care from daughters' and from sons' families. METHODS: This study utilizes the "Well-being of Elderly Survey in Anhui Province" (WESAP) from 2001 to 2021. Our sample included 2,797 individuals aged 60 years or older. Functional status was based on the activities of daily living and the instrumental activities of daily living. We employed a random-effects ordered logit model to examine the functional transitions among the older adults. RESULTS: Receiving care from daughters' families is significantly associated with a lower likelihood of functional decline compared to receiving care from sons' families in rural China. The advantage associated with daughter care becomes more pronounced among older individuals with a severe functional difficulty compared to those with a mild or moderate functional difficulty. The difference is prevalent among older adults aged 75 and older, with less wealth or multiple chronic diseases, or who live alone. Furthermore, among those with severe functional difficulties, the daughter advantage is more significant for fathers as compared to mothers. DISCUSSION: Nowadays, daughters' families can provide high-quality informal care, often surpassing that offered by sons' families. This daughter advantage becomes even more significant among older adults who have a higher need for family care, such as those with severe disabilities and limited financial resources.
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Atividades Cotidianas , Filhos Adultos , População Rural , Humanos , Masculino , Idoso , Feminino , China , Atividades Cotidianas/psicologia , População Rural/estatística & dados numéricos , Pessoa de Meia-Idade , Filhos Adultos/psicologia , Cuidadores/psicologia , Núcleo Familiar/psicologia , Idoso de 80 Anos ou mais , Estado FuncionalRESUMO
The Kirsten rat sarcoma virus-son of sevenless 1 (KRAS-SOS1) axis drives tumor growth preferentially in pancreatic, colon, and lung cancer. Now, KRAS G12C mutated tumors can be successfully treated with inhibitors that covalently block the cysteine of the switch II binding pocket of KRAS. However, the range of other KRAS mutations is not amenable to treatment and the G12C-directed agents Sotorasib and Adragrasib show a response rate of only approximately 40%, lasting for a mean period of 8 months. One approach to increase the efficacy of inhibitors is their inclusion into proteolysis-targeting chimeras (PROTACs), which degrade the proteins of interest and exhibit much higher antitumor activity through multiple cycles of activity. Accordingly, PROTACs have been developed based on KRAS- or SOS1-directed inhibitors coupled to either von Hippel-Lindau (VHL) or Cereblon (CRBN) ligands that invoke the proteasomal degradation. Several of these PROTACs show increased activity in vitro and in vivo compared to their cognate inhibitors but their toxicity in normal tissues is not clear. The CRBN PROTACs containing thalidomide derivatives cannot be tested in experimental animals. Resistance to such PROTACS arises through downregulation or inactivation of CRBN or factors of the functional VHL E3 ubiquitin ligase. Although highly active KRAS and SOS1 PROTACs have been formulated their clinical application remains difficult.
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Proteólise , Proteínas Proto-Oncogênicas p21(ras) , Proteína SOS1 , Humanos , Proteína SOS1/metabolismo , Proteína SOS1/genética , Proteínas Proto-Oncogênicas p21(ras)/genética , Proteínas Proto-Oncogênicas p21(ras)/metabolismo , Animais , Neoplasias/tratamento farmacológico , Neoplasias/metabolismo , Neoplasias/genética , Neoplasias/patologia , Antineoplásicos/farmacologia , Ubiquitina-Proteína Ligases/metabolismo , Ubiquitina-Proteína Ligases/genética , Proteínas Adaptadoras de Transdução de Sinal/metabolismo , Proteínas Adaptadoras de Transdução de Sinal/genética , Quimera de Direcionamento de ProteóliseRESUMO
Background: Rural-to-urban migrant workers are a vulnerable group at risk of developing depression. Based on the social-ecological systems theory, this study investigates the impact of the lack of social integration on depression, considering the mediating roles of migrant workers' microsystems (family happiness and job burnout). Additionally, the study explores whether having sons influences these associations. Methods: The sample of 4,618 rural-to-urban migrant workers was obtained from the 2018 wave of the China Labor Force Dynamics Survey (CLDS). All the measures in the survey exhibited good reliability, including the Center for Epidemiological Research Depression Scale (CES-D), family happiness, job burnout, and social integration. The data were primarily analyzed using a structural equation model. Results: Social integration had a direct impact on depression among migrant workers. Additionally, it indirectly affected depression through the mediating roles of family happiness not job burnout. The moderating effect of having sons mainly occurred on the path from social integration to family happiness. Limitations: The cross-sectional design impeded the ability to draw causal inferences. Conclusion: This finding highlights the potential benefits of social integration and family happiness in promoting early prevention of depression among migrant workers. It indicates that the inclination toward having sons among migrant workers continues to impact their mental health.
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Depressão , População Rural , Integração Social , Migrantes , Humanos , China/epidemiologia , Migrantes/psicologia , Migrantes/estatística & dados numéricos , Masculino , Adulto , Depressão/epidemiologia , Depressão/psicologia , Feminino , Estudos Transversais , População Rural/estatística & dados numéricos , Pessoa de Meia-Idade , Inquéritos e Questionários , Esgotamento Profissional/psicologia , Felicidade , População Urbana/estatística & dados numéricos , Família/psicologiaRESUMO
Isolated teeth of a lesser short-nosed fruit bat Cynopterus brachyotis (Müller, 1838), a fulvous fruit bat Rousettus leschenaultii (Desmarest, 1820), and a dawn bat Eonycteris spelaea (Dobson, 1871) are described from the Middle Pleistocene Tham Hai cave locality in northern Vietnam (Lang Son Province). These are the first fossil findings of the Old World fruit bats in Vietnam. The Middle Pleistocene association of Pteropodidae from the Tham Hai locality may largely reflect the composition of species that roosted in local caves.
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Quirópteros , Fósseis , Animais , Quirópteros/fisiologia , Quirópteros/classificação , Quirópteros/anatomia & histologia , Vietnã , Cavernas , Dente/anatomia & histologiaRESUMO
BACKGROUND: Lifestyle and habits, cardiovascular risk factors (CRF), bone and mental health, dietary habits, physical activity, among others are developed in childhood and adolescence. Family environment has shown to play an important role in these outcomes. However, whether the parent-child relationship lifestyle habits and health parameters can be influenced by physical activity patterns still unclear. The objective of this study will be to monitor and investigate the associations between lifestyle habits between parents and their children longitudinally, as well as verify whether in more active parents, the possible associations with lifestyle habits are different from those of parents considered less active. METHODS: The sample will consist of parents (father, mother, or both) and their children /adolescents. The participants will be recruited through public call by flyers spread across all the regions of the city and also through social media. The health parameters will include cardiovascular (cardiac autonomic modulation, blood pressure and resting heart rate), bone mineral density, anthropometric indices, handgrip strength, mental health (quality of life, anxiety and depression symptoms and stress), self-reported morbidities and musculoskeletal pain. Lifestyle habits will include physical activity levels, sedentary behavior, sleep parameters, eating patterns, smoking and alcohol consumption. Sociodemographic variables of age, sex, ethnicity and socioeconomic status will be considered as covariates. The follow-up visits of data collection will be scheduled after a period of 12 months from the baseline assessment during every twelve months. DISCUSSION: The family environment has great potential to determine lifestyle habits in children and adolescents. Based on the results presented in the present study, we hope that health promotion actions can be better designed in the family environment.
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Atmospheric water harvesting (AWH) technology has attracted significant attention as an effective strategy to tackle the global shortage of freshwater resources. Work has focused on the use of hydrogel-based composite adsorbents in water harvesting and water conservation. The approaches adopted to make use of hygroscopic inorganic salts which subject to a "salting out" effect. In this study, we report the first use of modified UIO-66-NH2 as a functional steric cross-linker and Sa-son seed gum was used as polymeric substrate to construct super hygroscopic hydrogels by free radical copolymerization. The maximum water uptake on SMAGs (572 cm3·g-1) outperforms pure UIO-66-NH2 (317 cm3·g-1). Simultaneously, our first attempt to use it for anti-evaporation applications in an arid environment (Lanzhou, China) simulating sandy areas. The evaporation rate of the anti-evaporation material treated with 0.20 % super moisture-absorbent gels (SMAGs) decreased by 6.1 % over 64 h period under natural condition in Lanzhou, China. The prepared material can not only absorb liquid water but also water vapor, which can provide a new way for water collection and conservation technology. The design strategy of this material has wide applications ranging from atmospheric water harvesting materials to anti-evaporation technology.
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Estruturas Metalorgânicas , Gomas Vegetais , Vapor , Água , Estruturas Metalorgânicas/química , Gomas Vegetais/química , Água/química , Hidrogéis/química , Sementes/química , Polímeros/química , AdsorçãoRESUMO
PURPOSE: There is limited research on the effects of maternal hyperandrogenism (MHA) on cardiometabolic risk factors in male offspring. We aimed to compare the risk of metabolic syndrome (MetS) in sons of women with preconceptional hyperandrogenism (HA) to those of non-HA women in later life. METHODS: Using data obtained from the Tehran Lipid and Glucose Cohort Study, with an average of 20 years follow-up, 1913 sons were divided into two groups based on their MHA status, sons with MHA (n = 523) and sons without MHA (controls n = 1390). The study groups were monitored from the baseline until either the incidence of events, censoring, or the end of the study period, depending on which occurred first. Age-scaled unadjusted and adjusted Cox regression models were utilized to evaluate the hazard ratios (HRs) and 95% confidence intervals (CIs) for the association between MHA and MetS in their sons. RESULTS: There was no significant association between MHA and HR of MetS in sons with MHA compared to controls, even after adjustment (unadjusted HR (95% CI) 0.94 (0.80-1.11), P = 0.5) and (adjusted HR (95% CI) 0.98 (0.81-1.18), P = 0.8). Sons with MHA showed a HR of 1.35 for developing high fasting blood sugar compared to controls (unadjusted HR (95% CI) 1.35 (1.01-1.81), P = 0.04), however, after adjustment this association did not remain significant (adjusted HR (95% CI) 1.25 (0.90-1.74), P = 0.1). CONCLUSION: The results suggest that preconceptional MHA doesn't increase the risk of developing MetS in sons in later life. According to this suggestion, preconceptional MHA may not have long-term metabolic consequences in male offspring.
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Hiperandrogenismo , Síndrome Metabólica , Efeitos Tardios da Exposição Pré-Natal , Humanos , Síndrome Metabólica/epidemiologia , Síndrome Metabólica/etiologia , Hiperandrogenismo/epidemiologia , Hiperandrogenismo/complicações , Feminino , Masculino , Adulto , Gravidez , Efeitos Tardios da Exposição Pré-Natal/epidemiologia , Efeitos Tardios da Exposição Pré-Natal/etiologia , Seguimentos , Fatores de Risco , Irã (Geográfico)/epidemiologia , Incidência , Estudos de CoortesRESUMO
A basic hypothesis is that cultural evolutionary processes sustain differences between groups, these differences have evolutionary relevance and they would not otherwise occur in a system without cultural transmission. The empirical challenge is that groups vary for many reasons, and isolating the causal effects of culture often requires appropriate data and a quasi-experimental approach to analysis. We address this challenge with historical data from the final Soviet census of 1989, and our analysis is an example of the epidemiological approach to identifying cultural variation. We find that the fertility decisions of Armenian, Georgian and Azeri parents living in Soviet-era Russia were significantly more son-biased than those of other ethnic groups in Russia. This bias for sons took the form of differential stopping rules; families with sons stopped having children sooner than families without sons. This finding suggests that the increase in sex ratios at birth in the Caucasus, which began in the 1990s, reflects a cultural preference for sons that predates the end of the Soviet Union. This result also supports one of the key hypotheses of gene-culture coevolution, namely that cultural evolutionary processes can support group-level differences in selection pressures that would not otherwise occur in a system without culture.
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BACKGROUND: Zhu-Tokita-Takenouchi-Kim syndrome (ZTTK syndrome) is a severe multi-systemic developmental disorder, caused by variants in the SON gene. A patient diagnosed with ZTTK syndrome who carried a de novo SON mutation and exhibited recurrent myocardial injury was described in this case. CASE PRESENTATION: A 7-year-old girl was admitted to the Cardiology Department of Beijing Children's Hospital in November 2019 due to myocardial injury following respiratory infection. She displayed elevated myocardial enzymes and severe T-wave changes on electrocardiogram. Over the past three years, she had experienced myocardial injury on three occasions. Additionally, she exhibited intellectual disability, congenital amblyopia, and dysmorphic facial features. Genetic analysis revealed a de novo heterozygous mutation c.3852_3856delGGTAT in the SON gene, which was confirmed by Sanger sequencing of her parents. She received anti-infection treatment and was administered metoprolol orally. Her condition was stable at the time of discharge. Over a 42-month follow-up period at the outpatient clinic, she complained intermittent fatigue and palpitation. CONCLUSIONS: The identified SON mutation, which plays a crucial role in heart development and mitochondrial function, may be associated with an increased susceptibility to myocardial injury or cardiomyopathy. This case report contributes novel insights into this rare condition and suggests the expansion of the ZTTK syndrome phenotype.
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Anormalidades do Olho , Deficiência Intelectual , Criança , Feminino , Humanos , Deficiência Intelectual/genética , Mutação , Heterozigoto , Fenótipo , Arritmias CardíacasRESUMO
Background: The benefits of recombinant interleukin-12 (rIL-12) as a multifunctional cytokine and potential immunotherapy for cancer have been sought for decades based on its efficacy in multiple mouse models. Unexpected toxicity in the first phase 2 study required careful attention to revised dosing strategies. Despite some signs of efficacy since then, most rIL-12 clinical trials have encountered hurdles such as short terminal elimination half-life (T½), limited tumor microenvironment targeting, and substantial systemic toxicity. We developed a strategy to extend the rIL-12 T½ that depends on binding albumin in vivo to target tumor tissue, using single-chain rIL-12 linked to a fully human albumin binding (FHAB) domain (SON-1010). After initiating a dose-escalation trial in patients with cancer (SB101), a randomized, double-blind, placebo-controlled, single-ascending dose (SAD) phase 1 trial in healthy volunteers (SB102) was conducted. Methods: SB102 (NCT05408572) focused on safety, tolerability, pharmacokinetic (PK), and pharmacodynamic (PD) endpoints. SON-1010 at 50-300 ng/kg or placebo administered subcutaneously on day 1 was studied at a ratio of 6:2, starting with two sentinels; participants were followed through day 29. Safety was reviewed after day 22, before enrolling the next cohort. A non-compartmental analysis of PK was performed and correlations with the PD results were explored, along with a comparison of the SON-1010 PK profile in SB101. Results: Participants receiving SON-1010 at 100 ng/kg or higher tolerated the injection but generally experienced more treatment-emergent adverse effects (TEAEs) than those receiving the lowest dose. All TEAEs were transient and no other dose relationship was noted. As expected with rIL-12, initial decreases in neutrophils and lymphocytes returned to baseline by days 9-11. PK analysis showed two-compartment elimination in SB102 with mean T½ of 104 h, compared with one-compartment elimination in SB101, which correlated with prolonged but controlled and dose-related increases in interferon-gamma (IFNγ). There was no evidence of cytokine release syndrome based on minimal participant symptoms and responses observed with other cytokines. Conclusion: SON-1010, a novel presentation for rIL-12, was safe and well-tolerated in healthy volunteers up to 300 ng/kg. Its extended half-life leads to a prolonged but controlled IFNγ response, which may be important for tumor control in patients. Clinical trial registration: https://clinicaltrials.gov/study/NCT05408572, identifier NCT05408572.
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Interleucina-12 , Neoplasias , Animais , Camundongos , Humanos , Citocinas , Voluntários Saudáveis , Neoplasias/tratamento farmacológico , Interferon gama , Interleucina-2 , Proteínas Recombinantes , Albuminas/efeitos adversos , Microambiente TumoralRESUMO
This study focused on the nuanced phenomenon of gendered parenting by exploring how maternal son preference is associated with depressive symptoms among Chinese early adolescents. Focusing on 1093 junior high school students from a relatively affluent city in Western China, this study examined the mediating roles of mother-child attachment and father-child attachment as well as the moderating role of school connectedness in the relationship between maternal son preference and depressive symptoms. The results revealed a noteworthy positive correlation between maternal son preference and depressive symptoms among female adolescents, with no significant association observed in males. In addition, mother-child attachment and father-child attachment mediated the relationship between maternal son preference and girls' depressive symptoms, supporting the "spillover effect" and "crossover effect". Moreover, a moderation effect analysis indicated that a higher level of school connectedness can buffer the effect of maternal son preference on girls' depressive symptoms, while a lower level of school connectedness can enhance the effect of maternal son preference on girls' depressive symptoms. In addition, maternal son preference was negatively correlated with boys' depressive symptoms in relation to high school connectedness. These insights help enhance people's understanding of gendered parenting, emphasizing the enduring necessity of addressing son preference within the broader context of promoting gender equality.
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Fisher proposed that female preference for mates with extreme traits could evolve as an essentially arbitrary outcome of a self-reinforcing process. Although Fisher's runaway has been shown to be a theoretical possibility, it is not clear whether it occurs in real populations, in part because existing models express the necessary conditions in terms of parameters that would be nearly impossible to estimate in the wild. Here, I reformulate models of the runaway in terms of two estimable parameters, the heritability and phenotypic variance of realized mate choices. Higher values of both quantities make the runaway more likely. In the most realistic model considered, in which mate choices are based on a mixture of absolute and relative criteria, a runaway cannot occur unless mate choice increases the variance of the male trait, which seems incompatible with the strong directional mating preferences typically observed in polygynous species. Even in the most favourable case for the runaway, purely relative preference without direct selection on preference, a substantial heritability of realized mate choices would be required if there is moderately strong stabilizing selection on the male trait. These results cast some doubt on whether the runaway is a plausible outcome in natural populations.
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Comunicação Celular , Mustelidae , Feminino , Masculino , Animais , Emoções , Fenótipo , ReproduçãoRESUMO
NMDA receptors (NMDARs) modulate glutamatergic excitatory tone in the brain via two complementary modalities: a phasic excitatory postsynaptic current and a tonic extrasynaptic modality. Here, we demonstrated that the tonic NMDAR-current (I NMDA) mediated by NR2A-containing NMDARs is an efficient biosensor detecting the altered ambient glutamate level in the supraoptic nucleus (SON). I NMDA of magnocellular neurosecretory cells (MNCs) measured by nonselective NMDARs antagonist, AP5, at holding potential (V holding) -70â mV in low concentration of ECF Mg2+ ([Mg2+]o) was transiently but significantly increased 1-week post induction of a DOCA salt hypertensive model rat which was compatible with that induced by a NR2A-selective antagonist, PEAQX (I PEAQX) in both DOCA-H2O and DOCA-salt groups. In agreement, NR2B antagonist, ifenprodil, or NR2C/D antagonist, PPDA, did not affect the holding current (I holding) at V holding -70â mV. Increased ambient glutamate by exogenous glutamate (10â mM) or excitatory amino acid transporters (EAATs) antagonist (TBOA, 50â mM) abolished the I PEAQX difference between two groups, suggesting that attenuated EAATs activity increased ambient glutamate concentration, leading to the larger I PEAQX in DOCA-salt rats. In contrast, only ifenprodil but not PEAQX and PPDA uncovered I NMDA at V holding +40â mV under 1.2â mM [Mg2+]o condition. I ifenprodil was not different in DOCA-H2O and DOCA-salt groups. Finally, NR2A, NR2B, and NR2D protein expression were not different in the SON of the two groups. Taken together, NR2A-containing NMDARs efficiently detected the increased ambient glutamate concentration in the SON of DOCA-salt hypertensive rats due to attenuated EAATs activity.
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Acetato de Desoxicorticosterona , Receptores de N-Metil-D-Aspartato , Ratos , Animais , Receptores de N-Metil-D-Aspartato/metabolismo , N-Metilaspartato/metabolismo , N-Metilaspartato/farmacologia , Ácido Glutâmico/metabolismo , Núcleo Supraóptico/metabolismo , Antagonistas de Aminoácidos Excitatórios/farmacologiaRESUMO
RAS (rat sarcoma) oncoproteins are crucial for the growth of some human cancers, including lung, colorectal, and pancreatic adenocarcinomas. The RAS family contains three known human isoforms H(Harvey)-RAS, N(Neuroblastoma)-RAS, and K(Kirsten)-RAS. Mutations in RAS proteins cause up to ~ 30% of cancer cases. For almost 30 years, mutant proteins druggable pockets remained undiscovered, they are nearly identical to their essential, wild-type counterparts and cause cancer. Recent research has increased our knowledge of RAS's structure, processing, and signaling pathways and revealed novel insights into how it works in cancer cells. We highlight several approaches that inhibit RAS activity with small compounds in this review: substances that blocked farnesyltransferase (FTase), isoprenylcysteine carboxyl methyltransferase (Icmt), and RAS-converting enzyme 1 (Rce1) three important enzymes required for RAS localization. Inhibitors block the son of sevenless (SOS) protein's role in nucleotide exchange activity, small molecules that interfered with the phosphodiesterase (PDEδ)-mediated intracellular RAS transport processes, substances that focused on inhibiting RAS-effector interactions. Inhibitors are made to suppress the oncogenic K-RAS G12C mutant only when the nucleophilic cysteine residue at codon 12 is present and many inhibitors with various mechanisms like breaking the organization membrane of K-RAS nano-clustering. So, this is a thorough analysis of the most recent advancements in K-RAS-targeted anticancer techniques, hopefully offering insight into the field's future.
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India has a high prevalence of stunting among children under five years of age, despite marginal improvement over the years. In 2019-21, 35.5 per cent of children below five years were stunted (National Family Health Survey (NFHS), 2019-21). This has been attributed to several factors including open defecation, poor maternal nutrition and food insecurity. This paper examines if the birth order of children is associated with variation in height among them, using nationally representative data from the India Human Development Survey (IHDS 2005 & 2011). The objectives of this paper are to: (i) assess the association of a child's birth order with height (ii) test if the association of birth order with height changes with the degree of son preference (iii) analyse the relationship between birth order and educational outcomes of children. Our results suggest that (i) the height-for-age z score is negatively associated with the birth order of the child (ii) the negative association of birth order with height is stronger for mothers who have a moderate or high degree of son preference, especially when children have an older brother (iii) maternal characteristics such as education could mitigate the negative relationship between birth order and height when son preference is low but not when son preference is high (iv) birth order has a negative association with the reading, writing and mathematical ability of children, especially if the child was stunted in childhood. This indicates that the fertility behaviour of families has both a direct and an indirect impact, which could influence both long term nutrition and education of children.
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Ordem de Nascimento , Desnutrição , Masculino , Feminino , Criança , Humanos , Lactente , Pré-Escolar , Saúde da Criança , Mães , Estado Nutricional , Prevalência , Índia/epidemiologiaRESUMO
Bans on sex-selective abortions are typically implemented to make sex ratios more equitable, but they may have adverse effects on surviving children. We examine the impacts of a ban on prenatal sex selection in India on postnatal health outcomes. We first show that the ban increased the share of female children born to mothers, especially among firstborn female families. Strikingly, we also find that the ban led to a worsening of mortality outcomes for both girls and boys in firstborn female families. In terms of mechanisms, we find that fertility increases in firstborn female families after the ban, pointing to the following channel: firstborn female families are disproportionately affected by the ban and are more likely to use the son-biased fertility stopping rule to achieve a desired number of sons. Children in firstborn female families likely face greater competition for parental resources, which may worsen their health.
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Saúde da Criança , Fertilidade , Gravidez , Masculino , Criança , Humanos , Feminino , Aborto Eugênico , Mães , PaisRESUMO
The one-child policy in China brought about a fast decline in fertility levels and an increasingly skewed sex ratio at birth in China. The deep-seated tradition of son preference has been regarded as the main cause. However, news and recent research have pointed out that having daughters appears more popular among young people in urban areas. The analysis reported in this paper was based on empirical evidence drawn from 47 in-depth interviews. Findings highlighted that regarding the preference of sex at birth, a relatively balanced composition is sought in most cases. Other than the absolute dominance of one son and one daughter together, a preference for having a son remains. Although having two daughters has gained greater popularity among young couples, this turns out to be a compromise to some extent. Daughter preference cannot be regarded as a major trend. In practice, a stronger preference for a certain sex increases the fertility rate as couples attempt to fulfil their preferences, whereas no preference signals the least likelihood to realise fertility intentions. In this sense, the desire to have two children with at least one son may help boost fertility.