• P53-regulated miR-320a targets PDL1 and is downregulated in malignant mesothelioma

      Costa, C; Indovina, P; Mattioli, E; Forte, IM; Iannuzzi, CA; Luzzi, L; Bellan, C; De Summa, S; Bucci, E; Di Marzo, D; De Feo, M; Mutti, L; Pentimalli, F; Giordano, A; Giordano, Antonio|0000-0002-5959-016X (2020-09-01)
      © 2020, The Author(s). Malignant pleural mesothelioma (MPM) is an aggressive cancer, related to asbestos exposure, which has a dismal prognosis. MPM diagnosis is late and often challenging, suggesting the need to identify more reliable molecular biomarkers. Here, we set out to identify differentially expressed miRNAs in epithelioid, biphasic, and sarcomatoid MPMs versus normal mesothelium and explored specific miRNA contribution to mesothelial tumorigenesis. We screened an LNA™-based miRNA-microrray with 14 formalin-fixed paraffin-embedded (FFPE) MPMs and 6 normal controls. Through real-time qRT-PCR we extended the analysis of a miRNA subset and further investigated miR-320a role through state-of-the-art techniques. We identified 16 upregulated and 32 downregulated miRNAs in MPMs versus normal tissue, including the previously identified potential biomarkers miR-21, miR-126, miR-143, miR-145. We showed in an extended series that miR-145, miR-10b, and miR-320a levels can discriminate tumor versus controls with high specificity and sensitivity. We focused on miR-320a because other family members were found downregulated in MPMs. However, stable miR-320a ectopic expression induced higher proliferation and migration ability, whereas miR-320a silencing reduced these processes, not supporting a classic tumor-suppressor role in MPM cell lines. Among putative targets, we found that miR-320a binds the 3′-UTR of the immune inhibitory receptor ligand PDL1 and, consistently, miR-320a modulation affects PDL1 levels in MPM cells. Finally, we showed that p53 over-expression induces the upregulation of miR-320a, along with miR-200a and miR-34a, both known to target PDL1, and reduces PDL1 levels in MPM cells. Our data suggest that PDL1 expression might be due to a defective p53-regulated miRNA response, which could contribute to MPM immune evasion or tumorigenesis through tumor-intrinsic roles.
    • Pairwise and higher-order correlations among drug-resistance mutations in HIV-1 subtype B protease

      Haq, O; Levy, RM; Morozov, AV; Andrec, M (2009-08-27)
      Background: The reaction of HIV protease to inhibitor therapy is characterized by the emergence of complex mutational patterns which confer drug resistance. The response of HIV protease to drugs often involves both primary mutations that directly inhibit the action of the drug, and a host of accessory resistance mutations that may occur far from the active site but may contribute to restoring the fitness or stability of the enzyme. Here we develop a probabilistic approach based on connected information that allows us to study residue, pair level and higher-order correlations within the same framework. Results: We apply our methodology to a database of approximately 13,000 sequences which have been annotated by the treatment history of the patients from which the samples were obtained. We show that including pair interactions is essential for agreement with the mutational data, since neglect of these interactions results in order-of-magnitude errors in the probabilities of the simultaneous occurence of many mutations. The magnitude of these pair correlations changes dramatically between sequences obtained from patients that were or were not exposed to drugs. Higher-order effects make a contribution of as much as 10% for residues taken three at a time, but increase to more than twice that for 10 to 15-residue groups. The sequence data is insufficient to determine the higher-order effects for larger groups. We find that higher-order interactions have a significant effect on the predicted frequencies of sequences with large numbers of mutations. While relatively rare, such sequences are more prevalent after multi-drug therapy. The relative importance of these higher-order interactions increases with the number of drugs the patient had been exposed to. Conclusion: Correlations are critical for the understanding of mutation patterns in HIV protease. Pair interactions have substantial qualitative effects, while higher-order interactions are individually smaller but may have a collective effect. Together they lead to correlations which could have an important impact on the dynamics of the evolution of cross-resistance, by allowing the virus to pass through otherwise unlikely mutational states. These findings also indicate that pairwise and possibly higher-order effects should be included in the models of protein evolution, instead of assuming that all residues mutate independently of one another. © 2009 Haq et al; licensee BioMed Central Ltd.
    • Parental Criminal Convictions and the Best Interest of the Child

      Katz, Sarah (2019-01)
      Although the impact of mass incarceration on families is universally recognized, less analyzed is what, if any, the family law response should be. In particular, once the parent is no longer incarcerated, what weight should a parent's criminal conviction be given in making determinations about the children of that parent? In Pennsylvania, where the author directs a family law clinic, the custody statute is hyper-criminalized. Since 1990, the Pennsylvania custody statute has had a rebuttable presumption of threat of harm attached to certain criminal convictions which were listed in the custody statute, but there were only 11 crimes enumerated in the statute. In 2010, Pennsylvania amended its custody statute to expand the list of crimes which create a rebuttable presumption of threat of harm to a child. If a party or household member of a party has been convicted of one of the crimes enumerated in the custody statute, that party may not be granted custody until a court has made an explicit finding that the party does not present a threat of harm to the child(ren). The central question this article seeks to address is as follows: are there good family law reasons for a presumption regarding criminal convictions in custody matters? By considering social science literature and legal sources, the article will evaluate the value of giving weighted consideration to certain crimes in determining the best interest of children. This article will also make recommendations regarding the weight that should be given to criminal convictions in making best interest custody decisions.
    • Parental influences on children's self-regulation of energy intake: Insights from developmental literature on emotion regulation

      Frankel, LA; Hughes, SO; O'Connor, TM; Power, TG; Fisher, JO; Hazen, NL (2012-09-19)
      The following article examines the role of parents in the development of children's self-regulation of energy intake. Various paths of parental influence are offered based on the literature on parental influences on children's emotion self-regulation. The parental paths include modeling, responses to children's behavior, assistance in helping children self-regulate, and motivating children through rewards and punishments. Additionally, sources of variation in parental influences on regulation are examined, including parenting style, child temperament, and child-parent attachment security. Parallels in the nature of parents' role in socializing children's regulation of emotions and energy intake are examined. Implications for future research are discussed. © 2012 Leslie A. Frankel et al.
    • Parental Involvement Laws and New Governance

      Rebouché, Rachel (2011)
      The stated objectives of parental involvement laws are to protect the health and well-being of minors and to encourage dialogue between parents and adolescents about pregnancy options. Yet decades of studies urge that parental involvement laws do not meet these purposes. Adding to this research, a new ethnography of professionals who implement parental involvement statutes seeks to demonstrate how notice and consent laws and the judicial bypass work in practice. Over the last two years, a non-profit organization, the National Partnership for Women & Families, interviewed 155 lawyers, advocates, judges, health care providers, and court clerks who assist minors in every state with parental notice or consent laws and judicial bypass petitions. The National Partnership's final report makes clear that a significant population of minors cannot consult their parents for logistical or personal reasons, and, for that cohort, the judicial bypass is not a meaningful alternative. In only a few places can the judicial bypass system be described as a functional process in which most minors, from any part of a state, can seek a bypass without significant delay, cost, or embarrassment. This Article explains why typical proposals for reform --to revise statutory language, to change public perceptions of the "good parent" and "bad teen," or to challenge aspects of consent or notice laws in court -- have limited potential. I argue that those interested in easing the burden that parental involvement laws impose on young women might intervene at the level of informal decision-making. Insights from new governance scholarship show how influencing local relationships among gatekeepers of services can help overcome obstacles to reform. Generally, new governance is a method of law reform that "responds to critiques of rights-based, state-centered, top-down litigative and regulatory strategies by turning toward experimental, flexible, collaborative public-private partnerships and by locating lawyers as problem solvers rather than as traditional advocates." The problem-solving method of new governance provides an approach that can address the complex web of state oversight, parental control, social stigma, and the discretion of individuallegal actors. I temper my suggestion that new governance could play a role in reform with an assessment of its risks and limitations. My purpose is not to suggest that new governance is a seamless fit for parental involvement laws or provides a clear, unproblematic path for change. My intent, rather, is to advance the current conversation among those interested in increasing minors' access to reproductive health care services and improving the operation of parental involvement laws.
    • Parenting around child snacking: Development of a theoretically-guided, empirically informed conceptual model

      Davison, KK; Blake, CE; Blaine, RE; Younginer, NA; Orloski, A; Hamtil, HA; Ganter, C; Bruton, YP; Vaughn, AE; Fisher, JO (2015-09-17)
      © 2015 Davison et al. Background: Snacking contributes to excessive energy intakes in children. Yet factors shaping child snacking are virtually unstudied. This study examines food parenting practices specific to child snacking among low-income caregivers. Methods: Semi-structured interviews were conducted in English or Spanish with 60 low-income caregivers of preschool-aged children (18 non-Hispanic white, 22 African American/Black, 20 Hispanic; 92% mothers). A structured interview guide was used to solicit caregivers' definitions of snacking and strategies they use to decide what, when and how much snack their child eats. Interviews were audio-recorded, transcribed verbatim and analyzed using an iterative theory-based and grounded approach. A conceptual model of food parenting specific to child snacking was developed to summarize the findings and inform future research. Results: Caregivers' descriptions of food parenting practices specific to child snacking were consistent with previous models of food parenting developed based on expert opinion [1, 2]. A few noteworthy differences however emerged. More than half of participants mentioned permissive feeding approaches (e.g., my child is the boss when it comes to snacks). As a result, permissive feeding was included as a higher order feeding dimension in the resulting model. In addition, a number of novel feeding approaches specific to child snacking emerged including child-centered provision of snacks (i.e., responding to a child's hunger cues when making decisions about snacks), parent unilateral decision making (i.e., making decisions about a child's snacks without any input from the child), and excessive monitoring of snacks (i.e., monitoring all snacks provided to and consumed by the child). The resulting conceptual model includes four higher order feeding dimensions including autonomy support, coercive control, structure and permissiveness and 20 sub-dimensions. Conclusions: This study formulates a language around food parenting practices specific to child snacking, identifies dominant constructs, and proposes a conceptual framework to guide future research.
    • Parsing social network survey data from hidden populations using stochastic context-free grammars

      Poon, AFY; Brouwer, KC; Strathdee, SA; Firestone-Cruz, M; Lozada, RM; Pond, SLK; Heckathorn, DD; Frost, SDW; Pond, Sergei L. Kosakovsky|0000-0003-4817-4029 (2009-09-07)
      Background: Human populations are structured by social networks, in which individuals tend to form relationships based on shared attributes. Certain attributes that are ambiguous, stigmatized or illegal can create a ÔhiddenÕ population, so-called because its members are difficult to identify. Many hidden populations are also at an elevated risk of exposure to infectious diseases. Consequently, public health agencies are presently adopting modern survey techniques that traverse social networks in hidden populations by soliciting individuals to recruit their peers, e.g., respondent-driven sampling (RDS). The concomitant accumulation of network-based epidemiological data, however, is rapidly outpacing the development of computational methods for analysis. Moreover, current analytical models rely on unrealistic assumptions, e.g., that the traversal of social networks can be modeled by a Markov chain rather than a branching process. Methodology/Principal Findings: Here, we develop a new methodology based on stochastic context-free grammars (SCFGs), which are well-suited to modeling tree-like structure of the RDS recruitment process. We apply this methodology to an RDS case study of injection drug users (IDUs) in Tijuana, México, a hidden population at high risk of blood-borne and sexually-transmitted infections (i.e., HIV, hepatitis C virus, syphilis). Survey data were encoded as text strings that were parsed using our custom implementation of the inside-outside algorithm in a publicly-available software package (HyPhy), which uses either expectation maximization or direct optimization methods and permits constraints on model parameters for hypothesis testing. We identified significant latent variability in the recruitment process that violates assumptions of Markov chain-based methods for RDS analysis: firstly, IDUs tended to emulate the recruitment behavior of their own recruiter; and secondly, the recruitment of like peers (homophily) was dependent on the number of recruits. Conclusions: SCFGs provide a rich probabilistic language that can articulate complex latent structure in survey data derived from the traversal of social networks. Such structure that has no representation in Markov chain-based models can interfere with the estimation of the composition of hidden populations if left unaccounted for, raising critical implications for the prevention and control of infectious disease epidemics. © 2009 Poon et al.
    • Particulate matter emissions from biochar-amended soils as a potential tradeoff to the negative emission potential

      Ravi, S; Sharratt, BS; Li, J; Olshevski, S; Meng, Z; Zhang, J; Ravi, Sujith|0000-0002-0425-9373 (2016-10-26)
      © 2016 The Author(s). Novel carbon sequestration strategies such as large-scale land application of biochar may provide sustainable pathways to increase the terrestrial storage of carbon. Biochar has a long residence time in the soil and hence comprehensive studies are urgently needed to quantify the environmental impacts of large-scale biochar application. In particular, black carbon emissions from soils amended with biochar may counteract the negative emission potential due to the impacts on air quality, climate, and biogeochemical cycles. We investigated, using wind tunnel experiments, the particulate matter emission potential of a sand and two agriculturally important soils amended with different concentrations of biochar, in comparison to control soils. Our results indicate that biochar application considerably increases particulate emissions possibly by two mechanisms-the accelerated emission of fine biochar particles and the generation and emission of fine biochar particles resulting from abrasion of large biochar particles by sand grains. Our study highlights the importance of considering the background soil properties (e.g., texture) and geomorphological processes (e.g., aeolian transport) for biochar-based carbon sequestration programs.
    • Patchiness of ciliate communities sampled at varying spatial scales along the New England shelf

      Grattepanche, JD; McManus, GB; Katz, LA; Grattepanche, Jean-David|0000-0002-1854-3762 (2016-12-01)
      © 2016 Grattepanche et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. Although protists (microbial eukaryotes) provide an important link between bacteria and Metazoa in food webs, we do not yet have a clear understanding of the spatial scales on which protist diversity varies. Here, we use a combination of DNA fingerprinting (denaturant gradient gel electrophoresis or DGGE) and high-throughput sequencing (HTS) to assess the ciliate community in the class Spirotrichea at varying scales of 1-3 km sampled in three locations separated by at least 25 km-offshore, midshelf and inshore-along the New England shelf. Analyses of both abundant community (DGGE) and the total community (HTS) members reveal that: 1) ciliate communities are patchily distributed inshore (i.e. the middle station of a transect is distinct from its two neighboring stations), whereas communities are more homogeneous among samples within the midshelf and offshore stations; 2) a ciliate closely related to Pelagostrobilidium paraepacrum 'blooms' inshore and; 3) environmental factors may differentially impact the distributions of individual ciliates (i.e. OTUs) rather than the community as a whole as OTUs tend to show distinct biogeographies (e.g. some OTUs are restricted to the offshore locations, some to the surface, etc.). Together, these data show the complexity underlying the spatial distributions of marine protists, and suggest that biogeography may be a property of ciliate species rather than communities.
    • Patently Non-Obvious II: Experimental Study on the Hindsight Bias Issue before the Supreme Court in KSR v. Teleflex

      Mandel, Gregory N. (2007)
      For the first time in thirty years, the Supreme Court will consider the core patent requirement that an invention be non-obvious. At the heart of the case lies the challenge of how to insulate non-obvious decisions from the distortion of the hindsight bias. This Article reports the latest empirical studies in a line of hindsight research, which present experimental data bearing directly on the issue before the Court: how individuals make non-obvious decisions under existing Supreme Court and Federal Circuit precedent. The study results indicate that the Federal Circuit's suggestion, teaching, or motivation requirement, the precedent challenged before the Supreme Court in KSR v. Teleflex, does not produce erroneous nonobvious outcomes. This result contradicts the claims of the petitioners in KSR and other critics of the suggestion requirement. On the other hand, the results do not demonstrate that the suggestion test ameliorates the hindsight bias in the manner usually claimed by its supporters. An additional study indicates that the Supreme Court's Graham framework does not resolve the hindsight problem either. Given the substantial and confirmed prejudicial effect of the hindsight bias, the Article concludes that the suggestion test should be retained for several reasons: it does not appear to cause the harms hypothesized by its critics, it potentially reduces the hindsight bias for complex technology inventions, and the problem the test confronts (erroneous decisions that an invention is obvious in hindsight) is known and significant while the problem the test is alleged to create (over-compensation for the hindsight bias) is unconfirmed and conjectural. The Article concludes with a recommendation for bifurcating the nonobvious decision at the Patent and Trademark Office. Combined with an earlier proposal for jury trials, these recommendations present the only known means for eliminating the hindsight effect and producing patent decisions that comport with the Patent Act and Supreme Court precedent.
    • Patently Non-Obvious: Empirical Demonstration that the Hindsight Bias Renders Patent Decisions Irrational

      Mandel, Gregory N. (2006)
      This Article reports an experimental study that provides the first empirical demonstration of the hindsight bias in patent law. The results are dramatic along several fronts: (1) the hindsight bias distorts patent decisions far more than anticipated, and to a greater extent than other legal judgments; (2) jury instructions that explicitly identify and warn against the hindsight bias do not ameliorate its impact; (3) the admission of secondary consideration evidence does not cure the hindsight bias; (4) neither the Federal Circuit's suggestion test nor the Supreme Court's Graham requirements appear to solve the hindsight problem; and (5) the hindsight problem pervades patent law to an extent not previously recognized - it biases decisions under the doctrine of equivalents, claim construction, the on-sale bar, and enablement. These findings run counter to the dominant patent analysis of the last decade and have significant implications for patent and innovation policy. The study results indicate that the non-obvious requirement actually often may be applied too stringently. Numerous critics of the current non-obvious requirement may need to reconsider the bases of their challenges and revisit their prescriptions for reform. Revising non-obvious doctrine or practice, for instance, will not provide the panacea that most assume. This Article concludes with recommendations for changes in patent doctrine and litigation to mitigate the impact of the hindsight bias.
    • Pathological Role of Peptidyl-Prolyl Isomerase Pin1 in the Disruption of Synaptic Plasticity in Alzheimer's Disease

      Xu, L; Ren, Z; Chow, FE; Tsai, R; Liu, T; Rizzolio, F; Boffo, S; Xu, Y; Huang, S; Lippa, CF; Gong, Y; Boffo, Silvia|0000-0002-6352-160X (2017-01-01)
      © 2017 Lingyan Xu et al. Synaptic loss is the structural basis for memory impairment in Alzheimer's disease (AD). While the underlying pathological mechanism remains elusive, it is known that misfolded proteins accumulate as β-Amyloid (Aβ) plaques and hyperphosphorylated Tau tangles decades before the onset of clinical disease. The loss of Pin1 facilitates the formation of these misfolded proteins in AD. Pin1 protein controls cell-cycle progression and determines the fate of proteins by the ubiquitin proteasome system. The activity of the ubiquitin proteasome system directly affects the functional and structural plasticity of the synapse. We localized Pin1 to dendritic rafts and postsynaptic density (PSD) and found the pathological loss of Pin1 within the synapses of AD brain cortical tissues. The loss of Pin1 activity may alter the ubiquitin-regulated modification of PSD proteins and decrease levels of Shank protein, resulting in aberrant synaptic structure. The loss of Pin1 activity, induced by oxidative stress, may also render neurons more susceptible to the toxicity of oligomers of Aβ and to excitation, thereby inhibiting NMDA receptor-mediated synaptic plasticity and exacerbating NMDA receptor-mediated synaptic degeneration. These results suggest that loss of Pin1 activity could lead to the loss of synaptic plasticity in the development of AD.
    • Patient-Physician Communication: Why and How

      Travaline, John M.; Ruchinskas, Robert; D'Alonzo, Gilbert E. (2005-01-01)
      Patient-physician communication is an integral part of clinical practice. When done well, such communication produces a therapeutic effect for the patient, as has been validated in controlled studies. Formal training programs have been created to enhance and measure specific communication skills. Many of these efforts, however, focus on medical schools and early postgraduate years and, therefore, remain isolated in academic settings. Thus, the communication skills of the busy physician often remain poorly developed, and the need for established physicians to become better communicators continues. In this article, the authors briefly review the why and how of effective patient-physician communication. They begin by reviewing current data on the benefits of effective communication in the clinical context of physicians caring for patients. The authors then offer specific guidance on how to achieve effective communication in the patient-physician relationship.
    • People Studying People: Artifacts and Ethics in Behavioral Research

      Rosenthal, Robert, 1933-; Rosnow, Ralph L. (1977)
      This is a lively and engaging look at the factors, known as `artifacts', that can confound behavioural experiments. By describing key research studies in a narrative style, Rosnow and Rosenthal address the issues of scientific method and clarify the difficulties that behavioural researchers will encounter. Their final chapter addresses ethical issues, again through narrative use of examples.
    • Perceptions of Pediatric Nurse Practitioners and How a Pulmonary Function Printout Influenced Practice

      Gresko, Susan; Dowdell, Elizabeth Burgess; Gresko, Susan|0000-0002-7782-2411 (2012)
      <jats:p>The rate of asthma in the pediatric population has risen over the last two decades and is now considered to be the most common serious chronic disease in children and adolescents as well as a serious public health concern. In one suburban, Pennsylvania nurse-managed clinic, a group of pediatric nurse practitioners (PNPs), noted an increase in the number of children with asthma and purchased a pulmonary function machine (Spirometer). The purpose of this paper is to discuss how the integration of a pulmonary function measurement printout influenced a small group of PNPs visit satisfaction, their delivery of nursing care, and the response of the families. As the incidence of asthma increases in the pediatric population, nurse practitioners and other healthcare professionals can take a leading role in patient teaching and provision of care by augmenting their practice with new technology combined with continued education for the client and family.</jats:p>
    • Performance of computational tools in evaluating the functional impact of laboratory-induced amino acid mutations

      Gray, VE; Kukurba, KR; Kumar, S; Kumar, Sudhir|0000-0002-9918-8212 (2012-08-01)
      Summary: Site-directed mutagenesis is frequently used by scientists to investigate the functional impact of amino acid mutations in the laboratory. Over 10 000 such laboratory-induced mutations have been reported in the UniProt database along with the outcomes of functional assays. Here, we explore the performance of state-of-the-art computational tools (Condel, PolyPhen-2 and SIFT) in correctly annotating the function-altering potential of 10 913 laboratory-induced mutations from 2372 proteins. We find that computational tools are very successful in diagnosing laboratory-induced mutations that elicit significant functional change in the laboratory (up to 92% accuracy). But, these tools consistently fail in correctly annotating laboratory-induced mutations that show no functional impact in the laboratory assays. Therefore, the overall accuracy of computational tools for laboratory-induced mutations is much lower than that observed for the naturally occurring human variants. We tested and rejected the possibilities that the preponderance of changes to alanine and the presence of multiple base-pair mutations in the laboratory were the reasons for the observed discordance between the performance of computational tools for natural and laboratory mutations. Instead, we discover that the laboratory-induced mutations occur predominately at the highly conserved positions in proteins, where the computational tools have the lowest accuracy of correct prediction for variants that do not impact function (neutral). Therefore, the comparisons of experimental-profiling results with those from computational predictions need to be sensitive to the evolutionary conservation of the positions harboring the amino acid change. © The Author(s) 2012. Published by Oxford University Press.
    • Perspectives of adolescents with severe obesity on social Media in Preparation for weight-loss surgery: A qualitative study

      Parks, EP; Finnerty, DD; Panganiban, J; Frasso, R; Bishop-Gilyard, C; Tewksbury, CM; Williams, NN; Dumon, KR; Cordero, G; Hill, DL; Sarwer, DB; Sarwer, David B|0000-0003-1033-5528 (2020-03-02)
      © 2020 The Author(s). Background: Currently the most effective treatment for severe obesity in adolescents is weight-loss surgery coupled with lifestyle behavior change. In preparation for weight-loss surgery, adolescents are required to make changes to eating and activity habits (lifestyle changes) to promote long term success. Social media support groups, which are popular among adolescents, have the potential to augment preoperative lifestyle changes. The purpose of this study was to qualitatively assess the perceived role of social media as a support tool for weight-loss, and to identify motivators and constraints to lifestyle changes and social media use in adolescents preparing for weight-loss surgery. Methods: Thematic analysis of social media comments from 13 (3 male, 10 female) adolescents aged 16 ± 1.3 years with a body mass index (BMI) 45 ± 7.3 kg/m2 enrolled in a weight-management program preparing for bariatric surgery and who participated in a 12-week pilot social media intervention was performed. Participants commented on moderator posts and videos of nutrition, physical activity, and motivation that were shared three to four times per week. Social media comments were coded using NVivo 11.0 to identify recurrent themes and subthemes. Results: 1) Social media provided accountability, emotional support, and shared behavioral strategies. 2) Motivators for lifestyle changes included family support, personal goals, and non-scale victories. 3) Challenges included negative peers, challenges with planning and tracking, and time constraints. Conclusion: Adolescents considering bariatric surgery identified social media as a tool for social support and reinforcement of strategies for successful behavior change. Important motivators and challenges to lifestyle changes were identified.
    • Perspectives on Directive 58

      Catholic Medical Association (2011-02-01)
      The United States Conference of Catholic Bishops recently revised directive 58, on the use of artificial nutrition and hydration, in its Ethical and Religious Directives for Catholic Health Care Services. Although the revision clarifies that the use of artificial nutrition and hydration is ordinary, proportionate, and therefore, in principle, morally obligatory, the ethical debate surrounding this issue continues. Furthermore, many clinicians remain confused about the implications of this directive, as well as its application to specific cases. This article seeks to clarify both the implications and the practical application of directive 58, pointing out that providing artificial nutrition and hydration is part of normal care giving, and there are few instances in which such care can be licitly withheld or withdrawn from a patient.
    • Perturbation of synapsins homeostasis through HIV-1 Tat-mediated suppression of BAG3 in primary neuronal cells

      Mohseni Ahooyi, T; Torkzaban, B; Shekarabi, M; Tahrir, FG; Decoppet, EA; Cotto, B; Langford, D; Amini, S; Khalili, K (2019-07-01)
      © 2019, The Author(s). HIV-1 Tat is known to be released by HIV infected non-neuronal cells in the brain, and after entering neurons, compromises brain homeostasis by impairing pro-survival pathways, thus contributing to the development of HIV-associated CNS disorders commonly observed in individuals living with HIV. Here, we demonstrate that synapsins, phosphoproteins that are predominantly expressed in neuronal cells and play a vital role in modulating neurotransmitter release at the pre-synaptic terminal, and neuronal differentiation become targets for Tat through autophagy and protein quality control pathways. We demonstrate that the presence of Tat in neurons results in downregulation of BAG3, a co-chaperone for heat shock proteins (Hsp70/Hsc70) that is implicated in protein quality control (PQC) processes by eliminating mis-folded and damaged proteins, and selective macroautophagy. Our results show that treatment of cells with Tat or suppression of BAG3 expression by siRNA in neuronal cells disturbs subcellular distribution of synapsins and synaptotagmin 1 (Syt1) leading to their accumulation in the neuronal soma and along axons in a punctate pattern, rather than being properly distributed at axon-terminals. Further, our results revealed that synapsins partially lost their stability and their removal via lysosomal autophagy was noticeably impaired in cells with low levels of BAG3. The observed impairment of lysosomal autophagy, under this condition, is likely caused by cells losing their ability to process LC3-I to LC3-II, in part due to a decrease in the ATG5 levels upon BAG3 knockdown. These observations ascribe a new function for BAG3 in controlling synaptic communications and illuminate a new downstream target for Tat to elicit its pathogenic effect in impacting neuronal cell function and behavior.