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A change of orbital state alters the coupling between ions and their surroundings drastically. Orbital excitations are hence key to understand and control interaction of ions. Rare-earth elements with strong magneto-crystalline anisotropy (MCA) are important ingredients for magnetic devices. Thus, control of their localized 4f magnetic moments and anisotropy is one major challenge in ultrafast spin physics. With time-resolved x-ray absorption and resonant inelastic scattering experiments, we show for Tb metal that 4f-electronic excitations out of the ground-state multiplet occur after optical pumping. These excitations are driven by inelastic 5d-4f-electron scattering, altering the 4f-orbital state and consequently the MCA with important implications for magnetization dynamics in 4f-metals and more general for the excitation of localized electronic states in correlated materials.
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National Family Health Survey (NFHS) has played a pivotal role in formulating policies and programs by providing nationally representative data on a wide range of monitoring and impact evaluation indicators in population, health and nutrition. However, due to measurement errors resulting in misreporting, the collection of accurate data on sensitive issues in sample surveys has always been a matter of concern. This study examines the fieldworker effect on the reporting of physical, sexual, and emotional Intimate Partner Violence (IPV) using fifth round of NFHS (2019-21) data in India. The cross-classified multi-level model was used to examine the fieldworker's effect on the reporting of IPV. The fieldworker effect accounted for around 32% of total variation in the reporting of intimate partner violence. The fieldworker's effect varied from 26% to 41 % for physical violence, 29% to 33% for emotional IPV and 30%-36% for sexual IPV. It was observed that variation due to fieldworker for non-sensitive outcomes was negligible.Of total variation, only 1.6% for information related to ever attending school, 4.8% for ever given birth, 5% for currently pregnant and 8.5% for information on ever terminated pregnancy was being explained by the fieldworker. Our results indicate a significant fieldworker influence on the likelihood of reporting intimate partner violence, underlining the need for an increased understanding of the impact of fieldworkers on data outputs, especially-but not exclusively-when queries contain delicate or stigmatized themes. This study highlights the importance of providing extra guidance and special training to the fieldworkers when collecting sensitive information related to IPV.
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Background: Wasting develops over a short period and can be reversed with short-term interventions. The prevalence of wasting typically varies from season to season-becoming higher during the monsoon (June to September) season as compared to the winter (October to January) and summer (February to May) seasons every year in a cyclical fashion. However, to the best of our knowledge, using nationally representative demographic surveys to extensively study the impact of the timing of the survey on the results and trends around wasting has not been done so far. Objectives: The goal of this study is to ascertain whether seasonality has an impact on the trend and levels of wasting between NFHS-3 (2005-2006) and NFHS-5 (2019-2021). Methods: The analysis was based on data on 51,555, 259,627, and 232,920 children under 5 years included in NFHS-3, NFHS-4, and NFHS-5 respectively. Multivariable logistic regression analysis and the predicted probabilities approach were employed to examine the effect of the months of interview on the prevalence of wasting. The analysis was conducted for 9 states of India which had data for comparable months to compute wasting levels. Results: We found that at the national level, wasting increased in India by one per cent from NFHS-3 to NFHS-4 but declined by 2% from NFHS-4 to NFHS-5. The results show that seasonality significantly influenced the prevalence of wasting. It was observed that compared to January, the odds of wasting were particularly higher in summer and monsoon seasons, especially in the month of August across all three rounds, indicating the influence of seasonality in the prevalence of wasting in the country. Discussion: The prevalence of wasting in India needs to be interpreted across seasonal changes as seasonality affects many of the variables intrinsically related to child health and nutritional status.
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Implementing a large-scale survey involves a string of intricate procedures exposed to numerous types of survey errors. Uniform and systematic training protocols, comprehensive survey manuals, and multilayer supervision during survey implementation help reduce survey errors, providing a consistent fieldwork environment that should not result in any variation in the quality of data collected across interviewers and teams. With this background, the present study attempts to delineate the effect of field investigator (FI) teams and survey implementation design on the selected outcomes. Data on four of the bigger Empowered Action Group (EAG) states of India, namely Uttar Pradesh, Madhya Pradesh, Bihar, and Rajasthan, were obtained from the fourth round of the National Family Health Survey (NFHS-4) for analysis. A fixed-effect binary logistic regression model was used to assess the effect of FI teams and survey implementation design on the selected outcomes. To study the variation in the outcome variables at the interviewer level, a cross-classified multilevel model was used. Since one interviewer had worked in more than one primary sampling unit (PSU) & district and did not follow a perfect hierarchical structure, the cross-classified multilevel model was deemed suitable. In addition, since NFHS-4 used a two-stage stratified sampling design, two-level weights were adjusted for the models to compute unbiased estimates. This study demonstrated the presence of interviewer-level variation in the selected outcomes at both inter- and intra-field agencies across the selected states. The interviewer-level intra-class correlation coefficient (ICC) for women who had not availed antenatal care (ANC) was the highest for eastern Madhya Pradesh (0.23) and central Uttar Pradesh (0.20). For 'immunisation card not seen', Rajasthan (0.16) and western Uttar Pradesh (0.13) had higher interviewer-level ICC. Interviewer-level variations were insignificant for women who gave birth at home across all regions of Uttar Pradesh. Eastern Madhya Pradesh, Rajasthan, and Bihar showed higher interviewer-level variation across the selected outcomes, underlining the critical role of agencies and skilled interviewers in different survey implementation designs. The analysis highlights non-uniform adherence to survey protocols, which implies that not all interviewers and agencies performed in a similar manner in the field. This study recommends a refined mechanism for field implementation and supervision, including focused training on the challenges faced by FIs, random vigilance, and morale building. In addition, examining interviewer-level characteristics, field challenges, and field agency effects may also highlight the roots of interviewer-level variation in the data. However, based on the interviewer's performance in the field, the present study offers an intriguing insight into interviewer-level variations in the quality of data.
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The adipose tissue-derived hormone leptin can drive decreases in food intake while increasing energy expenditure. In diet-induced obesity, circulating leptin levels rise proportionally to adiposity. Despite this hyperleptinemia, rodents and humans with obesity maintain increased adiposity and are resistant to leptin's actions. Here we show that inhibitors of the cytosolic enzyme histone deacetylase 6 (HDAC6) act as potent leptin sensitizers and anti-obesity agents in diet-induced obese mice. Specifically, HDAC6 inhibitors, such as tubastatin A, reduce food intake, fat mass, hepatic steatosis and improve systemic glucose homeostasis in an HDAC6-dependent manner. Mechanistically, peripheral, but not central, inhibition of HDAC6 confers central leptin sensitivity. Additionally, the anti-obesity effect of tubastatin A is attenuated in animals with a defective central leptin-melanocortin circuitry, including db/db and MC4R knockout mice. Our results suggest the existence of an HDAC6-regulated adipokine that serves as a leptin-sensitizing agent and reveals HDAC6 as a potential target for the treatment of obesity.
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Histona Desacetilasa 6/antagonistas & inhibidores , Inhibidores de Histona Desacetilasas/farmacología , Leptina/metabolismo , Obesidad/metabolismo , Tejido Adiposo/efectos de los fármacos , Tejido Adiposo/metabolismo , Animales , Peso Corporal , Dieta Alta en Grasa , Relación Dosis-Respuesta a Droga , Metabolismo Energético/efectos de los fármacos , Activación Enzimática , Regulación de la Expresión Génica/efectos de los fármacos , Histona Desacetilasa 6/genética , Histona Desacetilasa 6/metabolismo , Inhibidores de Histona Desacetilasas/química , Hígado/efectos de los fármacos , Hígado/metabolismo , Hígado/patología , Masculino , Ratones , Ratones Obesos , Modelos Biológicos , Obesidad/tratamiento farmacológico , Obesidad/etiología , Transducción de Señal/efectos de los fármacosRESUMEN
We study the optical-pump induced ultrafast transient change of x-ray absorption at L 3 absorption resonances of the transition metals Ni and Fe in the Fe0.5Ni0.5 alloy. We find the effect for both elements to occur simultaneously on a femtosecond timescale. This effect may hence be used as a handy cross correlation scheme, providing a time-zero reference for ultrafast optical-pump soft x-ray-probe measurement. The method benefits from a relatively simple experimental setup as the sample itself acts as time-reference tool. In particular, this technique works with low flux ultrafast soft x-ray sources. The measurements are compared to the cross correlation method introduced in an earlier publication.
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Chemical synthesis has been described as a central science. Its practice provides access to the chemical structures of known and/or designed function. In particular, human health is greatly impacted by synthesis that enables advancements in both basic science discoveries in chemical biology as well as translational research that can lead to new therapeutics. To support the chemical synthesis needs of investigators across campus, the Vanderbilt Institute of Chemical Biology established a chemical synthesis core as part of its foundation in 2008. Provided in this Review are examples of synthetic products, known and designed, produced in the core over the past 10 years.
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Técnicas de Química Sintética/métodos , Indicadores y Reactivos/síntesis química , Preparaciones Farmacéuticas/síntesis química , Animales , Productos Biológicos/síntesis química , Fenómenos Biofísicos , Medios de Contraste/síntesis química , Humanos , Tomografía Computarizada por Tomografía de Emisión de Positrones , Investigación , Estudios Retrospectivos , EstereoisomerismoRESUMEN
Lactate dehydrogenase (LDH) is a critical enzyme in the glycolytic metabolism pathway that is used by many tumor cells. Inhibitors of LDH may be expected to inhibit the metabolic processes in cancer cells and thus selectively delay or inhibit growth in transformed versus normal cells. We have previously disclosed a pyrazole-based series of potent LDH inhibitors with long residence times on the enzyme. Here, we report the elaboration of a new subseries of LDH inhibitors based on those leads. These new compounds potently inhibit both LDHA and LDHB enzymes, and inhibit lactate production in cancer cell lines.
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Compuestos de Anilina/farmacología , Antineoplásicos/farmacología , Diseño de Fármacos , Éteres/farmacología , L-Lactato Deshidrogenasa/antagonistas & inhibidores , L-Lactato Deshidrogenasa/metabolismo , Compuestos de Anilina/química , Antineoplásicos/química , Línea Celular Tumoral , Éteres/química , Humanos , L-Lactato Deshidrogenasa/químicaRESUMEN
Lactate dehydrogenase (LDH) catalyzes the conversion of pyruvate to lactate, with concomitant oxidation of reduced nicotinamide adenine dinucleotide as the final step in the glycolytic pathway. Glycolysis plays an important role in the metabolic plasticity of cancer cells and has long been recognized as a potential therapeutic target. Thus, potent, selective inhibitors of LDH represent an attractive therapeutic approach. However, to date, pharmacological agents have failed to achieve significant target engagement in vivo, possibly because the protein is present in cells at very high concentrations. We report herein a lead optimization campaign focused on a pyrazole-based series of compounds, using structure-based design concepts, coupled with optimization of cellular potency, in vitro drug-target residence times, and in vivo PK properties, to identify first-in-class inhibitors that demonstrate LDH inhibition in vivo. The lead compounds, named NCATS-SM1440 (43) and NCATS-SM1441 (52), possess desirable attributes for further studying the effect of in vivo LDH inhibition.
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Inhibidores Enzimáticos/farmacología , L-Lactato Deshidrogenasa/antagonistas & inhibidores , Pirazoles/farmacología , Animales , Inhibidores Enzimáticos/química , Inhibidores Enzimáticos/farmacocinética , Semivida , Humanos , Ratones , Relación Estructura-Actividad , Ensayos Antitumor por Modelo de XenoinjertoRESUMEN
Prostaglandin E2 is produced in response to inflammation, often associated with human disease. As prostaglandins are rapidly metabolized, quantification of end urinary metabolites depend on chemical synthesis of isotopically labeled standards to support metabolite quantification. A concise synthesis of tetranor-PGE1 is described including a late stage incorporation of an isotopically labeled side-chain.
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The magnetic ground states in highly ordered double perovskites LaSr1-xCaxNiReO6 (x = 0.0, 0.5, 1.0) are studied in view of the Goodenough-Kanamori rules of superexchange interactions in this paper. In LaSrNiReO6, Ni and Re sublattices are found to exhibit curious magnetic states separately, but no long range magnetic ordering is achieved. The magnetic transition at ~255 K is identified with the independent Re sublattice magnetic ordering. Interestingly, the sublattice interactions are tuned by modifying the Ni-O-Re bond angles through Ca doping. Upon Ca doping, the Ni and Re sublattices start to display a ferrimagnetically ordered state at low temperature. The neutron powder diffraction data reveals long range ferrimagnetic ordering of the Ni and Re magnetic sublattices along the crystallographic b-axis. The transition temperature of the ferrimagnetic phase increases monotonically with increasing Ca concentration.
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The mitotic spindle is a microtubule-based machine that segregates a replicated set of chromosomes during cell division. Many cancer drugs alter or disrupt the microtubules that form the mitotic spindle. Microtubule-dependent molecular motors that function during mitosis are logical alternative mitotic targets for drug development. Eg5 (Kinesin-5) and Kif15 (Kinesin-12), in particular, are an attractive pair of motor proteins, as they work in concert to drive centrosome separation and promote spindle bipolarity. Furthermore, we hypothesize that the clinical failure of Eg5 inhibitors may be (in part) due to compensation by Kif15. In order to test this idea, we screened a small library of kinase inhibitors and identified GW108X, an oxindole that inhibits Kif15 in vitro. We show that GW108X has a distinct mechanism of action compared with a commercially available Kif15 inhibitor, Kif15-IN-1 and may serve as a lead with which to further develop Kif15 inhibitors as clinically relevant agents.
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Inhibidores Enzimáticos/farmacología , Cinesinas/antagonistas & inhibidores , Sondas Moleculares/farmacología , Oxindoles/farmacología , Quinazolinonas/farmacología , Relación Dosis-Respuesta a Droga , Inhibidores Enzimáticos/síntesis química , Inhibidores Enzimáticos/química , Humanos , Cinesinas/metabolismo , Sondas Moleculares/síntesis química , Sondas Moleculares/química , Estructura Molecular , Oxindoles/síntesis química , Oxindoles/química , Quinazolinonas/síntesis química , Quinazolinonas/química , Relación Estructura-ActividadRESUMEN
The total synthesis of hemiketal E2 (HKE2) has been accomplished using a gold(I)-mediated cycloisomerization followed by oxidation of the enol ether product to introduce a unique keto-hemiketal, the core structure of HKE2. Synthetic hemiketal E2 reproduced biosynthetically derived HKE2 in the inhibition of human platelet aggregation.
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Ácido Araquidónico/química , Plaquetas , Humanos , Estructura Molecular , Oxidación-ReducciónRESUMEN
The "northern" sector of the cembranoid diterpene providencin containing a tetrasubstituted cyclobutane was synthesized from the bis(acetonide) of d-glucose using dicyclopentadienylzirconium(0)-mediated oxygen abstraction from a furanose. Oxidative scission of the vinyl substituent of this cyclobutane gave an aldehyde, which was reacted with an alkynylstannane to provide an allenol. Cyclization of the derived allenone with silver nitrate led to a cyclobutylfuran comprising the northern subunit of providencin. The "southern" sector of the cembranoid skeleton containing a trisubstituted iodoalkene attached to an α-phenylselenyl-γ-lactone was synthesized from (R)-glycidol. Negishi carbometalation-iodination established the (E)-iodoalkene, and addition of the lithio dianion of phenylselenoacetic acid to a tosylate generated the substituted lactone. The two sectors were joined via stannylation of the furan of the northern component followed by Stille cross-coupling of the furylstannane with the iodoalkene of the southern subunit. Linkage of the two segments was also made at C12-C13 of providencin using intermolecular aldol condensation of the enolate from the selenyl lactone of the southern portion with an acetaldehyde appendage on the cyclobutane of the northern sector. Closure of the providencin macrocycle from these conjoined subunits was unsuccessful.
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Ciclobutanos/química , Diterpenos/síntesis química , Hidrocarburos Yodados/química , Lactonas/química , Diterpenos/química , Conformación MolecularRESUMEN
The generation of indolines and benzofurans from the combination of Suzuki-Miyaura coupling reactions with oxidative cyclizations is described.
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Benzofuranos/síntesis química , Indoles/síntesis química , Benzofuranos/química , Catálisis , Ciclización , Indoles/química , Estructura Molecular , Oxidación-ReducciónRESUMEN
Multifunctional nanomaterials with combined magnetic and optical properties remain one of the most demanded materials in upcoming research. To obtain these materials, we report here several doped semiconductor nanocrystals that simultaneously show tunable emission in a visible and NIR spectral window, above-room-temperature ferromagnetism, and improved conductivity. These nanocrystals are designed by inserting Ni(II) as a dopant in various semiconducting hosts with binary, alloyed, and ternary composition, and the induced multifunctional properties are observed to be stable and reproducible. These semiconducting materials combined with fluorescence and magnetic properties would be useful for a wide range of applications spanning from life science to modern developing device technology.
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An unusual magnetoresistance (MR) behavior in Sr(2)FeMoO(6), recently termed as spin-valve-type MR (SVMR), presents several anomalies that are little understood so far. The formation of a magnetically distorted skin layer around every soft, ferromagnetic grain seems to be the reason behind such an unprecedented tunneling MR (TMR) response. However, initially it appeared that Sr(2)FeMoO(6) is an exclusive TMR material showing an unusual SVMR effect, while other well-known magnetoresistive compounds do not exhibit such behavior. Instead, in this present work, we show that SVMR is a generic feature of the extremely important class of the metallic, ferromagnetic double perovskite family as a whole. Our detailed magnetic study also offers a serious correction to our previous SVMR model, where the strong exchange coupling between the ferromagnetic core and the magnetically frustrated skin of each grain, generating the famous 'exchange bias' effect and consequently the 'valve' for SVMR, needs to be considered.
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A portion of the macrocyclic cembrenoid diterpene providencin possessing conjoined cyclobutane and furancarboxylate units was synthesized from D-glucose using deoxygenative ring contraction methodology to construct the tetrasubstituted cyclobutane and a Knoevenagel condensation of glyceraldehyde to fabricate the trisubstituted furan.