Maternal obesity has little effect on the immediate offspring but impacts on the next generation

Maternal obesity during pregnancy has been linked to an increased risk of obesity and cardiometabolic disease in the offspring, a phenomenon attributed to developmental programming. Programming effects may be transmissible across generations through both maternal and paternal inheritance, although the mechanisms remain unclear. Using a mouse model, we explored the effects of moderate maternal diet-induced obesity (DIO) on weight gain and glucose-insulin homeostasis in first-generation (F1) and second-generation offspring. DIO was associated with insulin resistance, hyperglycemia and dyslipidemia before pregnancy. Birth weight was reduced in female offspring of DIO mothers (by 6%, P = .039), and DIO offspring were heavier than controls at weaning (males by 47%, females by 27%), however there were no differences in glucose tolerance, plasma lipids, or hepatic gene expression at 6 months. Despite the relative lack of effects in the F1, we found clear fetal growth restriction and persistent metabolic changes in otherwise unmanipulated second-generation offspring with effects on birth weight, insulin levels, and hepatic gene expression that were transmitted through both maternal and paternal lines. This suggests that the consequences of the current dietary obesity epidemic may also have an impact on the descendants of obese individuals, even when the phenotype of the F1 appears largely unaffected

Synthetic glycolate metabolism pathways stimulate crop growth and productivity in the field

y © The Authors, some rights reserved Photorespiration is required in C3 plants to metabolize toxic glycolate formed when ribulose-1,5-bisphosphate carboxylase-oxygenase oxygenates rather than carboxylates ribulose-1,5-bisphosphate. Depending on growing temperatures, photorespiration can reduce yields by 20 to 50% in C3 crops. Inspired by earlier work, we installed into tobacco chloroplasts synthetic glycolate metabolic pathways that are thought to be more efficient than the native pathway. Flux through the synthetic pathways was maximized by inhibiting glycolate export from the chloroplast. The synthetic pathways tested improved photosynthetic quantum yield by 20%. Numerous homozygous transgenic lines increased biomass productivity by \u3e40% in replicated field trials. These results show that engineering alternative glycolate metabolic pathways into crop chloroplasts while inhibiting glycolate export into the native pathway can drive increases in C3 crop yield under agricultural field conditions

Disagreeable Privacy Policies: Mismatches between Meaning and Users’ Understanding

Privacy policies are verbose, difficult to understand, take too long to read, and may be the least-read items on most websites even as users express growing concerns about information collection practices. For all their faults, though, privacy policies remain the single most important source of information for users to attempt to learn how companies collect, use, and share data. Likewise, these policies form the basis for the self-regulatory notice and choice framework that is designed and promoted as a replacement for regulation. The underlying value and legitimacy of notice and choice depends, however, on the ability of users to understand privacy policies. This paper investigates the differences in interpretation among expert, knowledgeable, and typical users and explores whether those groups can understand the practices described in privacy policies at a level sufficient to support rational decision-making. The paper seeks to fill an important gap in the understanding of privacy policies through primary research on user interpretation and to inform the development of technologies combining natural language processing, machine learning and crowdsourcing for policy interpretation and summarization. For this research, we recruited a group of law and public policy graduate students at Fordham University, Carnegie Mellon University, and the University of Pittsburgh (“knowledgeable users”) and presented these law and policy researchers with a set of privacy policies from companies in the e-commerce and news & entertainment industries. We asked them nine basic questions about the policies’ statements regarding data collection, data use, and retention. We then presented the same set of policies to a group of privacy experts and to a group of non-expert users. The findings show areas of common understanding across all groups for certain data collection and deletion practices, but also demonstrate very important discrepancies in the interpretation of privacy policy language, particularly with respect to data sharing. The discordant interpretations arose both within groups and between the experts and the two other groups. The presence of these significant discrepancies has critical implications. First, the common understandings of some attributes of described data practices mean that semi-automated extraction of meaning from website privacy policies may be able to assist typical users and improve the effectiveness of notice by conveying the true meaning to users. However, the disagreements among experts and disagreement between experts and the other groups reflect that ambiguous wording in typical privacy policies undermines the ability of privacy policies to effectively convey notice of data practices to the general public. The results of this research will, consequently, have significant policy implications for the construction of the notice and choice framework and for the US reliance on this approach. The gap in interpretation indicates that privacy policies may be misleading the general public and that those policies could be considered legally unfair and deceptive. And, where websites are not effectively conveying privacy policies to consumers in a way that a “reasonable person” could, in fact, understand the policies, “notice and choice” fails as a framework. Such a failure has broad international implications since websites extend their reach beyond the United States

A conceptual review on reconstructive peri-implantitis therapy: Challenges and opportunities

OBJECTIVES The current strategies to reconstruct lost peri-implant tissues due to the disease have been largely unpredictable. The aim of this conceptual review is to discuss relevant biological and biomechanical challenges of applying reconstructive means to treat peri-implantitis. Additionally, opportunities to improve treatment predictability are presented. MATERIAL AND METHODS A narrative review was conducted to fulfill the aim. RESULTS The four interrelated negative conditions hampering effective reconstruction are: inferior tissue perfusion, unfavorable bone topography, ineffective surface treatment, and unstable wound. First, peri-implant tissues resemble scars with reduced cellularity and vascularity, coupled with the absence of the periodontal ligament plexuses and the avascular implant and biomaterials, maintaining primary closure is a challenge, which is critical for regeneration. Second, defect morphology and bone topography surrounding implants determine the reconstructive potential. Unfortunately, noncontained defects are frequently encountered, with a combination of suprabony (horizontal bone loss) and infrabony (vertical usually involving circumferential bone loss) defects. Third, current attempts for implant surface decontamination are insufficient due to inaccessible macrostructure and rough surfaces in the micro-scale. Histologic evaluation has shown bacteria aggregation and calcified deposits around implants. Lastly, wound stability is difficult to achieve due to inherent soft tissue biomechanical quality and quantity deficiencies and mobile bone particulates. Opportunities to tackle the abovementioned challenges include the use of novel imaging technologies, such as high-frequency dental ultrasound and laser speckle imaging to evaluate tissue perfusion, soft tissue quality/quantity, and bone topography pre-surgically. The use of the operating microscope could allow better visualization and removal of etiologic factors. Strategies to improve soft tissue quality may include preoperative control of soft tissue inflammation and the potential use of biologics. Methods such as fixation to stabilize the biomaterials could be beneficial. CONCLUSIONS A more nuanced understanding of the current challenges and opportunities can lead to more effective preoperative and postoperative care protocols, ultimately improving the success rate of reconstructive procedures

The Role of Palliative Surgery for Malignant Bowel Obstruction and Perforation in Advanced Microsatellite Instability-High Colorectal Carcinoma in the Era of Immunotherapy: Case Report.

The role of palliative surgery in the management of acute complications in patients with disseminated malignancy remains controversial given the complexity of assessing acute surgical risk and long-term oncologic outcome. With the emergence of checkpoint blockade immunotherapy, there appears to be an increasing role for historically palliative procedures as a bridge to systemic immunotherapy. This is especially evident in advanced microsatellite instability-high (MSI-H) colorectal cancer where malignant obstruction and fistula formation are more common and where immunotherapy with checkpoint blockade (anti-PD-1/PD-L1, anti-CTLA-4) has a high response rate with potential for favorable oncologic outcomes. We present a series of three patients with MSI-H metastatic colorectal cancer complicated by malignant bowel obstruction and fistula formation, who having progressed on standard chemotherapy, underwent palliative intervention as a bridge to immune checkpoint blockade with durable and clinically meaningful anti-cancer responses. These cases highlight the need to re-evaluate the role of historically palliative operations in the setting of disease progression for immunotherapy-responsive tumors

Stepwise O atom Transfer in Heme-Based Tryptophan Dioxygenase: Role of Substrate Ammonium in Epoxide Ring Opening

This document is the Accepted Manuscript version of a Published Work that appeared in final form in Journal of the American Chemical Society, copyright © American Chemical Society after peer review and technical editing by the publisher. To access the final edited and published work see http://doi.org/10.1021/jacs.8b00262.Heme-based tryptophan dioxygenases are established immunosuppressive metalloproteins with significant biomedical interest. Here, we synthesized two mechanistic probes to specifically test if the α-amino group of the substrate directly participates in a critical step of the O atom transfer during catalysis in human tryptophan 2,3-dioxygenase (TDO). Substitution of the nitrogen atom of the substrate to a carbon (probe 1) or oxygen (probe 2) slowed the catalytic step following the first O atom transfer such that transferring the second O atom becomes less likely to occur, although the dioxygenated products were observed with both probes. A monooxygenated product was also produced from probe 2 in a significant quantity. Analysis of this new product by HPLC coupled UV–vis spectroscopy, high-resolution mass spectrometry, 1H NMR, 13C NMR, HSQC, HMBC, and infrared (IR) spectroscopies concluded that this monooxygenated product is a furoindoline compound derived from an unstable epoxyindole intermediate. These results prove that small molecules can manipulate the stepwise O atom transfer reaction of TDO and provide a showcase for a tunable mechanism by synthetic compounds. The product analysis results corroborate the presence of a substrate-based epoxyindole intermediate during catalysis and provide the first substantial experimental evidence for the involvement of the substrate α-amino group in the epoxide ring-opening step during catalysis. This combined synthetic, biochemical, and biophysical study establishes the catalytic role of the α-amino group of the substrate during the O atom transfer reactions and thus represents a substantial advance to the mechanistic comprehension of the heme-based tryptophan dioxygenases

What Else Do I Need to Know? The Effect of Background Information on Users' Reliance on QA Systems

NLP systems have shown impressive performance at answering questions by retrieving relevant context. However, with the increasingly large models, it is impossible and often undesirable to constrain models' knowledge or reasoning to only the retrieved context. This leads to a mismatch between the information that the models access to derive the answer and the information that is available to the user to assess the model predicted answer. In this work, we study how users interact with QA systems in the absence of sufficient information to assess their predictions. Further, we ask whether adding the requisite background helps mitigate users' over-reliance on predictions. Our study reveals that users rely on model predictions even in the absence of sufficient information needed to assess the model's correctness. Providing the relevant background, however, helps users better catch model errors, reducing over-reliance on incorrect predictions. On the flip side, background information also increases users' confidence in their accurate as well as inaccurate judgments. Our work highlights that supporting users' verification of QA predictions is an important, yet challenging, problem

Use of proton pump inhibitors and histamine-2 receptor antagonists and risk of gastric cancer in two population-based studies

Acknowledgements Access to UK Biobank data was approved and facilitated by UK Biobank (application number: 34374). Access to Primary Care Clinical Informatics Unit (PCCIU) data was approved and facilitated by the PCCIU Research team, University of Aberdeen. Access to the UK Biobank was funded by a Cancer Research UK Population Research Postdoctoral Fellowship awarded to ÚCMcM. Funding: Access to the UK Biobank was funded by a Cancer Research UK Population Research Postdoctoral Fellowship awarded to ÚCMcM. Liu P was supported by a joint scholarship from Queen's University Belfast and the Chinese Scholarship Council (201708060458). Data availability: The UK Biobank data (https://www.ukbiobank.ac.uk/) and PCCIU data (https://www.abdn.ac.uk/iahs/research/primary-care/pcciur/) are available, following the access procedures, for researchers to access to conduct health related research in the public interest.Peer reviewedPostprin