Understanding the complex relationship between multidimensional poverty and depressive symptoms among young South Africans: A cross-sectional study.

BACKGROUND: We use the Global Multidimensional Poverty Index (MPI) to explore how different dimensions of poverty more directly linked to young people are associated with depressive symptoms among South African youth. METHODS: Data came from the 2017 wave of the nationally-representative National Income Dynamics Study (NIDS) in South Africa. We focused on a sample of 15-24-year-olds whose depressive symptoms were assessed using an adapted version of the 10-item Centre for Epidemiological Studies Depression Scale. We examine how individual dimensions and indicators of the MPI relate to depression, in comparison to more conventional measures, including household income, subjective social standing, overcrowding and personal assets. Cross-sectional analyses were adjusted for clustering to account for sampling design. RESULTS: The MPI index was not associated with probable depression (OR = 1.02, 95 % CI 0.81-1.29). Only lack of access to the labour market emerged as a key individual dimension associated with probable depression (OR = 5.29, 95 % CI 1.70-16.47), a relationship driven by an increased odds for those not in employment, education or training. Lack of household assets, living in an informal dwelling and lower perceived social standing were also associated with increased odds for depression. No gender differences were noted. LIMITATIONS: The study is cross-sectional and not suitable to examine the causal nature of the association between multidimensional poverty and depression. CONCLUSIONS: Poverty dimensions that measure youth's access to employment or training have a strong association with depression. Further research is needed to assess whether improved access to employment or training contributes to improving mental health among young South Africans.

Cash transfers and the mental health of young people: Evidence from South Africa's child support grant.

This study examines the longitudinal impact of the South African Child Support Grant (CSG) on risk for depression and life satisfaction among young people (15-19 years). We analysed data from the last three waves of the National Income Dynamics Study (NIDS), a nationally representative panel survey that took place every two years from 2008 to 2017. We used an instrumental variable (IV) approach that exploits multiple changes in age eligibility from 1998 to 2012. Depressive symptoms were assessed using an 8-item version of the Centre for Epidemiological Studies Depression Scale; participants who scored above 8 were considered at risk for depression. Life satisfaction was rated on a scale of 1 ('very dissatisfied') to 10 ('very satisfied'); participants who scored 8 or above were classified as satisfied. We also examined impacts on educational deficit (≥2 years behind) and not being in education, employment or training (NEET) as secondary outcomes, as these are also important for mental health. Age eligibility strongly predicted CSG receipt at Wave 3. In instrumental variable models, CSG receipt did not influence the risk for depression (ß = 0.10, SE = 0.10, p = 0.316), nor life satisfaction (ß = -0.07, SE = 0.09, p = 0.420) at Wave 3, nor at Waves 4 or 5. Some improvements in educational deficit were observed at Wave 3 among CSG beneficiaries compared to non-beneficiaries. These results were robust to multiple specifications. CSG receipt did not improve the psychological wellbeing of adolescents and young adults, nor did it improve their education or employment outcomes. Our findings highlight the need to identify alternative social policies that address the root causes of youth social disadvantage, in conjunction with targeted approaches to improve the mental health of young South Africans living in poverty.

Complexation reduces nickel toxicity to purple sea urchin embryos (Strongylocentrotus purpuratus), a test of biotic ligand principles in seawater.

The potential for Ni toxicity in seawater is of concern because of mining and processing activities in coastal regions. Determining Ni speciation is vital to understanding and predicting Ni toxicity and for bioavailability-based nickel risk assessment. The goal of this study was to characterize the complexation of Ni in relation to toxicity using embryological development of purple sea urchin (S. purpuratus). It was predicted that free ion [Ni2+] would be a better predictor of toxicity than total dissolved Ni concentrations (NiD). Synthetic ligands with known logKf values (Ethylenediaminetetraacetic acid (EDTA), Nitrilotriacetic acid (NTA), tryptophan (TRP), glutamic acid (GA), histidine (HD), and citric acid (CA)) were used to test the assumptions of the biotic ligand model (BLM) for Ni in seawater. [NiD] was measured by graphite furnace atomic absorption spectroscopy (GFAAS) and Ni2+ was first quantified using the ion-exchange technique (IET) and then concentrations were measured by GFAAS; [Ni2+] was also estimated using aquatic geochemistry modelling software (Visual Minteq). The mean EC50 values for [NiD] in unmodified artificial seawater control was 3.6 µM (95% CI 3.0-4.5) [211 µg/L 95% CI 176-264] and the addition of ligands provided protection, up to 6.5-fold higher [NiD] EC50 for EDTA. Compared to the control, measured EC50 values based on total dissolved nickel were higher in the presence of ligands. As predicted by BLM theory, [Ni2+] was a better predictor of Ni toxicity with 17% variability in EDTA and CA media while there was 72% variability in the prediction of Ni toxicity with total dissolved Ni. The results of this research provide support for the application of BLM- based prediction models for estimating Ni impacts in seawater.

Impact of integrated district level mental health care on clinical and functioning outcomes of people with depression and alcohol use disorder in Nepal: a non-randomised controlled study.

BACKGROUND: Integration of mental health services into primary healthcare is proliferating in low-resource countries. We aimed to evaluate the impact of different compositions of primary care mental health services for depression and alcohol use disorder (AUD), when compared to usual primary care services. METHODS: We conducted a non-randomized controlled study in rural Nepal. We compared treatment outcomes among patients screening positive and receiving: (a) primary care mental health services without a psychological treatment component (TG); (b) the same services including a psychological treatment (TG + P); and (c) primary care treatment as usual (TAU). Primary outcomes included change in depression and AUD symptoms, as well as disability. Disability was measured using the 12-item WHO Disability Assessment Schedule. Symptom severity was assessed using the 9-item Patient Health Questionnaire for depression, the 10-item Alcohol Use Disorders Identification Test for AUD. We used negative binomial regression models for the analysis. RESULTS: For depression, when combining both treatment groups (TG, n = 77 and TG + P, n = 60) compared to TAU (n = 72), there were no significant improvements. When only comparing the psychological treatment group (TG + P) with TAU, there were significant improvements for symptoms and disability (aß = - 2.64; 95%CI - 4.55 to - 0.74, p = 0.007; aß = - 12.20; 95%CI - 19.79 to - 4.62; p = 0.002, respectively). For AUD, when combining both treatment groups (TG, n = 92 and TG + P, n = 80) compared to TAU (n = 57), there were significant improvements in AUD symptoms and disability (aß = - 15.13; 95%CI - 18.63 to - 11.63, p < 0.001; aß = - 9.26; 95%CI - 16.41 to - 2.12, p = 0.011; respectively). For AUD, there were no differences between TG and TG + P. Patients' perceptions of health workers' skills in common psychological factors were associated with improvement in depression patient outcomes (ß = - 0.36; 95%CI - 0.55 to - 0.18; p < 0.001) but not for AUD patients. CONCLUSION: Primary care mental health services for depression may only be effective when psychological treatments are included. Health workers' competencies as perceived by patients may be an important indicator for treatment effect. AUD treatment in primary care appears to be beneficial even without additional psychological services.

Evaluation of the impacts of a district-level mental health care plan on contact coverage, detection and individual outcomes in rural Uganda: a mixed methods approach.

BACKGROUND: The burden of mental disorders in low- and middle-income countries is large. Yet there is a major treatment gap for these disorders which can be reduced by integrating the care of mental disorders in primary care. AIM: We aimed to evaluate the impact of a district mental health care plan (MHCP) on contact coverage for and detection of mental disorders, as well as impact on mental health symptom severity and individual functioning in rural Uganda. RESULTS: For adults who attended primary care facilities, there was an immediate positive effect of the MHCP on clinical detection at 3 months although this was not sustained at 12 months. Those who were treated in primary care experienced significant reductions in symptom severity and functional impairment over 12 months. There was negligible change in population-level contact coverage for depression and alcohol use disorder. CONCLUSION: The study found that it is possible to integrate mental health care into primary care in rural Uganda. Treatment by trained primary care workers improves clinical and functioning outcomes for depression, psychosis and epilepsy. Challenges remain in accessing the men for care, sustaining the improvement in detection over time, and creating demand for services among those with presumed need.

Impact of integrated district level mental health care on clinical and social outcomes of people with severe mental illness in rural Ethiopia: an intervention cohort study.

AIM: There is limited evidence of the safety and impact of task-shared care for people with severe mental illnesses (SMI; psychotic disorders and bipolar disorder) in low-income countries. The aim of this study was to evaluate the safety and impact of a district-level plan for task-shared mental health care on 6 and 12-month clinical and social outcomes of people with SMI in rural southern Ethiopia. METHODS: In the Programme for Improving Mental health carE, we conducted an intervention cohort study. Trained primary healthcare (PHC) workers assessed community referrals, diagnosed SMI and initiated treatment, with independent research diagnostic assessments by psychiatric nurses. Primary outcomes were symptom severity and disability. Secondary outcomes included discrimination and restraint. RESULTS: Almost all (94.5%) PHC worker diagnoses of SMI were verified by psychiatric nurses. All prescribing was within recommended dose limits. A total of 245 (81.7%) people with SMI were re-assessed at 12 months. Minimally adequate treatment was received by 29.8%. All clinical and social outcomes improved significantly. The impact on disability (standardised mean difference 0.50; 95% confidence interval (CI) 0.35-0.65) was greater than impact on symptom severity (standardised mean difference 0.28; 95% CI 0.13-0.44). Being restrained in the previous 12 months reduced from 25.3 to 10.6%, and discrimination scores reduced significantly. CONCLUSIONS: An integrated district level mental health care plan employing task-sharing safely addressed the large treatment gap for people with SMI in a rural, low-income country setting. Randomised controlled trials of differing models of task-shared care for people with SMI are warranted.

The effects of estradiol on avoidance learning in ovariectomized adult rats.

The present study examined the effects of ovariectomy and subsequent estradiol replacement on learning in young adult rats using a set of instrumental avoidance paradigms differing in the nature and extent of prior experience in the learning context. Thus, one group of animals was placed directly into avoidance learning (AV). A second group was trained on an appetitive task first, and then transferred into the aversive context (AP-AV). The third group was exposed to the training context without any specific appetitive response requirement, and then required to learn an active avoidance response (Context-AV). We found that estradiol (OVX+E) impaired avoidance acquisition in all cases relative ovariectomized controls (OVX). In contrast, while avoidance learning is improved following appetitive training or context exposure in both OVX+E and OVX animals, the OVX+E animals profit to a greater extent from the appetitive or context experience than do the OVX controls. We suggest that this difference may be due to enhanced attentional processes or improved hippocampal processing of contextual factors. Thus, estradiol negatively influences simple associative avoidance learning in ovariectomized rats, but appears to promote positive transfer.

Lesions of the rat nucleus basalis magnocellularis disrupt appetitive-to-aversive transfer learning.

Rats with selective lesions of the nucleus basalis magnocellularis (NBM) and sham-lesion control animals were tested in an operant appetitive-to-aversive transfer task. We hypothesized that NBM lesions would not affect performance in the appetitive phase, but that performance would be impaired during subsequent transfer to the aversive phase of the task. Additional groups of NBM lesion and control rats were tested in the avoidance condition only, where we hypothesized that NBM lesions would not disrupt performance. These hypotheses were based on the argument that the NBM is not necessary for simple association learning that does not tax attention. Both the appetitive phase of the transfer task and the avoidance only task depend only on simple associative learning and are argued not to tax attention. Consequently, performance in these tasks was predicted to be spared following NBM lesions. Complex, attention-demanding associative learning, however, is argued to depend on the NBM. Performance in the aversive phase of the transfer task is both attentionally demanding and associatively more complex than in either the appetitive or aversive tasks alone; thus, avoidance performance in the NBM lesion group was predicted to be impaired following transfer from prior appetitive conditioning. Results supported our hypotheses, with the NBM lesion group acquiring the appetitive response normally, but showing impaired performance following transfer to the aversive conditioning phase of the transfer task. Impairments were not attributable to disrupted avoidance learning per se, as avoidance behavior was normal in the NBM lesion group tested in the avoidance condition only.

Acute reductions in GABAA receptor binding in layer IV of adult primate somatosensory cortex after peripheral nerve injury.

Following peripheral nerve transection, reorganizational plasticity has been reported to occur in two phases, one immediate and one more protracted. GABA (gamma-aminobutyric acid) has been implicated in the immediate "unmasking" phase of reorganization. We have used quantitative autoradiography to assess potential changes in GABA(A) and GABA(B) receptor binding in primate somatosensory cortex following peripheral nerve injury. Here we report reductions in GABA(A) receptor binding in layer IV of primate somatosensory cortex deprived of its normal activating inputs for 2-5 h by peripheral nerve transection.

A 1.8 A resolution structure of pig muscle 3-phosphoglycerate kinase with bound MgADP and 3-phosphoglycerate in open conformation: new insight into the role of the nucleotide in domain closure.

3-phosphoglycerate kinase (PGK) is a typical kinase with two structural domains. The domains each bind one of the two substrates, 3-phosphoglycerate (3-PG) and MgATP. For the phospho-transfer reaction to take place the substrates must be brought closer by a hinge-bending domain closure. Open and closed structures of the enzyme with different relative domain positions have been determined from different species, but a comprehensive description of this conformational transition is yet to be attained. Crystals of pig muscle PGK in complex with MgADP and 3-phosphoglycerate were grown under the conditions which have previously resulted in crystals of the closed, catalytically competent conformation of Trypanosoma brucei PGK. The X-ray structure of the pig muscle ternary complex was determined at 1.8 A and the model was refined to R=20.8% and Rfree=24.1%. Contrary to expectation, however, it represents an essentially open conformation compared to that of T. brucei PGK. In addition, the beta-phosphate group of ADP is mobile in the new structure, in contrast to its well-defined position in T. brucei PGK. An extensive comparison of the ternary complexes from these remote species has been carried out in order to establish general differences between the two conformations and is reported here. A second pair of the open and closed structures was also compared. These analyses have made it possible to define several characteristic changes which accompany the structural transition, in addition to those identified previously: (1) the operation of a hinge at beta-strand L in the inter-domain region which greatly affects the relative domain positions; (2) the rearrangement and movement of helix 8, regulated through the interactions with the nucleotide phosphate; and (3) the existence of another hinge between helix 14 and the rest of the C-terminal part of the chain, which allows fine adjustment of the N-domain position. The main hinge at beta-strand L acts in concert with the C-terminal hinge at helix 7 described previously. Simultaneous interactions of the nucleotide phosphate groups with the loop that precedes helix 8, beta-strand J and the N terminus of helix 13 are required for propagation of the nucleotide effect towards the beta-strand L molecular hinge. A detailed description of the role of nucleotide binding in the hinge operation is presented.

Identification of novel purine and pyrimidine cyclin-dependent kinase inhibitors with distinct molecular interactions and tumor cell growth inhibition profiles.

Substituted guanines and pyrimidines were tested as inhibitors of cyclin B1/CDK1 and cyclin A3/CDK2 and soaked into crystals of monomeric CDK2. O6-Cyclohexylmethylguanine (NU2058) was a competitive inhibitor of CDK1 and CDK2 with respect to ATP (Ki values: CDK1, 5 +/- 1 microM; CDK2, 12 +/- 3 microM) and formed a triplet of hydrogen bonds (i.e., NH-9 to Glu 81, N-3 to Leu 83, and 2-NH2 to Leu 83). The triplet of hydrogen bonding and CDK inhibition was reproduced by 2,6-diamino-4-cyclohexylmethyloxy-5-nitrosopyrimidine (NU6027, Ki values: CDK1, 2.5 +/- 0.4 microM; CDK2, 1.3 +/- 0.2 microM). Against human tumor cells, NU2058 and NU6027 were growth inhibitory in vitro (mean GI50 values of 13 +/- 7 microM and 10 +/- 6 microM, respectively), with a pattern of sensitivity distinct from flavopiridol and olomoucine. These CDK inhibition and chemosensitivity data indicate that the distinct mode of binding of NU2058 and NU6027 has direct consequences for enzyme and cell growth inhibition.

A DNA-porphyrin minor-groove complex at atomic resolution: the structural consequences of porphyrin ruffling.

The crystal structure of a B-type DNA hexanucleotide duplex complexed with the porphyrin molecule nickel-[tetra-N-methyl-pyridyl] porphyrin has been solved by multiwavelength anomalous diffraction phasing and refined to an R factor of 11.5% at a resolution of 0.9 A. The structure has been solved and refined as two crystallographically independent duplexes, stacked end to end. Contrary to expectation, the porphyrin molecule is not intercalated into the duplex but is stacked onto the ends of the two-duplex stack. The porphyrin molecule is highly buckled as a consequence of the nickel coordination, which produces large changes in local DNA structure. A second mode of porphyrin binding is apparent as a consequence of crystal packing, which places the ligand in the minor groove of an adjacent duplex. This structure thus provides, to our knowledge, the first atomic visualization of minor-groove binding for a porphyrin molecule. The geometry of groove binding provides a ready explanation for porphyrin-induced DNA strand cleavage at deoxyribose residues.

Mutations at critical N-glycosylation sites reduce tyrosinase activity by altering folding and quality control.

Tyrosinase is a copper-containing enzyme that regulates melanin biosynthesis in mammals. Mutations at a single N-glycosylation sequon of tyrosinase have been reported to be responsible for oculocutaneous albinism type IA in humans, characterized by inactive tyrosinase and the total absence of pigmentation. To probe the role that each N-glycosylation site plays in the synthesis of biologically active tyrosinase, we analyzed the calnexin mediated folding of tyrosinase N-glycosylation mutants. We have determined that four of the six potential N-glycosylation sites, including that associated with albinism, are occupied. Analysis of the folding pathway and activity of 15 tyrosinase mutants lacking one or more of the occupied N-glycosylation sites shows that glycans at any two N-glycosylation sites are sufficient to interact with calnexin and give partial activity, but a specific pair of sites (Asn(86) and Asn(371)) is required for full activity. The mutants with less than two N-glycosylation sites do not interact with calnexin and show a complete absence of enzyme activity. Copper analysis of selected mutants suggests that the observed partial activity is due to two populations with differential copper content. By correlating the degree of folding with the activity of tyrosinase, we propose a local folding mechanism for tyrosinase that can explain the mechanism of inactivation of tyrosinase N-glycosylation mutants found in certain pigmentation disorders.

Cool data: quantity AND quality.

The use of cryo-techniques in macromolecular crystallography has increased enormously over the last eight years and has become a vital part of modern X-ray data-collection methods. This paper presents some reasons for the rise in popularity of cryo-techniques and a brief outline of the basic methods, followed by a detailed discussion of factors to be considered when trying to optimize both the quantity and quality of the data collected. As more experimenters at synchrotrons observe significant radiation damage to crystals held near 100 K, the available options for further prolonging crystal lifetime and extending the techniques become worth investigating. Some possibilities and parameters to be considered are presented, although these must remain speculative until more experimental data are available.

Continuous and discontinuous changes in the unit cell of HIV-1 reverse transcriptase crystals on dehydration.

A crystal form of HIV-1 reverse transcriptase (RT) complexed with inhibitors showed diffraction to a high-resolution limit of 3.7 A. Instability in the unit-cell dimensions of these crystals was observed during soaking experiments, but the range of this variability and consequent change in lattice order was revealed by a chance observation of dehydration. Deliberately induced dehydration results in crystals having a variety of unit cells, the best-ordered of which show diffraction to a minimum Bragg spacing of 2.2 A. In order to understand the molecular basis for this phenomenon, the initial observation of dehydration, the data sets from dehydrated crystals, the crystal packing and the domain conformation of RT are analysed in detail here. This analysis reveals that the crystals undergo remarkable changes following a variety of possible dehydration pathways: some changes occur gradually whilst others are abrupt and require significant domain rearrangements. Comparison of domain arrangements in different crystal forms gives insight into the flexibility of RT which, in turn, may reflect the internal motions allowing this therapeutically important enzyme to fulfill its biological function.

The structure of a glycogen phosphorylase glucopyranose spirohydantoin complex at 1.8 A resolution and 100 K: the role of the water structure and its contribution to binding.

A glucopyranose spirohydantoin (a pyranose analogue of the potent herbicide, hydantocidin) has been identified as the highest affinity glucose analogue inhibitor of glycogen phosphorylase b (GPb). In order to elucidate the structural features that contribute to the binding, the structures of GPb in the native T state conformation and in complex with glucopyranose spirohydantoin have been determined at 100 K to 2.0 A and 1.8 A resolution, respectively, and refined to crystallographic R values of 0.197 (R[free] 0.248) and 0.182 (R[free] 0.229), respectively. The low temperature structure of GPb is almost identical to that of the previously determined room temperature structure, apart from a decrease in overall atomic temperature factors ((B) room temperature GPb = 34.9 A2; (B) 100 K GPb = 23.4 A2). The glucopyranose spirohydantoin inhibitor (Ki = 3.0 microM) binds at the catalytic site and induces small changes in two key regions of the protein: the 280s loop (residues 281-286) that results in a decrease in mobility of this region, and the 380s loop (residues 377-385) that undergoes more significant shifts in order to optimize contact to the ligand. The hydantoin group, that is responsible for increasing the affinity of the glucose compound by a factor of 10(3), makes only one hydrogen bond to the protein, from one of its NH groups to the main chain oxygen of His377. The other polar groups of the hydantoin group form hydrogen bonds to five water molecules. These waters are involved in extensive networks of hydrogen bonds and appear to be an integral part of the protein structure. Analysis of the water structure at the catalytic site of the native enzyme, shows that five waters are displaced by ligand binding and that there is a significant decrease in mobility of the remaining waters on formation of the GPb-hydantoin complex. The ability of the inhibitor to exploit existing waters, to displace waters and to recruit new waters appears to be important for the high affinity of the inhibitor.