On the Effectiveness of Offline RL for Dialogue Response Generation

A common training technique for language models is teacher forcing (TF). TF attempts to match human language exactly, even though identical meanings can be expressed in different ways. This motivates use of sequence-level objectives for dialogue response generation. In this paper, we study the efficacy of various offline reinforcement learning (RL) methods to maximize such objectives. We present a comprehensive evaluation across multiple datasets, models, and metrics. Offline RL shows a clear performance improvement over teacher forcing while not inducing training instability or sacrificing practical training budgets.Comment: Accepted at ICML 2023. 18 pages, 12 figures. Code available at https://github.com/asappresearch/dialogue-offline-r

Vitamin d and psoriasis pathology in the mediterranean region, valencia (Spain)

Vitamin D has important immunomodulatory effects on psoriasis in the Mediterranean region. To measure vitamin D intake in subjects with and without psoriasis, and to find an association with relevant clinical features, a case-control study was performed using cases (n = 50, 50% participation rate) clinically diagnosed with psoriasis and 200 healthy subjects (39.5% participation rate), leaving a final sample of 104 people. A survey was conducted using a food frequency questionnaire and clinical histories. Cases and controls were compared using univariate and multivariate analyses. We observed insufficient intake of cholecalciferol (vitamin D3) or ergocalciferol (vitamin D2) for both cases and controls. Patients with psoriasis were at greater risk of associated pathologies: dyslipidaemia (OR: 3.6, 95% CI: 0.8-15.2); metabolic syndrome (OR: 3.3, 95% CI: 0.2-53.9); hypertension (OR: 1.7, 95% CI: 0.4-7.2). Insufficient vitamin D intake in both psoriasis patients and controls in the Mediterranean population, and cardiovascular comorbility is more frequent in patients with psoriasis

Copper-containing mesoporous bioactive glass promotes angiogenesis in an in vivo zebrafish model

The osteogenic and angiogenic responses of organisms to the ionic products of degradation of bioactive glasses (BGs) are being intensively investigated. The promotion of angiogenesis by copper (Cu) has been known for more than three decades. This element can be incorporated to delivery carriers, such as BGs, and the materials used in biological assays. In this work, Cu-containing mesoporous bioactive glass (MBG) in the SiO2-CaO-P2O5 compositional system was prepared incorporating 5% mol Cu (MBG-5Cu) by replacement of the corresponding amount of Ca. The biological effects of the ionic products of MBG biodegradation were evaluated on a well-known endothelial cell line, the bovine aorta endothelial cells (BAEC), as well as in an in vivo zebrafish (Danio rerio) embryo assay. The results suggest that ionic products of both MBG (Cu free) and MBG-5Cu materials promote angiogenesis. In vitro cell cultures show that the ionic dissolution products of these materials are not toxic and promote BAEC viability and migration. In addition, the in vivo assay indicates that both exposition and microinjection of zebrafish embryos with Cu free MBG material increase vessel number and thickness of the subintestinal venous plexus (SIVP), whereas assays using MBG-5Cu enhance this effect.The authors gratefully acknowledge the financial support provided by the Andalusian Ministry of Economy, Science and Innovation (Proyectos Excelencia Grants no. P10-CTS-6681 and no. P12-CTS-1507) and Spanish Ministry of Economy and Competitivity (BIO2014-56092-R). LBRS acknowledges the CONACYT-Mexico Fellowship PhD Program

Estimativa da economia governamental advinda do emprego do fator previdenciário

O presente trabalho tem como escopo estimar a economia proporcionada pelo emprego do fator previdenciário, introduzido pela Lei 9.876/99. Este tema ganhou notoriedade devido às discussões referentes à extinção do fator no primeiro semestre de 2010, questão originada do Projeto de Lei 3.299/08. A partir de informações do Instituto Brasileiro de Geografia e Estatística (IBGE) e de cruzamentos de dados obtidos do Anuário Estatístico da Previdência Social InfoLogo (AEPS InfoLogo), foi desenvolvido um exercício empírico contrafactual. Este possibilitou o cálculo da economia obtida pelo governo para as Aposentadorias por Tempo de Contribuição (ATC) concedidas de 2000 até 2009, desde o seu deferimento até a morte de todos os requerentes do período analisado. Verifica-se, como resultado, que o governo gastaria a mais cerca de R$10 bilhões anuais e que a aplicação do fator resultou em economia de mais de 30% dos gastos totais com as ATCs desse período. A principal conclusão do estudo é que, se o fator previdenciário fosse extinto, o governo teria um dispêndio maior, que possivelmente seria intensificado pelo envelhecimento demográfico brasileiro. Desta forma, percebe-se a relevância do mecanismo para a manutenção do sistema previdenciário do país

Oral particle uptake and organ targeting drives the activity of amphotericin B nanoparticles

There are very few drug delivery systems that target key organs via the oral route, as oral delivery advances normally address gastrointestinal drug dissolution, permeation, and stability. Here we introduce a nanomedicine in which nanoparticles, while also protecting the drug from gastric degradation, are taken up by the gastrointestinal epithelia and transported to the lung, liver, and spleen, thus selectively enhancing drug bioavailability in these target organs and diminishing kidney exposure (relevant to nephrotoxic drugs). Our work demonstrates, for the first time, that oral particle uptake and translocation to specific organs may be used to achieve a beneficial therapeutic response. We have illustrated this using amphotericin B, a nephrotoxic drug encapsulated within <i>N</i>-palmitoyl-<i>N</i>-methyl-<i>N</i>,<i>N</i>-dimethyl-<i>N</i>,<i>N</i>,<i>N</i>-trimethyl-6-<i>O</i>-glycol chitosan (GCPQ) nanoparticles, and have evidenced our approach in three separate disease states (visceral leishmaniasis, candidiasis, and aspergillosis) using industry standard models of the disease in small animals. The oral bioavailability of AmB-GCPQ nanoparticles is 24%. In all disease models, AmB-GCPQ nanoparticles show comparable efficacy to parenteral liposomal AmB (AmBisome). Our work thus paves the way for others to use nanoparticles to achieve a specific targeted delivery of drug to key organs via the oral route. This is especially important for drugs with a narrow therapeutic index

DC-SIGN(+) Macrophages Control the Induction of Transplantation Tolerance

Tissue effector cells of the monocyte lineage can differentiate into different cell types with specific cell function depending on their environment. The phenotype, developmental requirements, and functional mechanisms of immune protective macrophages that mediate the induction of transplantation tolerance remain elusive. Here, we demonstrate that costimulatory blockade favored accumulation of DC-SIGN-expressing macrophages that inhibited CD8(+) T cell immunity and promoted CD4(+)Foxp3(+) Treg cell expansion in numbers. Mechanistically, that simultaneous DC-SIGN engagement by fucosylated ligands and TLR4 signaling was required for production of immunoregulatory IL-10 associated with prolonged allograft survival. Deletion of DC-SIGN-expressing macrophages in vivo, interfering with their CSF1-dependent development, or preventing the DC-SIGN signaling pathway abrogated tolerance. Together, the results provide new insights into the tolerogenic effects of costimulatory blockade and identify DC-SIGN(+) suppressive macrophages as crucial mediators of immunological tolerance with the concomitant therapeutic implications in the clinic.This work was supported by the COST Action BM1305: Action to Focus and Accelerate Cell Tolerogenic Therapies (A FACTT), the Mount Sinai Recanati/Miller Transplantation Institute developmental funds, AST/Pfizer Basic Science Faculty Development Grant, Ministerio de Educacióny Ciencia SAF2010-15062, SAF2013-48834-R, and Fundación Mutua Madrileñ a grants to J.O. A portion of this work appears as part of the doctoral thesis of P.C.S

A new species of Argyromys (Rodentia, Mammalia) from the oligocene of the valley of lakes (Mongolia): its importance for palaeobiogeographical homogeneity across Mongolia, China and Kazakhstan

We describe a new species of Rodentia (Mammalia), Argyromys cicigei sp. nov. from Toglorhoi (fossil bed TGW-A/2a) in Mongolia and Ulantatal (fossil beds UTL 1 and UTL 7) in China. Its tooth morphology differs from the type species Argyromys aralensis from Akespe in Kazakhstan by smaller size and simpler structures. Argyromys has been assigned in different families of Muroidea, such as Tachyoryctoididae and Spalacidae. However, the presence of common characters indicates a closer relationship of Argyromys with the genera of Cricetidae s.l. (subfamilies Eucricetodontinae; Cricetopinae; Cricetodontinae and Gobicricetodontinae among others) from Asia than with the earliest representatives of Spalacidae or the endemic Tachyoryctoididae. Argyromys cicigei sp. nov. possesses a simple anterocone and anteroconid in the upper and lower first molars, respectively, which is characteristic for Cricetidae s.l. It has a flat occlusal surface in worn specimens; weakly-developed posterolophs; an oblique protolophule and metaloph on the upper molars and it lacks a labial anterolophid on the m1. These traits are also typical of the Oligocene genera Aralocricetodon and Plesiodipus, included in the subfamilies Cricetodontinae and Gobicricetodontinae respectively. The cladistic analysis performed here supports this hypothesis. The clade formed by Argyromys species is grouped with other cricetid taxa (s.l). Spalacids, however, form a different clade, as do the tachyoryctoids. Previous authors state that the Aral Formation (Kazakhstan) should be dated to the Oligocene instead of the Miocene, based on the presence of several taxa. The finds of Argyromys in both regions supports the statement that they are closer in age than previously thought. The occurrence of Argyromys in Kazakhstan, Mongolia and China evidences the biogeographic unity of the Central Asian bioprovince during the Oligocene