Plastin 3 in health and disease: a matter of balance.

For a long time, PLS3 (plastin 3, also known as T-plastin or fimbrin) has been considered a rather inconspicuous protein, involved in F-actin-binding and -bundling. However, in recent years, a plethora of discoveries have turned PLS3 into a highly interesting protein involved in many cellular processes, signaling pathways, and diseases. PLS3 is localized on the X-chromosome, but shows sex-specific, inter-individual and tissue-specific expression variability pointing towards skewed X-inactivation. PLS3 is expressed in all solid tissues but usually not in hematopoietic cells. When escaping X-inactivation, PLS3 triggers a plethora of different types of cancers. Elevated PLS3 levels are considered a prognostic biomarker for cancer and refractory response to therapies. When it is knocked out or mutated in humans and mice, it causes osteoporosis with bone fractures; it is the only protein involved in actin dynamics responsible for osteoporosis. Instead, when PLS3 is upregulated, it acts as a highly protective SMN-independent modifier in spinal muscular atrophy (SMA). Here, it seems to counteract reduced F-actin levels by restoring impaired endocytosis and disturbed calcium homeostasis caused by reduced SMN levels. In contrast, an upregulation of PLS3 on wild-type level might cause osteoarthritis. This emphasizes that the amount of PLS3 in our cells must be precisely balanced; both too much and too little can be detrimental. Actin-dynamics, regulated by PLS3 among others, are crucial in a lot of cellular processes including endocytosis, cell migration, axonal growth, neurotransmission, translation, and others. Also, PLS3 levels influence the infection with different bacteria, mycosis, and other pathogens.

The Effect of Integrating Primary Care and Mental Health Services on Diabetes and Depression: A Multi-site Impact Evaluation on the US-Mexico Border.

BACKGROUND: Health care delivery systems are increasingly integrating physical and mental health services to address patients' complex needs, contain costs, and improve satisfaction. Therefore, it is critical to understand whether adoption of integrated care models is effective in diverse settings. OBJECTIVE: This study examined the effect of integrated care on physical and mental health outcomes among low-income Latino participants on the US-Mexico border. RESEARCH DESIGN: In this quasi-experimental multisite study, individual-level data were pooled from 8 studies of locally adapted integrated care models. SUBJECTS: Participants were 18 years or older and had 1 or more chronic conditions: diabetes, depression, hypertension, or obesity. The study enrolled 4226 participants with 2254 participants in the intervention group and 1972 in the comparison group. MEASURES: Primary outcomes were depressive symptoms as measured by the Patient Health Questionnaire-9 score and blood glucose measured by hemoglobin A1c (HbA1c). Blood pressure, body mass index, and quality of life were secondary outcomes. RESULTS: Multivariable linear regression analyses indicated intervention participants had significantly lower Patient Health Questionnaire-9 scores (ß=-0.39, P=0.03) and HbA1c (ß=-0.14, P=0.02) at 12 months compared with comparison group participants. Stratified analyses showed improvements in HbA1c were even greater among intervention participants who had diabetes, depression, severe and persistent mental illness, were older or female compared with their counterparts in the comparison group. CONCLUSIONS: Health care is constantly transforming, making it critical to study these changes across populations and settings. Findings from this study indicate that integrated care can significantly improve mental and physical health in an underserved Latino population.

Comprehensive Evaluation of Biological Effects of Pentathiepins on Various Human Cancer Cell Lines and Insights into Their Mode of Action.

Pentathiepins are polysulfur-containing compounds that exert antiproliferative and cytotoxic activity in cancer cells, induce oxidative stress and apoptosis, and inhibit glutathione peroxidase (GPx1). This renders them promising candidates for anticancer drug development. However, the biological effects and how they intertwine have not yet been systematically assessed in diverse cancer cell lines. In this study, six novel pentathiepins were synthesized to suit particular requirements such as fluorescent properties or improved water solubility. Structural elucidation by X-ray crystallography was successful for three derivatives. All six underwent extensive biological evaluation in 14 human cancer cell lines. These studies included investigating the inhibition of GPx1 and cell proliferation, cytotoxicity, and the induction of ROS and DNA strand breaks. Furthermore, selected hallmarks of apoptosis and the impact on cell cycle progression were studied. All six pentathiepins exerted high cytotoxic and antiproliferative activity, while five also strongly inhibited GPx1. There is a clear connection between the potential to provoke oxidative stress and damage to DNA in the form of single- and double-strand breaks. Additionally, these studies support apoptosis but not ferroptosis as the mechanism of cell death in some of the cell lines. As the various pentathiepins give rise to different biological responses, modulation of the biological effects depends on the distinct chemical structures fused to the sulfur ring. This may allow for an optimization of the anticancer activity of pentathiepins in the future.

Synthesis, Structure and Cytotoxicity Testing of Novel 7-(4,5-dihydro-1H-imidazol-2-yl)-2-aryl-6,7-dihydro-2H-imidazo[2,1-c][1,2,4]triazol-3(5H)-Imine Derivatives.

The appropriate 1-arylhydrazinecarbonitriles 1a-c are subjected to the reaction with 2-chloro-4,5-dihydro-1H-imidazole (2), yielding 7-(4,5-dihydro-1H-imidazol-2-yl)-2-aryl-6,7-dihydro-2H-imidazo[2,1-c][1,2,4]triazol-3(5H)-imines 3a-c, which are subsequently converted into the corresponding amides 4a-e, 8a-c, sulfonamides 5a-n, 9, ureas 6a-I, and thioureas 7a-d. The structures of the newly prepared derivatives 3a-c, 4a-e, 5a-n, 6a-i, 7a-d, 8a-c, and 9 are confirmed by IR, NMR spectroscopic data, as well as single-crystal X-ray analyses of 5e and 8c. The in vitro cytotoxic potency of these compounds is determined on a panel of human cancer cell lines, and the relationships between structure and antitumor activity are discussed. The most active 4-chloro-N-(2-(4-chlorophenyl)-7-(4,5-dihydro-1H-imidazol-2-yl)-6,7-dihydro-2H-imidazo[2,1-c][1,2,4]triazol-3(5H)-ylidene)benzamide (4e) and N-(7-(4,5-dihydro-1H-imidazol-2-yl)-2-(p-tolyl)-6,7-dihydro-2H-imidazo[2,1-c][1,2,4]triazol-3(5H)-ylidene)-[1,1'-biphenyl]-4-sulfonamide (5l) inhibits the growth of the cervical cancer SISO and bladder cancer RT-112 cell lines with IC50 values in the range of 2.38-3.77 µM. Moreover, N-(7-(4,5-dihydro-1H-imidazol-2-yl)-2-phenyl-6,7-dihydro-2H-imidazo[2,1-c][1,2,4]triazol-3(5H)-ylidene)-4-phenoxybenzenesulfonamide (5m) has the best selectivity towards the SISO cell line and induces apoptosis in this cell line.

CLUH maintains functional mitochondria and translation in motoneuronal axons and prevents peripheral neuropathy.

Transporting and translating mRNAs in axons is crucial for neuronal viability. Local synthesis of nuclear-encoded mitochondrial proteins protects long-lived axonal mitochondria from damage; however, the regulatory factors involved are largely unknown. We show that CLUH, which binds mRNAs encoding mitochondrial proteins, prevents peripheral neuropathy and motor deficits in the mouse. CLUH is enriched in the growth cone of developing spinal motoneurons and is required for their growth. The lack of CLUH affects the abundance of target mRNAs and the corresponding mitochondrial proteins more prominently in axons, leading to ATP deficits in the growth cone. CLUH interacts with ribosomal subunits, translation initiation, and ribosome recycling components and preserves axonal translation. Overexpression of the ribosome recycling factor ABCE1 rescues the mRNA and translation defects, as well as the growth cone size, in CLUH-deficient motoneurons. Thus, we demonstrate a role for CLUH in mitochondrial quality control and translational regulation in axons, which is essential for their development and long-term integrity and function.

Efficient stabilization of therapeutic hepatitis B vaccine components by amino-acid formulation maintains its potential to break immune tolerance.

Background & Aims: Induction of potent, HBV-specific immune responses is crucial to control and finally cure HBV. The therapeutic hepatitis B vaccine TherVacB combines protein priming with a Modified Vaccinia virus Ankara (MVA)-vector boost to break immune tolerance in chronic HBV infection. Particulate protein and vector vaccine components, however, require a constant cooling chain for storage and transport, posing logistic and financial challenges to vaccine applications. We aimed to identify an optimal formulation to maintain stability and immunogenicity of the protein and vector components of the vaccine using a systematic approach. Methods: We used stabilizing amino acid (SAA)-based formulations to stabilize HBsAg and HBV core particles (HBcAg), and the MVA-vector. We then investigated the effect of lyophilization and short- and long-term high-temperature storage on their integrity. Immunogenicity and safety of the formulated vaccine was validated in HBV-naïve and adeno-associated virus (AAV)-HBV-infected mice. Results: In vitro analysis proved the vaccine's stability against thermal stress during lyophilization and the long-term stability of SAA-formulated HBsAg, HBcAg and MVA during thermal stress at 40 °C for 3 months and at 25 °C for 12 months. Vaccination of HBV-naïve and AAV-HBV-infected mice demonstrated that the stabilized vaccine was well tolerated and able to brake immune tolerance established in AAV-HBV mice as efficiently as vaccine components constantly stored at 4 °C/-80 °C. Even after long-term exposure to elevated temperatures, stabilized TherVacB induced high titre HBV-specific antibodies and strong CD8+ T-cell responses, resulting in anti-HBs seroconversion and strong suppression of the virus in HBV-replicating mice. Conclusion: SAA-formulation resulted in highly functional and thermostable HBsAg, HBcAg and MVA vaccine components. This will facilitate global vaccine application without the need for cooling chains and is important for the development of prophylactic as well as therapeutic vaccines supporting vaccination campaigns worldwide. Impact and implications: Therapeutic vaccination is a promising therapeutic option for chronic hepatitis B that may enable its cure. However, its application requires functional cooling chains during transport and storage that can hardly be guaranteed in many countries with high demand. In this study, the authors developed thermostable vaccine components that are well tolerated and that induce immune responses and control the virus in preclinical mouse models, even after long-term exposure to high surrounding temperatures. This will lower costs and ease application of a therapeutic vaccine and thus be beneficial for the many people affected by hepatitis B around the world.

Association between IgG responses against the nucleocapsid proteins of alphacoronaviruses and COVID-19 severity.

Understanding immune responses to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is crucial to contain the COVID-19 pandemic. Using a multiplex approach, serum IgG responses against the whole SARS-CoV-2 proteome and the nucleocapsid proteins of endemic human coronaviruses (HCoVs) were measured in SARS-CoV-2-infected donors and healthy controls. COVID-19 severity strongly correlated with IgG responses against the nucleocapsid (N) of SARS-CoV-2 and possibly with the number of viral antigens targeted. Furthermore, a strong correlation between COVID-19 severity and serum responses against N of endemic alpha- but not betacoronaviruses was detected. This correlation was neither caused by cross-reactivity of antibodies, nor by a general boosting effect of SARS-CoV-2 infection on pre-existing humoral immunity. These findings raise the prospect of a potential disease progression marker for COVID-19 severity that allows for early stratification of infected individuals.

Improving the alcohol retail environment to reduce youth access: a randomized community trial of a best practices toolkit intervention.

Underage alcohol use remains a significant public health problem throughout the United States and has important consequences for the health of individuals and communities. The objective of this study was to assess the impact of distributing an alcohol retailer toolkit via direct mail on increasing positive alcohol retailer attitudes towards checking IDs, encouraging retail managers to formalize ID checking procedures with their employees, and promoting consumers to be prepared to show ID when purchasing alcohol. This community randomized study included five matched Massachusetts community pairs. Our analysis sample consisted of 209 retailers (77 intervention; 132 control). In models adjusted for baseline response and matching community and establishment characteristics, intervention communities reported posting, on average, one additional sign or wall decal in their establishments (ß = 0.937, P = 0.0069), and a twofold higher odds of handing out written materials on ID checking to staff (OR: 2.074, 95%CI: 1.003-4.288) compared to control establishments. However, the intervention was not found to have an effect on changing establishment policies, retailer attitudes, or other establishment practices. Intervention retailers perceived all components of the toolkit to be very useful for their establishments, and nearly all reported having shared materials with their employees and customers. These results suggest that some significant changes in alcohol retailer establishment practices can be achieved among motivated owners or managers through the distribution of a toolkit targeting best retailer practices. We do, however, recommend that future program planners consider alternative dissemination and marketing strategies beyond direct mail to encourage greater utilization.

Medical decision-making among Hispanics and non-Hispanic Whites with chronic back and knee pain: a qualitative study.

BACKGROUND: Musculoskeletal disorders affect all racial and ethnic groups, including Hispanics. Because these disorders are not life-threatening, decision-making is generally preference-based. Little is known about whether Hispanics in the U.S. differ from non-Hispanic Whites with respect to key decision making preferences. METHODS: We assembled six focus groups of Hispanic and non-Hispanic White patients with chronic back or knee pain at an urban medical center to discuss management of their conditions and the roles they preferred in medical decision-making. Hispanic groups were further stratified by socioeconomic status, using neighborhood characteristics as proxy measures. Discussions were led by a moderator, taped, transcribed and analyzed using a grounded theory approach. RESULTS: The analysis revealed ethnic differences in several areas pertinent to medical decision-making. Specifically, Hispanic participants were more likely to permit their physician to take the predominant role in making health decisions. Also, Hispanics of lower socioeconomic status generally preferred to use non-internet sources of health information to make medical decisions and to rely on advice obtained by word of mouth. Hispanics emphasized the role of faith and religion in coping with musculoskeletal disability. The analysis also revealed broad areas of concordance across ethnic strata including the primary role that pain and achieving pain relief play in patients' experiences and decisions. CONCLUSIONS: These findings suggest differences between Hispanics and non-Hispanic Whites in preferred information sources and decision-making roles. These findings are hypothesis-generating. If confirmed in further research, they may inform the development of interventions to enhance preference-based decision-making among Hispanics.

Picomolar inhibition of SARS-CoV-2 variants of concern by an engineered ACE2-IgG4-Fc fusion protein.

SARS-CoV-2 enters host cells after binding through its spike glycoprotein to the angiotensin-converting enzyme 2 (ACE2) receptor. Soluble ACE2 ectodomains bind and neutralize the virus, yet their short in vivo half-live limits their therapeutic use. This limitation can be overcome by fusing the fragment crystallizable (Fc) part of human immunoglobulin G (IgG) to the ACE2 ectodomain, but this bears the risk of Fc-receptor activation and antibody-dependent cellular cytotoxicity. Here, we describe optimized ACE2-IgG4-Fc fusion constructs that avoid Fc-receptor activation, preserve the desired ACE2 enzymatic activity and show promising pharmaceutical properties. The engineered ACE2-IgG4-Fc fusion proteins neutralize the original SARS-CoV, pandemic SARS-CoV-2 as well as the rapidly spreading SARS-CoV-2 alpha, beta and delta variants of concern. Importantly, these variants of concern are inhibited at picomolar concentrations proving that ACE2-IgG4 maintains - in contrast to therapeutic antibodies - its full antiviral potential. Thus, ACE2-IgG4-Fc fusion proteins are promising candidate anti-antivirals to combat the current and future pandemics.

Single-cell RNA sequencing reveals ex vivo signatures of SARS-CoV-2-reactive T cells through 'reverse phenotyping'.

The in vivo phenotypic profile of T cells reactive to severe acute respiratory syndrome (SARS)-CoV-2 antigens remains poorly understood. Conventional methods to detect antigen-reactive T cells require in vitro antigenic re-stimulation or highly individualized peptide-human leukocyte antigen (pHLA) multimers. Here, we use single-cell RNA sequencing to identify and profile SARS-CoV-2-reactive T cells from Coronavirus Disease 2019 (COVID-19) patients. To do so, we induce transcriptional shifts by antigenic stimulation in vitro and take advantage of natural T cell receptor (TCR) sequences of clonally expanded T cells as barcodes for 'reverse phenotyping'. This allows identification of SARS-CoV-2-reactive TCRs and reveals phenotypic effects introduced by antigen-specific stimulation. We characterize transcriptional signatures of currently and previously activated SARS-CoV-2-reactive T cells, and show correspondence with phenotypes of T cells from the respiratory tract of patients with severe disease in the presence or absence of virus in independent cohorts. Reverse phenotyping is a powerful tool to provide an integrated insight into cellular states of SARS-CoV-2-reactive T cells across tissues and activation states.

Validating a health consumer segmentation model: behavioral and attitudinal differences in disease prevention-related practices.

While researchers typically have segmented audiences by demographic or behavioral characteristics, psychobehavioral segmentation schemes may be more useful for developing targeted health information and programs. Previous research described a four segment psychobehavioral segmentation scheme-and a 10-item screening instrument used to identify the segments-based predominantly on people's orientation to their health (active vs. passive) and their degree of independence in health care decision making (independent vs. dependent). This study builds on this prior research by assessing the screening instrument's validity with an independent dataset and exploring whether people with distinct psychobehavioral orientations have different disease prevention attitudes and preferences for receiving information in the primary care setting. Data come from 1,650 respondents to a national mail panel survey. Using the screening instrument, respondents were segmented into four groups-independent actives, doctor-dependent actives, independent passives, and doctor-dependent passives. Consistent with the earlier research, there were clear differences in health-related attitudes and behaviors among the four segments. Members of three segments appear quite receptive to receiving disease prevention information and assistance from professionals in the primary care setting. Our findings provide further indication that the screening instrument and corresponding segmentation strategy may offer a simple, effective tool for targeting and tailoring information and other health programming to the unique characteristics of distinct audience segments.

Opportunities and barriers to disease prevention counseling in the primary care setting: a multisite qualitative study with US health consumers.

The purpose of this study is to understand people's receptivity to seeking out disease prevention counseling from their primary care provider. Since patients' openness to health messages may vary depending on how they seek out their health information, participants were segmented into one of four unique information-seeking groups. This study explores the differences among these groups, what approaches would be most effective in motivating different health consumers to seek out behavioral counseling in the primary care setting and the opportunities during the medical visit most appropriate for this counseling. To this end, a total of 32 focus groups were conducted with American adults. Participants were segmented by information-seeking orientation (independent actives, doctor-dependent actives, independent passives and doctor-dependent passives), age and gender. Findings showed that participants of the four information-seeking groups possessed distinct differences in their desire for and perceived barriers to requesting counseling from their provider. Overall, participants wanted prevention counseling to include tailored information, encouragement and follow-up. Participants among the various segments identified two key windows of opportunity-during a routine checkup and when discussing their family history-where patients and providers can incorporate more in-depth prevention discussions into the medical visit. Findings from this study suggest that targeting health messages according to health consumers' information-seeking orientations may provide an effective tool for practitioners. Additionally, many health consumers are open to behavioral counseling in the primary care setting and would be satisfied if this counseling were integrated into traditional procedures, such as during a routine checkup or when discussing their family medical history.

The Effect of Glutathione Peroxidase-1 Knockout on Anticancer Drug Sensitivities and Reactive Oxygen Species in Haploid HAP-1 Cells.

The role of glutathione peroxidases (GPx) in cancer and their influence on tumor prognosis and the development of anticancer drug resistance has been extensively and controversially discussed. The aim of this study was to evaluate the influence of GPx1 expression on anticancer drug cytotoxicity. For this purpose, a GPx1 knockout of the near-haploid human cancer cell line HAP-1 was generated and compared to the native cell line with regards to morphology, growth and metabolic rates, and oxidative stress defenses. Furthermore, the IC50 values of two peroxides and 16 widely used anticancer drugs were determined in both cell lines. Here we report that the knockout of GPx1 in HAP-1 cells has no significant effect on cell size, viability, growth and metabolic rates. Significant increases in the cytotoxic potency of hydrogen peroxide and tert-butylhydroperoxide, the anticancer drugs cisplatin and carboplatin as well as the alkylating agents lomustine and temozolomide were found. While a concentration dependent increases in intracellular reactive oxygen species (ROS) levels were observed for both HAP-1 cell lines treated with either cisplatin, lomustine or temozolamide, no significant enhancement in ROS levels was observed in the GPx1 knockout compared to the native cell line except at the highest concentration of temozolamide. On the other hand, a ca. 50% decrease in glutathione levels was noted in the GPx1 knockout relative to the native line, suggesting that factors other than ROS levels alone play a role in the increased cytotoxic activity of these drugs in the GPx1 knockout cells.

Striking a Balance between Program-Specific and Portfolio-Level Evaluation: Lessons Learned from a Multi-Site Evaluation on the Texas-Mexico Border.

Funders are increasingly making strategic investments across multiple grantees, aiming for their portfolio to improve targeted outcomes in a specific issue area. To this end, funders might use multi-site evaluation (MSE) approaches to examine the impact of their collective investments. However, it is important to recognize that each program-and its own program evaluation-must be tailored to its setting, population, and local context to best meet the needs of its target population. Therefore, multi-site evaluations need to account for this complexity. This paper describes the Sí Texas project, a large initiative of eight grantees implementing different integrated behavioral health models to improve physical and mental health outcomes along the Texas-Mexico border. With over 4,200 MSE study participants, the evaluation for Sí Texas used a partnership-centered approach to both enhance the evidence base and build local organizational capacity. This paper describes this approach, the process of tailoring evaluation practices to the grantees' context, and the challenge of balancing consistency at the grantee-level for the portfolio multi-site evaluation. Successes, challenges, and lessons learned related to study design, data collection, grantee partnership, and capacity building are discussed.

Pentathiepins: A Novel Class of Glutathione Peroxidase 1 Inhibitors that Induce Oxidative Stress, Loss of Mitochondrial Membrane Potential and Apoptosis in Human Cancer Cells.

A novel class of glutathione peroxidase 1 (GPx1) inhibitors, namely tri- and tetracyclic pentathiepins, has been identified that is approximately 15 times more potent than the most active known GPx1 inhibitor, mercaptosuccinic acid. Enzyme kinetic studies with bovine erythrocyte GPx1 indicate that pentathiepins reversibly inhibit oxidation of the substrate glutathione (GSH). Moreover, no inhibition of superoxide dismutase, catalase, thioredoxin reductase or glutathione reductase was observed at concentrations that effectively inhibit GPx1. As well as potent enzyme inhibitory activity, the pentathiepins show strong anticancer activity in various human cancer cell lines, with IC50 values in a low-micromolar range. A representative tetracyclic pentathiepin causes the formation of reactive oxygen species in these cells, the fragmentation of nuclear DNA and induces apoptosis via the intrinsic pathway. Moreover, this pentathiepin leads to a rapid and strong loss of mitochondrial membrane potential in treated cancer cells. On the other hand, evidence for the induction of ferroptosis as a form of cell death was negative. These new findings show that pentathiepins possess interesting biological activities beyond those originally ascribed to these compounds.

Dispensability of nanos mRNA localization for abdominal patterning but not for germ cell development.

The development of a functional germline is essential for species propagation. The nanos (nos) gene plays an evolutionarily conserved role in germline development and is also essential for abdominal patterning in Drosophila. A small fraction of nos mRNA is localized to the germ plasm at the posterior pole of the Drosophila embryo, where it becomes incorporated into the germ cells. Germ plasm associated nos mRNA is translated to produce a gradient of Nos protein that patterns the abdomen, whereas the remaining unlocalized RNA is translationally repressed to allow anterior development. Using transgenes that compromise nos mRNA localization and translational regulation, we show that wild-type body patterning can ensue without nos mRNA localization provided that nos translation is properly modulated. In contrast, localization of nos to the germ plasm, but not translational regulation, is essential for nos function in the developing germ cells. We propose that an imperative for nos localization in producing a functional germline has preserved an inefficient localization mechanism.

PLS3 Overexpression Delays Ataxia in Chp1 Mutant Mice.

Many neurodegenerative disorders share common pathogenic pathways such as endocytic defects, Ca2+ misregulation and defects in actin dynamics. Factors acting on these shared pathways are highly interesting as a therapeutic target. Plastin 3 (PLS3), a proven protective modifier of spinal muscular atrophy across species, is a remarkable example of the former, and thereby offers high potential as a cross-disease modifier. Importantly, PLS3 has been linked to numerous proteins associated with various neurodegenerative diseases. Among them, PLS3 directly interacts with calcineurin like EF-hand protein 1 (CHP1), whose loss-of-function results in ataxia. In this study, we aimed to determine whether PLS3 is a cross-disease modifier for ataxia caused by Chp1 mutation in mice. For this purpose, we generated Chp1 mutant mice, named vacillator mice, overexpressing a PLS3 transgene. Here, we show that PLS3 overexpression (OE) delays the ataxic phenotype of the vacillator mice at an early but not later disease stage. Furthermore, we demonstrated that PLS3 OE ameliorates axon hypertrophy and axonal swellings in Purkinje neurons thereby slowing down neurodegeneration. Mechanistically, we found that PLS3 OE in the cerebellum shows a trend of increased membrane targeting and/or expression of Na+/H+ exchanger (NHE1), an important CHP1 binding partner and a causative gene for ataxia, when mutated in humans and mice. This data supports the hypothesis that PLS3 is a cross-disease genetic modifier for CHP1-causing ataxia and spinal muscular atrophy.

Protection of halogenated DNA from strand breakage and sister-chromatid exchange induced by the topoisomerase I inhibitor camptothecin.

The fundamental nuclear enzyme DNA topoisomerase I (topo I), cleaves the double-stranded DNA molecule at preferred sequences within its recognition/binding sites. We have recently reported that when cells incorporate halogenated nucleosides analogues of thymidine into DNA, it interferes with normal chromosome segregation, as shown by an extraordinarily high yield of endoreduplication, and results in a protection against DNA breakage induced by the topo II poison m-AMSA [F. Cortés, N. Pastor, S. Mateos, I. Domínguez, The nature of DNA plays a role in chromosome segregation: endoreduplication in halogen-substituted chromosomes, DNA Repair 2 (2003) 719-726; G. Cantero, S. Mateos, N. Pastor; F. Cortés, Halogen substitution of DNA protects from poisoning of topoisomerase II that results in DNA double-strand breaks (DSBs), DNA Repair 5 (2006) 667-674]. In the present investigation, we have assessed whether the presence of halogenated nucleosides in DNA diminishes the frequency of interaction of topo I with DNA and thus the frequency with which the stabilisation of cleavage complexes by the topo I poison camptothecin (CPT) takes place, in such a way that it protects from chromosome breakage and sister-chromatid exchange. This protective effect is shown to parallel a loss in halogen-substituted cells of the otherwise CPT-increased catalytic activity bound to DNA.

Adapting evidence-based strategies to increase physical activity among African Americans, Hispanics, Hmong, and Native Hawaiians: a social marketing approach.

INTRODUCTION: Using a social marketing approach, we studied how best to adapt proven, evidence-based strategies to increase physical activity for use with underserved racial or ethnic groups. METHODS: We conducted focus groups with low-income Hispanic women in Texas, Hmong parents and their children in California, low-income African American women and men in the Mississippi Delta, and Native Hawaiian college students in Hawaii. We also interviewed key leaders of these communities. Topics of discussion were participants' perceptions about 1) the benefits of engaging in physical activity, 2) the proposed evidence-based strategies for increasing each community's level of physical activity, and 3) the benefits and barriers to following the proposed interventions for increasing physical activity. A total of 292 individuals participated in the study. RESULTS: All groups considered that being physically active was part of their culture, and participants found culturally relevant suggestions for physical activities appealing. Overwhelmingly, strategies that aimed to create or improve social support and increase access to physical activity venues received the most positive feedback from all groups. Barriers to physical activity were not culturally specific; they are common to all underserved people (lack of time, transportation, access, neighborhood safety, or economic resources). CONCLUSION: Results indicate that evidence-based strategies to increase physical activity need to be adapted for cultural relevance for each racial or ethnic group. Our research shows that members of four underserved populations are likely to respond to strategies that increase social support for physical activity and improve access to venues where they can be physically active. Further research is needed to test how to implement such strategies in ways that are embraced by community members.