The Parenting Sense of Competence scale: Updating a classic.

BACKGROUND: The Parenting Sense of Competence (PSOC) is a self-report measure of parenting efficacy and satisfaction that is widely used by researchers and clinicians in many countries. Despite its popularity, there have been some criticisms of the instrument. The aims of the current study were to identify and address shortcomings of the PSOC and to produce a revised measure that reflected the original constructs and that demonstrated robust psychometric properties. METHODS: The researchers examined the original PSOC and proposed changes to overcome identified issues. A sample of 3056 Australian mothers provided data for the revised instrument's factor structure and psychometric analyses. RESULTS: We identified a number of problems with the original instrument, including factorial inconsistency, and multipart or potentially ambiguous questions. Of particular concern was the fact that all negatively worded items load onto one subscale and all positively worded questions load onto the other subscale. In addressing these issues, we produced a 16-item instrument (the Parenting Sense of Competence-Revised; PSOC-R) with strong internal consistency, excellent test-retest reliability and good evidence of construct validity including factorial validity and criterion-related validity. CONCLUSIONS: The PSOC-R maintains the intent of the original measure in assessing parenting Efficacy (10 items) and Satisfaction (6 items). It represents improvements in item construction including reductions in complexity, with no multipart items and a lower reading level requirement than previously. Data across four child age groups enhance the instrument's clinical utility.

Maternal interactive beliefs and style as predictors of language development in preterm and full term children.

Previous research has shown that the quality of mother-child interactions between pre-term children and their mothers tends to be poorer than that of full-term children and their mothers (Forcada-Guex, Pierrehumbert, Borghini, Moessinger & Muller-Nix, 2006). Mothers of pre-term children are less responsive and more intrusive in interactions with their children than mothers of full-term children (Forcada-Guex et al., 2006; Ionio, Lista, Mascheroni, Olivari, Confalonieri, Mastrangelo, Brazzoduro, Balestriero, Banfi, Bonanomi, Bova, Castoldi, Colombo, Introvini & Scelsa, 2017; Laing, McMahon, Ungerer, Taylor, Badawi & Spence, 2010). The current research explored differences between mothers of pre-term and full-term children in terms of interactive beliefs and style, and the potential for language development to be differentially predicted by maternal interactive beliefs and styles in pre-term versus full-term children. Independent t-tests were conducted to compare pre-term and full-term groups in relation to the measures of maternal interactive beliefs and styles. A series of multiple regression analyses were then performed separately for each group to examine the shared and unique contributions of maternal interactive beliefs and styles on full-term versus pre-term children's language development. The results showed that mothers of pre-term children were more intrusive-directive than mothers of full-term children; in contrast, mothers of full-term children were more responsive and supportive-directive in interactions with their children. Moreover, predictors of language development were different in full-term versus pre-term children; in full-term children, maternal supportive beliefs and responsiveness were significant predictors of language development evaluated by both the Bayley Scales of Infant and Toddler Development and the MacArthur Communicative Development Inventory; in the pre-term group, maternal supportive and directive beliefs, as well as supportive and intrusive directiveness, were significant predictors, with the latter being negatively associated with language development indicators. This research can shed light on how to prevent language delay in children and improve mother-child interactions that contribute to language development, which may in turn improve language development in vulnerable children, children born pre-term in particular.

Perceptions of schizophrenia in the Australian community: 2005-2017.

BACKGROUND: Community perceptions of schizophrenia potentially influence the wellbeing and quality of life of individuals with the disorder. There is some evidence of improved community knowledge of schizophrenia in recent years; however, misconceptions still remain. AIMS: The aims were to investigate community perceptions of schizophrenia at two points in time. METHOD: Two cross-sectional surveys were used to assess perceptions of schizophrenia. Using personal contacts and a snowball approach, members of the Australian community were recruited in 2005 (n = 1214) and in 2017 (n = 985). Participants were asked "What is the first thing that comes to mind when you think about schizophrenia?" RESULTS: Analyses revealed that community knowledge of schizophrenia was more accurate at the second time point and prosocial tendencies were more evident. Perceptions of dangerousness, aggressiveness and unpredictability did not differ at the two time points. Despite there being fewer responses that confused schizophrenia with dissociative identity disorder, this misconception was still evident. CONCLUSIONS: Although community knowledge about schizophrenia appears to have become more accurate and empathic, the endurance of negative stereotypes and misunderstandings highlights the need for community education programmes to combat stigma and discrimination.

Pyruvate kinase from Plasmodium falciparum: Structural and kinetic insights into the allosteric mechanism.

During its intra-erythrocytic growth phase, the malaria parasite Plasmodium falciparum relies heavily on glycolysis for its energy requirements. Pyruvate kinase (PYK) is essential for regulating glycolytic flux and for ATP production, yet the allosteric mechanism of P. falciparum PYK (PfPYK) remains poorly understood. Here we report the first crystal structure of PfPYK in complex with substrate analogues oxalate and the ATP product. Comparisons of PfPYK structures in the active R-state and inactive T-state reveal a 'rock-and-lock' allosteric mechanism regulated by rigid-body rotations of each subunit in the tetramer. Kinetic data and structural analysis indicate glucose 6-phosphate is an activator by increasing the apparent maximal velocity of the enzyme. Intriguingly, the trypanosome drug suramin inhibits PfPYK, which points to glycolysis as a set of potential therapeutic targets against malaria.

Neurodevelopmental and health-related quality-of-life outcomes in adolescence after surgery for congenital heart disease in infancy.

AIM: To assess outcomes in adolescence after surgery for congenital heart disease (CHD) in infancy. Domains analysed included cognition and executive function, social and emotional well-being, adaptive behaviour, academic achievement, and health-related quality of life (HRQoL). METHOD: Twenty-one participants (10 males, 11 females) ranged in age from 14 to 17 years (mean 15y 4.8mo, SD 8.4mo). Twenty had biventricular repairs. All were classified as New York Heart Association class I. Measures included: Wechsler Intelligence and Achievement scales; Wide Range Assessment of Memory and Learning, Second Edition; California Verbal Learning Test - Children's Version; Behaviour Rating Inventory of Executive Function; Conners, Third Edition; Adaptive Behavior Assessment System, Second Edition; Behavior Assessment System for Children, Second Edition; Rey-Osterrieth Complex Figure; and Pediatric Quality of Life Inventory. RESULTS: Outcomes were significantly lower (p≤0.01) than population norms for processing speed, mathematical achievement, attention, and visual-spatial ability. Participants reported more frequent learning problems but more positive family relations. HRQoL was significantly lower across most domains by self- and parent-proxy report. INTERPRETATION: Individuals with CHD may experience difficulties across a range of domains. These findings emphasize the importance of comprehensive screening, early intervention, and long-term follow-up, as deficits may extend into young adulthood. WHAT THIS PAPER ADDS: Identified cognitive, learning, and attentional impairments in adolescents after congenital heart disease surgery in infancy. Combined self-report, caregiver report, and laboratory tasks in a comprehensive neurodevelopmental assessment protocol. Health-related quality of life was lower across most domains.

An allostatic mechanism for M2 pyruvate kinase as an amino-acid sensor.

We have tested the effect of all 20 proteinogenic amino acids on the activity of the M2 isoenzyme of pyruvate kinase (M2PYK) and show that, within physiologically relevant concentrations, phenylalanine, alanine, tryptophan, methionine, valine, and proline act as inhibitors, while histidine and serine act as activators. Size exclusion chromatography has been used to show that all amino acids, whether activators or inhibitors, stabilise the tetrameric form of M2PYK. In the absence of amino-acid ligands an apparent tetramer-monomer dissociation Kd is estimated to be ∼0.9 µM with a slow dissociation rate (t1/2 ∼ 15 min). X-ray structures of M2PYK complexes with alanine, phenylalanine, and tryptophan show the M2PYK locked in an inactive T-state conformation, while activators lock the M2PYK tetramer in the active R-state conformation. Amino-acid binding in the allosteric pocket triggers rigid body rotations (11°) stabilising either T or R states. The opposing inhibitory and activating effects of the non-essential amino acids serine and alanine suggest that M2PYK could act as a rapid-response nutrient sensor to rebalance cellular metabolism. This competition at a single allosteric site between activators and inhibitors provides a novel regulatory mechanism by which M2PYK activity is finely tuned by the relative (but not absolute) concentrations of activator and inhibitor amino acids. Such 'allostatic' regulation may be important in metabolic reprogramming and influencing cell fate.

Food Photography Is Not an Accurate Measure of Energy Intake in Obese, Pregnant Women.

Background: To improve weight management in pregnant women, there is a need to deliver specific, data-based recommendations on energy intake. Objective: This cross-sectional study evaluated the accuracy of an electronic reporting method to measure daily energy intake in pregnant women compared with total daily energy expenditure (TDEE). Methods: Twenty-three obese [mean ± SEM body mass index (kg/m2): 36.9 ± 1.3] pregnant women (aged 28.3 ±1.1 y) used a smartphone application to capture images of their food selection and plate waste in free-living conditions for ≥6 d in early (13-16 wk) and late (35-37 wk) pregnancy. Energy intake was evaluated by the smartphone application SmartIntake and compared with simultaneous assessment of TDEE obtained by doubly labeled water. Accuracy was defined as reported energy intake compared with TDEE (percentage of TDEE). Ecological momentary assessment prompts were used to enhance data reporting. Two-one-sided t tests for the 2 methods were used to assess equivalency, which was considered significant when accuracy was >80%. Results: Energy intake reported by the SmartIntake application was 63.4% ± 2.3% of TDEE measured by doubly labeled water (P = 1.00). Energy intake reported as snacks accounted for 17% ± 2% of reported energy intake. Participants who used their own phones compared with participants who used borrowed phones captured more images (P = 0.04) and had higher accuracy (73% ± 3% compared with 60% ± 3% of TDEE; P = 0.01). Reported energy intake as snacks was significantly associated with the accuracy of SmartIntake (P = 0.03). To improve data quality, excluding erroneous days of likely underreporting (<60% TDEE) improved the accuracy of SmartIntake, yet this was not equivalent to TDEE (-22% ± 1% of TDEE; P = 1.00). Conclusions: Energy intake in obese, pregnant women obtained with the use of an electronic reporting method (SmartIntake) does not accurately estimate energy intake compared with doubly labeled water. However, accuracy improves by applying criteria to eliminate erroneous data. Further evaluation of electronic reporting in this population is needed to improve compliance, specifically for reporting frequent intake of small meals. This trial was registered at www.clinicaltrials.gov as NCT01954342.

M2 pyruvate kinase provides a mechanism for nutrient sensing and regulation of cell proliferation.

We show that the M2 isoform of pyruvate kinase (M2PYK) exists in equilibrium between monomers and tetramers regulated by allosteric binding of naturally occurring small-molecule metabolites. Phenylalanine stabilizes an inactive T-state tetrameric conformer and inhibits M2PYK with an IC50 value of 0.24 mM, whereas thyroid hormone (triiodo-L-thyronine, T3) stabilizes an inactive monomeric form of M2PYK with an IC50 of 78 nM. The allosteric activator fructose-1,6-bisphosphate [F16BP, AC50 (concentration that gives 50% activation) of 7 µM] shifts the equilibrium to the tetrameric active R-state, which has a similar activity to that of the constitutively fully active isoform M1PYK. Proliferation assays using HCT-116 cells showed that addition of inhibitors phenylalanine and T3 both increased cell proliferation, whereas addition of the activator F16BP reduced proliferation. F16BP abrogates the inhibitory effect of both phenylalanine and T3, highlighting a dominant role of M2PYK allosteric activation in the regulation of cancer proliferation. X-ray structures show constitutively fully active M1PYK and F16BP-bound M2PYK in an R-state conformation with a lysine at the dimer-interface acting as a peg in a hole, locking the active tetramer conformation. Binding of phenylalanine in an allosteric pocket induces a 13° rotation of the protomers, destroying the peg-in-hole R-state interface. This distinct T-state tetramer is stabilized by flipped out Trp/Arg side chains that stack across the dimer interface. X-ray structures and biophysical binding data of M2PYK complexes explain how, at a molecular level, fluctuations in concentrations of amino acids, thyroid hormone, and glucose metabolites switch M2PYK on and off to provide the cell with a nutrient sensing and growth signaling mechanism.

Pyruvate kinases have an intrinsic and conserved decarboxylase activity.

The phosphotransfer mechanism of PYKs (pyruvate kinases) has been studied in detail, but the mechanism of the intrinsic decarboxylase reaction catalysed by PYKs is still unknown. 1H NMR was used in the present study to follow OAA (oxaloacetate) decarboxylation by trypanosomatid and human PYKs confirming that the decarboxylase activity is conserved across distantly related species. Crystal structures of TbPYK (Trypanosoma brucei PYK) complexed with the product of the decarboxylase reaction (pyruvate), and a series of substrate analogues (D-malate, 2-oxoglutarate and oxalate) show that the OAA analogues bind to the kinase active site with similar binding modes, confirming that both decarboxylase and kinase activities share a common site for substrate binding and catalysis. Decarboxylation of OAA as monitored by NMR for TbPYK has a relatively low turnover with values of 0.86 s-1 and 1.47 s-1 in the absence and presence of F26BP (fructose 2,6-bisphosphate) respectively. Human M1PYK (M1 isoform of PYK) has a measured turnover value of 0.50 s-1. The X-ray structures explain why the decarboxylation activity is specific for OAA and is not general for α-oxo acid analogues. Conservation of the decarboxylase reaction across divergent species is a consequence of piggybacking on the conserved kinase mechanism which requires a stabilized enol intermediate.

Trypanosomatid phosphoglycerate mutases have multiple conformational and oligomeric states.

Three structurally distinct forms of phosphoglycerate mutase from the trypanosomatid parasite Leishmania mexicana were isolated by standard procedures of bacterial expression and purification. Analytical size-exclusion chromatography coupled to a multi-angle scattering detector detected two monomeric forms of differing hydrodynamic radii, as well as a dimeric form. Structural comparisons of holoenzyme and apoenzyme trypanosomatid cofactor-independent phosphoglycerate mutase (iPGAM) X-ray crystal structures show a large conformational change between the open (apoenzyme) and closed (holoenzyme) forms accounting for the different monomer hydrodynamic radii. Until now iPGAM from trypanosomatids was considered to be only monomeric, but results presented here show the appearance of a dimeric form. Taken together, these observations are important for the choice of screening strategies to identify inhibitors of iPGAM for parasite chemotherapy and highlight the need to select the most biologically or functionally relevant form of the purified enzyme.

Impact of Pretreatment Weight Loss on Radiotherapy Utilization and Clinical Outcomes in Non-Small Cell Lung Cancer.

BACKGROUND: Cancer cachexia is a syndrome of unintentional weight loss resulting in progressive functional impairment. Knowledge of radiation therapy utilization in patients with cancer cachexia is limited. We evaluated the use of curative and palliative-intent radiation for the management of patients with non-small cell lung cancer (NSCLC) with cachexia to determine whether tumor-directed therapy affected cachexia-associated outcomes. METHODS: Using an Institutional Tumor Registry, we evaluated all patients with stages of NSCLC treated at a tertiary care system from 2006 to 2013. We adopted the international consensus definition for cachexia, with staging designated by the registry and positron emission tomography. Radiotherapy delivery and intent were retrospectively assessed. RESULTS: In total, 1330 patients with NSCLC were analyzed. Curative-intent radiotherapy was utilized equally between patients with cachexia and non-cachexia with stages I to III NSCLC. Conversely, significantly more patients with stage IV disease and cachexia received palliative radiotherapy versus those without (74% vs 63%, P = 0.006). Cachexia-associated survival was unchanged irrespective of tumor-directed radiation therapy with curative or palliative intent. In fact, pretreatment cachexia was associated with reduced survival for patients with stage III NSCLC receiving curative-intent radiotherapy (median survival = 23.9 vs 15.0 mo, P = 0.009). Finally, multivariate analysis identified pretreatment cachexia as an independent variable associated with worsened survival (hazard ratio = 1.31, CI: 1.14,1.52). CONCLUSION: Patients with advanced NSCLC with cachexia received more palliative-intent radiation than those without weight loss. Tumor-directed therapy in either a curative or palliative approach failed to alter cachexia patient survival across all stages of the disease. These findings offer critical information on the appropriate utilization of radiation in the management of patients with NSCLC with cachexia.

`In crystallo' substrate binding triggers major domain movements and reveals magnesium as a co-activator of Trypanosoma brucei pyruvate kinase.

The active site of pyruvate kinase (PYK) is located between the AC core of the enzyme and a mobile lid corresponding to domain B. Many PYK structures have already been determined, but the first `effector-only' structure and the first with PEP (the true natural substrate) are now reported for the enzyme from Trypanosoma brucei. PEP soaked into crystals of the enzyme with bound allosteric activator fructose 2,6-bisphosphate (F26BP) and Mg(2+) triggers a substantial 23° rotation of the B domain `in crystallo', resulting in a partially closed active site. The interplay of side chains with Mg(2+) and PEP may explain the mechanism of the domain movement. Furthermore, it is apparent that when F26BP is present but PEP is absent Mg(2+) occupies a position that is distinct from the two canonical Mg(2+)-binding sites at the active site. This third site is adjacent to the active site and involves the same amino-acid side chains as in canonical site 1 but in altered orientations. Site 3 acts to sequester Mg(2+) in a `priming' position such that the enzyme is maintained in its R-state conformation. In this way, Mg(2+) cooperates with F26BP to ensure that the enzyme is in a conformation that has a high affinity for the substrate.

A new family of covalent inhibitors block nucleotide binding to the active site of pyruvate kinase.

PYK (pyruvate kinase) plays a central role in the metabolism of many organisms and cell types, but the elucidation of the details of its function in a systems biology context has been hampered by the lack of specific high-affinity small-molecule inhibitors. High-throughput screening has been used to identify a family of saccharin derivatives which inhibit LmPYK (Leishmania mexicana PYK) activity in a time- (and dose-) dependent manner, a characteristic of irreversible inhibition. The crystal structure of DBS {4-[(1,1-dioxo-1,2-benzothiazol-3-yl)sulfanyl]benzoic acid} complexed with LmPYK shows that the saccharin moiety reacts with an active-site lysine residue (Lys335), forming a covalent bond and sterically hindering the binding of ADP/ATP. Mutation of the lysine residue to an arginine residue eliminated the effect of the inhibitor molecule, providing confirmation of the proposed inhibitor mechanism. This lysine residue is conserved in the active sites of the four human PYK isoenzymes, which were also found to be irreversibly inhibited by DBS. X-ray structures of PYK isoforms show structural differences at the DBS-binding pocket, and this covalent inhibitor of PYK provides a chemical scaffold for the design of new families of potentially isoform-specific irreversible inhibitors.

The impacts of typically developing siblings on the developmental outcomes of children with disability: A scoping review.

BACKGROUND: Siblings represent an important influence on children's development. It is possible that sibling influence on developmental outcomes differs in sibling pairs when one of the children has a disability. Previous research has tended to focus on outcomes for typically developing siblings when they have a brother/sister with a disability. AIMS: The purpose of this scoping review was to explore empirical studies reporting on the impact of siblings on the developmental outcomes of children with disability to better understand the areas that are influenced by siblings and the factors that contribute to this influence. METHOD: To identify relevant studies, the electronic databases of EBSCO, ERIC, Informit, Ovid, ProQuest and Scopus were searched. These searches were supplemented by direction from the authors on relevant literature and citation searches of papers identified for inclusion. Descriptive details were extracted, followed by details related to research design and findings of the studies. OUTCOMES AND RESULTS: Twenty-two papers were determined to meet inclusion criteria. Investigations of sibling influence have concentrated on children with ASD; other groups are not well represented. There is some evidence that having older siblings may be protective for children with ASD; however, this was not an invariable finding. There is too little consistency across studies to determine whether and how siblings influence development of children with disability. CONCLUSIONS AND IMPLICATIONS: Further work is required to understand the potentially crucial influence that siblings may have on developmental outcomes of children with disability.

Race, Ethnicity, and Socioeconomic Factors as Determinants of Cachexia Incidence and Outcomes in a Retrospective Cohort of Patients With Gastrointestinal Tract Cancer.

PURPOSE: Cachexia is a paraneoplastic syndrome of unintentional adipose and muscle tissue wasting with severe impacts to functionality and quality of life. Although health inequities across minority and socioeconomically disadvantaged groups are known, the role of these factors in cachexia progression is poorly characterized. This study aims to evaluate the relationship between these determinants and cachexia incidence and survival in patients with gastrointestinal tract cancer. METHODS: Through retrospective chart review from a prospective tumor registry, we established a cohort of 882 patients with gastroesophageal or colorectal cancer diagnosed between 2006 and 2013. Patient race, ethnicity, private insurance coverage, and baseline characteristics were evaluated through multivariate, Kaplan-Meier, and Cox regression analyses to determine associations with cachexia incidence and survival outcomes. RESULTS: When controlling for potentially confounding covariates (age, sex, alcohol and tobacco history, comorbidity score, tumor site, histology, and stage), Black (odds ratio [OR], 2.447; P < .0001) and Hispanic (OR, 3.039; P < .0001) patients are at an approximately 150% and 200%, respectively, greater risk of presenting with cachexia than non-Hispanic White patients. Absence of private insurance coverage was associated with elevated cachexia risk (OR, 1.439; P = .0427) compared to privately insured patients. Cox regression analyses with previously described covariates and treatment factors found Black race (hazard ratio [HR], 1.304; P = .0354) to predict survival detriments, while cachexia status did not reach significance (P = .6996). CONCLUSION: Our findings suggest that race, ethnicity, and insurance play significant roles in cachexia progression and related outcomes that are not accounted for by conventional predictors of health. Disproportionate financial burdens, chronic stress, and limitations of transportation and health literacy represent targetable factors for mitigating these health inequities.

Racial, Ethnic, and Socioeconomic Characteristics Independently Predict for Cachexia Risk and Associated Survival Outcomes in Stage IV NSCLC: A Brief Report.

Introduction: Cancer cachexia, found in more than a third of patients with NSCLC, directly leads to functional and survival detriments. As screening and interventions for cachexia and NSCLC improve, deficits in health care access and quality among patients disadvantaged by racial-ethnic and socioeconomic factors must be addressed. Methods: We retrospectively evaluated 957 patients diagnosed with having stage IV NSCLC between 2014 and 2020 in Dallas, Texas. Cachexia was retrospectively assessed by applying criteria for substantial unintentional weight loss in the time leading up to cancer diagnosis. Nonparametric, parametric, multivariate logistic regression, and Kaplan-Meier analyses were conducted to evaluate for variables potentially associated with cachexia incidence and survival. Results: In multivariate analysis including age, sex, comorbidities, body mass index, risk behaviors, and tumor characteristics, Black race and Hispanic ethnicity were independently associated with more than a 70% increased risk of presenting with cachexia at the time of NSCLC diagnosis (p < 0.05). When private insurance status was included as a covariate, this association was diminished for Hispanic patients only. Black patients presented with stage IV disease at an average of approximately 3 years younger than White patients (Kruskal-Wallis p = 0.0012; t test p = 0.0002). Cachexia status at diagnosis consistently predicted for survival detriments, further highlighting the importance of addressing differential cachexia risk across racial-ethnic groups. Conclusions: Fundamentally, our findings reveal elevated cachexia risk in Black and Hispanic patients with stage IV NSCLC with associated survival detriments. These differences are not fully accounted for by traditional determinants of health and suggest novel avenues for addressing oncologic health inequities.

The trypanocidal drug suramin and other trypan blue mimetics are inhibitors of pyruvate kinases and bind to the adenosine site.

Ehrlich's pioneering chemotherapeutic experiments published in 1904 (Ehrlich, P., and Shiga, K. (1904) Berlin Klin. Wochenschrift 20, 329-362) described the efficacy of a series of dye molecules including trypan blue and trypan red to eliminate trypanosome infections in mice. The molecular structures of the dyes provided a starting point for the synthesis of suramin, which was developed and used as a trypanocidal drug in 1916 and is still in clinical use. Despite the biological importance of these dye-like molecules, the mode of action on trypanosomes has remained elusive. Here we present crystal structures of suramin and three related dyes in complex with pyruvate kinases from Leishmania mexicana or from Trypanosoma cruzi. The phenyl sulfonate groups of all four molecules (suramin, Ponceau S, acid blue 80, and benzothiazole-2,5-disulfonic acid) bind in the position of ADP/ATP at the active sites of the pyruvate kinases (PYKs). The binding positions in the two different trypanosomatid PYKs are nearly identical. We show that suramin competitively inhibits PYKs from humans (muscle, tumor, and liver isoenzymes, K(i) = 1.1-17 µM), T. cruzi (K(i) = 108 µM), and L. mexicana (K(i) = 116 µM), all of which have similar active sites. Synergistic effects were observed when examining suramin inhibition in the presence of an allosteric effector molecule, whereby IC(50) values decreased up to 2-fold for both trypanosomatid and human PYKs. These kinetic and structural analyses provide insight into the promiscuous inhibition observed for suramin and into the mode of action of the dye-like molecules used in Ehrlich's original experiments.

A preponderance of gastrointestinal cancer patients transition into cachexia syndrome.

BACKGROUND: Cancer cachexia is frequently documented by self-reported, single time-point weight histories. This approach lacks the granularity needed to fully elucidate the progression of cachexia syndrome. This study aimed to longitudinally assess body weight changes pre- and post-cancer diagnosis in gastrointestinal (GI) cancer patients. METHODS: Body weights and relevant clinical data recorded in the electronic health record 12 months pre- and post-GI cancer (colorectal, gastroesophageal, hepatobiliary and pancreatic) diagnosis were extracted. Weight loss was categorized by the International Consensus Definition for cachexia. RESULTS: A total of 879 patients were included in the final cohort including patients diagnosed with colorectal (n = 317), hepatocellular (n = 185), biliary (n = 72), pancreatic (n = 186) or gastroesophageal (n = 119) cancer. Stage of disease was equally distributed. Patients without cachexia at diagnosis (n = 608) remained weight stable during the 12 months pre-diagnosis (+0.5 ± 0.5% body weight; P = 0.99). Patients with cachexia at diagnosis (n = 271) remained weight stable 6 to 12 months prior to diagnosis (+0.4 ± 0.8%; P > 0.9999) and lost 8.7 ± 0.6% (P < 0.0001) within the 6 months pre-diagnosis. Patients without cachexia at diagnosis lost more weight post-diagnosis (6.3 ± 0.6%) than patients with cachexia at diagnosis (4.7 ± 1.0%; P = 0.01). Pre-diagnosis weight trajectories did not differ between primary malignancies or stage of disease in patients without or with cachexia at diagnosis (all P ≥ 0.05). Post-diagnosis weight trajectories did differ by primary malignancy (P ≤ 0.0002) and stage (P < 0.0001). In both patients without and with cachexia at diagnosis, colorectal patients lost the least amount of weight post-diagnosis and gastroesophageal patients lost the most amount of weight post-diagnosis. Stage 4 patients without or with cachexia at diagnosis lost the most weight post-diagnosis (P ≤ 0.0003). Regardless of cachexia status at diagnosis, patients lost more weight when treated with systemic therapy (7.1 ± 0.7%; P < 0.0001; n = 419) or radiation therapy (8.4 ± 1.4%; P = 0.02; n = 116) compared to those who did not. Patients who did not have surgery lost more weight post-diagnosis (7.6 ± 1.1%; P < 0.0001; n = 355) compared to those who did have surgery. By 12 months post-diagnosis, 83% of the surviving GI cancer patients in this cohort had transitioned into cachexia syndrome. CONCLUSIONS: Significant weight loss in patients with GI cancer cachexia at diagnosis initiates at least 6 months prior to diagnosis, and most patients will transition into cachexia syndrome post-diagnosis, regardless of pre-diagnosis weight change and stage of disease. These findings punctuate the importance of weight surveillance in cancer detection and earlier palliative interventions post-diagnosis in the GI cancer patient population.

Allosteric mechanism of pyruvate kinase from Leishmania mexicana uses a rock and lock model.

Allosteric regulation provides a rate management system for enzymes involved in many cellular processes. Ligand-controlled regulation is easily recognizable, but the underlying molecular mechanisms have remained elusive. We have obtained the first complete series of allosteric structures, in all possible ligated states, for the tetrameric enzyme, pyruvate kinase, from Leishmania mexicana. The transition between inactive T-state and active R-state is accompanied by a simple symmetrical 6 degrees rigid body rocking motion of the A- and C-domain cores in each of the four subunits. However, formation of the R-state in this way is only part of the mechanism; eight essential salt bridge locks that form across the C-C interface provide tetramer rigidity with a coupled 7-fold increase in rate. The results presented here illustrate how conformational changes coupled with effector binding correlate with loss of flexibility and increase in thermal stability providing a general mechanism for allosteric control.