University of New Haven

In 2008 we published the first set of guidelines for standardizing research in autophagy. Since then, research on this topic has continued to accelerate, and many new scientists have entered the field. Our knowledge base and relevant new technologies have also been expanding. Accordingly, it is important to update these guidelines for monitoring autophagy in different organisms. Various reviews have described the range of assays that have been used for this purpose. Nevertheless, there continues to be confusion regarding acceptable methods to measure autophagy, especially in multicellular eukaryotes. A key point that needs to be emphasized is that there is a difference between measurements that monitor the numbers or volume of autophagic elements (e.g., autophagosomes or autolysosomes) at any stage of the autophagic process vs. those that measure flux through the autophagy pathway (i.e., the complete process); thus, a block in macroautophagy that results in autophagosome accumulation needs to be differentiated from stimuli that result in increased autophagic activity, defined as increased autophagy induction coupled with increased delivery to, and degradation within, lysosomes (in most higher eukaryotes and some protists such as Dictyostelium) or the vacuole (in plants and fungi). In other words, it is especially important that investigators new to the field understand that the appearance of more autophagosomes does not necessarily equate with more autophagy. In fact, in many cases, autophagosomes accumulate because of a block in trafficking to lysosomes without a concomitant change in autophagosome biogenesis, whereas an increase in autolysosomes may reflect a reduction in degradative activity. Here, we present a set of guidelines for the selection and interpretation of methods for use by investigators who aim to examine macroautophagy and related processes, as well as for reviewers who need to provide realistic and reasonable critiques of papers that are focused on these processes. These guidelines are not meant to be a formulaic set of rules, because the appropriate assays depend in part on the question being asked and the system being used. In addition, we emphasize that no individual assay is guaranteed to be the most appropriate one in every situation, and we strongly recommend the use of multiple assays to monitor autophagy. In these guidelines, we consider these various methods of assessing autophagy and what information can, or cannot, be obtained from them. Finally, by discussing the merits and limits of particular autophagy assays, we hope to encourage technical innovation in the field.

Journal Article Liquidity Preference as Behavior Towards Risk Get access J. Tobin J. Tobin New Haven, Conn. U.S.A. Search for other works by this author on: Oxford Academic Google Scholar The Review of Economic Studies, Volume 25, Issue 2, February 1958, Pages 65–86, https://doi.org/10.2307/2296205 Published: 01 February 1958

The complexity of chronic pain has represented a major dilemma for clinical researchers interested in the reliable and valid assessment of the problem and the evaluation of treatment approaches. The West Haven-Yale Multidimensional Pain Inventory (WHYMPI) was developed in order to fill a widely recognized void in the assessment of clinical pain. Assets of the inventory are its brevity and clarity, its foundation in contemporary psychological theory, its multidimensional focus, and its strong psychometric properties. Three parts of the inventory, comprised of 12 scales, examine the impact of pain on the patients' lives, the responses of others to the patients' communications of pain, and the extent to which patients participate in common daily activities. The instrument is recommended for use in conjunction with behavioral and psychophysiological assessment strategies in the evaluation of chronic pain patients in clinical settings. The utility of the WHYMPI in empirical investigations of chronic pain is also discussed.

Recent studies have demonstrated that fatty acids induce insulin resistance in skeletal muscle by blocking insulin activation of insulin receptor substrate-1 (IRS-1)-associated phosphatidylinositol 3-kinase (PI3-kinase). To examine the mechanism by which fatty acids mediate this effect, rats were infused with either a lipid emulsion (consisting mostly of 18:2 fatty acids) or glycerol. Intracellular C18:2 CoA increased in a time-dependent fashion, reaching an approximately 6-fold elevation by 5 h, whereas there was no change in the concentration of any other fatty acyl-CoAs. Diacylglycerol (DAG) also increased transiently after 3-4 h of lipid infusion. In contrast there was no increase in intracellular ceramide or triglyceride concentrations during the lipid infusion. Increases in intracellular C18:2 CoA and DAG concentration were associated with protein kinase C (PKC)-theta activation and a reduction in both insulin-stimulated IRS-1 tyrosine phosphorylation and IRS-1 associated PI3-kinase activity, which were associated with an increase in IRS-1 Ser(307) phosphorylation. These data support the hypothesis that an increase in plasma fatty acid concentration results in an increase in intracellular fatty acyl-CoA and DAG concentrations, which results in activation of PKC-theta leading to increased IRS-1 Ser(307) phosphorylation. This in turn leads to decreased IRS-1 tyrosine phosphorylation and decreased activation of IRS-1-associated PI3-kinase activity resulting in decreased insulin-stimulated glucose transport activity.

Graphene-based materials are gaining heightened attention as novel materials for environmental applications. The unique physicochemical properties of graphene, notably its exceptionally high surface area, electron mobility, thermal conductivity, and mechanical strength, can lead to novel or improved technologies to address the pressing global environmental challenges. This critical review assesses the recent developments in the use of graphene-based materials as sorbent or photocatalytic materials for environmental decontamination, as building blocks for next generation water treatment and desalination membranes, and as electrode materials for contaminant monitoring or removal. The most promising areas of research are highlighted, with a discussion of the main challenges that we need to overcome in order to fully realize the exceptional properties of graphene in environmental applications.

The tight junction protein ZO-1 belongs to a family of multidomain proteins known as the membrane-associated guanylate kinase homologs (MAGUKs). ZO-1 has been demonstrated to interact with the transmembrane protein occludin, a second tight junction-specific MAGUK, ZO-2, and F-actin, although the nature and functional significance of these interactions is poorly understood. To further elucidate the role of ZO-1 within the epithelial tight junction, we have introduced epitope-tagged fragments of ZO-1 into cultured MDCK cells and identified domains critical for the interaction with ZO-2, occludin, and F-actin. A combination of in vitro and in vivo binding assays indicate that both ZO-2 and occludin interact with specific domains within the N-terminal (MAGUK-like) half of ZO-1, whereas the unique proline-rich C-terminal half of ZO-1 cosediments with F-actin. Consistent with these observations, we found that a construct encoding the N-terminal half of ZO-1 is specifically associated with tight junctions, whereas the unique C-terminal half of ZO-1 is distributed over the entire lateral surface of the plasma membrane and other actin-rich structures. In addition, we have identified a 244-amino acid domain within the N-terminal half of ZO-1, which is required for the stable incorporation of ZO-1 into the junctional complex of polarized MDCK cells. These observations suggest that one functional role of ZO-1 is to organize components of the tight junction and link them to the cortical actin cytoskeleton.

One of the greatest challenges to the sustainability of modern society is an inadequate supply of clean water. Due to its energy-saving and cost-effective features, membrane technology has become an indispensable platform technology for water purification, including seawater and brackish water desalination as well as municipal or industrial wastewater treatment. However, membrane fouling, which arises from the nonspecific interaction between membrane surface and foulants, significantly impedes the efficient application of membrane technology. Preparing antifouling membranes is a fundamental strategy to deal with pervasive fouling problems from a variety of foulants. In recent years, major advancements have been made in membrane preparation techniques and in elucidating the antifouling mechanisms of membrane processes, including ultrafiltration, nanofiltration, reverse osmosis and forward osmosis. This review will first introduce the major foulants and the principal mechanisms of membrane fouling, and then highlight the development, current status and future prospects of antifouling membranes, including antifouling strategies, preparation techniques and practical applications. In particular, the strategies and mechanisms for antifouling membranes, including passive fouling resistance and fouling release, active off-surface and on-surface strategies, will be proposed and discussed extensively.

BACKGROUND: Whether elective surgical repair of small abdominal aortic aneurysms improves survival remains controversial. METHODS: We randomly assigned patients 50 to 79 years old with abdominal aortic aneurysms of 4.0 to 5.4 cm in diameter who did not have high surgical risk to undergo immediate open surgical repair of the aneurysm or to undergo surveillance by means of ultrasonography or computed tomography every six months with repair reserved for aneurysms that became symptomatic or enlarged to 5.5 cm. Follow-up ranged from 3.5 to 8.0 years (mean, 4.9). RESULTS: A total of 569 patients were randomly assigned to immediate repair and 567 to surveillance. By the end of the study, aneurysm repair had been performed in 92.6 percent of the patients in the immediate-repair group and 61.6 percent of those in the surveillance group. The rate of death from any cause, the primary outcome, was not significantly different in the two groups (relative risk in the immediate-repair group as compared with the surveillance group, 1.21; 95 percent confidence interval, 0.95 to 1.54). Trends in survival did not favor immediate repair in any of the prespecified subgroups defined by age or diameter of aneurysm at entry. These findings were obtained despite a low total operative mortality of 2.7 percent in the immediate-repair group. There was also no reduction in the rate of death related to abdominal aortic aneurysm in the immediate-repair group (3.0 percent) as compared with the surveillance group (2.6 percent). Eleven patients in the surveillance group had rupture of abdominal aortic aneurysms (0.6 percent per year), resulting in seven deaths. The rate of hospitalization related to abdominal aortic aneurysm was 39 percent lower in the surveillance group. CONCLUSIONS: Survival is not improved by elective repair of abdominal aortic aneurysms smaller than 5.5 cm, even when operative mortality is low.

This critical review investigates the potential for membrane distillation to desalinate high-salinity waters using low-grade heat at the water-energy nexus.

A compound flap is described that utilizes skin from the anterior chest on a narrow segment of pectoralis major muscle, with its underlying axial neurovascular bundle. This flap has been used successfully to reconstruct large defects in 4 consecutive patients. Our experience with this flap suggests that it may be more versatile than the deltopectoral flap.

The effects of five nanomaterials (multiwalled carbon nanotubes [MWCNTs], Ag, Cu, ZnO, Si) and their corresponding bulk counterparts on seed germination, root elongation, and biomass of Cucurbita pepo (zucchini) were investigated. The plants were grown in hydroponic solutions amended with nanoparticles or bulk material suspensions at 1000 mg/L. Seed germination was unaffected by any of the treatments, but Cu nanoparticles reduced emerging root length by 77% and 64% relative to unamended controls and seeds exposed to bulk Cu powder, respectively. During a 15-day hydroponic trial, the biomass of plants exposed to MWCNTs and Ag nanoparticles was reduced by 60% and 75%, respectively, as compared to control plants and corresponding bulk carbon and Ag powder solutions. Although bulk Cu powder reduced biomass by 69%, Cu nanoparticle exposure resulted in 90% reduction relative to control plants. Both Ag and Cu ion controls (1-1000 mg/L) and supernatant from centrifuged nanoparticle solutions (1000 mg/L) indicate that half the observed phytotoxicity is from the elemental nanoparticles themselves. The biomass and transpiration volume of zucchini exposed to Ag nanoparticles or bulk powder at 0-1000 mg/mL for 17 days was measured. Exposure to Ag nanoparticles at 500 and 100 mg/L resulted in 57% and 41% decreases in plant biomass and transpiration, respectively, as compared to controls or to plants exposed to bulk Ag. On average, zucchini shoots exposed to Ag nanoparticles contained 4.7 greater Ag concentration than did the plants from the corresponding bulk solutions. These findings demonstrate that standard phytotoxicity tests such as germination and root elongation may not be sensitive enough or appropriate when evaluating nanoparticle toxicity to terrestrial plant species.

Interleukin (IL)-13 is a key mediator of tissue fibrosis caused by T helper cell type 2 inflammation. We hypothesized that the fibrogenic effects of IL-13 are mediated by transforming growth factor (TGF)-beta. To test this hypothesis we compared the regulation of TGF-beta in lungs from wild-type mice and CC10-IL-13 mice in which IL-13 overexpression causes pulmonary fibrosis. IL-13 selectively stimulated TGF-beta(1) production in transgenic animals and macrophages were the major site of TGF-beta(1) production and deposition in these tissues. IL-13 also activated TGF-beta(1) in vivo. This activation was associated with decreased levels of mRNA encoding latent TGF-beta-binding protein-1 and increased mRNA encoding urinary plasminogen activator, matrix metalloproteinase (MMP)-9, and CD44. TGF-beta(1) activation was abrogated by the plasmin/serine protease antagonist aprotinin. It was also decreased in progeny of crosses of CC10-IL-13 mice and MMP-9 null mice but was not altered in crosses with CD44 null animals. IL-13-induced fibrosis was also significantly ameliorated by treatment with the TGF-beta antagonist soluble TGFbetaR-Fc (sTGFbetaR-Fc). These studies demonstrate that IL-13 is a potent stimulator and activator of TGF-beta(1) in vivo. They also demonstrate that this activation is mediated by a plasmin/serine protease- and MMP-9-dependent and CD44-independent mechanism(s) and that the fibrogenic effects of IL-13 are mediated, in great extent, by this TGF-beta pathway.

The beta-amyloid protein (beta/A4), derived from a larger amyloid precursor protein (APP), is the principal component of senile plaques in Alzheimer's disease. APP is an integral membrane glycoprotein and is secreted as a carboxyl-terminal truncated molecule. APP cleavage, which is a membrane-associated event, occurred at a site located within the beta/A4 region. This suggests that an intact amyloidogenic beta/A4 fragment is not generated during normal APP catabolism. Therefore, an early event in amyloid formation may involve altered APP processing that results in the release and subsequent deposition of intact beta/A4.

This phase 3, multicenter, randomized (1:1), double-blind, placebo-controlled study evaluated the safety and efficacy of plerixafor with granulocyte colony-stimulating factor (G-CSF) in mobilizing hematopoietic stem cells in patients with multiple myeloma. Patients received G-CSF (10 microg/kg) subcutaneously daily for up to 8 days. Beginning on day 4 and continuing daily for up to 4 days, patients received either plerixafor (240 microg/kg) or placebo subcutaneously. Starting on day 5, patients began daily apheresis for up to 4 days or until more than or equal to 6 x 10(6) CD34(+) cells/kg were collected. The primary endpoint was the percentage of patients who collected more than or equal to 6 x 10(6) CD34(+) cells/kg in less than or equal to 2 aphereses. A total of 106 of 148 (71.6%) patients in the plerixafor group and 53 of 154 (34.4%) patients in the placebo group met the primary endpoint (P < .001). A total of 54% of plerixafor-treated patients reached target after one apheresis, whereas 56% of the placebo-treated patients required 4 aphereses to reach target. The most common adverse events related to plerixafor were gastrointestinal disorders and injection site reactions. Plerixafor and G-CSF were well tolerated, and significantly more patients collected the optimal CD34(+) cell/kg target for transplantation earlier compared with G-CSF alone. This study is registered at www.clinicaltrials.gov as #NCT00103662.

A broad overview of the achievements and emerging areas in the field of Green Chemistry.

We provide a critical review of<italic>green</italic>processes enabling the fractionation and/or depolymerization of lignin towards value-added products.

Thirty-two patients with the onset of erythema chronicum migrans, Lyme arthritis, or both in mid-1976 were studied prospectively. The skin lesion (24 patients) typically lasted about 3 weeks, beginning as a red macule or papule that expanded to form a large ring with central clearing. Associated symptoms ranged from none to malaise, fatigue, chills and fever, headache, stiff neck, backache, myalgias, nausea, vomiting, and sore throat. Three patients had been bitten by ticks at the site of the initial lesion 4 to 20 days before its onset. Nineteen patients suddenly developed a monoarticular or oligoarticular arthritis 4 days to 22 weeks (median, 4 weeks) after onset of the skin lesion; eight developed arthritis without a preceding skin lesion. Seven of these 27 experienced migratory joint pains. Arthritis attacks, most commonly in the knee, were typically short (median, 8 days) but sometimes persisted for months. Other manifestations included neurologic abnormalties, myocardial conduction abnormalities, serum cryoprecipitates, elevated serum IgM levels, and elevated erythrocyte sedimentation rates. The diagnostic marker is the skin lesion; without it, geographic clustering is the most important clue.

We recently reported that fluoxetine or paroxetine, two selective serotonin reuptake inhibitors (SSRIs), when administered to rats, increase the brain content of the neurosteroid 3alpha-hydroxy-5alpha-pregnane-20-one (3alpha5alpha-ALLO) without altering the brain content of other neurosteroids. ALLO (3alpha5alpha and 3alpha5beta isomers) binds with high affinity to various gamma-aminobutyric acid (GABA) receptor A subtypes and facilitates the action of GABA at these receptors. We hypothesized that the increase of ALLO brain content induced by treatment with SSRIs could contribute to alleviating the anxiety and dysphoria associated with the symptomatology of major unipolar depression. We measured ALLO content in four cisternal-lumbar fractions of cerebrospinal fluid (CSF) before and 8-10 weeks after treatment with fluoxetine or fluvoxamine in 15 patients with unipolar major depression. The concentration of ALLO ( approximately 40 fmol/ml in each CSF fraction of three control subjects) was about 60% lower in patients with major unipolar depression. However, in the same patients, fluoxetine or fluvoxamine treatment normalized the CSF ALLO content. Moreover, a statistically significant correlation (r = 0.58; P < 0.023; n = 15) existed between symptomatology improvement (Hamilton Rating Scale for Depression scores) and the increase in CSF ALLO after fluoxetine or fluvoxamine treatment. The CSF content of PREG and PROG remained unaltered after treatment and failed to correlate with the SSRI-induced increase of CSF ALLO. The normalization of CSF ALLO content in depressed patients appears to be sufficient to mediate the anxiolytic and antidysphoric actions of fluoxetine or fluvoxamine via its positive allosteric modulation of GABA type A receptors.

Purpose The purpose of this paper is to critically review the core findings from recently published place‐based crime prevention research. The paper aims to critically evaluate the available evidence on the contribution of crime prevention through environmental design as a crime prevention strategy. Design/methodology/approach Large‐scale evaluations of crime prevention through environmental design (CPTED) are reviewed with a view to clarifying current knowledge on the evidence of crime prevention through environmental design. Findings The review concludes that there is a growing body of research that supports the assertion that crime prevention through environmental design is effective in reducing both crime and fear of crime in the community. Research limitations/implications Although the paper may not review all the evaluations of CPTED, it nonetheless provides a detailed compilation and overview of the most significant research in the area, including an extensive and modern bibliography on the subject. Research implications will be the subject of a forthcoming paper. Practical implications CPTED is an increasingly fashionable approach and is being implemented on a global scale. Additionally, individual components such as territoriality, surveillance, maintenance, access control, activity support and target‐hardening are being widely deployed. However, the evidence currently available is inconclusive and much criticised, which effectively prevents widespread intervention and investment by central government. The paper details the difficulties associated with demonstrating the effectiveness of CPTED. Originality/value The paper concludes that although empirical proof has not been definitively demonstrated, there is a large and growing body of research, which supports the assertion that crime prevention through environmental design is a pragmatic and effective crime prevention tool. This review provides an extensive bibliography of contemporary crime prevention through environmental design and a follow‐up paper will discuss the future research priorities for it.

Membrane desalination is a promising technology for addressing the global challenge of water scarcity by augmenting fresh water supply. Continuous progress in this technology relies on development of membrane materials. The state-of-the-art membranes used in a wide range of desalination applications are polyamide thin-film composite (TFC) membranes which are formed by interfacial polymerization (IP). Despite the wide use of such membranes in desalination, their real-world application is still hampered by several technical obstacles. These challenges of the TFC membranes largely stem from the inherent limitations of the polyamide chemistry, as well as the IP reaction mechanisms. In the past decade, we have witnessed substantial progress in the understanding of polyamide formation mechanisms and the development of new IP strategies that can potentially lead to the redesign of TFC membranes. In this Tutorial, we first present a brief history of the development of desalination membranes and highlight the major challenges of the existing TFC membranes. We then proceed to discuss the pros and cons of emerging IP-based fabrication strategies aiming at improving the performance of TFC membranes. Next, we present technical obstacles and recent efforts in the characterization of TFC membranes to enable fundamental understanding of relevant mechanisms. We conclude with a discussion of the current gap between industrial needs and academic research in designing high-performance TFC membranes, and provide an outlook on future research directions for advancing IP-based fabrication processes.