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ACS Chemical Biology Apr 2021Dysfunction of YEATS-domain-containing MLLT1, an acetyl/acyl-lysine dependent epigenetic reader domain, has been implicated in the development of aggressive cancers....
Dysfunction of YEATS-domain-containing MLLT1, an acetyl/acyl-lysine dependent epigenetic reader domain, has been implicated in the development of aggressive cancers. Mutations in the YEATS domain have been recently reported as a cause of MLLT1 aberrant reader function. However, the structural basis for the reported alterations in affinity for acetylated/acylated histone has remained elusive. Here, we report the crystal structures of both insertion and substitution mutants present in cancer, revealing significant conformational changes of the YEATS-domain loop 8. Structural comparison demonstrates that not only did such alteration alter the binding interface for acetylated/acylated histones, but the sequence alterations in the loop in T1 mutant may enable dimeric assembly consistent with inducing self-association behavior. Nevertheless, we show that also the MLLT1 mutants can be targeted by developed acetyllysine mimetic inhibitors with affinities similarly to wild-type. Our report provides a structural basis for the altered behaviors and a potential strategy for targeting oncogenic MLLT1 mutants.
Topics: Humans; Mutation; Neoplasm Proteins; Nuclear Proteins; Protein Conformation; Transcription Factors
PubMed: 33749253
DOI: 10.1021/acschembio.0c00960 -
Cell Systems Mar 2024Autoinhibition is a prevalent allosteric regulatory mechanism in signaling proteins. Reduced autoinhibition underlies the tumorigenic effect of some known cancer...
Autoinhibition is a prevalent allosteric regulatory mechanism in signaling proteins. Reduced autoinhibition underlies the tumorigenic effect of some known cancer drivers, but whether autoinhibition is altered generally in cancer remains elusive. Here, we demonstrate that cancer-associated missense mutations, in-frame insertions/deletions, and fusion breakpoints are enriched within inhibitory allosteric switches (IASs) across all cancer types. Selection for IASs that are recurrently mutated in cancers identifies established and unknown cancer drivers. Recurrent missense mutations in IASs of these drivers are associated with distinct, cancer-specific changes in molecular signaling. For the specific case of PPP3CA, the catalytic subunit of calcineurin, we provide insights into the molecular mechanisms of altered autoinhibition by cancer mutations using biomolecular simulations, and demonstrate that such mutations are associated with transcriptome changes consistent with increased calcineurin signaling. Our integrative study shows that autoinhibition-modulating genetic alterations are positively selected for by cancer cells.
Topics: Humans; Calcineurin; Neoplasms; Mutation; Carcinogenesis; Mutation, Missense
PubMed: 38366601
DOI: 10.1016/j.cels.2024.01.009 -
Pediatric Nephrology (Berlin, Germany) Mar 2010There have been relatively few studies of bone mass in children with idiopathic hypercalciuria (IH). When performed, bone mineral density (BMD) measurements have... (Review)
Review
There have been relatively few studies of bone mass in children with idiopathic hypercalciuria (IH). When performed, bone mineral density (BMD) measurements have consistently disclosed decreased Z-scores for children with IH at the lumbar spine and, to a lesser extent, at the femoral neck. Few investigations have delineated the nature of the mechanism(s) that may contribute to the bone loss in these children. Some studies have been consistent, showing increased bone resorption as the probable mechanism of bone loss. To date, there have been no reports regarding the assessment of biochemical markers specific for bone formation in children with IH. However, since most of the children with IH in these reports had demonstrated normal longitudinal growth, it seems less likely that there is an alteration in bone formation. The causes for increased bone resorption also are not firmly established, but genetics, dietary indiscretions, and altered cytokine production have been proposed as being contributory to the decreased BMD observed in these children with IH. Optimal bone mineral accretion during childhood and adolescence is important in attaining peak bone mass and may serve to prevent the development of osteoporosis in adulthood. Thus, a better understanding of bone loss in children with IH is warranted.
Topics: Bone Density; Bone Development; Bone Diseases; Bone Resorption; Child; Humans; Hypercalciuria; Organ Size
PubMed: 19885683
DOI: 10.1007/s00467-009-1338-z -
Archives of Toxicology. Supplement. =... 1995Both marihuana and cigarettes appear implicated, in a differential fashion, in the neurobehaviour of infants and children born to women who used these substances during... (Review)
Review
Both marihuana and cigarettes appear implicated, in a differential fashion, in the neurobehaviour of infants and children born to women who used these substances during pregnancy. In a low-risk upper middle class sample, marihuana use was associated, in the newborn, with mild withdrawal symptoms and some autonomic disruption of nervous system state regulation. However, between 6 months and 3 years of age no behavioural consequences of marihuana exposure (once confounding factors were controlled) were noted. At four years of age, although global tests of intelligence did not differentiate exposed from non-marihuana exposed children, verbal ability and memory were associated with in utero marihuana exposure. At five and six years of age these general areas were also noted to be associated with maternal cannabis use as was sustained attention. These areas of neurobehavior that appear affected by marihuana exposure during fetal development are ones that are consistent with the cognitive construct of 'executive functioning' which is thought to be a marker of prefrontal lobe functioning. Consistent with the observations derived from these children is that prefrontal functioning may not be apparent until approximately four years of age and that executive functioning is disassociated from measures of global intelligence. Exposure to cigarettes during pregnancy appears to be associated with neurobehavioural deficits in the auditory domain. In the newborn this is manifested by decreased responsivity to sound and altered auditory habituation. Between the ages of one and 11 years the performance on auditory related tasks (verbal memory, language, auditory processing) were consistently the domains that differentiated the cigarette exposed from the non exposed children. The possible role of the cholinergic mediated efferent auditory system is discussed. Also associated with in utero exposure to cigarettes were general cognitive performance and parental reports and objectively derived measures of impulsivity. The striking degree of consistency over the years lends strength to the interpretation that the observations in childhood have, at least as their partial etiology, the prenatal exposure to cigarettes. However, in interpreting the evidence presented it must be recognized that the alterations in the child's behaviour may well affect the parenting behaviour. This potential transactional interaction must remain an integral part of drawing conclusions about both marihuana and cigarette's effects.
Topics: Behavior; Cannabis; Child; Child, Preschool; Female; Humans; Infant; Infant, Newborn; Nervous System Diseases; Plants, Toxic; Pregnancy; Prenatal Exposure Delayed Effects; Substance-Related Disorders; Nicotiana
PubMed: 7786162
DOI: 10.1007/978-3-642-79451-3_21 -
Clinical Pharmacokinetics Jan 1995Although it has been recognised that alterations in gastrointestinal motility, whether induced by physiological or pathological processes, have significant effects on... (Review)
Review
Although it has been recognised that alterations in gastrointestinal motility, whether induced by physiological or pathological processes, have significant effects on the pharmacokinetics of orally administered drugs, this subject has received inappropriately little attention. Studies relating to this topic have focused on healthy volunteers and animals and have largely been confined to the effects of single drug doses. There is limited information about the effects of disease on pharmacokinetics under steady-state conditions. Changes in gastrointestinal motility may affect the pharmacokinetics of orally administered drugs by altering the rate of delivery, bioavailability or mucosal absorption of the drug. In general the rate of absorption and time taken to achieve maximal plasma concentrations for well absorbed drugs may be modified by changes in gastrointestinal motility, but overall bioavailability is not usually affected. In these cases the therapeutic and clinical effects of the alteration in pharmacokinetics will, therefore, depend on which parameters are important for the action of the drug. For poorly absorbed drugs both the rate of absorption and bioavailability are likely to be altered by changes in gastrointestinal motility. However, the complex effects of food and disease, as well as the properties and formulation of any drug (solubility, ease of dispersion, delayed release formulation) often make the prediction of the magnitude, or even the direction, of any effect difficult to predict. Drugs with direct effects on gastrointestinal motility may influence their own patterns of absorption. In patients with gastrointestinal motility disorders, drugs administered in a controlled release formulation, or those with poor bioavailability, are most likely to have a poorly predictable therapeutic effect. Care should be taken to ensure that the formulation of the drug, its timing of administration in relation to meals and the use of coadministered drugs optimise, or at least ensure consistent absorption.
Topics: Administration, Oral; Adrenergic beta-Antagonists; Benzamides; Gastrointestinal Diseases; Gastrointestinal Motility; Histamine H2 Antagonists; Humans; Opioid Peptides; Pharmacokinetics
PubMed: 7712661
DOI: 10.2165/00003088-199528010-00005 -
Physiology & Behavior Oct 2022Insulin receptors are expressed throughout the adult brain, and insulin from the periphery reaches the central nervous system. In humans and rodents, actions of insulin...
Insulin receptors are expressed throughout the adult brain, and insulin from the periphery reaches the central nervous system. In humans and rodents, actions of insulin in the brain decrease food intake. Furthermore, insulin receptor activation alters dopamine and glutamate transmission within mesolimbic regions that influence food-seeking and feeding including the nucleus accumbens (NAc). Here we determined how intra-NAc insulin affects conditioned approach (a measure of cue-triggered food-seeking), free food intake, and the motivation to obtain food in hungry rats using Pavlovian and instrumental approaches. Intra-NAc insulin did not affect conditioned approach but did reduce home cage chow intake immediately following conditioned approach testing. Consistent with reduced chow intake, intra-NAc insulin also reduced the motivation to work for flavored food pellets (assessed by a progressive ratio procedure). This effect was partially reversed by insulin receptor blockade and was not driven by insulin-induced sickness or malaise. Taken together, these data show that insulin within the NAc does not alter behavioral responses to a food cue, but instead reduces the motivation to work for and consume food in hungry animals. These data are discussed in light of insulin's role in the regulation of feeding, and its dysregulation by obesity.
Topics: Animals; Cues; Eating; Insulin; Motivation; Nucleus Accumbens; Rats; Receptor, Insulin
PubMed: 35753434
DOI: 10.1016/j.physbeh.2022.113892 -
Journal of Neurogastroenterology and... Jan 2019Probiotics are expected to confer benefits on patients with constipation, but how probiotics act on constipated patients with variable stool consistencies remains...
BACKGROUND/AIMS
Probiotics are expected to confer benefits on patients with constipation, but how probiotics act on constipated patients with variable stool consistencies remains unclear. We investigated the effect of strain Shirota (LcS) on constipation-related symptoms, especially stool consistency, of constipated patients.
METHODS
Constipated patients meeting the Rome III criteria were divided into 3 groups according to the Bristol Stool Form Scale (BSFS): hard (hard stool [HS], BSFS < 3), normal (normal stool [NS], ≤ 3 BSFS ≤ 4), and soft (soft stool [SS], 4 < BSFS ≤ 5) stools. Subjects in each group consumed a probiotic beverage containing 10¹⁰ colony-forming units of LcS daily for 28 days.
RESULTS
LcS intervention significantly alleviated constipation-related symptoms and increased defecation frequency in all subjects. Four weeks of LcS supplementation softened the hard stools in HS, hardened the soft stools in SS, and did not alter the ideal stool consistency in NS. The short-chain fatty acid (SCFA) concentrations were highest in SS, followed by NS and HS. LcS intervention increased the stool SCFA levels in HS but reduced or did not alter the levels in NS and SS. LcS intervention increased the and abundances in HS and decreased the abundance in SS.
CONCLUSIONS
LcS supplementation improved the constipation-related symptoms in constipated subjects. Differences in baseline stool consistency could result in different anti-constipation effects of LcS intervention. LcS balanced the stool consistency-softened the HS and hardened the SS. These effects could be associated with modulation of the gut microbiota and SCFA production.
PubMed: 30646486
DOI: 10.5056/jnm17085 -
Neuroscience and Biobehavioral Reviews 1994Many neurotransmitters and neuropeptides can affect the rodent feminine sexual behavior, lordosis, when administered in the ventromedial hypothalamus (VMH), midbrain... (Review)
Review
Many neurotransmitters and neuropeptides can affect the rodent feminine sexual behavior, lordosis, when administered in the ventromedial hypothalamus (VMH), midbrain central gray (MCG), or other brain regions. A survey of the electrophysiological and biochemical actions of these neural agents revealed that there is a very consistent association between lordosis facilitation with both the activation of the phosphoinositide (PI) pathway and the excitation of VMH and MCG neurons. In contrast, lordosis inhibition is associated, less consistently, with alterations of the adenylate cyclase (AC) system and the inhibition of neuronal activity. The findings that lordosis could be facilitated by going beyond membrane receptors and directly activating the PI pathway, suggest that this second-messenger pathway is a common mediator for the lordosis-facilitating agents. Furthermore, as in the case of stimulating membrane receptors, direct activation of this common mediator also requires estrogen priming for lordosis facilitation. Therefore, it is likely that the PI pathway is modulated by estrogen in the permissive action of estrogen priming. Indeed, a literature review shows that estrogen can affect selective isozymes of key enzyme families of the PI pathway at various levels. Such selective modulations, at several levels, could easily alter the course of a PI cascade; thence, the eventual functional outcome. These findings prompt us to propose that estrogen enables lordosis to be facilitated by a selective modulation of the PI pathway.
Topics: Animals; Estrogens; Female; Neurons; Neuropeptides; Neurotransmitter Agents; Posture; Second Messenger Systems; Sexual Behavior, Animal
PubMed: 7914686
DOI: 10.1016/0149-7634(94)90028-0 -
Environmental Evidence 2022Altering the natural flow regime, an essential component of healthy fluvial systems, through hydropower operations has the potential to negatively impact freshwater fish... (Review)
Review
BACKGROUND
Altering the natural flow regime, an essential component of healthy fluvial systems, through hydropower operations has the potential to negatively impact freshwater fish populations. Establishing improved management of flow regimes requires better understanding of how fish respond to altered flow components, such as flow magnitude. Based on the results of a recent systematic map on the impacts of flow regime changes on direct outcomes of freshwater or estuarine fish productivity, evidence clusters on fish abundance and biomass responses were identified for full systematic review. The primary goal of this systematic review is to address one of those evidence clusters, with the following research question: how do changes in flow magnitude due to hydropower operations affect fish abundance and biomass?
METHODS
This review follows the guidelines of the Collaboration for Environmental Evidence. It examined commercially published and grey literature originally identified during the systematic map process and a systematic search update. All articles were screened using an a priori eligibility criteria at two stages (title and abstract, and full-text) and consistency checks were performed at all stages. All eligible articles were assessed for study validity and specifically designed data extraction and study validity tools were used. A narrative synthesis included all available evidence and meta-analysis using the standardized mean difference (Hedges' ) was conducted where appropriate.
REVIEW FINDINGS
A total of 133 studies from 103 articles were included in this systematic review for data extraction and critical appraisal. Most studies were from North America (60%) and were conducted at 146 different hydropower dams/facilities. Meta-analysis included 268 datasets from 58 studies, separated into three analyses based on replication type [temporal (within or between year replication) or spatial]. Fish abundance (226 datasets) and biomass (30 datasets) had variable responses to changes in flow magnitude with estimated overall mean effect sizes ranging from positive to negative and varying by study design and taxa. In studies with temporal replication, we found a detectable effect of alterations to the direction of flow magnitude, the presence of other flow components, sampling methods, season, and fish life stage. However, we found no detectable effect of these moderators for studies with spatial replication. Taxonomic analyses indicated variable responses to changes in flow magnitude and a bias towards salmonid species.
CONCLUSIONS
This synthesis did not find consistent patterns in fish abundance or biomass responses to alterations or changes in flow magnitude. Fish responses to flow magnitude alterations or changes were highly variable and context dependent. Our synthesis suggests that biotic responses may not be generalizable across systems impacted by hydroelectric power production and operations, where specific features of the system may be highly influential. Site-specific and adaptive management may be necessary. To improve study validity and interpretability, studies with long-term continuous monitoring, and both temporal and spatial replication are needed. When this gold standard is unfeasible, studies should strive, at minimum, to maximize replication within both intervention and comparator groups for either temporal or spatial designs. To further address knowledge gaps, studies are needed that focus on non-salmonids, multiple seasons, and systems outside of North America.
SUPPLEMENTARY INFORMATION
The online version contains supplementary material available at 10.1186/s13750-021-00254-8.
PubMed: 35136590
DOI: 10.1186/s13750-021-00254-8 -
Journal of Biomechanics Jul 2019Much is still unknown about walking stability, including which aspects of gait contribute to higher stability. Walking stability appears to be related to walking speed,...
Much is still unknown about walking stability, including which aspects of gait contribute to higher stability. Walking stability appears to be related to walking speed, although the exact relationship is unclear. As walking speed decreases, the double support (DS) period of gait increases both in time and as a percentage of the gait cycle. Because humans have more control over their center of mass movement during DS, increasing DS duration may alter stability. This study examined how human gait is affected by changing DS percentage independent of walking speed. Sixteen young, healthy adults walked on a treadmill at a single speed for six one-minute trials. These trials included normal gait as well as longer- and shorter-than-normal DS percentage gaits. Subjects were consistently able to decrease DS percentage but had difficulty increasing DS percentage. In some cases, subjects altered their cadence when changing DS percentage, particularly when attempting to increase DS percentage. The changes to gait when decreasing DS percentage were similar to changes when increasing walking speed but occurred mainly during the swing period. These changes include increased hip and knee flexion during the swing period, increased swing foot height, and larger magnitude peaks in ground reaction forces. The changes in gait when attempting to increase DS percentage trended toward changes when decreasing walking speed. Altering DS percentage induced gait changes that were similar to, yet clearly distinct from, gait changes due to walking speed. Further, the difficulty of increasing DS percentage when walking at a constant speed suggests that people walk more slowly when they want to increase time spent in DS.
Topics: Adolescent; Adult; Ankle Joint; Biomechanical Phenomena; Female; Foot; Hip Joint; Humans; Knee Joint; Male; Walking; Young Adult
PubMed: 31171369
DOI: 10.1016/j.jbiomech.2019.05.028