Loneliness and its Association with Health Behaviors in People with a Lived Experience of a Serious Mental Illness

To explore the association between loneliness and efficacy to engage in health behaviors that are known to reduce the risk of early mortality in people with serious mental illness (SMI). This secondary data analysis was based on a cross-sectional study of 113 participants with SMI residing in New Hampshire. Ordinary Least Squares regressions were used to examine bivariate relationships between variables of interest. Participants had a primary mental health diagnosis of major depressive disorder (37.2%), schizophrenia spectrum disorder (28.3%), bipolar disorder (29.2%), or posttraumatic stress disorder (5.3%). High levels of loneliness were associated with low levels of self-efficacy to manage chronic diseases (p =?0.0001), as well as low levels of self-efficacy to manage psychological well-being (R² =?.31; F =?9.49, p =?0.0001; RMSE =?1.66). Loneliness may serve as a barrier to healthy behaviors, and thus, contribute to early mortality among people with SMI. The growing body of literature that demonstrates the importance of addressing loneliness in people with SMI should stimulate policymakers and researchers to target loneliness as a mechanism to address early mortality in people with SMI.

     

Prevalence and diversity of Babesia,Hepatozoon, Ehrlichia,and Bartonella in wild and domestic carnivores from Zambia,Africa

A molecular survey was conducted for several hemoparasites of domestic dogs and three species of wild carnivores from two sites in Zambia. Three Babesia spp. were detected including Babesia felis and Babesia leo in lions (Panthera leo) and a Babesia sp. (similar to Babesia lengau) in spotted hyenas (Crocuta crocuta) and a single lion. All wild dogs (Lycaon pictus) and domestic dogs were negative for Babesia. High prevalences for Hepatozoon were noted in all three wild carnivores (38–61 %) and in domestic dogs (13 %). Significantly higher prevalences were noted in hyenas and wild dogs compared with domestic dogs and lions. All carnivores were PCR negative for Ehrlichia canis, Ehrlichia ewingii, and Bartonella spp. Overall, high prevalences and diversity of Babesia and Hepatozoon were noted in wild carnivores from Zambia. This study is the first molecular characterization of Babesia from any hyena species and is the first report of a Babesia sp. closely related to B. lengau, a parasite previously only reported from cheetahs (Acinonyx jubatus), in lions and hyenas. Although usually benign in wild carnivores, these hemoparasites can be pathogenic under certain circumstances. Importantly, data on vectors for these parasites are lacking, so studies are needed to identify vectors as well as determine transmission routes, infection dynamics, and host specificity of these hemoparasites in wildlife in Africa and also the risk of transmission between domestic animals and wildlife.     

Arenium ions are not obligatory intermediates in electrophilic aromatic substitution

Our computational and experimental investigation of the reaction of anisole with Cl₂ in nonpolar CCl₄ solution challenges two fundamental tenets of the traditional S_EAr (arenium ion) mechanism of aromatic electrophilic substitution. Instead of this direct substitution process, the alternative addition–elimination (AE) pathway is favored energetically. This AE mechanism rationalizes the preferred ortho and para substitution orientation of anisole easily. Moreover, neither the S_EAr nor the AE mechanisms involve the formation of a σ-complex (Wheland-type) intermediate in the rate-controlling stage. Contrary to the conventional interpretations, the substitution (S_EAr) mechanism proceeds concertedly via a single transition state. Experimental NMR investigations of the anisole chlorination reaction course at various temperatures reveal the formation of tetrachloro addition by-products and thus support the computed addition–elimination mechanism of anisole chlorination in nonpolar media. The important autocatalytic effect of the HCl reaction product was confirmed by spectroscopic (UV-visible) investigations and by HCl-augmented computational modeling.Interest in the chemistry of electrophilic aromatic substitution reactions continues because of their widespread application for the production of a great variety of chemicals and materials (1–4). Electrophilic substitution, considered to be the most characteristic reaction of aromatic systems, is typically described in textbooks, monographs, and reviews by the two-stage S_EAr mechanism depicted in Fig. 1 (5–11). Arenium ion (σ-complex) intermediates are often ascribed to Wheland (9) inaccurately, since Pfeiffer and Wizinger (10) laid out the principles of such species for bromination in 1928. Following Brown and Pearsall (11), they are widely believed to have σ-complex structures. Arenium ions (σ-complexes) (9–11) are widely accepted to be obligatory intermediates and are used to rationalize ortho/para vs. meta position orientation preferences (6–11).Open in a separate windowFig. 1.Typical depiction of the arenium ion mechanism for S_EAr reactions.We now reinforce our challenges (12, 13) of this conventional “reaction mechanism paradigm” (14) by a combined computational and experimental study of the facile chlorination of anisole (methoxybenzene) with Cl₂ in CCl₄ solution (15, 16). We find that Fig. 1 is not the favored pathway. Instead, addition reactions of Cl₂ to anisole have the lowest activation energies (Fig. 2). Ready HCl elimination from the initially formed adducts leads to ortho- and para-chloroanisole as the predominate products. This addition–elimination (AE) mechanism (the historical antecedent to Fig. 1) (17–26) predicts the same positional orientation as the usually assumed direct substitution (“S_EAr”) alternative. Instead of this classic S_EAr mechanism (Fig. 1), we find that direct concerted substitution, not involving an arenium ion, σ-complex (“Wheland”) (9–11) intermediate, competes energetically with the AE route. Like some earlier computational studies on aromatic substitution (12, 13, 27, 28) (Rzepa H, www.ch.imperial.ac.uk/rzepa/blog/?p=2423, accessed March 10, 2013), our study finds no such intermediates in the direct substitution of anisole by Cl₂. A concerted mechanism without an arenium ion intermediate was computed at some levels for the related arene nitrosation, but reaction medium and counter ion effects were not considered. Gwaltney et al. (28) reported a single concerted transition state after reoptimizing all saddle points at CCSD(T)/6-31G(d,p) and modeling bulk solvation by the Onsager approximation, and Rzepa (www.ch.imperial.ac.uk/rzepa/blog/?p=2423, accessed March 10, 2013) also found a concerted transition state including a trifluoroacetate counterion. Instead, one-step reactions via single transition states take place (Fig. 2). Our experimental investigations of the chlorination of anisole in CCl₄ solution revealed tetrachloro by-products, which must have arisen by further reaction of intermediate dichloro-adducts. Both our UV-visible (UV-VIS) spectroscopic investigation and our theoretical modeling of this reaction clearly verified the autocatalytic effect of the HCl by-product, in harmony with Andrews and Keefer’s (29, 30) early experimental kinetic studies of the chlorination of arenes, which found that HCl reduces the activation barriers significantly.Open in a separate windowFig. 2.The HCl-catalyzed concerted and addition–elimination pathways of para-chlorination of anisole in nonpolar media.We also applied reliable theoretical methods to model a typical experimental example of the highly investigated S_EAr electrophilic aromatic halogenations, the electrophilic chlorination of anisole by molecular chlorine in simulated CCl₄ solution (15, 16). Although the elucidation of the classic S_EAr mechanism [Fig. 1, involving the initial formation of a π-complex, followed by a transition state leading to a σ-complex (arenium) intermediate in the rate-controlling stage, and, finally, proton loss from the ipso-position leading to the reaction product] is considered to be a triumph of physical organic chemistry (1, 31–37), an alternative addition–elimination pathway leading to substitution products has been discussed since the 19th century (19–26, 38, 39). Nevertheless, it is commonly believed that the classic multistep S_EAr mechanism involving the formation of a σ-complex intermediate in the rate-controlling stage is the only mechanistic route to aromatic substitution products. Our present and previous (12, 13) results challenge the generality of such traditional interpretations. Although the initial stages of the alternative AE route seem unattractive because aromaticity is lost, many arenes are known experimentally to give addition products in considerable amounts (19–26, 38, 39). Thus, de la Mare (21, 25, 38, 39) demonstrated the formation of halogen adduct intermediates. Polybenzenoid hydrocarbons (PBHs) react with halogens to give isolable addition products, which then give substitution products easily by hydrogen halide elimination (23). Our computational investigations of arene bromination with molecular bromine (12) and sulfonation with SO₃ (13) provided clear evidence that the mechanisms of the inherent substitution reactions (i.e., uncatalyzed, gas phase, or weakly solvated) are concerted and do not involve the conventional σ-complex (or any other) intermediates. Moreover, the energetics of the bromination processes document the significance of competition between AE and direct substitution mechanisms leading to the same substitution products. Thus, the computed barrier in a simulated nonpolar (CCl₄) medium is 4 kcal/mol lower for Br₂ addition to benzene (followed by HBr elimination) than that for the direct substitution pathway to bromobenzene (12).Previous theoretical studies of electrophilic aromatic halogenation processes have been based on the classic S_EAr mechanism, involving arenium ion intermediates (Fig. 1). Osamura et al.’s (40) Hartree-Fock computations of the AlCl₃-catalyzed electrophilic aromatic chlorination mechanism found an initial π-complex, a transition state preceding the intermediate σ-complex, and a second transition state leading to final products. Aluminum chloride was important as a Lewis acid catalyst throughout the process. AlCl₃ coordination polarizes Cl₂ and thereby assists its reaction with the arene. Rasokha and Kochi (41) considered the interaction of Br₂ with benzene and toluene in detail in their survey of theoretical and experimental data on the prereactive charge-transfer complexes in electrophilic aromatic substitutions. They argued that the structures and properties of the prereactive complexes provide important mechanistic insights for the S_EAr reactions. Wei et al.’s (42) theoretical study of the iodination of anisole by iodine monochloride at the B3LYP/6-311G* and MP2//B3LYP/6-311G* levels (B3LYP, Becke''s three parameter hybrid functional, using the Lee-Yang-Parr correlation functional; MP2, second order Møller-Plesset perturbation theory computations) found that the highest energy transition state precedes the formation of an intermediate, which they interpreted to be a σ-complex. Instead, the structure of this complex represents a protonated iodobenzene. Volkov et al.’s MP2/LANL2DZ(d)+ study (43) of the chlorination of benzene established that dimers of group 13 metal halides catalyzed the processes more effectively. Optimized geometries of π- and σ-complexes as well as transition structures were reported. Theoretical investigations by Ben-Daniel et al. (44) and by Filimonov et al. (45) of the chlorination of benzene with Cl₂ (and other related processes) reported structural details of transition states purported to lead to the chlorobenzene product. Our reinvestigations revealed errors in major suppositions of both these studies. Our IRC computations show clearly that the transition states in question lead to 1,2 Cl₂–benzene addition products (rather than to chlorobenzene). Zhang and Lund (46) investigated the neat chlorination of toluene by Cl₂ experimentally and theoretically at B3LYP/cc-pVTZ(-f) [cc-pVTZ(-f), correlation consistent polarized triple-zeta without f-functions basis set]. Although we verified their reported geometry of the concerted transition state (figure 6 in ref. 46), our stability check revealed that its wavefunction is unstable. This casts doubt on their conclusions because of the homolysis vs. heterolysis issues. In contrast, all wavefunctions in our paper were checked and all are stable. Most prior theoretical studies of S_EAr halogenations did not consider the connections between transition states, intermediates, and products explicitly, as we have done.Experimental findings not always have been in accord with the prevailing mechanistic assumption for aromatic halogenation: that arenium ion formation is the rate-limiting step. Thus, Olah et al. (47), Kochi and coworkers (48), and Fukuzumi and Kochi (49) have emphasized that substrate and positional selectivity are inconsistent (e.g., low toluene/benzene reactivity ratios but high toluene ortho–para vs. meta regiospecificity) for some electrophiles under certain conditions. This disparity indicates the existence of at least one other mechanistic pathway. It has been suggested that π-complexes may control product formation. Olah et al.’s (47) kinetics of the ferric chloride-catalyzed bromination of benzene and alkyl benzenes provided strong evidence for low substrate selectivity in the rate-determining step, which precedes the formation of a σ-complex intermediate (Fig. 1). High positional selectivity is governed by the transition state associated with the second step of the reaction.However, our earlier study (50) examined the possible participation of π-complexes in the key mechanistic steps of S_EAr bromination reactions in detail but found no link between the energy of formation of these complexes and the overall reactivity. Although there is no doubt that π-complexes form easily (via essentially barrierless processes) in most S_EAr reactions after mixing the electrophile and the aromatic substrate, it is unlikely that these low-energy “bystander” structures influence rates of S_EAr reactions significantly. Thus, the lack of accord between substrate and positional selectivity, established by Olah et al. (47), Kochi and coworkers (48), and Fukuzumi and Kochi (49) may be due to other mechanistic differences. De la Mare and Bolton (21) and de la Mare (51) have stressed the plurality of aromatic substitution mechanisms, depending on the substrate and the conditions.Reactive substrates are known to undergo uncatalyzed aromatic substitution in nonpolar solvents at room temperature. Thus, our computational investigations modeled Watson’s careful experiments on the chlorination of anisole in CCl₄ at 25 °C (15, 16). His low conversion (25%) conditions for chlorophenol permitted more accurate determination of the initial product ratios (and avoided further Cl₂ additions to 4-chloroanisole, which ultimately gave 1,3,4,5,6-pentachloro-4-methoxycyclohexene). After introduction of gaseous Cl₂ into a CCl₄ solution of anisole for 1 h, the products were 4-chloroanisole (76%), 2-chloroanisole (13.6%), 2,6-dichloro anisole (2.1%), 2,4-dichloroanisole (3.0%), and 2,4,6-trichloroanisole (0.4%).Analogous chlorinations of phenol, 2-methylphenol, and 2-chlorophenol in CCl₄ also have been carried out with high conversion rates at the reflux temperature (79 °C) (16). Chlorination of phenol with Cl₂ in CCl₄ has been reported by other groups (52, 53).     

Engineering of blended nanoparticle platform for delivery of mitochondria-acting therapeutics

Mitochondrial dysfunctions cause numerous human disorders. A platform technology based on biodegradable polymers for carrying bioactive molecules to the mitochondrial matrix could be of enormous potential benefit in treating mitochondrial diseases. Here we report a rationally designed mitochondria-targeted polymeric nanoparticle (NP) system and its optimization for efficient delivery of various mitochondria-acting therapeutics by blending a targeted poly(d,l-lactic-co-glycolic acid)-block (PLGA-b)-poly(ethylene glycol) (PEG)-triphenylphosphonium (TPP) polymer (PLGA-b-PEG-TPP) with either nontargeted PLGA-b-PEG-OH or PLGA-COOH. An optimized formulation was identified through in vitro screening of a library of charge- and size-varied NPs, and mitochondrial uptake was studied by qualitative and quantitative investigations of cytosolic and mitochondrial fractions of cells treated with blended NPs composed of PLGA-b-PEG-TPP and a triblock copolymer containing a fluorescent quantum dot, PLGA-b-PEG-QD. The versatility of this platform was demonstrated by studying various mitochondria-acting therapeutics for different applications, including the mitochondria-targeting chemotherapeutics lonidamine and α-tocopheryl succinate for cancer, the mitochondrial antioxidant curcumin for Alzheimer’s disease, and the mitochondrial uncoupler 2,4-dinitrophenol for obesity. These biomolecules were loaded into blended NPs with high loading efficiencies. Considering efficacy, the targeted PLGA-b-PEG-TPP NP provides a remarkable improvement in the drug therapeutic index for cancer, Alzheimer’s disease, and obesity compared with the nontargeted construct or the therapeutics in their free form. This work represents the potential of a single, programmable NP platform for the diagnosis and targeted delivery of therapeutics for mitochondrial dysfunction-related diseases.     

Plasmodium chabaudi AS induces pregnancy loss in association with systemic pro-inflammatory immune responses in A/J and C57BL/6 mice

The molecular mechanisms that underlie poor birth outcomes in malaria during pregnancy remain poorly defined. To assess the role of host immune responses, mice known to respond differentially to Plasmodium chabaudi AS infection were studied. Following infection at day 0 of pregnancy, A/J mice developed significantly higher parasitemia than C57BL/6 (B6) mice and succumbed to infection. Both strains had evidence of parasite accumulation in the placenta at mid-gestation and aborted, with significantly higher embryo loss in infected A/J mice on day 9. While infection-induced systemic tumour necrosis factor (TNF) and interleukin (IL)-1β in the latter were significantly higher at day 11, day 10 IL-10 levels were higher in B6 mice. No differences in the levels of splenic lymphocyte subsets, neutrophils or monocytes between infected pregnant A/J and B6 mice were observed, with most cell types expanding in response to infection regardless of pregnancy. Antibody ablation of TNF exacerbated infection in A/J mice and did not ameliorate pregnancy outcome. Thus, malaria induces poor pregnancy outcome in both the mouse strains in the context of quantitatively different systemic inflammatory responses. Further evaluation of the roles of soluble and cellular immune components, particularly at the uteroplacental level, will be required to define the most critical pregnancy-compromising mechanisms.     

Self-concept in adolescence: A longitudinal study on reciprocal effects of self-perceptions in academic and social domains

Fostering social and academic self-concepts are central educational goals. During mid-adolescence academic engagement and success seem to be devalued by peers and to be negatively associated with students' social standing. For this age group, is the development of a positive academic self-concept compatible with the development of a positive social self-concept? We investigated relations among academic self-concept, social self-concept, and academic achievement. 1282 students (47.60% female) participated in three-waves of measurement in Grade 5, 6, and 8. Earlier social self-concept of acceptance negatively predicted changes in academic self-concept over time while earlier social self-concept of assertion positively predicted changes in academic self-concept. There were no significant relations between social self-concepts and achievement but positive reciprocal relations between academic self-concept and achievement. Results indicate that fostering adolescents self-concept in social and academic domains are compatible goals. However, some students need support in managing the challenge to coordinate social and academic goals.     

Addressing career barriers for high risk adolescent girls: The PATHS curriculum intervention

The study evaluated a gender-specific comprehensive career development curriculum designed to target career barriers faced by high risk adolescent girls – those with disabilities and at risk for school failure. The goal of the curriculum was to promote social cognitive career and self determination outcomes associated with adaptive career development and adjustment. A pre-post control group design was used to evaluate the curriculum. Findings suggest that participation in the curriculum resulted in significant and large gains in autonomy and in disability and gender-related knowledge. Meaningful gains were noted in perceptions of social support and relevance of school. Participants in a high fidelity sample made significant and large gains in vocational skills self-efficacy and disability and gender-related knowledge. Meaningful improvements were noted in self-advocacy, autonomy, and vocational outcome expectations. The findings suggest that the curriculum can improve important indicators of positive career development and adjustment in high risk adolescent girls.