Salt forms of sulfadiazine with alkali metal and organic cations

The structures of four salt forms of sulfadiazine (SDH) with alkali metal cations are presented. Three contain the deprotonated SD anion. These are the discrete complex [Li(SD)(OH2)2], (I), and the coordination polymers [Na(SD)]n, (II), and [K(SD)(OH2)2]n, (III). The Na complex (II) is a three-dimensional coordination polymer whilst the K complex (III) has two crystallographically independent [K(SD)(OH2)2] units per asymmetric unit, Z′ = 2, and gives a two dimensional coordination polymer whose layers propagate parallel to the crystallographic ab plane. The different bonding modes of the SD anion in these three complexes is discussed. Structure (IV) contains protonated SDH2 cations and the Orange G (OG), C16H10N2O7S2, dianion in a structure with formula [SDH2]2[Na(OG)(OH2)4]2·3H2O. The [Na(OG)(OH2)4]2 dimers have antiparallel naphthol ring structures joined through two Na centres that bond to the hydrazone anions through the O atoms of the ketone and sulfonate substituents. The structures of the salts formed on reaction of SDH with 2-aminopyridine and ethanolamine are also presented as [C5H7N2][SD], (V), and [HOCH2CH2NH3][SD]·H2O, (VI), respectively. Structure (V) features a heterodimeric R2 2(8) hydrogen bond motif between the cation and the anion whilst structure (VI) has a tetrameric core of two cations linked by a central R2 2(10) hydrogen bonded motif which supports two anions linked to this core by R3 3(8) motifs

Allosteric rescue of catalytically impaired ATP phosphoribosyltransferase variants links protein dynamics to active-site electrostatic preorganisation

Funding: This work was supported by the Biotechnology and Biological Sciences Research Council (BBSRC) [Grant BB/M010996/1] via EASTBIO Doctoral Training Partnership studentships to B. J. R. and G. F., by Stiftelsen Olle Engkvist Byggmästare [Grant 190-0335] and the Knut and Alice Wallenberg Foundation [Grants 2018.0140 and 2019.0431] to S.C.L.K., and by the European Union’s Horizon 2020 Research and Innovation Programme via a Marie Sklodowska-Curie fellowship [Grant 890562] to M.C. The simulations were enabled by resources provided by the Swedish National Infrastructure for Supercomputing (SNIC, UPPMAX), partially funded by the Swedish Research Council [Grant 2016-07213].ATP phosphoribosyltransferase catalyses the first step of histidine biosynthesis and is controlled via a complex allosteric mechanism where the regulatory protein HisZ enhances catalysis by the catalytic protein HisGS while mediating allosteric inhibition by histidine. Activation by HisZ was proposed to position HisGS Arg56 to stabilise departure of the pyrophosphate leaving group. Here we report active-site mutants of HisGS with impaired reaction chemistry which can be allosterically restored by HisZ despite the HisZ:HisGS interface lying ~20 Å away from the active site. MD simulations indicate HisZ binding constrains the dynamics of HisGS to favour a preorganised active site where both Arg56 and Arg32 are poised to stabilise leaving-group departure in WT-HisGS. In the Arg56Ala-HisGS mutant, HisZ modulates Arg32 dynamics so that it can partially compensate for the absence of Arg56. These results illustrate how remote protein-protein interactions translate into catalytic resilience by restoring damaged electrostatic preorganisation at the active site.Publisher PDFPeer reviewe

Do metacognitive beliefs predict rumination and psychological distress independently of illness representations in adults with diabetes mellitus? A prospective mediation study

ObjectiveAdults with Diabetes Mellitus (DM) experience high levels of depression and anxiety that are not always effectively ameliorated by current therapeutic approaches. The Self-Regulatory Executive Function (S-REF) model, which underpins metacognitive therapy (MCT), posits that depression and anxiety become persistent when stored metacognitive beliefs guide an individual to respond to common thoughts and feelings in a certain way. We hypothesized that (i) metacognitive beliefs would predict depression and anxiety independently of participants' representations of their illness; and (ii) rumination would mediate independent prediction of depression and anxiety by metacognitive beliefs.DesignA prospective mediation study.MethodsFour hundred and forty-one adults with DM (Types 1 and 2) completed a two time-point survey. Metacognitive beliefs, illness representations and rumination were measured at baseline, and depression and anxiety measured at baseline and 6-months later. Data were analysed using structural equation modelling. Baseline illness representations, depression and anxiety were used as control variables.ResultsA structural equation analysis showed potential mediation, by baseline rumination, of any effects of baseline metacognitive variables on 6-month distress in Type 1 and 2 diabetes samples. Significant standardized coefficients for relationships between the metacognitive latent variable and rumination were .67 (Type 1) and .75 (Type 2) and between rumination and distress of .36 and .43, respectively. These effects were independent of direct and independent effects of illness representation variables.ConclusionsFindings are consistent with metacognitive beliefs playing a key role in depression and anxiety by increasing the likelihood of rumination in adults with DM. MCT may be an effective intervention for this population, subsequent to further longitudinal testing of the S-REF model

Sleep Quality, Fatigue, and Quality of Life Among Teenage and Young Adult Cancer Survivors

Purpose: Teenage and young adult (TYA) cancer survivors experience a range of health-related problems during and beyond the active treatment period. This study examined associations between fatigue, sleep quality, and health-related quality of life (HRQOL) among TYA survivors.Methods: Self-reported data on sleep quality (Pittsburgh Sleep Quality Index), fatigue (Functional Assessment of Chronic Illness Therapy Fatigue), and HRQOL (EuroQoL-5) were gathered from United Kingdom TYA survivors between 13 and 24 years of age. TYA survivors were stratified into those on (n = 67) and off (n = 135) treatment. Linear regression analyses were used with HRQOL as the dependent variable to investigate potential associations. Fatigue and sleep were entered separately and together in the same model. Age at survey and diagnosis, gender, and ethnicity were included as covariates.Results: 85.07% of TYAs on and 62.69% of TYAs off treatment had sleep quality scores suggestive of clinically significant sleep disorders. 56.72% of TYAs on and 26.67% of TYAs off treatment reported clinically significant levels of fatigue. Strong independent associations between sleep (B = 0.05, 95% confidence intervals [CI] = 0.03–0.07, p < 0.001), fatigue (B = 0.02, 95% CI = 0.01–0.03, p < 0.001), and HRQOL were observed among TYA survivors on treatment. TYAs off treatment showed moderate to strong associations between sleep (B = 0.04, 95% CI = 0.02–0.05, p < 0.001) and fatigue (B = 0.02, 95% CI = 0.01–0.02, p < 0.001), and HRQOL, when examined separately. Sleep was not independently associated with HRQOL among TYAs off treatment (B = 0.01, 95% CI = −0.01 to 0.02, p = 0.296).Conclusion: The significant associations reported suggest that sleep quality and fatigue are potential modifiable factors associated with HRQOL. Further research is warranted to understand the direction of associations

Sleep Quality, Fatigue, and Quality of Life Among Teenage and Young Adult Cancer Survivors

Purpose: Teenage and young adult (TYA) cancer survivors experience a range of health-related problems during and beyond the active treatment period. This study examined associations between fatigue, sleep quality, and health-related quality of life (HRQOL) among TYA survivors.Methods: Self-reported data on sleep quality (Pittsburgh Sleep Quality Index), fatigue (Functional Assessment of Chronic Illness Therapy Fatigue), and HRQOL (EuroQoL-5) were gathered from United Kingdom TYA survivors between 13 and 24 years of age. TYA survivors were stratified into those on (n = 67) and off (n = 135) treatment. Linear regression analyses were used with HRQOL as the dependent variable to investigate potential associations. Fatigue and sleep were entered separately and together in the same model. Age at survey and diagnosis, gender, and ethnicity were included as covariates.Results: 85.07% of TYAs on and 62.69% of TYAs off treatment had sleep quality scores suggestive of clinically significant sleep disorders. 56.72% of TYAs on and 26.67% of TYAs off treatment reported clinically significant levels of fatigue. Strong independent associations between sleep (B = 0.05, 95% confidence intervals [CI] = 0.03–0.07, p < 0.001), fatigue (B = 0.02, 95% CI = 0.01–0.03, p < 0.001), and HRQOL were observed among TYA survivors on treatment. TYAs off treatment showed moderate to strong associations between sleep (B = 0.04, 95% CI = 0.02–0.05, p < 0.001) and fatigue (B = 0.02, 95% CI = 0.01–0.02, p < 0.001), and HRQOL, when examined separately. Sleep was not independently associated with HRQOL among TYAs off treatment (B = 0.01, 95% CI = −0.01 to 0.02, p = 0.296).Conclusion: The significant associations reported suggest that sleep quality and fatigue are potential modifiable factors associated with HRQOL. Further research is warranted to understand the direction of associations

Experience sampling methodology study of anxiety and depression in adolescents with epilepsy: The role of metacognitive beliefs and perseverative thinking.

Emotional distress is common in young people with epilepsy (YPwE). According to the Self-Regulatory Executive Function (S-REF) model, maladaptive metacognitive beliefs and perseverative thinking are fundamental in the development and maintenance of emotional distress. As emotional distress and perseverative thinking can highly fluctuate over short intervals in YPwE, it is important to account for this variability when testing the utility of psychological models. Experience sampling methodology (ESM) was therefore used to explore the momentary relationship between metacognitive beliefs, perseverative thinking, and emotional distress in YPwE. Eighteen participants diagnosed with epilepsy (aged 12-17 years) completed the 10-day ESM period. Participants were prompted to complete the ESM assessment five times daily. The ESM assessment assessed participant's momentary levels of metacognitive beliefs, perseverative thinking (i.e., worry and rumination), and emotional distress (i.e., anxiety and depression). A series of multilevel regression analyses indicated that metacognitive beliefs were significantly positively associated with worry, rumination, anxiety and depression. After controlling for worry and rumination, respectively, metacognitive beliefs did not account for additional variance in anxiety or depression. Findings provide preliminary support for the utility of the S-REF model for emotional distress in YPwE. Metacognitive therapy, which is underpinned by the S-REF model, may be an appropriate intervention for emotional distress in YPwE. Future studies should assess the mediational relationship between metacognitive beliefs, perseverative thinking, and emotional distress using time-lagged models

Therapists’ experiences of remote working during the COVID-19 pandemic

ObjectivesTo explore the experiences of therapists who delivered remote psychological therapy during the COVID-19 pandemic.DesignThis was a qualitative, phenomenological study. Interpretative Phenomenological Analysis elicited themes from semi-structured interviews.MethodsA purposive sample of eight therapists was recruited from breast cancer services in the United Kingdom.ResultsAnalysis identified three superordinate themes. Participants spoke about how their experience of remote working changed over time from an initial crisis response to a new status quo. They adapted to the specific practical and personal challenges of remote working and struggled to connect with clients as the use of technology fundamentally changed the experience of therapy.ConclusionConsideration should be given to the impact of remote working on therapists and the quality of their practise. Adjustments to ways of working can help to maximize the advantages of remote working while minimizing potential issues

The Association Between Maladaptive Metacognitive Beliefs and Emotional Distress in People Living With Amyotrophic Lateral Sclerosis

ObjectiveApproximately half of all people living with amyotrophic lateral sclerosis (ALS) experience persistent or recurrent emotional distress, yet little is known about the psychological processes that maintain emotional distress in this population. The self-regulatory executive functioning (S-REF) model specifies that maladaptive metacognitive beliefs and processes are central to the development and maintenance of emotional distress. This study explored whether maladaptive metacognitive beliefs are associated with emotional distress after controlling for demographic factors, time since diagnosis, and current level of physical functioning.DesignIn a cross-sectional design, 75 adults with a diagnosis of ALS completed self-report questionnaires. Participants had a mean age of 60.40 years, mean duration of symptoms 63.92 months, and male:female gender ratio of 14:11.Main Outcome MeasuresQuestionnaires assessed emotional distress (HADS, adapted for ALS), physical functioning (ALSFRS-R), repetitive negative thinking (RTQ-10), metacognitive beliefs (MCQ-30), and demographic factors.ResultsMaladaptive metacognitive beliefs explained additional variance in emotional distress after controlling for age, gender, time since diagnosis, physical functioning, and repetitive negative thinking. Repetitive negative thinking partially mediated the relationships between positive and negative metacognitive beliefs and emotional distress.ConclusionsThese data support the utility of the metacognitive model in understanding emotional distress in people with ALS. Examination of the temporal relationship between maladaptive metacognitive beliefs and emotional distress in people living with ALS may help to guide the development of therapeutic approaches.</jats:sec

Factors Associated With Fear of Cancer Recurrence in Family Caregivers of Cancer Survivors: A Systematic Review

Objective: Fear of cancer recurrence (FCR) is a significant concern for family caregivers of cancer survivors and is associated with many adverse outcomes, including increased emotional distress and poorer quality of life. Although several theoretical models have been proposed to account for FCR in cancer survivors, their applicability to caregivers is unknown. The aim of this review was to identify clinical, demographic and psychological factors that are associated with, and predict, FCR in caregivers of cancer survivors.Method: AMED, CINAHL, Medline, PsycINFO, and Scopus were systematically searched for relevant studies reporting quantitative data on factors associated with FCR or similar constructs (e.g., worry or anxiety about cancer recurrence) in family caregivers of adult cancer survivors. Included studies were assessed for methodological quality using a standardized checklist adapted from the Agency for Healthcare Research and Quality.Results: Sixteen studies, half of which were cross-sectional, were included and summarized narratively. Non-modifiable factors, including age (n = 6) and treatment modality (n = 4), were found to be associated with increased FCR. Significant positive associations were also reported between illness perceptions and FCR (n = 3). However, there was heterogeneity across included studies with regards to factors examined and most were conducted in the USA. There were also several methodological limitations to the included studies.Conclusions: Research examining FCR in caregivers of cancer survivors has predominantly focused on demographic and clinical factors. Given the paucity of research exploring the psychological mechanisms underpinning FCR, future research should investigate theoretical underpinnings of FCR in caregivers of cancer survivors to support the development of psychological interventions for this population.Systematic Review Registration: PROSPERO, identifier [CRD42019119729].</jats:p

Mapping the structural path for allosteric inhibition of a short-form ATP phosphoribosyltransferase by histidine

Funding: This work was supported by a Wellcome Trust Institutional Strategic Support Fund to the University of St Andrews and the Biotechnology and Biological Sciences Research Council (BBSRC) [grant number BB/M010996/1] via an EASTBIO Doctoral Training Partnership studentship to GF. X-ray diffraction data were collected at Diamond Light Source in the UK.ATP phosphoribosyltransferase (ATPPRT) catalyses the first step of histidine biosynthesis, being allosterically inhibited by the final product of the pathway. Allosteric inhibition of long-form ATPPRTs by histidine has been extensively studied, but inhibition of short-form ATPPRTs is poorly understood. Short-form ATPPRTs are hetero-octamers formed by four catalytic subunits (HisGS) and four regulatory subunits (HisZ). HisGS alone is catalytically active and insensitive to histidine. HisZ enhances catalysis by HisGS in the absence of histidine but mediates allosteric inhibition in its presence. Here, steady-state and pre-steady-state kinetics establish that histidine is a non-competitive inhibitor of short-form ATPPRT, and that inhibition does not occur by dissociating HisGS from the hetero-octamer. The crystal structure of ATPPRT in complex with histidine and the substrate 5-phospho-α-D-ribosyl-1-pyrophosphate (PRPP) was solved, showing histidine bound solely to HisZ, with four histidine molecules per hetero-octamer. Histidine binding involves the repositioning of two HisZ loops. The histidine-binding loop moves closer to histidine to establish polar contacts. This leads to a hydrogen bond between its Tyr263 and His104 in the Asp101–Leu117 loop. The Asp101–Leu117 loop leads to the HisZ/HisGS interface, and in the absence of histidine its motion prompts HisGS conformational changes responsible for catalytic activation. Following histidine binding, interaction with the histidine-binding loop may prevent the Asp101–Leu117 loop from efficiently sampling conformations conducive to catalytic activation. Tyr263Phe-PaHisZ-containing PaATPPRT, however, is less susceptible though not insensitive to histidine inhibition, suggesting the Tyr263-His104 interaction may be relevant to, yet not solely responsible for transmission of the allosteric signal.Publisher PDFPeer reviewe