A Comparative Molecular Dynamics, MM−PBSA and Thermodynamic Integration Study of Saquinavir Complexes with Wild-Type HIV‑1 PR and L10I, G48V, L63P, A71V, G73S, V82A and I84V Single Mutants

A great challenge toward Acquired Immunodeficiency Syndrome (AIDS) treatment is to combat the HIV-1 virus. The major problem of drug resistance has kept the virus one step ahead of the medical community, and the call for more effective drugs remains as urgent as ever. Saquinavir, the first inhibitor against HIV-1 protease, offers the most extensive clinical data regarding resistance mutations. In this work, we examine L10I, G48V, L63P, A71V, G73S, V82A, and I84V single mutant HIV-1 PR strains in complexes with saquinavir to elucidate drug–protease interactions and dynamics. A comparative analysis of these mutations at the molecular level may lead to a deeper understanding of saquinavir resistance. The G48V mutation induces structural changes to the protease that reflect upon the drug’s binding affinity, as shown by MM–PBSA and thermodynamic integration (TI) calculations (ΔΔGTI = 0.3 kcal/mol; ΔΔGMM–PBSA = 1.2 kcal/mol). It was shown that mutations, which increase the flexibility of the flaps (G48V, L63P, L10I) diminish binding. The preservation of hydrogen bonds of saquinavir with both the active site and flap residues in the wild-type and certain single mutants (A71V, V82A) is also crucial for effective inhibition. It was shown that mutations conferring major resistance (G48V, L63P, I84V) did not present these interactions. Finally, it was indicated that a water-mediated hydrogen bond between saquinavir and Asp29 in the active site (wild-type, A71V, G73S) facilitates a proper placement of the drug into the binding cavity that favors binding. Mutants lacking this interaction (G48V, V82A, I84V) demonstrated reduced binding affinities. This systematic and comparative study is a contribution to the elucidation of the drug resistance mechanism in HIV-1 PR

Avances en los estudios arqueológicos, geoarqueológicos y paleoambientales en las Sierras Orientales de Tandilia: resultados preliminares de los sitios Alero El Mirador y Abrigo La Grieta

Este trabajo presenta las características de los registros arqueológicos de dos sitios recientemente retomados, denominados Alero El Mirador y Abrigo La Grieta. Se dan a conocer los resultados del análisis de los conjuntos líticos, del registro zooarqueológico y paleoambiental (obtenidos a partir de la evidencias de diatomeas, antracología y fitolitos), y su relación con las unidades estratigráficas. Esta información proxy permite hipotetizar aspectos del manejo antrópico de recursos naturales locales y de eventos paleoclimáticos ocurridos en el sector serrano de Tandilia oriental durante distintos tramos de la secuencia Pleistoceno-Holoceno.This paper presents the characteristics of the archaeological record of two sites recently taken up, called Alero El Mirador and Abrigo La Grieta. The study of different proxy data like lithic assemblages, zooarchaeological and paleoenvironmental record (obtained by diatoms, phytoliths and anthracology inferences) and their relationship to stratigraphic units, allows us to hypothesize anthropic management aspects of local natural resources and paleoclimatic events occurred in the eastern of Tandilia hill during different moments of the Pleistocene-Holocene archaeological sequence.Facultad de Ciencias Naturales y Muse

Avances en los estudios arqueológicos, geoarqueológicos y paleoambientales en las Sierras Orientales de Tandilia: resultados preliminares de los sitios Alero El Mirador y Abrigo La Grieta

Este trabajo presenta las características de los registros arqueológicos de dos sitios recientemente retomados, denominados Alero El Mirador y Abrigo La Grieta. Se dan a conocer los resultados del análisis de los conjuntos líticos, del registro zooarqueológico y paleoambiental (obtenidos a partir de la evidencias de diatomeas, antracología y fitolitos), y su relación con las unidades estratigráficas. Esta información proxy permite hipotetizar aspectos del manejo antrópico de recursos naturales locales y de eventos paleoclimáticos ocurridos en el sector serrano de Tandilia oriental durante distintos tramos de la secuencia Pleistoceno-Holoceno.This paper presents the characteristics of the archaeological record of two sites recently taken up, called Alero El Mirador and Abrigo La Grieta. The study of different proxy data like lithic assemblages, zooarchaeological and paleoenvironmental record (obtained by diatoms, phytoliths and anthracology inferences) and their relationship to stratigraphic units, allows us to hypothesize anthropic management aspects of local natural resources and paleoclimatic events occurred in the eastern of Tandilia hill during different moments of the Pleistocene-Holocene archaeological sequence.Facultad de Ciencias Naturales y Muse

To which world regions does the valence–dominance model of social perception apply?

Over the past 10 years, Oosterhof and Todorov’s valence–dominance model has emerged as the most prominent account of how people evaluate faces on social dimensions. In this model, two dimensions (valence and dominance) underpin social judgements of faces. Because this model has primarily been developed and tested in Western regions, it is unclear whether these findings apply to other regions. We addressed this question by replicating Oosterhof and Todorov’s methodology across 11 world regions, 41 countries and 11,570 participants. When we used Oosterhof and Todorov’s original analysis strategy, the valence–dominance model generalized across regions. When we used an alternative methodology to allow for correlated dimensions, we observed much less generalization. Collectively, these results suggest that, while the valence–dominance model generalizes very well across regions when dimensions are forced to be orthogonal, regional differences are revealed when we use different extraction methods and correlate and rotate the dimension reduction solution.C.L. was supported by the Vienna Science and Technology Fund (WWTF VRG13-007); L.M.D. was supported by ERC 647910 (KINSHIP); D.I.B. and N.I. received funding from CONICET, Argentina; L.K., F.K. and Á. Putz were supported by the European Social Fund (EFOP-3.6.1.-16-2016-00004; ‘Comprehensive Development for Implementing Smart Specialization Strategies at the University of Pécs’). K.U. and E. Vergauwe were supported by a grant from the Swiss National Science Foundation (PZ00P1_154911 to E. Vergauwe). T.G. is supported by the Social Sciences and Humanities Research Council of Canada (SSHRC). M.A.V. was supported by grants 2016-T1/SOC-1395 (Comunidad de Madrid) and PSI2017-85159-P (AEI/FEDER UE). K.B. was supported by a grant from the National Science Centre, Poland (number 2015/19/D/HS6/00641). J. Bonick and J.W.L. were supported by the Joep Lange Institute. G.B. was supported by the Slovak Research and Development Agency (APVV-17-0418). H.I.J. and E.S. were supported by a French National Research Agency ‘Investissements d’Avenir’ programme grant (ANR-15-IDEX-02). T.D.G. was supported by an Australian Government Research Training Program Scholarship. The Raipur Group is thankful to: (1) the University Grants Commission, New Delhi, India for the research grants received through its SAP-DRS (Phase-III) scheme sanctioned to the School of Studies in Life Science; and (2) the Center for Translational Chronobiology at the School of Studies in Life Science, PRSU, Raipur, India for providing logistical support. K. Ask was supported by a small grant from the Department of Psychology, University of Gothenburg. Y.Q. was supported by grants from the Beijing Natural Science Foundation (5184035) and CAS Key Laboratory of Behavioral Science, Institute of Psychology. N.A.C. was supported by the National Science Foundation Graduate Research Fellowship (R010138018). We acknowledge the following research assistants: J. Muriithi and J. Ngugi (United States International University Africa); E. Adamo, D. Cafaro, V. Ciambrone, F. Dolce and E. Tolomeo (Magna Græcia University of Catanzaro); E. De Stefano (University of Padova); S. A. Escobar Abadia (University of Lincoln); L. E. Grimstad (Norwegian School of Economics (NHH)); L. C. Zamora (Franklin and Marshall College); R. E. Liang and R. C. Lo (Universiti Tunku Abdul Rahman); A. Short and L. Allen (Massey University, New Zealand), A. Ateş, E. Güneş and S. Can Özdemir (Boğaziçi University); I. Pedersen and T. Roos (Åbo Akademi University); N. Paetz (Escuela de Comunicación Mónica Herrera); J. Green (University of Gothenburg); M. Krainz (University of Vienna, Austria); and B. Todorova (University of Vienna, Austria). The funders had no role in study design, data collection and analysis, decision to publish or preparation of the manuscript.https://www.nature.com/nathumbehav/am2023BiochemistryGeneticsMicrobiology and Plant Patholog

A multi-country test of brief reappraisal interventions on emotions during the COVID-19 pandemic.

The COVID-19 pandemic has increased negative emotions and decreased positive emotions globally. Left unchecked, these emotional changes might have a wide array of adverse impacts. To reduce negative emotions and increase positive emotions, we tested the effectiveness of reappraisal, an emotion-regulation strategy that modifies how one thinks about a situation. Participants from 87 countries and regions (n = 21,644) were randomly assigned to one of two brief reappraisal interventions (reconstrual or repurposing) or one of two control conditions (active or passive). Results revealed that both reappraisal interventions (vesus both control conditions) consistently reduced negative emotions and increased positive emotions across different measures. Reconstrual and repurposing interventions had similar effects. Importantly, planned exploratory analyses indicated that reappraisal interventions did not reduce intentions to practice preventive health behaviours. The findings demonstrate the viability of creating scalable, low-cost interventions for use around the world

A Comparative Molecular Dynamics, MM−PBSA and Thermodynamic Integration Study of Saquinavir Complexes with Wild-Type HIV-1 PR and L10I, G48V, L63P, A71V, G73S, V82A and I84V Single Mutants

A great challenge toward Acquired Immunodeficiency Syndrome (AIDS) treatment is to combat the HIV-1 virus. The major problem of drug resistance has kept the virus one step ahead of the medical community, and the call for more effective drugs remains as urgent as ever. Saquinavir, the first inhibitor against HIV-1 protease, offers the most extensive clinical data regarding resistance mutations. In this work, we examine L10I, G48V, L63P, A71V, G73S, V82A, and I84V single mutant HIV-1 PR strains in complexes with saquinavir to elucidate drug−protease interactions and dynamics. A comparative analysis of these mutations at the molecular level may lead to a deeper understanding of saquinavir resistance. The G48V mutation induces structural changes to the protease that reflect upon the drug’s binding affinity, as shown by MM−PBSA and thermodynamic integration (TI) calculations (ΔΔGTI = 0.3 kcal/mol; ΔΔGMM−PBSA = 1.2 kcal/mol). It was shown that mutations, which increase the flexibility of the flaps (G48V, L63P, L10I) diminish binding. The preservation of hydrogen bonds of saquinavir with both the active site and flap residues in the wild-type and certain single mutants (A71V, V82A) is also crucial for effective inhibition. It was shown that mutations conferring major resistance (G48V, L63P, I84V) did not present these interactions. Finally, it was indicated that a water-mediated hydrogen bond between saquinavir and Asp29 in the active site (wild-type, A71V, G73S) facilitates a proper placement of the drug into the binding cavity that favors binding. Mutants lacking this interaction (G48V, V82A, I84V) demonstrated reduced binding affinities. This systematic and comparative study is a contribution to the elucidation of the drug resistance mechanism in HIV-1 PR

Selection and use of the timber resource in hunter-gatherers in the Pleistocene-Holocene transition and middle Holocene, eastern Tandilia range, Argentina

Este trabajo analiza los carbones arqueológicos hallados en seis sitios arqueológicos con cronologías en la transición Pleistoceno–Holoceno (9570 ±150–10465 ± 65 años AP) y Holoceno medio (5089 ± 40–6654 ± 42 años AP) ubicados en las Sierras de Tandilia oriental, provincia de Buenos Aires, Argentina. Los carbones arqueológicos fueron usados para inferir el uso del recurso forestal como un signo de selección humana, la caracterización florística y las condiciones ambientales durante esos períodos. La asociación de carbones identificada para la transición Pleistoceno–Holoceno fue: Celtis tala (Cannabaceae), Salix humboldtiana (Salicaceae), Baccharis sp. y Senecio sp. (Asteraceae). Mientras que para el Holoceno medio fueron registradas: Celtis tala, Baccharis sp., Colletia sp. (Rhamnaceae) y Schinus sp. (Anacardiaceae). Colletia sp., Baccharis sp. y Celtis tala tienen alto poder calórico y larga duración de combustión y fueron una excelente fuente de calor y probablemente fueron usados por los cazadores-recolectores como calefacción, para cocinar y para iluminar. El registro de Celtis tala en tres sitios arqueológicos durante la transición Pleistoceno–Holoceno indica la presencia de bosques xerofíticos al menos desde ca. 10000 años AP en las Sierras de Tandilia oriental. La vegetación se desarrolló bajo un clima frío árido a semi-árido.This paper analyses the anthracological records founded in six archeological sites with chronologies in Pleistocene–Holocene transition (9570 ±150–10,465 ± 65 years BP) and middle Holocene (5089 ± 40–6654 ± 42 years BP) located in the eastern Tandilia range, Buenos Aires province, Argentina. The archaeological charcoals were used to infer the use of forest resources as a sign of human selection, floristic characterization and the environmental conditions during this period. The charcoal assemblages identified for Pleistocene–Holocene transition was: Celtis tala (Cannabaceae), Salix humboldtiana (Salicaceae), Baccharis sp. and Senecio sp. (Asteraceae). While for the middle Holocene were recorded: Celtis tala, Baccharis sp., Colletia sp. (Rhamnaceae) and Schinus sp. (Anacardiaceae). Colletia sp., Baccharis sp. and Celtis tala have high caloric values and long combustible duration and were an excellent source of heat and were probably used by hunter-gatherers for heating, cooking and lighting. The record of Celtis tala in three archaeological sites during the Pleistocene–Holocene transition indicates the presence of xerophytic forests at least from the ca. 10,000 years BP in the eastern Tandilia range. The vegetation developed under a cold arid to semi-arid climate.Fil: Brea, Mariana. Provincia de Entre Ríos. Centro de Investigaciones Científicas y Transferencia de Tecnología a la Producción. Universidad Autónoma de Entre Ríos. Centro de Investigaciones Científicas y Transferencia de Tecnología a la Producción. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Santa Fe. Centro de Investigaciones Científicas y Transferencia de Tecnología a la Producción; ArgentinaFil: Mazzanti, Diana Leonis. Provincia de Entre Ríos. Centro de Investigaciones Científicas y Transferencia de Tecnología a la Producción. Universidad Autónoma de Entre Ríos. Centro de Investigaciones Científicas y Transferencia de Tecnología a la Producción. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Santa Fe. Centro de Investigaciones Científicas y Transferencia de Tecnología a la Producción; Argentina. Universidad Nacional de Mar del Plata. Facultad de Humanidades. Departamento de Historia. Laboratorio de Arqueología Regional Bonaerense; ArgentinaFil: Martínez, G.. Universidad Nacional de Mar del Plata. Facultad de Ciencias Exactas y Naturales. Instituto de Geología de Costas y del Cuaternario. Provincia de Buenos Aires. Gobernación. Comisión de Investigaciones Científicas. Instituto de Geología de Costas y del Cuaternario; Argentina. Universidad Nacional de Mar del Plata. Facultad de Humanidades. Departamento de Historia. Laboratorio de Arqueología Regional Bonaerense; Argentin

Exploring the interactions of irbesartan-2-hydroxypropyl-β-cyclodextrin complex in micelles

Irbesartan is a beneficial drug against hypertension and other diseases. Although it is a polydynamic drug, it suffers from high lipophilicity. New formulations of the drug may increase its efficient pharmacological profile. Towards this aim, we have studied the interactions of irbesartan in simple or complexed form with 2- hydroxypropyl-cyclodextrin in micelles. The interactions of the drug in the two forms in the micelle environment are discussed. Of special interest, is the highly flexibility of the spacer phenyl rin