Crystal structures, Hirshfeld analysis, and energy framework analysis of two differently 3'-substituted 4-methylchalcones: 3'-(N=CHC6H4-p-CH3)-4-methylchalcone and 3'-(NHCOCH3)-4-methylchalcone.

Two crystal structures of chalcones, or 1,3-diarylprop-2-en-1-ones, are presented; both contain a p-methyl substitution on the 3-Ring, but differ with respect to the m-substitution on the 1-Ring. Their systematic names are (2E)-3-(4-methylphenyl)-1-(3-{[(4-methylphenyl)methylidene]amino}phenyl)prop-2-en-1-one (C24H21NO) and N-{3-[(2E)-3-(4-methylphenyl)prop-2-enoyl]phenyl}acetamide (C18H17NO2), which are abbreviated as 3'-(N=CHC6H4-p-CH3)-4-methylchalcone and 3'-(NHCOCH3)-4-methylchalcone, respectively. Both chalcones represent the first reported acetamide-substituted and imino-substituted chalcone crystal structures, adding to the robust library of chalcone structures within the Cambridge Structural Database. The crystal structure of 3'-(N=CHC6H4-p-CH3)-4-methylchalcone exhibits close contacts between the enone O atom and the substituent arene ring, in addition to C...C interactions between the substituent arene rings. The structure of 3'-(NHCOCH3)-4-methylchalcone exhibits a unique interaction between the enone O atom and the 1-Ring substituent, contributing to its antiparallel crystal packing. In addition, both structures exhibit π-stacking, which occurs between the 1-Ring and R-Ring for 3'-(N=CHC6H4-p-CH3)-4-methylchalcone, and between the 1-Ring and 3-Ring for 3'-(NHCOCH3)-4-methylchalcone.

Bromodomain Inhibitors Modulate FcγR-Mediated Mononuclear Phagocyte Activation and Chemotaxis.

IgG antibodies form immune complexes (IC) that propagate inflammation and tissue damage in autoimmune diseases such as systemic lupus erythematosus. IgG IC engage Fcγ receptors (FcγR) on mononuclear phagocytes (MNP), leading to widespread changes in gene expression that mediate antibody effector function. Bromodomain and extra-terminal domain (BET) proteins are involved in governing gene transcription. We investigated the capacity of BET protein inhibitors (iBET) to alter IgG FcγR-mediated MNP activation. We found that iBET dampened IgG IC-induced pro-inflammatory gene expression and decreased activating FcγR expression on MNPs, reducing their ability to respond to IgG IC. Despite FcγR downregulation, iBET-treated macrophages demonstrated increased phagocytosis of protein antigen, IgG IC, and apoptotic cells. iBET also altered cell morphology, generating more amoeboid MNPs with reduced adhesion. iBET treatment impaired chemotaxis towards a CCL19 gradient in IC-stimulated dendritic cells (DC) in vitro, and inhibited IC-induced DC migration to draining lymph nodes in vivo, in a DC-intrinsic manner. Altogether, our data show that iBET modulates FcγR-mediated MNP activation and migration, revealing the therapeutic potential of BET protein inhibition in antibody-mediated diseases.

The impact of age, sex, cardio-respiratory fitness, and cardiovascular disease risk on dynamic cerebral autoregulation and baroreflex sensitivity.

BACKGROUND: Humans display an age-related decline in cerebral blood flow and increase in blood pressure (BP), but changes in the underlying control mechanisms across the lifespan are less well understood. We aimed to; (1) examine the impact of age, sex, cardiovascular disease (CVD) risk, and cardio-respiratory fitness on dynamic cerebral autoregulation and cardiac baroreflex sensitivity, and (2) explore the relationships between dynamic cerebral autoregulation (dCA) and cardiac baroreflex sensitivity (cBRS). METHODS: 206 participants aged 18-70 years were stratified into age categories. Cerebral blood flow velocity was measured using transcranial Doppler ultrasound. Repeated squat-stand manoeuvres were performed (0.10 Hz), and transfer function analysis was used to assess dCA and cBRS. Multivariable linear regression was used to examine the influence of age, sex, CVD risk, and cardio-respiratory fitness on dCA and cBRS. Linear models determined the relationship between dCA and cBRS. RESULTS: Age, sex, CVD risk, and cardio-respiratory fitness did not impact dCA normalised gain, phase, or coherence with minimal change in all models (P > 0.05). cBRS gain was attenuated with age when adjusted for sex and CVD risk (young-older; ß = - 2.86 P < 0.001) along with cBRS phase (young-older; ß = - 0.44, P < 0.001). There was no correlation between dCA normalised gain and phase with either parameter of cBRS. CONCLUSION: Ageing was associated with a decreased cBRS, but dCA appears to remain unchanged. Additionally, our data suggest that sex, CVD risk, and cardio-respiratory fitness have little effect.

Structural effects of halogen bonding in iodochalcones.

The structures of three iodochalcones, functionalized with fluorine or a nitro group, have been investigated to explore the impact of different molecular electrostatic distributions on the halogen bonding within each crystal structure. The strongly withdrawing nitro group presented a switch of the halogen bond from a lateral to a linear motif. Surprisingly, this appears to be influenced by a net positive shift in charge distribution around the lateral edges of the σ-hole, making the lateral I...I bonding motif less preferable. A channel of amphoteric I...I type II halogen bonds is observed for a chalcone molecule, which was not previously reported in chalcones, alongside an example of the common synthon involving extended linear chains of I...O2N donor-acceptor halogen bonds. This work shows that halogenated chalcones may be an interesting target for developing halogen bonding as a significant tool within crystal engineering, a thus far underexplored area for this common structural motif.

Exploring the impact of COVID-19 on the willingness of older adults to participate in physiology research: views from past and potential volunteers.

We explored the views of older (≥65 years) past and potential volunteers in regard to participating in physiology research during the COVID-19 pandemic. Using an online questionnaire and focus groups, we found that past volunteers (n = 55) were more likely to take part in both acute (p < 0.05) and chronic (p < 0.05) physiology studies, compared with potential future volunteers (n = 57). Both cohorts demonstrated a positive attitude towards volunteering during the COVID-19 pandemic, although concern was evident. Novelty: Volunteers demonstrated a positive attitude and also concern towards participating in physiology research during COVID-19.

A phase 2 trial of inhaled nitrous oxide for treatment-resistant major depression.

Nitrous oxide at 50% inhaled concentration has been shown to improve depressive symptoms in patients with treatment-resistant major depression (TRMD). Whether a lower concentration of 25% nitrous oxide provides similar efficacy and persistence of antidepressant effects while reducing the risk of adverse side effects is unknown. In this phase 2 clinical trial (NCT03283670), 24 patients with severe TRMD were randomly assigned in a crossover fashion to three treatments consisting of a single 1-hour inhalation with (i) 50% nitrous oxide, (ii) 25% nitrous oxide, or (iii) placebo (air/oxygen). The primary outcome was the change on the Hamilton Depression Rating Scale (HDRS-21). Whereas nitrous oxide significantly improved depressive symptoms versus placebo (P = 0.01), there was no difference between 25 and 50% nitrous oxide (P = 0.58). The estimated differences between 25% and placebo were -0.75 points on the HDRS-21 at 2 hours (P = 0.73), -1.41 points at 24 hours (P = 0.52), -4.35 points at week 1 (P = 0.05), and -5.19 points at week 2 (P = 0.02), and the estimated differences between 50% and placebo were -0.87 points at 2 hours (P = 0.69), -1.93 points at 24 hours (P = 0.37), -2.44 points at week 1 (P = 0.25), and -7.00 points at week 2 (P = 0.001). Adverse events declined substantially with dose (P < 0.001). These results suggest that 25% nitrous oxide has comparable efficacy to 50% nitrous oxide in improving TRMD but with a markedly lower rate of adverse effects.

Crystal structures of three functionalized chalcones: 4'-di-methyl-amino-3-nitro-chalcone, 3-di-methyl-amino-3'-nitrochalcone and 3'-nitro-chalcone.

The structure of three functionalized chalcones (1,3-di-aryl-prop-2-en-1-ones), containing combinations of nitro and di-methyl-amino functional groups, are presented, namely, 1-[4-(di-methyl-amino)-phen-yl]-3-(3-nitro-phen-yl)prop-2-en-1-one, C17H16N2O3, Gp8m, 3-[3-(di-methyl-amino)-phen-yl]-1-(3-nitro-phen-yl)prop-2-en-1-one, C17H16N2O3, Hm7m and 1-(3-nitro-phen-yl)-3-phenyl-prop-2-en-1-one, C15H11NO3, Hm1-. Each of the mol-ecules contains bonding motifs seen in previously solved crystal structures of functionalized chalcones, adding to the large dataset available for these small organic mol-ecules. The structures of all three of the title compounds contain similar bonding motifs, resulting in two-dimensional planes of mol-ecules formed via C-H⋯O hydrogen-bonding inter-actions involving the nitro- and ketone groups. The structure of Hm1- is very similar to the crystal structure of a previously solved isomer [Jing (2009 ▸). Acta Cryst. E65, o2510].

Crystal structure and Hirshfeld analysis of 3'-bromo-4-methyl-chalcone and 3'-cyano-4-methyl-chalcone.

Two crystal structures of chalcones, or 1,3-di-aryl-prop-2-en-1-ones, are presented; both contain a methyl substitution on the 3-Ring, but differ on the 1-Ring, bromo versus cyano. The compounds are 3'-bromo-4-methyl-chalcone [systematic name: 1-(2-bromo-phen-yl)-3-(4-methyl-phen-yl)prop-2-en-1-one], C16H13BrO, and 3'-cyano-4-methyl-chalcone {systematic name: 2-[3-(4-methyl-phen-yl)prop-2-eno-yl]benzo-nitrile}, C17H13NO. Both chalcones meaningfully add to the large dataset of chalcone structures. The crystal structure of 3'-cyano-4-methyl-chalcone exhibits close contacts with the cyano nitro-gen that do not appear in previously reported disubstituted cyano-chalcones, namely inter-actions between the cyano nitro-gen atom and a ring hydrogen atom as well as a methyl hydrogen atom. The structure of 3'-bromo-4-methyl-chalcone exhibits a type I halogen bond, similar to that found in a previously reported structure for 4-bromo-3'-methyl-chalcone.

The solubility and stability of heterocyclic chalcones compared with trans-chalcone.

Heterocyclic chalcones are a recently explored subgroup of chalcones that have sparked interest due to their significant antibacterial and antifungal capabilities. Herein, the structure and solubility of two such compounds, (E)-1-(1H-pyrrol-2-yl)-3-(thiophen-2-yl)prop-2-en-1-one and (E)-3-phenyl-1-(1H-pyrrol-2-yl)prop-2-en-1-one, are assessed. Single crystals of (E)-1-(1H-pyrrol-2-yl)-3-(thiophen-2-yl)prop-2-en-1-one were grown, allowing structural comparisons between the heterocyclic chalcones and (2E)-1,3-diphenylprop-2-en-1-one, trivially known as trans-chalcone. The two heterocyclic chalcones were found to be less soluble in all solvents tested and to have higher melting points than trans-chalcone, probably due to their stronger intermolecular interactions arising from the functionalized rings. Interestingly, however, it was found that the addition of the thiophene ring in (E)-1-(1H-pyrrol-2-yl)-3-(thiophen-2-yl)prop-2-en-1-one increased both the melting point and solubility of the sample compared with (E)-3-phenyl-1-(1H-pyrrol-2-yl)prop-2-en-1-one. This observation may be key for the future crystal engineering of heterocyclic chalcones for pharmaceutical applications.

Macrophage metabolic reprogramming presents a therapeutic target in lupus nephritis.

IgG antibodies cause inflammation and organ damage in autoimmune diseases such as systemic lupus erythematosus (SLE). We investigated the metabolic profile of macrophages isolated from inflamed tissues in immune complex (IC)-associated diseases, including SLE and rheumatoid arthritis, and following IgG Fcγ receptor cross-linking. We found that human and mouse macrophages undergo a switch to glycolysis in response to IgG IC stimulation, mirroring macrophage metabolic changes in inflamed tissue in vivo. This metabolic reprogramming was required to generate a number of proinflammatory mediators, including IL-1ß, and was dependent on mTOR and hypoxia-inducible factor (HIF)1α. Inhibition of glycolysis, or genetic depletion of HIF1α, attenuated IgG IC-induced activation of macrophages in vitro, including primary human kidney macrophages. In vivo, glycolysis inhibition led to a reduction in kidney macrophage IL-1ß and reduced neutrophil recruitment in a murine model of antibody-mediated nephritis. Together, our data reveal the molecular mechanisms underpinning FcγR-mediated metabolic reprogramming in macrophages and suggest a therapeutic strategy for autoantibody-induced inflammation, including lupus nephritis.

Cat ownership and Proximity to Significant Ecological Areas Influence Attitudes Towards Cat Impacts and Management Practices.

Cat ownership is increasing globally, representing a growing threat to urban wildlife. Although some cities have policies and strategies for managing owned cats, the companionship value placed on cats makes such management contentious. Prioritizing cat management in urban residential zones adjacent to large significant ecological areas (SEAs; areas designated on the basis of representativeness, threat status or rarity, diversity, connectedness, or uniqueness) could maximize return on management effort. Residents in these areas may place a relatively higher value on nature than residents in suburbs with minimal or no SEAs, and therefore may be comparatively more likely to perceive cats' wildlife impacts as important. We used a quantitative survey to compare SEA and non-SEA suburbs' residents' attitudes towards cat impacts and management in Tamaki Makaurau-Auckland, Aotearoa-New Zealand. Participants were asked to rate the importance of different feral and owned cat impacts, the importance of feral-cat control in different locations, and various ownership behaviors in terms of acceptability and best practice. SEA suburb residents placed more importance on wildlife predation impacts of feral cats and were more likely to regard 24-h cat confinement as best practice than non-SEA suburb residents. However, we also found that cat ownership and youth were negatively associated with perception of cat impacts, and owners were less likely to accept belled collars and cat confinement than nonowners. Therefore, although targeting SEA adjacent areas for cat management holds promise for reducing resident contention, proximity to such areas is a relatively minor influence for cat owners.

Crystal structure and Hirshfeld surface analysis of (E)-3-(3-iodo-phen-yl)-1-(4-iodo-phen-yl)prop-2-en-1-one.

The title compound, C15H10I2O, is a halogenated chalcone formed from two iodine substituted rings, one para-substituted and the other meta-substituted, linked through a prop-2-en-1-one spacer. In the mol-ecule, the mean planes of the 3-iodo-phenyl and the 4-iodo-phenyl groups are twisted by 46.51 (15)°. The calculated electrostatic potential surfaces show the presence of σ-holes on both substituted iodines. In the crystal, the mol-ecules are linked through type II halogen bonds, forming a sheet structure parallel to the bc plane. Between the sheets, weak inter-molecular C-H⋯π inter-actions are observed. Hirshfeld surface analysis showed that the most significant contacts in the structure are C⋯H/H⋯C (31.9%), followed by H⋯H (21.4%), I⋯H/H⋯I (18.4%). I⋯I (14.5%) and O⋯H/H⋯O (8.1%).

Seven-day remote ischaemic preconditioning improves endothelial function in patients with type 2 diabetes mellitus: a randomised pilot study.

BACKGROUND: Remote ischaemic preconditioning (rIPC) may improve cardiac/cerebrovascular outcomes of ischaemic events. Ischaemic damage caused by cardiovascular/cerebrovascular disease are primary causes of mortality in type 2 diabetes mellitus (T2DM). Due to the positive effects from a bout of rIPC within the vasculature, we explored if daily rIPC could improve endothelial and cerebrovascular function. The aim of this pilot study was to obtain estimates for the change in conduit artery and cerebrovascular function following a 7-day rIPC intervention. METHODS: Twenty-one patients with T2DM were randomly allocated to either 7-day daily upper-arm rIPC (4 × 5 min 220 mmHg, interspaced by 5-min reperfusion) or control. We examined peripheral endothelial function using flow mediated dilation (FMD) before and after ischemia-reperfusion injury (IRI, 20 min forearm ischaemic-20 min reperfusion) and cerebrovascular function, assessed by dynamic cerebral autoregulation (dCA) at three time points; pre, post and 8 days post intervention. RESULTS: For exploratory purposes, we performed statistical analysis on our primary comparison (pre-to-post) to provide an estimate of the change in the primary and secondary outcome variables. Using pre-intervention data as a covariate, the change from pre-post in FMD was 1.3% (95% CI: 0.69 to 3.80; P = 0.09) and 0.23 %cm/s %/mmHg mmHg/% (-0.12, 0.59; P = 0.18) in dCA normalised gain with rIPC versus control. Based upon this, a sample size of 20 and 50 for FMD and normalised gain, respectively, in each group would provide 90% power to detect statistically significant (P < 0.05) between-group difference in a randomised controlled trial. CONCLUSION: We provide estimates of sample size for a randomised control trial exploring the impact of daily rIPC for 7 days on peripheral endothelial and cerebrovascular function. The directional changes outline from our pilot study suggest peripheral endothelial function can be enhanced by daily rIPC in patients with T2DM.

Spirituality and spiritual care in nursing: A literature review

@#<p style="text-align: justify;">Spirituality is a multifaceted concept with varied definitions. In the nursing literature, it is commonly described based on its significance in the lives of individuals. Exploring the perspectives of nurses, nursing students, and patients regarding spirituality and spiritual care is crucial to gain a sound understanding of how these concepts impact the nursing profession. This literature review explored the perspectives on spirituality and spiritual care of four population groups: nurse educators, nursing students, clinical nurses, and patients. A literature search was done using worldwide databases. The 84 articles included dealt with the perceptions of nurse educators, nursing students, clinical nurses, and patients regarding spirituality and spiritual care.</p><p style="text-align: justify;">The four main categories of perspectives from the nurse educators, nursing students, nurse clinicians, and patients yielded ten sub-categories: (a) meaning of spirituality and spiritual care, (b) role of spirituality and spiritual care in nursing practice, (c) role of nursing education in developing spirituality and spiritual care competence of nursing students, (d) manner of integrating spirituality and spiritual care in nursing curriculum, (e) methods of teaching spirituality and spiritual care, (f) manner of spiritual care delivery, (g) barriers and challenges to the teaching and learning of spirituality and spiritual care, (h) barriers and challenges to spiritual care delivery, (i) ways of enhancing nurse educators' competence in curricular integration and teaching spirituality and spiritual care, and (j) ways of enhancing nurses' competence in spiritual care delivery.</p><p style="text-align: justify;">Nurse educators, nursing students, clinical nurses, and patients presented similar and diverse perspectives, but they all recognized the significance of spirituality and spiritual care in the profession. The information derived from this study can contribute to the existing knowledge base and spur strategies at individual and institutional levels to enhance teaching and learning of the concepts, improve practice, and promote holistic care.</p>

Economic Evaluation of an Internet-Based Preventive Cognitive Therapy With Minimal Therapist Support for Recurrent Depression: Randomized Controlled Trial.

BACKGROUND: Major depressive disorder (MDD) is highly recurrent and has a significant disease burden. Although the effectiveness of internet-based interventions has been established for the treatment of acute MDD, little is known about their cost effectiveness, especially in recurrent MDD. OBJECTIVES: Our aim was to evaluate the cost effectiveness and cost utility of an internet-based relapse prevention program (mobile cognitive therapy, M-CT). METHODS: The economic evaluation was performed alongside a single-blind parallel group randomized controlled trial. Participants were recruited via media, general practitioners, and mental health care institutions. In total, 288 remitted individuals with a history of recurrent depression were eligible, of whom 264 were randomly allocated to M-CT with minimal therapist support added to treatment as usual (TAU) or TAU alone. M-CT comprised 8 online lessons, and participants were advised to complete 1 lesson per week. The economic evaluation was performed from a societal perspective with a 24-month time horizon. The health outcomes were number of depression-free days according to Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition, (DSM-IV) criteria assessed with the Structured Clinical Interview for DSM-IV axis I disorders by blinded interviewers after 3, 12, and 24 months. Quality-adjusted life years (QALYs) were self-assessed with the three level version of the EuroQol Five Dimensional Questionnaire (EQ-5D-3L). Costs were assessed with the Trimbos and Institute for Medical Technology Assessment Questionnaire on Costs Associated with Psychiatric Illness (TiC-P). Incremental cost-effectiveness ratios were calculated and cost-effectiveness planes and cost-effectiveness acceptability curves were displayed to assess the probability that M-CT is cost effective compared to TAU. RESULTS: Mean total costs over 24 months were €8298 (US $9415) for M-CT and €7296 (US $8278) for TAU. No statistically significant differences were found between M-CT and TAU regarding depression-free days and QALYs (P=.37 and P=.92, respectively). The incremental costs were €179 (US $203) per depression-free day and €230,816 (US $261,875) per QALY. The cost-effectiveness acceptability curves suggested that for depression-free days, high investments have to be made to reach an acceptable probability that M-CT is cost effective compared to TAU. Regarding QALYs, considerable investments have to be made but the probability that M-CT is cost effective compared to TAU does not rise above 40%. CONCLUSIONS: The results suggest that adding M-CT to TAU is not effective and cost effective compared to TAU alone. Adherence rates were similar to other studies and therefore do not explain this finding. The participants scarcely booked additional therapist support, resulting in 17.3 minutes of mean total therapist support. More studies are needed to examine the cost effectiveness of internet-based interventions with respect to long-term outcomes and the role and optimal dosage of therapist support. Overall, more research is needed on scalable and cost-effective interventions that can reduce the burden of recurrent MDD. TRIAL REGISTRATION: Netherlands Trial Register NTR2503; http://www.trialregister.nl/trialreg/admin/rctview.asp?TC=2503 (Archived by WebCite at http://www.webcitation.org/73aBn41r3).