Secondary endpoints included changes in areal bone mineral density (BMD by dual-energy X-ray absorptiometry [DXA]) and serum markers of bone turnover including type I collagen peptides CrossLaps (CTX), procollagen type 1 amino-terminal propeptide (P1NP), and osteocalcin (OC). At baseline, cancellous bone matrix mineralization from mOP was lower than published reference data (mean degree of mineralization Cn.CaMean -1.8%, p smaller than 0.01). IBN treatment increased calcium concentrations versus baseline (Cn.CaMean +2.4%, Ct.CaMean, +3.0% both p smaller than 0.01), and reduced heterogeneity of mineralization (Cn.CaWidth -14%, p=0.044; Ct.CaWidth, -16%, p=0.001),

leading to cancellous BMDD within normal range. IBN treatment was associated with a decrease in porosity APR-246 Apoptosis inhibitor of mineralized cortical tissue (-25%, p=0.01); increases in BMD at the lumbar spine, the femoral neck, and the total hip (+3.3%, +1.9%, and +5.6%, respectively, p 0.01); and reductions in CTX (-37.5%), P1NP (-44.4%), and OC (-36.3%, all

p smaller than 0.01). Our BMDD findings are in line with the reduction of bone turnover markers and the increase in BMD by IBN in our patients and suggest that DZNeP the latter mainly reflects the increase in matrix mineralization and the reduction of cortical porosity in this cohort with mOP. (c) 2014 American Society for Bone and Mineral Research.”
“Polymerizable lipids have been used in research and medical applications such as membrane models, imaging platforms,

drug delivery systems, vaccine carriers, biosensors, and coating materials. The polymerization AZD5363 of these lipid molecules forms a covalent bond between lipid moieties, which improves the noncovalent interactions that maintain the lipid lamellar phase architecture and increases the stability of the polymerized system. Because such lipid molecules form nanoassemblies with modifiable structures that acquire the stability of polymers following covalent bond formation, these lipids are of considerable Interest in the emerging field of theranostics.\n\nIn this Account, we summarize the biomedical applications of polymerizable lipids (primarily phospholipids) in the context of various nanoplatforms. We discuss stable nanoplatforms, which have been used in a variety of theranostics applications. In addition, we describe methods for assembling triggerable theranostics by combining appropriate nonpolymerizable lipids with polymerizable lipids.\n\nPolymeric lipids hold promise as nanotools in the field of medical imaging, targeting, and on-demand drug delivery. Because of their similarity to biological lipids, long-term toxicity issues from polymerizable lipid nanoplatforms are predicted to be minimal. Although the field of polymeric nanocapsules is still in development, intensive efforts are underway to produce systems which could be applied to disease diagnosis and treatment.

“
“The modified busulfan-cyclophosphamide (mBuCy) regimen, combined with hydroxyurea, cytarabine and semustine, is the most frequently used myeloablative conditioning regimen for allogeneic hematopoietic stem cell transplantation in our unit. It is unknown, however, whether fludarabine can be substituted for cyclophosphamide in the mBuCy regimen. We carried out a prospective study to compare modified busulfan-fludarabine (mBuF) with mBuCy, aiming to reduce the treatment-related

mortality, with non-inferiority of other outcomes. The mBuCy regimen consisted of hydroxyurea 80 mg/kg on day -10; cytarabine 2 g/m(2) on day -9; busulfan 9.6 mg/kg, intravenously on day -8 through -6; and cyclophosphamide 3.6 g/m(2) on

day -5 and -4 and semustine AZ 628 mouse 250 mg/m(2) on day -3. In the mBuF regimen, cyclophosphamide was substituted with fludarabine 30 mg/m(2) through day -5 to -1. Mobilized blood and marrow selleckchem stem cells were collected from HLA-matched siblings. The trial was suspended due to a tendency of higher incidence of severe pneumonia in the mBuF arm, in which 105 patients were enrolled. After follow-up for another 22 months, a significantly increased incidence of severe pneumonia (31.1 %) was observed in the mBuF arm (11.6 % in mBuCy). This finding suggests that it is uncertain whether it is appropriate to substitute fludarabine for cyclophosphamide under any drug combination. This study was registered at www.chictr.org/cn under identifier ChiCTR-TRC-09000470.”
“The extraction device used in rotating-disk sorptive extraction consists of a Teflon disk in which a sorptive phase is fixed on one of its surfaces. Depending GSK461364 cell line on the configuration, the rotation axis of the disk device can be either perpendicular or parallel to its radius, giving rise to two different mass transfer patterns when rotating-disk sorptive extraction is applied in liquid samples. In the perpendicular case (configuration 1), which is the typical configuration,

the disk contains an embedded miniature stir bar that allows the disk rotation to be driven using a common laboratory magnetic stirrer. In the parallel case (configuration 2), the disk is driven by a rotary rod connected to an electric stirrer. In this study, triclosan and its degradation product methyl triclosan were used as analyte models to demonstrate the significant effect of the rotation configuration of the disk on the efficiency of analyte mass transfer from water to a sorptive phase of polydimethylsiloxane. Under the same experimental conditions and at a rotation velocity of 1,250 rpm, extraction equilibrium was reached at 80 min when the disk was rotated in configuration 1 and at 30 min when the disk was rotated in configuration 2. The extraction equilibration time decreased to 14 min when the rotation velocity was increased to 2,000 rpm in configuration 2.

These conditions which are sometimes underdiagnosed in clinical practice

must be addressed by appropriate adjunctive psychosocial approaches or other treatments. Treatment adherence has a crucial role in the prevention of aggressive behavior in schizophrenia patients.”
“Metabolic profiling was carried out in the forage grass Lolium perenne L. (perennial ryegrass) to uncover mechanisms involved in the plants response to water stress. When leaf and root materials from two genotypes, with a contrasting water stress response, were analysed by GC-MS, a clear difference in the metabolic profiles of the leaf tissue under water stress was observed. Differences were principally due to a reduction in fatty acid levels in the more susceptible Cashel genotype and an increase in sugars and compatible solutes in the more tolerant PI 462336 genotype. Sugars with a significant increase included: 17DMAG in vivo raffinose, trehalose, glucose, fructose and maltose. Increasing

the ability of perennial ryegrass to accumulate these sugars in response to a water deficit may lead to more tolerant varieties. The metabolomics approach was combined with a transcriptomics approach in the water stress tolerant genotype PI 462336, which has identified perennial ryegrass genes regulated underwater stress.”
“The Netherlands Organization for Applied Scientific Research (TNO) has Pexidartinib clinical trial installed a compact 1 MV multi-element AMS system manufactured by High Voltage Engineering Europa B.V., The Netherlands. TNO performs clinical research programs for pharmaceutical and innovative foods industry to obtain early pharmacokinetic data and to provide anti-osteoporotic efficacy data of new treatments. The AMS system will analyze carbon, iodine and calcium samples for this purpose. The first measurements on blank samples

indicate background levels in the low 10(-12) for calcium and iodine, making the system well suited for these biomedical applications. Carbon blanks have been measured at low 10(-16). For unattended, around-the-clock analysis, the system features GSK690693 nmr the 200 sample version of the SO110 hybrid ion source and user friendly control software. (c) 2012 Published by Elsevier B.V.”
“Weekly monitoring of dissolved methane (CH4) at two sites along an similar to 2-km stretch of the Willamette River (Oregon) between October 2008 and November 2010 revealed persistent supersaturation (24-170X atmospheric equilibrium). The CH4 concentration difference (Delta CH4: 0-200 nmol L-1) between the two sites varied inversely with river flow, which ranged from 125 m(3) s(-1) to 1500 m(3) s(-1) over the time series. At the downstream site, an ‘excess’ of <= 125% was observed, with groundwater input being the likely CH4 source. Quasi-synoptic studies of spatial trends in summer (2010, 2011) revealed steady CH4 decrease along a 12-km river stretch downstream of the time-series sites.

The objective of this study was to determine the relationship between overweight and survival in this setting.\n\nMethods. We evaluated 271 cardiac transplant recipients engrafted from 1991 to 2009 whose age was 50.3 +/- 12.1 (mean; SD) years. Their body mass index (BMI) was 25.7 +/- 3.9 kg/m(2). Regarding gender, 85.2% were males. Patients were classified by pretransplantation BMI into group A (>25 kg/m(2)) and group B PI3K inhibitor (<25 kg/m(2)). We analyzed the differences in mortality and related factors.\n\nResults. One hundred fifty Group A patients (55.4%) showed a slightly lower median survival (7.35 vs 8.62 years; P = .152). Group A patients were at higher

risk of death within 1 year of follow-up (HR, 1.71; confidence interval [CI], 0.996-2.939; P = .051). Overweight was associated with increased mortality at 1 year after adjustment for age, recipient gender, hypertension, diabetes mellitus, hypercholesterolemia, coronary artery disease, and donor-recipient heart size mismatch. The incidence

of primary graft failure was also significantly increased in group A (HR, 2.74; CI, 1.17-6.40; P = .017) after adjustment for the same variables. There were no significant differences between the groups concerning surgical ischemic time, number of acute rejection episodes, and infections during the first year.\n\nConclusion. AICAR concentration In our sample, overweight was associated with increased mortality and an increased incidence of primary graft failure within 1 year after cardiac transplantation.”
“We report the design of a two-dimensional gradient-index phononic crystal (GRIN PC) structure, which effectively

demonstrates the “acoustic mirage” effect on the wavelength scale. Using the GRIN PC, the propagating direction of acoustic waves can be continuously bent along an arc-shaped trajectory by gradually tuning the filling ratio of PCs. We investigate the acoustic mirage effect through both Duvelisib ic50 plane wave expansion and finite-difference time-domain methods. By controlling the incident angle or operating frequency, the arc-shaped trajectory of acoustic wave propagation can be dynamically adjusted. The GRIN PC structure is composed of steel cylinders, positioned in a square lattice, and immersed in an epoxy. It can be fabricated through a simple process and seamlessly integrated with existing acoustic devices. In addition, we establish that such an acoustic effect can be used in the design of tunable acoustic waveguides, which could find applications in acoustic switching, filtering, and biosensing.”
“Through the hydrogen bonds and the deprotonation, the vancomycin-chitosan composite has been originally deposited on Ti4Al4V by electrochemical technology. However, the rapid destruction of the hydrogen bonding between them by polar water molecules during immersion tests revealed 80% drug burst in a few hours.

This suggests the existence of less severe forms of BCD related to relatively mild CYP4V2 mutations.”
“Background and objectiveExacerbations of chronic obstructive pulmonary disease (COPD) are a major cause of morbidity, mortality and reduced health status. Thus,

to predict and prevent exacerbations is essential for the management of COPD. The aims of this study were to determine whether nutritional status BLZ945 mw as assessed by the Mini Nutritional Assessment Short-Form (MNA-SF) predicts COPD exacerbation and to compare the ability of the MNA-SF to predict COPD exacerbation with that of the COPD Assessment Test (CAT). MethodsPulmonary function, the modified Medical Research Council (mMRC) scale and body mass index (BMI) were evaluated in 60 stable patients with COPD (mean age, 72years; mean forced expiratory P005091 volume in 1s (FEV1), 51.1% predicted). The MNA-SF and CAT were also completed. Exacerbations were recorded prospectively for 1 year after the initial assessment. ResultsThe mean MNA-SF score was 11.42.4 (well nourished, 51%; at risk, 37%; and malnourished, 12%). The mean CAT score

was 14.47.5 (low impact, 37%; medium impact, 38%; high impact, 20%; and very high impact, 5%). The CAT scores were significantly associated with the mMRC scale and %FEV1, but were not associated with BMI and the MNA-SF score. The exacerbation frequency was associated with the MNA-SF score but not with the CAT score. ConclusionsThe MNA-SF predicts COPD exacerbation independently of the CAT. Nutritional impairment is an important systemic manifestation associated with a poor prognosis in COPD. The Mini Nutritional Assessment Short-Form (MNA-SF) is a useful nutritional assessment tool of elderly patients. Although MNA-SF score did not correlate with COPD Assessment Test (CAT) score, it predicted exacerbation frequency in COPD independently of CAT.”
“In Halobacterium salinarum, up to 18 sensory Omipalisib manufacturer transducers (Htrs) relay environmental stimuli to an intracellular signaling system to induce tactic responses. As known from the extensively studied enterobacterial system,

sensory adaptation to persisting stimulus intensities involves reversible methylation of certain transducer glutamate residues, some of which originate from glutamine residues by deamidation. This study analyzes the in vivo deamidation and methylation of membrane-bound Htrs under physiological conditions. Electrospray ionization tandem mass spectrometry of chromatographically separated proteolytic peptides identified 19 methylation sites in 10 of the 12 predicted membrane-spanning Htrs. Matrix-assisted laser desorption/ionization mass spectrometry additionally detected three sites in two soluble Htrs. Sensory transducers contain a cytoplasmic coiled-coil region, composed of hydrophobic heptads, seven-residue repeats in which the first and the fourth residues are mostly hydrophobic.

For the peptides, the optimal binding ratios were consistent with ratios established previously for the binding of these peptides to monolayers of anionic lipids. The optimal AMPK inhibitor formulation containing these peptides were able to reach low minimum surface tension in systems containing 500 mu l/ml of serum, matching the effectiveness of a lung surfactant extract that had not undergone post-separation processes and therefore

contained all its proteins and lipids (complete lung surfactant). (C) 2010 Elsevier B.V. All rights reserved.”
“Objective: To document neurologic, oncologic, and serologic associations of patients in whom voltage-gated potassium channel (VGKC) autoantibodies were detected in the course of serologic evaluation for neuronal, glial, and muscle autoantibodies.\n\nMethods: Indirect immunofluorescence screening of sera from 130,000 patients performed on a service basis for markers of paraneoplastic neurologic autoimmunity identified 80 patients whose IgG bound to the synapse-rich molecular layer of mouse cerebellar cortex in a pattern consistent with VGKC immunoreactivity. Antibody specificity was confirmed in all cases by immunoprecipitation of see more detergent-solubilized brain synaptic proteins complexed with I-125-alphadendrotoxin.\n\nResults: Clinical information was available

for 72 patients: 51% women, median age at symptom onset 65 years, and median follow-up period 14 months. Neurologic manifestations were acute to subacute in onset in 71% and multifocal in 46%; 71% had cognitive impairment, 58% seizures, 33% dysautonomia, 29% myoclonus, 26% dyssomnia, 25% peripheral nerve dysfunction, 21% extrapyramidal dysfunction, and 19% brainstem/cranial nerve dysfunction. Creutzfeldt-Jakob disease was a common misdiagnosis (14%). Neoplasms encountered (confirmed histologically in 33%) included 18 carcinomas, 5 adenomas, 1 thymoma, and 3 hematologic malignancies. Hyponatremia was documented in 36%, other organ-specific autoantibodies in 49%, and a co-existing autoimmune disorder in 33% (including thyroiditis 21%, type

1 diabetes mellitus 11%). Benefit buy SIS3 was reported for 34 of 38 patients (89%) receiving immunotherapy and was marked in 50%.\n\nConclusions: The spectrum of neurologic manifestations and neoplasms associated with voltage-gated potassium channel (VGKC) autoimmunity is broader than previously recognized. Evaluation for VGKC antibodies is recommended in the comprehensive autoimmune serologic testing of subacute idiopathic neurologic disorders.”
“Lithium diisopropylamide (LDA)-mediated ortholithiations of 2-fluoropyridine and 2,6-difluoropyridine in tetrahydrofuran at -78 degrees C were studied using a combination of IR and NMR spectroscopic and computational methods. Rate studies show that a substrate-assisted deaggregation of LDA dimer occurs parallel to an unprecedented tetramer-based pathway.

Correspondingly levels

of cross-linked carboxyterminal telopeptide of type I collagen (ICTP) were higher in the CDET and tissue fluorescence lower suggesting more rapid turnover of the collagenous component. Reduced or inhibited collagen turnover in the SDFT may account for the high level of degeneration and subsequent injury compared to the CDET. (C) 2007 Elsevier B.V/International Society of Matrix Biology. All rights reserved.”
“Sepsis is a major cause of mortality and morbidity in trauma patients despite aggressive treatment. Traumatic injury may trigger infective or non-infective systemic inflammatory response syndrome (SIRS) and sepsis. Sepsis and SIRS are accompanied by an inability to regulate the inflammatory response but the cause of this perturbation is still unknown. The major pathophysiological selleck kinase inhibitor characteristic of sepsis is the vascular collapse (i.e., loss of control of vascular tone); however, at the cellular level the final mediator of extreme vasodilatation has yet to be identified. After trauma, cellular injury releases endogenous damage-associated molecular patterns (DAMPS)

that activate the innate immune system. Mitochondrial DAMPS express at least two molecular signatures, N-formyl peptides and LBH589 molecular weight mitochondrial DNA that act on formyl peptide receptors (FPRs) and Toll-like receptor 9, respectively. N-Formyl peptides are potent immunocyte activators and, once released in the circulation, they induce modulation of vascular tone by cellular mechanisms that are not completely understood. We have observed that N-formyl peptides from bacterial (FMLP) and mitochondrial (FMIT) sources induce FPR-mediated vasodilatation in resistance arteries.

Accordingly, we propose that tissue and cellular trauma induces the release of N-formyl peptides from mitochondria triggering inflammation and vascular collapse via activation of FPR and contributing to the development of sepsis. The proposed hypothesis provides clinically significant information linking trauma, mitochondrial N-formyl peptides and inflammation to vascular collapse and sepsis. If our hypothesis is true, it may lead to new strategies in the management of sepsis that can help clinicians effectively manage non-infectious and infectious inflammatory responses. (C) 2013 Elsevier Ltd. All rights reserved.”
“Systemic lupus erythematosus AS1842856 order (SLE) is a complex heterogeneous disease, posing challenges to clinical trials. As in other autoimmune diseases, B-lymphocytes play a central role in lupus pathogenesis. The finding that selection and survival of B cells are controlled by a variety of signals, including those provided by the longevity factor BAFF (B-cell activating factor), also called BLyS (B-lymphocyte stimulator), led to preclinical trials that revealed that BAFF represents a promising therapeutic target for human lupus. Belimumab is a fully human monoclonal antibody directed against BAFF.

Patients who experienced an INR higher than 5 were designated as case patients; those who received warfarin for at least as many days as the case patients but who did not experience an INR more than 5 were deemed control

patients. Controls were matched to cases in a 2:1 ratio by age, sex, INR Selleck Belnacasan goal, and type of warfarin therapy (new start or continuation).\n\nMeasurements and Main ResultsA total of 87 case patients were matched to 174 controls. Ten different hypothesized risk factors were examined. Two variables, severity of illness score (odds ratio [OR] 4.89, p<0.001) and poor nutritional status (OR 4.27, p<0.001), demonstrated strong independent associations with risk of excessive anticoagulation. Administration of interacting drugs that highly potentiate warfarin’s effect (OR 2.26, p=0.011) and concurrent diarrheal illness (OR 4.75, p<0.001) also displayed a statistically significant risk for excessive anticoagulation.\n\nConclusionEven in a highly standardized system for warfarin dosing by a pharmacist-managed protocol, higher disease severity and poor nutritional status placed hospitalized patients at greater GSK690693 risk of experiencing excessive anticoagulation. In addition, administration of interacting drugs that highly potentiate warfarin’s effect or the occurrence of diarrheal

illness may predict increased risk.”
“Objective. Initial optimized prescription of Chinese herb medicine for unstable angina (UA). Methods. Based on partially observable Markov decision process model (POMDP), we choose hospitalized Etomoxir patients of 3 syndrome elements, such as qi deficiency, blood stasis, and turbid phlegm for the data mining, analysis, and objective evaluation of the diagnosis and treatment of UA at a deep level in order to optimize the prescription of Chinese herb medicine for UA. Results. The recommended treatment options of UA for qi deficiency, blood stasis, and phlegm syndrome patients were as follows: Milkvetch Root + Tangshen + Indian Bread + Largehead Atractylodes Rhizome (ADR = 0.96630); Danshen Root + Chinese Angelica + Safflower + Red Peony Root

+ Szechwan Lovage Rhizome Orange Fruit (ADR = 0.76); Snakegourd Fruit + Longstamen Onion Bulb + Pinellia Tuber + Dried Tangerine peel + Largehead Atractylodes Rhizome + Platycodon Root (ADR = 0.658568). Conclusion. This study initially optimized prescriptions for UA based on POMDP, which can be used as a reference for further development of UA prescription in Chinese herb medicine.”
“Barriers to migration are numerous in stream environments and can occur from anthropogenic activities (such as dams and culverts) or natural processes (such as log jams or dams constructed by beaver (Castor canadensis)). Identification of barriers can be difficult when obstructions are temporary or incomplete providing passage periodically.

e. messages contesting industry marketing) make pre-adolescent children less susceptible to the influence of food promotions. Since children have lower media literacy levels due to their immature cognitive abilities, specific research questions explored were: (1) whether the effectiveness of counter-ads is contingent on children having understood them; and (2) whether counter-ads may be detrimental when they are misinterpreted. A between-subjects experimental design using a web-based methodology was employed. 1351 grade 5-6 students (mean

age 11 years) from schools located in metropolitan Navitoclax research buy Melbourne, Australia participated. Participants were randomly shown an animated web banner advertisement (counter-ad challenging front-of-package promotion or control ad) and a pair of food packages from the same product category comprising an unhealthy product featuring a front-of-package promotion (nutrient content claim or sports celebrity endorsement) and a healthier control pack without a front-of-package promotion. Responses to the assigned advertisement, choice of product (healthy versus ALK inhibitor unhealthy) and ratings of the unhealthy product and front-of-package promotion on various nutritional and image-related

attributes LY3023414 were recorded for each child. Sixty-six percent of children who viewed a counter-ad understood its main message. These children rated the front-of-package promotion as less believable and rated the unhealthy product bearing the front-of-package promotion as less healthy compared to the control group. However, children who misunderstood the counter-ad rated the unhealthy product bearing a front-of-package

promotion as more healthy and rated the front-of-package promotion more favourably than those who correctly understood the counter-ad. Counter-advertising may have unintended consequences when misunderstood. If public health organizations or government pursue counter-advertising as a strategy to reduce the negative influence of unhealthy food marketing among children, caution is needed in designing counter-ads to guard against possible contradictory effects. (C) 2014 Elsevier Ltd. All rights reserved.”
“AZO (Al:ZnO) nanostructured thin film was prepared by a dip coating technique. An improved sol-gel method was used for the preparation of stable AZO sal with 2 at% Al dopant concentration. Optical properties of AZO thin film have been studied by UV-visible absorption and photoluminescence spectroscopy.

Antibodies to pregnancy-specific

and non-pregnancy-specific Plasmodium falciparum variant surface antigens (VSA) and concentrations of cytokines TNF, IFN gamma, IL-1 beta, IL-6, IL-8 and IL-10 were measured. Results. Pregnant women with SM demonstrated significantly lower antibody levels to pregnancy-specific VSA (P = .020) and higher plasma IFN gamma (P = .020), IL-10 (P = .0002) and IL-6 levels (P smaller than .0001) than uninfected pregnant women. Concentrations of inflammatory cytokines IL-1 beta https://www.selleckchem.com/products/epz015666.html (P = .001), IL-6 (P = .004) and IL-8 (P = .020) were inversely correlated with antibodies to VAR2CSA-DBL5 in pregnant women with SM. Lower haemoglobin levels and higher parasite densities Pevonedistat chemical structure were associated with lack of pregnancy-specific antibodies (P = .028) and higher levels of inflammatory cytokines, in particular IL-6 and IL-8. Conclusions. Pregnant women with SM lack pregnancy-specific malaria immunity, and this correlates with heightened inflammatory cytokine concentrations, low haemoglobin levels and high parasite density, suggesting that failure of antibody to control parasitaemia may contribute to SM pathogenesis.”
“Endometriosis is defined as the existence of endometrial tissue outside the uterine

cavity, and it includes a chronic, inflammatory reaction associated with female infertility and pelvic pain. Endometriosis occurs in 7 to 10% of women. Although it has been studied for more than 50 years, the pathogenesis and development of endometriosis are still poorly understood. There is no curative therapy for endometriosis, which often recurs after surgical or medical treatment. There is a consensus that the adverse current of menstrual blood plays a crucial role in the development of endometriosis. This places a major limitation on research using rodent models of endometriosis, although these are still widely employed, because rodents do not menstruate and

endometriosis does not occur spontaneously in these animals. In fact, menstruation and spontaneous endometriosis only occur Angiogenesis inhibitor in women and some non-human primates, making models that employ non-human primates the best animal models for research into the pathogenesis, pathophysiology, spontaneous onset, and treatment of endometriosis. This review assesses the effectiveness and potential of the non-human primate models of endometriosis. It also describes the current findings and theories on the pathogenesis of endometriosis that have been obtained by research using non-human primates.”
“The development of systemic therapy drug resistance for breast cancer treatment is an ongoing problem, thus, so are the potential molecular mechanisms of it.