Rescreening on RBANS Delayed Memory Index? Forget About It!

OBJECTIVE: To assess the value of rescreening patients with Alzheimer's disease who do not meet the inclusion criteria for the Repeatable Battery for the Assessment of Neuropsychological Status Delayed Memory Index (RBANS DMI) at the initial assessment. PATIENTS AND METHODS: Participants (aged 50-85 years, without dementia, Mini-Mental State Examination score ≥22, valid Clinical Dementia Rating [CDR] global score, and amyloid status at baseline) were identified in the European Prevention of Alzheimer's Dementia database. Changes from baseline in RBANS DMI were estimated using a mixed model for repeated measurements. Logistic regressions were used to estimate the probability of participants with baseline RBANS DMI 86-95 having RBANS DMI ≤85, CDR global score ≥0.5, and amyloid positivity at 6 and 12 months. RESULTS: There was significant variability in the change in RBANS DMI scores over time (median change at 6 months: 2.0). An estimated 15% of participants with RBANS DMI 86-95 at baseline progressed to ≤85 at 6 months; 8% also achieved CDR global score ≥0.5 and 5% were also amyloid positive. CONCLUSIONS: The results from our analysis indicate that there is limited value in rescreening patients based on their initial RBANS DMI score.

Potential preventive properties of GLP-1 receptor agonists against prostate cancer: a nationwide cohort study.

AIMS/HYPOTHESIS: Glucagon-like peptide-1 receptor agonists (GLP-1RAs) have been suggested to possess antineoplastic properties against prostate cancer. We examined the association between GLP-1RA use and prostate cancer risk in a real-world setting. METHODS: We performed a nationwide register-based cohort study using an active-comparator, new-user design. We included all men in Denmark aged ≥50 years who commenced use of GLP-1RAs or basal insulin during 2007-2019. HRs and 95% CIs for incident prostate cancer were estimated using multivariable Cox regression in 'intention-to-treat' (ITT)- and 'per-protocol'-like analyses. RESULTS: Among 14,206 initiators of GLP-1RAs and 21,756 initiators of basal insulin, we identified 697 patients with prostate cancer during a mean follow-up period of about 5 years from initiation of the study drugs. In comparison with basal insulin use, GLP-1RA use was associated with an adjusted HR of 0.91 (95% CI 0.73, 1.14) in the 'ITT' analysis and 0.80 (95% CI 0.64, 1.01) in the 'per-protocol' analysis. Stronger inverse associations were seen among older men (≥70 years) ('ITT' HR 0.56; 95% CI 0.38, 0.82; 'per-protocol' HR 0.47; 95% CI 0.30, 0.74), and in patients with CVD ('ITT' HR 0.75; 95% CI 0.53, 1.06; 'per-protocol' HR 0.60; 95% CI 0.39, 0.91). CONCLUSIONS/INTERPRETATION: GLP-1RA use was inversely associated with prostate cancer risk compared with use of basal insulin in the 'per-protocol' analysis. Older men and patients with CVD exhibited stronger inverse associations in both the 'ITT' and 'per-protocol' analyses. Our results may indicate that GLP-1RA use could protect against prostate cancer.

Kidney function loss and albuminuria progression with GLP-1 receptor agonists versus basal insulin in patients with type 2 diabetes: real-world evidence.

BACKGROUND: In clinical trials enrolling patients with type 2 diabetes (T2D) at high cardiovascular risk, many glucagon-like peptide-1 receptor agonists (GLP-1 RAs) improved albuminuria status and possibly mitigated kidney function loss. However, limited data are available regarding the effects of GLP-1 RAs on albuminuria status and kidney function in real-world settings, including populations with a lower baseline cardiovascular and kidney risk. We assessed the association of GLP-1 RAs initiation with long-term kidney outcomes in the Maccabi Healthcare Services database, Israel. METHODS: Adults with T2D treated with ≥ 2 glucose-lowering agents who initiated GLP-1 RAs or basal insulin from 2010 to 2019 were propensity-score matched (1:1) and followed until October 2021 (intention-to-treat [ITT]). In an as-treated (AT) analysis, follow-up was also censored at study-drug discontinuation or comparator-initiation. We assessed the risk of a composite kidney outcome, including confirmed ≥ 40% eGFR loss or end-stage kidney disease, and the risk of new macroalbuminuria. Treatment-effect on eGFR slopes was assessed by fitting a linear regression model per patient, followed by a t-test to compare the slopes between the groups. RESULTS: Each propensity-score matched group constituted 3424 patients, 45% women, 21% had a history of cardiovascular disease, and 13.9% were treated with sodium-glucose cotransporter-2 inhibitors at baseline. Mean eGFR was 90.6 mL/min/1.73 m2 (SD 19.3) and median UACR was 14.6 mg/g [IQR 0.0-54.7]. Medians follow-up were 81.1 months (ITT) and 22.3 months (AT). The hazard-ratios [95% CI] of the composite kidney outcome with GLP-1 RAs versus basal insulin were 0.96 [0.82-1.11] (p = 0.566) and 0.71 [0.54-0.95] (p = 0.020) in the ITT and AT analyses, respectively. The respective HRs for first new macroalbuminuria were 0.87 [0.75-0.997] and 0.80 [0.64-0.995]. The use of GLP-1 RA was associated with a less steep eGFR slope compared with basal insulin in the AT analysis (mean annual between-group difference of 0.42 mL/min/1.73 m2/year [95%CI 0.11-0.73]; p = 0.008). CONCLUSION: Initiation of GLP-1 RAs in a real-world setting is associated with a reduced risk of albuminuria progression and possible mitigation of kidney function loss in patients with T2D and mostly preserved kidney function.

Risk of cardiovascular diseases following residential exposure to airborne polychlorinated biphenyls: A register-based cohort study.

BACKGROUND: Indoor air in buildings constructed with materials containing polychlorinated biphenyls (PCBs) may be contaminated with especially lower-chlorinated PCBs. So far, the cardiovascular consequences of living with such contamination are unknown. OBJECTIVES: To determine the risk of cardiovascular disease (CVD) following residential exposure to predominantly lower-chlorinated PCBs in indoor air. METHODS: The Health Effects of PCBs in Indoor Air (HESPAIR) cohort is register-based with 51 921 residents of two residential areas near Copenhagen: Farum Midtpunkt and Brøndby Strand Parkerne. Here, indoor air was contaminated with PCB in one third of the apartments due to construction with materials containing PCB. Individual PCB exposure was estimated based on register-based information on relocation dates and indoor air PCB measurements in subsets of the apartments. Information on CVD was retrieved from the Danish National Patient Register for the follow-up period of 1977-2018. We estimated adjusted hazard ratios using Cox regression with time-varying exposure. RESULTS: Cumulative residential exposure to airborne PCB was not associated with a higher overall risk for CVD (HR for highly exposed (≥3300 ng/m3 PCB × year): 1.02, 95% CI 0.94-1.10). This was also the case for most of the specific cardiovascular diseases, apart from acute myocardial infarction where a higher risk was observed for residents exposed to ≥3300 ng/m3 PCB × year compared to the reference group (HR 1.17, 95% CI 1.00-1.35). However, no exposure-response relationship was apparent and additional adjustment for education attenuated the risk estimate. DISCUSSION: In this, to our knowledge, first study ever to examine the risk of CVD following residential exposure to PCBs in indoor air, we observed limited support for cardiovascular effects of living in PCB-contaminated indoor air. Considering the prevalence of exposure to airborne PCBs and lack of literature on their potential health effects, these findings need to be corroborated in other studies.

Exposure to airborne polychlorinated biphenyls and type 2 diabetes in a Danish cohort.

BACKGROUND: Previous research indicates an association between higher-chlorinated polychlorinated biphenyls (PCBs) and type 2 diabetes (T2D). However, less is known about the extent to which PCB exposure in indoor air, composed primarily of lower-chlorinated PCBs, affects T2D risk. We assessed the association between indoor air exposure to PCBs in residential buildings and T2D incidence. METHODS: The register-based 'Health Effects of PCBs in Indoor Air' (HESPAIR) cohort comprises 51,921 Danish residents of two residential areas with apartments built with and without PCB-containing materials (reference apartments). We assessed exposure status by combining register-based information on relocation history with extrapolated values of exposure based on PCB-measurements in indoor air from subsets of the apartments. T2D cases were identified in the Danish registers during 1977-2018. We estimated adjusted hazard ratios (HR) and 95% confidence intervals (CI) using Cox regression analyses with time-varying exposure. RESULTS: We identified 2737 incident T2D cases during the follow-up. Exposure to ≥3300 ng/m3 PCB × year (3rd tertile of PCByear) was associated with higher risk of T2D (HR 1.15, 95% CI 1.02-1.30) compared with exposure to <300 ng/m3 PCB × year (reference). However, among individuals with lower cumulated PCByear, the risk was similar to residents with exposure <300 ng/m3 PCB × year (300-899 ng/m3 PCB × year: HR 0.98, 95% CI 0.87-1.11; 900-3299 ng/m3 PCB × year: HR 0.96, 95% CI 0.83-1.10). DISCUSSION: We observed a marginally higher risk of T2D, but there was no evidence of an exposure-response relationship. The results should be interpreted with caution until confirmed in other independent studies of PCB exposure in indoor air.

PDBe: improved findability of macromolecular structure data in the PDB.

The Protein Data Bank in Europe (PDBe), a founding member of the Worldwide Protein Data Bank (wwPDB), actively participates in the deposition, curation, validation, archiving and dissemination of macromolecular structure data. PDBe supports diverse research communities in their use of macromolecular structures by enriching the PDB data and by providing advanced tools and services for effective data access, visualization and analysis. This paper details the enrichment of data at PDBe, including mapping of RNA structures to Rfam, and identification of molecules that act as cofactors. PDBe has developed an advanced search facility with ∼100 data categories and sequence searches. New features have been included in the LiteMol viewer at PDBe, with updated visualization of carbohydrates and nucleic acids. Small molecules are now mapped more extensively to external databases and their visual representation has been enhanced. These advances help users to more easily find and interpret macromolecular structure data in order to solve scientific problems.

Daytime and nighttime smartphone use: A study of associations between multidimensional smartphone behaviours and sleep among 24,856 Danish adults.

The around-the-clock smartphone use and its relation to disturbed sleep is a public health concern. The present study aimed to quantify the effects of different dimensions of smartphone behaviours (frequency of daytime use, problematic use, use before sleep and use during the sleep period) on disturbed sleep (sleep quality and sleep quantity) and to disentangle their inter-relationship in a large population-based sample of 24,856 Danish adults aged ≥16 years. Data come from the SmartSleep Experiment, which is a web-based survey carried out using a citizen science approach. Tested items were used to evaluate smartphone use and disturbed sleep was evaluated with the Karolinska Sleep Questionnaire (KSQ). Linear and multinomial logistic regression was employed to evaluate the relationship between smartphone use and disturbed sleep. While several of the smartphone measures were associated with disturbed sleep when assessed individually, smartphone use during the sleep period was the only dimension consistently associated with disturbed sleep when assessed independently of other smartphone behaviours. Weekly smartphone use during the sleep period versus no use was associated on average with a 0.96 point higher score (95% confidence interval [CI] 0.90-1.02) on the 5-point KSQ scale, and a higher risk of both short (odds ratio [OR] 1.32, 95% CI 1.08-1.62) and long (OR 1.94, 95% CI 1.63-2.32) sleep duration. Smartphone use during the sleep period is the factor strongest associated to disturbed sleep relative to other dimensions of smartphone use. Recommendations around smartphone use during the sleep period are warranted in order to protect the fundamentally important biological and mental processes of sleep.

Synthesis and Antifungal Activity Evaluation of Phloeodictine Analogues.

The phloeodictine-based 6-hydroxy-2,3,4,6-tetrahydropyrrolo[1,2-a]pyrimidinium structural moiety with an n-tetradecyl side chain at C-6 has been demonstrated to be a new antifungal template. Thirty-four new synthetic analogues with modifications of the bicyclic tetrahydropyrrolopyrimidinium skeleton and the N-1 side chain have been prepared and evaluated for in vitro antifungal activities against the clinically important fungal pathogens including Cryptococcus neoformans ATCC 90113, Candida albicans ATCC 90028, Candida glabrata ATCC 90030, Candida krusei ATCC 6258, and Aspergillus fumigatus ATCC 90906. Nineteen compounds (5, 21-31, 34-38, 44, and 48) showed antifungal activities against the aforementioned five fungal pathogens with minimum inhibitory concentrations (MICs) in the range 0.88-10 µM, and all were fungicidal with minimum fungicidal concentrations (MFCs) similar to the respective MIC values. Compounds 24, 36, and 48 were especially active against C. neoformans ATCC 90113 with MIC/MFC values of 1.0/1.0, 1.6/1.6, and 1.3/2.0 µM but exhibited low cytotoxicity with an IC50 > 40 µM against the mammalian Vero cells. The structure and antifungal activity relationship indicates that synthetic modifications of the phloeodictines can afford analogues with potent antifungal activity and reduced cytotoxicity, necessitating further preclinical studies of this new class of antifungal compounds.

The impact of work-place social capital in hospitals on patient-reported quality of care: a cohort study of 5205 employees and 23,872 patients in Denmark.

BACKGROUND: Decision-makers increasingly consider patient-reported outcomes as important measures of care quality. Studies on the importance of work-place social capital-a collective work-place resource-for the experience of care quality are lacking. We determined the association between the level of work-place social capital and patient-reported quality of care in 148 hospital sections in the Capital Region of Denmark. METHODS: This cross-sectional study combined section-level social capital from 5205 health care professionals and 23,872 patient responses about care quality. Work-place social capital encompassed three dimensions: trust, justice and collaboration. Patient-reported quality of care was measured as: overall satisfaction, patient involvement, and medical errors. Linear regression analysis and generalized linear models assessed the mean differences in patient reported experience outcomes and the risk of belonging to the lowest tertile of care quality. RESULTS: A higher level of work-place social capital (corresponding to the interquartile range) was associated with higher patient-reported satisfaction and inpatient and acute care patient involvement. The risk of a section belonging to the lowest tertile of patient involvement was lower in sections with higher social capital providing inpatient (RR = 0.39, 0.19-0.81 per IQR increase) and acute care (RR = 0.53, 0.31-0.89). Patient-reported errors were fewer in acute care sections with higher social capital (RR = 0.65, 0.43 to 0.99). The risk of being in the lowest tertile of patient-reported satisfaction was supported for acute care sections (RR = 0.47, 0.28-0.79). CONCLUSIONS: Although we found small absolute differences in the association between patient-reported experience measures and social capital, even a small upward shift in the distribution of social capital in the hospital sector would, at the population level, have a large positive impact on patients' care experience.

Changes in Emotional Vitality as a Predictor of Levels and Change in Allostatic Load: Longitudinal Results From the Whitehall II Cohort Study.

OBJECTIVE: Increasing evidence has shown an association between reduced psychological well-being and long-term morbidity. However, longitudinal studies addressing potential biobehavioral mechanisms, such as physiological function, are lacking. The aim of this study is to examine the association between changes in emotional vitality on levels and changes in allostatic load (AL), a measure of multisystem physiological dysregulation, as well as its composite risk markers. METHODS: Participants comprised 5919 British civil servants from phases 3, 5, and 7 of the Whitehall II study. Psychological well-being was operationalized as emotional vitality. AL was measured using nine biomarkers of the cardiovascular, metabolic, and immune system. Linear mixed-effect models were used to determine the association between changes in emotional vitality between phases 3 and 5 and subsequent levels and change in AL from phases 5 to 7. Generalized linear models were used to address the association between changes in emotional vitality and individual risk markers. RESULTS: Increase in emotional vitality was associated with a lower mean level of AL, whereas the AL slope was not markedly affected. Among the included risk markers, only interleukin-6 was weakly associated with changes in emotional vitality, with a 7% reduced risk of high levels of interleukin-6 per one-unit increase in emotional vitality. CONCLUSION: This study found that an increase in emotional vitality was associated with subsequent lower levels, but not rate of change, of AL over time. Further research is needed to address the relationship between trajectories of psychological well-being and physiological dysregulation.

PDBe: towards reusable data delivery infrastructure at protein data bank in Europe.

The Protein Data Bank in Europe (PDBe, pdbe.org) is actively engaged in the deposition, annotation, remediation, enrichment and dissemination of macromolecular structure data. This paper describes new developments and improvements at PDBe addressing three challenging areas: data enrichment, data dissemination and functional reusability. New features of the PDBe Web site are discussed, including a context dependent menu providing links to raw experimental data and improved presentation of structures solved by hybrid methods. The paper also summarizes the features of the LiteMol suite, which is a set of services enabling fast and interactive 3D visualization of structures, with associated experimental maps, annotations and quality assessment information. We introduce a library of Web components which can be easily reused to port data and functionality available at PDBe to other services. We also introduce updates to the SIFTS resource which maps PDB data to other bioinformatics resources, and the PDBe REST API.

Can work-unit social capital buffer the association between workplace violence and long-term sickness absence? A prospective cohort study of healthcare employees.

PURPOSE: To determine the prospective relation between workplace violence and the risk of long-term sickness absence (LTSA), and study if work-unit social capital could buffer this effect. As an explorative analysis, the association between work-unit social capital and workplace violence is also tested. METHODS: The study is based on the Well-being in HospitAL Employees (WHALE) cohort, including healthcare employees in Denmark. The study sample consisted of 30,044 employees nested within 2304 work-units. Exposure to workplace violence and threats of violence during the past 12 months was measured by self-report. Work-unit social capital was computed by aggregating the mean individual responses within work-units. LTSA was defined as one or more episodes of ≥ 29 consecutive sickness absence days initiated within 2 years following baseline. RESULTS: Employees experiencing workplace violence had a higher risk of LTSA (OR = 1.55; 95% CI 1.39-1.72), but there was no evidence in support of work-unit social capital buffering the effect of workplace violence on LTSA (RERI = 0.24; 95%CI: - 0.36 to 0.84; p = 0.12 for multiplicative interaction). High compared to low work-unit social capital was associated with a lower prevalence of workplace violence (OR = 0.47; 95% CI 0.36-0.61). CONCLUSION: There was a prospective association between workplace violence and LTSA, but work-unit social capital did not buffer this effect. Furthermore, the results revealed an inverse association between work-unit social capital and workplace violence. The findings indicate that  in order to effectively reduce LTSA, preventive interventions need to both prevent workplace violence and strengthen social capital.

Tribute to the Late Dr. Charles D. Hufford.

This Special Issue is dedicated to the late Dr. Charles (Charlie) D. Hufford, former Professor of Pharmacognosy and Associate Dean for Research and Graduate Studies at the University of Mississippi [...].

Two plant-derived aporphinoid alkaloids exert their antifungal activity by disrupting mitochondrial iron-sulfur cluster biosynthesis.

Eupolauridine and liriodenine are plant-derived aporphinoid alkaloids that exhibit potent inhibitory activity against the opportunistic fungal pathogens Candida albicans and Cryptococcus neoformans However, the molecular mechanism of this antifungal activity is unknown. In this study, we show that eupolauridine 9591 (E9591), a synthetic analog of eupolauridine, and liriodenine methiodide (LMT), a methiodide salt of liriodenine, mediate their antifungal activities by disrupting mitochondrial iron-sulfur (Fe-S) cluster synthesis. Several lines of evidence supported this conclusion. First, both E9591 and LMT elicited a transcriptional response indicative of iron imbalance, causing the induction of genes that are required for iron uptake and for the maintenance of cellular iron homeostasis. Second, a genome-wide fitness profile analysis showed that yeast mutants with deletions in iron homeostasis-related genes were hypersensitive to E9591 and LMT. Third, treatment of wild-type yeast cells with E9591 or LMT generated cellular defects that mimicked deficiencies in mitochondrial Fe-S cluster synthesis including an increase in mitochondrial iron levels, a decrease in the activities of Fe-S cluster enzymes, a decrease in respiratory function, and an increase in oxidative stress. Collectively, our results demonstrate that E9591 and LMT perturb mitochondrial Fe-S cluster biosynthesis; thus, these two compounds target a cellular pathway that is distinct from the pathways commonly targeted by clinically used antifungal drugs. Therefore, the identification of this pathway as a target for antifungal compounds has potential applications in the development of new antifungal therapies.

Work-unit social capital and long-term sickness absence: a prospective cohort study of 32 053 hospital employees.

OBJECTIVE: There is a lack of studies investigating social capital at the workplace level in small and relatively homogeneous work-units. The aim of the study was to investigate whether work-unit social capital predicts a lower risk of individual long-term sickness absence among Danish hospital employees followed prospectively for 1 year. METHODS: This study is based on the Well-being in HospitAL Employees cohort. The study sample consisted of 32 053 individuals nested within 2182 work-units in the Capital Region of Denmark. Work-unit social capital was measured with an eight-item scale covering elements of trust, justice and collaboration between employees and leaders. Social capital at the work-unit level was computed as the aggregated mean of individual-level social capital within each work-unit. Data on long-term sickness absence were retrieved from the employers' payroll system and were operationalised as ≥29 consecutive days of sickness absence. We used a 12-point difference in social capital as the metric in our analyses and conducted two-level hierarchical logistic regression analysis. Adjustments were made for sex, age, seniority, occupational group and part-time work at the individual level, and work-unit size, the proportion of female employees and the proportion of part-time work at the work-unit level. RESULTS: The OR for long-term sickness absence associated with a 12-point higher work-unit social capital was 0.73 (95% CI 0.68 to 0.78). Further, we found an association between higher work-unit social capital and lower long-term sickness absence across quartiles of social capital: compared with the lowest quartile, the OR for long-term sickness absence in the highest quartile was 0.51 (95% CI 0.44 to 0.60). CONCLUSION: Our study provides support for work-unit social capital being a protective factor for individual long-term sickness absence among hospital employees in the Capital Region of Denmark.

PDBe: improved accessibility of macromolecular structure data from PDB and EMDB.

The Protein Data Bank in Europe (http://pdbe.org) accepts and annotates depositions of macromolecular structure data in the PDB and EMDB archives and enriches, integrates and disseminates structural information in a variety of ways. The PDBe website has been redesigned based on an analysis of user requirements, and now offers intuitive access to improved and value-added macromolecular structure information. Unique value-added information includes lists of reviews and research articles that cite or mention PDB entries as well as access to figures and legends from full-text open-access publications that describe PDB entries. A powerful new query system not only shows all the PDB entries that match a given query, but also shows the 'best structures' for a given macromolecule, ligand complex or sequence family using data-quality information from the wwPDB validation reports. A PDBe RESTful API has been developed to provide unified access to macromolecular structure data available in the PDB and EMDB archives as well as value-added annotations, e.g. regarding structure quality and up-to-date cross-reference information from the SIFTS resource. Taken together, these new developments facilitate unified access to macromolecular structure data in an intuitive way for non-expert users and support expert users in analysing macromolecular structure data.

Differences in solution dynamics between lens ß-crystallin homodimers and heterodimers probed by hydrogen-deuterium exchange and deamidation.

BACKGROUND: Lens transparency is due to the ordered arrangement of the major structural proteins, called crystallins. ßB2 crystallin in the lens of the eye readily forms dimers with other ß-crystallin subunits, but the resulting heterodimer structures are not known and were investigated in this study. METHODS: Structures of ßA3 and ßB2 crystallin homodimers and the ßA3/ßB2 crystallin heterodimers were probed by measuring changes in solvent accessibility using hydrogen-deuterium exchange with mass spectrometry. We further mimicked deamidation in ßB2 and probed the effect on the ßA3/ßB2 heterodimer. Results were confirmed with chemical crosslinking and NMR. RESULTS: Both ßA3 and ßB2 had significantly decreased deuterium levels in the heterodimer compared to their respective homodimers, suggesting that they had less solvent accessibility and were more compact in the heterodimer. The compact structure of ßB2 was supported by the identification of chemical crosslinks between lysines in ßB2 within the heterodimer that were inconsistent with ßB2's extended homodimeric structure. The compact structure of ßA3 was supported by an overall decrease in mobility of ßA3 in the heterodimer detected by NMR. In ßB2, peptides 70-84 and 121-134 were exposed in the homodimer, but buried in the heterodimer with ≥50% decreases in deuterium levels. Homologous peptides in ßA3, 97-109 and 134-149, had 25-50% decreases in deuterium levels in the heterodimer. These peptides are probable sites of interaction between ßB2 and ßA3 and are located at the predicted interface between subunits with bent linkers. Deamidation at Q184 in ßB2 at this predicted interface led to a less compact ßB2 in the heterodimer. The more compact structure of the ßA3/ßB2 heterodimer was also more heat stable than either of the homodimers. CONCLUSIONS: The major structural proteins in the lens, the ß-crystallins, are not static, but dynamic in solution, with differences in accessibility between the homo-and hetero-dimers. This structural flexibility, particularly of ßB2, may facilitate formation of different size higher-ordered structures found in the transparent lens. GENERAL SIGNIFICANCE: Understanding complex hetero-oligomer interactions between ß-crystallins in normal lens and how these interactions change during aging is fundamental to understanding the cause of cataracts. This article is part of a Special Issue entitled Crystallin Biochemistry in Health and Disease.

The synthesis and biological evaluation of alkyl and benzyl naphthyridinium analogs of eupolauridine as potential antimicrobial and cytotoxic agents.

Eupolauridine, an indenonaphthyridine alkaloid, has been previously reported by us to exhibit antifungal activity. This study describes the synthesis of new alkyl and benzyl naphthyridinium/pyridinium analogs of eupolauridine as potential antifungal agents. A majority of the analogs exhibited antifungal activity against opportunistic pathogens such as Candida albicans and Cryptococcus neoformans. Several of them were also effective against bacteria (Staphylococcus aureus, MRS, Pseudomonas and Mycobacterium) and the malaria parasite (Plasmodium falciparum) to variable extents. A number of analogs were also cytotoxic to human cancer cell lines.

LC-MS- and (1)H NMR Spectroscopy-Guided Identification of Antifungal Diterpenoids from Sagittaria latifolia.

Antifungal screening of small-molecule natural product libraries showed that a column fraction (CF) derived from the plant extract of Sagittaria latifolia was active against the fungal pathogen Cryptococcus neoformans. Dereplication analysis by liquid chromatography-mass spectrometry (LC-MS) and proton nuclear magnetic resonance spectroscopy ((1)H NMR) indicated the presence of new compounds in this CF. Subsequent fractionation of the plant extract resulted in the identification of two new isopimaradiene-type diterpenoids, 1 and 2. The structures of 1 and 2 were determined by chemical methods and spectroscopic analysis as isopimara-7,15-dien-19-ol 19-O-α-l-arabinofuranoside and isopimara-7,15-dien-19-ol 19-O-α-l-(5'-acetoxy)arabinofuranoside, respectively. Compound 1 exhibited IC50 values of 3.7 and 1.8 µg/mL, respectively, against C. neoformans and C. gattii. Its aglycone, isopimara-7,15-dien-19-ol (3), resulting from acid hydrolysis of 1, was also active against the two fungal pathogens, with IC50 values of 9.2 and 6.8 µg/mL, respectively. This study demonstrates that utilization of the combined LC-MS and (1)H NMR analytical tools is an improved chemical screening approach for hit prioritization in natural product drug discovery.

Psychosocial risk factors for hospitalisation and death from chronic obstructive pulmonary disease: a prospective cohort study.

Only a few smaller studies have addressed the effect of psychosocial factors on risk of chronic obstructive pulmonary disease (COPD) in spite of the potential for psychosocial stress to affect development of the disease through immunological and behavioural pathways. The aim of this study is to determine the relation between various psychosocial risk factors, individually and accumulated, and COPD hospitalisation and deaths. A total of 8728 women and men free of asthma and COPD participating in the Copenhagen City Heart Study, were asked comprehensive questions on major life events, work-related stress, social network, vital exhaustion, economic hardship, and sleep medication in 1991-1993 and followed in nationwide registers until 2009, with <2% loss to follow-up. During follow-up, 461 women and 352 men were hospitalized with or died from COPD. Major life events in adult life and vital exhaustion were both associated with a higher risk of COPD in an exposure-dependent manner, with high vital exhaustion being associated with a hazard ratio [HR] of 2.31 (95% CI 1.69-3.16) for women and 2.48 (1.69-3.64) for men. A higher risk of COPD was also found in participants who experienced economic hardship or had a dysfunctional social network. Furthermore, the accumulation of psychosocial risk factors was associated with a higher risk of COPD in both women (HR = 2.40, 1.78-3.22) and men (HR = 1.93, 1.33-2.80). Psychosocial vulnerability may be important to consider both in clinical practice and when planning future preventive strategies against COPD.