A conserved SREBP-1/phosphatidylcholine feedback circuit regulates lipogenesis in metazoans.

Sterol regulatory element-binding proteins (SREBPs) activate genes involved in the synthesis and trafficking of cholesterol and other lipids and are critical for maintaining lipid homeostasis. Aberrant SREBP activity, however, can contribute to obesity, fatty liver disease, and insulin resistance, hallmarks of metabolic syndrome. Our studies identify a conserved regulatory circuit in which SREBP-1 controls genes in the one-carbon cycle, which produces the methyl donor S-adenosylmethionine (SAMe). Methylation is critical for the synthesis of phosphatidylcholine (PC), a major membrane component, and we find that blocking SAMe or PC synthesis in C. elegans, mouse liver, and human cells causes elevated SREBP-1-dependent transcription and lipid droplet accumulation. Distinct from negative regulation of SREBP-2 by cholesterol, our data suggest a feedback mechanism whereby maturation of nuclear, transcriptionally active SREBP-1 is controlled by levels of PC. Thus, nutritional or genetic conditions limiting SAMe or PC production may activate SREBP-1, contributing to human metabolic disorders.

A Pragmatic Clinical Trial of Hearing Screening in Primary Care Clinics: Effect of Setting and Provider Encouragement.

OBJECTIVES: The prevalence of hearing loss increases with age. Untreated hearing loss is associated with poorer communication abilities and negative health consequences, such as increased risk of dementia, increased odds of falling, and depression. Nonetheless, evidence is insufficient to support the benefits of universal hearing screening in asymptomatic older adults. The primary goal of the present study was to compare three hearing screening protocols that differed in their level of support by the primary care (PC) clinic and provider. The protocols varied in setting (in-clinic versus at-home screening) and in primary care provider (PCP) encouragement for hearing screening (yes versus no). DESIGN: We conducted a multisite, pragmatic clinical trial. A total of 660 adults aged 65 to 75 years; 64.1% female; 35.3% African American/Black completed the trial. Three hearing screening protocols were studied, with 220 patients enrolled in each protocol. All protocols included written educational materials about hearing loss and instructions on how to complete the self-administered telephone-based hearing screening but varied in the level of support provided in the clinic setting and by the provider. The protocols were as follows: (1) no provider encouragement to complete the hearing screening at home, (2) provider encouragement to complete the hearing screening at home, and (3) provider encouragement and clinical support to complete the hearing screening after the provider visit while in the clinic. Our primary outcome was the percentage of patients who completed the hearing screening within 60 days of a routine PC visit. Secondary outcomes following patient access of hearing healthcare were also considered and consisted of the percentage of patients who completed and failed the screening and who (1) scheduled, and (2) completed a diagnostic evaluation. For patients who completed the diagnostic evaluation, we also examined the percentage of those who received a hearing loss intervention plan by a hearing healthcare provider. RESULTS: All patients who had provider encouragement and support to complete the screening in the clinic completed the screening (100%) versus 26.8% with encouragement to complete the screening at home. For patients who were offered hearing screening at home, completion rates were similar regardless of provider encouragement (26.8% with encouragement versus 22.7% without encouragement); adjusted odds ratio of 1.25 (95% confidence interval 0.80-1.94). Regarding the secondary outcomes, roughly half (38.9-57.1% depending on group) of all patients who failed the hearing screening scheduled and completed a formal diagnostic evaluation. The percentage of patients who completed a diagnostic evaluation and received a hearing loss intervention plan was 35.0% to 50.0% depending on the group. Rates of a hearing loss intervention plan by audiologists ranged from 28.6% to 47.5% and were higher compared with those by otolaryngology providers, which ranged from 15.0% to 20.8% among the groups. CONCLUSIONS: The results of the pragmatic clinical trial showed that offering provider encouragement and screening facilities in the PC clinic led to a significantly higher rate of adherence with hearing screening associated with a single encounter. However, provider encouragement did not improve the significantly lower rate of adherence with home-based hearing screening.

OMA-gosh, where's that TAF?

How transcription is silenced in early embryos has long been a mystery. In this issue, Guven-Ozkan et al. (2008) report that transcriptional repression during worm embryogenesis is mediated through sequestration of the general transcription factor TAF-4 and is regulated by mechanisms that orchestrate the transition between maternal and zygotic gene expression.

Clinical service delivery implications of the COVID-19 pandemic on people with Inflammatory bowel disease: a qualitative study.

BACKGROUND: During the COVID-19 pandemic, clinical services were severely disrupted, restricted, or withdrawn across the country. People living with Inflammatory Bowel Disease (IBD) - an auto-immune disorder for which medical treatment often results in immunosuppression, thus requiring regular monitoring-may have struggled to access clinical support. As part of a larger qualitative study, we investigated experiences of access to clinical services during the pandemic, and patient concerns about and preferences for services in the future. METHODS: This exploratory qualitative study used semi-structured interviews to explore participants' experiences of clinical services across the UK during the pandemic. All data were collected remotely (March - May 2021) using online video-calling platforms or by telephone. Audio files were transcribed professionally and anonymised for analysis. Data were analysed using thematic analysis. RESULTS: Of the eight themes found across all data, four related specifically to accessing GP, local (district) hospital, and specialist (tertiary) referral services for IBD: 1) The Risk of Attending Hospital; 2) Missing Routine Monitoring or Treatment; 3) Accessing Care as Needed, and 4) Remote Access and The Future. CONCLUSIONS: Our findings support other studies reporting changes in use of health services, and concerns about future remote access methods. Maintenance of IBD services in some form is essential throughout crisis periods; newly diagnosed patients need additional support; future dependence on IBD services could be reduced through use of treatment / self-management plans. As the NHS digitalises it's future services, the mode of appointment-remote (telephone, video call), or in-person - needs to be flexible and suit the patient.

In vivo observations of biofilm adhering to a dialkylcarbamoyl chloride-coated mesh dressing when applied to diabetes-related foot ulcers: A proof of concept study.

In this proof-of-concept study of twenty participants, we sought to determine if a DACC (Dialkylcarbamoyl chloride)-coated mesh dressing demonstrates an ability to adhere biofilm when placed on Diabetes Related Foot Ulcers (DRFUs) with chronic infection. The study also sought to determine if removal of the DACC-coated mesh dressings contributes to reducing the total number of bacteria in DRFUs, by exploring the total microbial loads, microbial community composition, and diversity. Standard of care was provided in addition to the application of DACC or DACC hydrogel every three days for a total of two weeks. Wound swabs, tissue curettage, and soiled dressings were collected pre and post-treatment. Tissue specimens obtained pre-treatment were analysed with scanning electron microscopy (SEM) and peptide nucleic acid fluorescent in situ hybridisation (PNA-FISH) with confocal laser scanning microscopy and confirmed the presence of biofilm in all DRFUs. SEM confirmed the presence of biofilms readily adhered to soiled DACC-coated mesh dressings pre- and post-treatment in all participants. Real-time quantitative polymerase chain reaction (qPCR) demonstrated the mean total microbial load of DRFUs in 20 participants did not change after two weeks of therapy (pre-treatment = 4.31 Log10 16 S copies (±0.8) versus end of treatment = 4.32 Log10 16 S copies (±0.9), P = .96, 95% CI -0.56 to 0.5). 16 S sequencing has shown the microbial composition of DACC dressings and wound swabs pre- and post-treatment remained similar (DACC; R = -.047, P = .98, Swab; R = -.04, P = .86), indicating the microbial communities originate from the ulcer. Biofilms adhere to DACC-coated mesh dressings; however, this may not reduce the total microbial load present within DRFU tissue. Wound dressings for use in hard-to-heal wounds should be used as an adjunct to a good standard of care which includes debridement and wound bed preparation.

A pragmatic clinical trial of hearing screening in primary care clinics: cost-effectiveness of hearing screening.

BACKGROUND: Hearing loss is a high prevalence condition among older adults, is associated with higher-than-average risk for poor health outcomes and quality of life, and is a public health concern to individuals, families, communities, professionals, governments, and policy makers. Although low-cost hearing screening (HS) is widely available, most older adults are not asked about hearing during health care visits. A promising approach to addressing unmet needs in hearing health care is HS in primary care (PC) clinics; most PC providers (PCPs) do not inquire about hearing loss. However, no cost assessment of HS in community PC settings has been conducted in the United States. Thus, this study conducted a cost-effectiveness analysis of HS using results from a pragmatic clinic trial that compared three HS protocols that differed in the level of support and encouragement provided by the PC office and the PCPs to older adults during their routine visits. Two protocols included HS at home (one with PCP encouragement and one without) and one protocol included HS in the PC office. METHODS: Direct costs of the HS included costs of: (1) educational materials about hearing loss, (2) PCP educational and encouragement time, and (3) access to the HS system. Indirect costs for in-office HS included cost of space and minimal staff time. Costs were tracked and modeled for each phase of care during and following the HS, including completion of a diagnostic assessment and follow-up with the recommended treatment plan. RESULTS: The cost-effectiveness analysis showed that the average cost per patient is highest in the patient group who completed the HS during their clinic visit, but the average cost per patient who failed the HS is by far the lowest in that group, due to the higher failure rate, that is, rate of identification of patients with suspected hearing loss. Estimated benefits of HS in terms of improvements in quality of life were also far greater when patients completed the HS during their clinic visit. CONCLUSIONS: Providing HS to older adults during their PC visit is cost-effective and accrues greater estimated benefits in terms of improved quality of life. TRIAL REGISTRATION: clinicaltrials.gov (Registration Identification Number: NCT02928107).

Development of a vendor neutral MRI distortion quality assurance workflow.

With the utilization of magnetic resonance (MR) imaging in radiotherapy increasing, routine quality assurance (QA) of these systems is necessary. The assessment of geometric distortion in images used for radiotherapy treatment planning needs to be quantified and monitored over time. This work presents an adaptable methodology for performing routine QA for systematic MRI geometric distortion. A software tool and compatible protocol (designed to work with any CT and MR compatible phantom on any scanner) were developed to quantify geometric distortion via deformable image registration. The MR image is deformed to the CT, generating a deformation field, which is sampled, quantifying geometric distortion as a function of distance from scanner isocenter. Configurability of the QA tool was tested, and results compared to those provided from commercial solutions. Registration accuracy was investigated by repeating the deformable registration step on the initial deformed MR image to define regions with residual distortions. The geometric distortion of four clinical systems was quantified using the customisable QA method presented. Maximum measured distortions varied from 2.2 to 19.4 mm (image parameter and sampling volume dependent). The workflow was successfully customized for different phantom configurations and volunteer imaging studies. Comparison to a vendor supplied solution showed good agreement in regions where the two procedures were sampling the same imaging volume. On a large field of view phantom across various scanners, the QA tool accurately quantified geometric distortions within 17-22 cm from scanner isocenter. Beyond these regions, the geometric integrity of images in clinical applications should be considered with a higher degree of uncertainty due to increased gradient nonlinearity and B0 inhomogeneity. This tool has been successfully integrated into routine QA of the MRI scanner utilized for radiotherapy within our department. It enables any low susceptibility MR-CT compatible phantom to quantify the geometric distortion on any MRI scanner with a configurable, user friendly interface for ease of use and consistency in data collection and analysis.

Cuprous or cupric? How substrate polarity can select for different phases of copper sulfide films in chemical bath deposition.

Copper sulfides have many applications from thermoelectrics to biotechnology. While the properties of different copper sulfide phases are well understood, controlling the deposited copper sulfide stoichiometry remains a significant challenge, especially in solution-phase synthesis techniques. In this work, we investigate the chemical bath deposition of CuxS on functionalized self-assembled monolayers (SAMs). Time-of-flight mass spectrometry, Raman spectroscopy, and x-ray photoelectron spectroscopy are employed to analyze the deposited films. We show that the use of thiourea as a sulfur source leads to the deposition of different copper sulfide phases and is controlled by the interaction of sulfur-containing ions in solution with the functionalized SAMs. For -COOH terminated SAMs, copper sulfide deposition is controlled by the surface polarity of the substrate. At the bath pH used in these experiments, the -COOH terminal groups are deprotonated. The resulting -COO- terminated SAM surface repels negatively charged sulfur-containing ions, leading to the deposition of Cu2S. For -CH3 terminated SAMs, which are non-polar, there is no specific interaction between the SAM terminal group and sulfur-containing ions and CuS is deposited. For -OH terminated SAMs, which have a polar terminal group, there are two competing effects: the repulsion of S-containing ions by the small negative charge of the terminal -OH group and the increase in the concentration of sulfur-containing ions in solution as the bath pH increases. This competition leads to the deposit stoichiometry changing from Cu2S at pH 9 to CuS at pH 12.

6-Phenylhexyl silane derivatized, sputtered silicon solid phase microextraction fiber for the parts-per-trillion detection of polyaromatic hydrocarbons in water and baby formula.

We report the fabrication of 6-phenylhexylsilane derivatized, sputtered silicon, solid phase microextraction fibers that show parts per trillion detection limits for polyaromatic hydrocarbons, and negligible carry over and phase bleed. Their fabrication involves sputtering silicon on silica fibers under various conditions. Six different fibers were evaluated by generating three different thicknesses of sputtered silicon at two different throw distances, which altered the morphologies of the silicon surfaces. All of the fibers were coated with similar thicknesses of 6-phenylhexylsilane (ca. 2 nm). These fibers were characterized with multiple analytical techniques. The optimum fiber configuration was then used to analyze polyaromatic hydrocarbons via direct immersion, gas chromatography mass spectrometry. Our best fiber for the extraction of low molecular weight polyaromatic hydrocarbons in water had similar performance to that of a commercial fiber. However, our fiber demonstrated ca. 3 times the extraction efficiency for higher molecular weight polyaromatic hydrocarbons. In addition, it outperformed the commercial fiber by showing better linearity, repeatability, and detection limits. A method for analyzing polyaromatic hydrocarbons in baby formula was developed, which showed very good linearity (0.5-125 ppb), repeatability (2-26%), detection limits (0.12-0.81 ppb), and recoveries (103-135%). In addition, our fiber showed much less (negligible) carry over and phase bleed than the commercially available fibers.

Stress-responsive and metabolic gene regulation are altered in low S-adenosylmethionine.

S-adenosylmethionine (SAM) is a donor which provides the methyl groups for histone or nucleic acid modification and phosphatidylcholine production. SAM is hypothesized to link metabolism and chromatin modification, however, its role in acute gene regulation is poorly understood. We recently found that Caenorhabditis elegans with reduced SAM had deficiencies in H3K4 trimethylation (H3K4me3) at pathogen-response genes, decreasing their expression and limiting pathogen resistance. We hypothesized that SAM may be generally required for stress-responsive transcription. Here, using genetic assays, we show that transcriptional responses to bacterial or xenotoxic stress fail in C. elegans with low SAM, but that expression of heat shock genes are unaffected. We also found that two H3K4 methyltransferases, set-2/SET1 and set-16/MLL, had differential responses to survival during stress. set-2/SET1 is specifically required in bacterial responses, whereas set-16/MLL is universally required. These results define a role for SAM in the acute stress-responsive gene expression. Finally, we find that modification of metabolic gene expression correlates with enhanced survival during stress.

Determining the longitudinal accuracy and reproducibility of T1 and T2 in a 3T MRI scanner.

PURPOSE: To determine baseline accuracy and reproducibility of T1 and T2 relaxation times over 12 months on a dedicated radiotherapy MRI scanner. METHODS: An International Society of Magnetic Resonance in Medicine/National Institute of Standards and Technology (ISMRM/NIST) System Phantom was scanned monthly on a 3T MRI scanner for 1 year. T1 was measured using inversion recovery (T1 -IR) and variable flip angle (T1 -VFA) sequences and T2 was measured using a multi-echo spin echo (T2 -SE) sequence. For each vial in the phantom, accuracy errors (%bias) were determined by the relative differences in measured T1 and T2 times compared to reference values. Reproducibility was measured by the coefficient of variation (CV) of T1 and T2 measurements across monthly scans. Accuracy and reproducibility were mainly assessed on vials with relaxation times expected to be in physiological ranges at 3T. RESULTS: A strong linear correlation between measured and reference relaxation times was found for all sequences tested (R2  > 0.997). Baseline bias (and CV[%]) for T1 -IR, T1 -VFA and T2 -SE sequences were +2.0% (2.1), +6.5% (4.2), and +8.5% (1.9), respectively. CONCLUSIONS: The accuracy and reproducibility of T1 and T2 on the scanner were considered sufficient for the sequences tested. No longitudinal trends of variation were deduced, suggesting less frequent measurements are required following the establishment of baselines.

Modulating the Electronic Properties of Au-MoS2 Interfaces Using Functionalized Self-Assembled Monolayers.

Molybdenum disulfide (MoS2) is a transition-metal dichalcogenide with many applications including in electronic devices and sensors. A critical issue in the development of these devices is the high resistance between the metal contact and the molybdenum disulfide layer. In this study, we employ Raman spectroscopy and X-ray photoelectron spectroscopy to investigate the modification of Au-MoS2 contact properties using functionalized alkanethiolate self-assembled monolayers (SAMs). We demonstrate that both 2H and 1T MoS2 strongly interact with the underlying Au substrate. The electronic properties of the interface are mediated by the dipole moment of the alkanethiolate SAM, which have a -CH3, -CO2C6F5, -OH, or -COOH terminal group. Finally, we demonstrate the site-selective deposition of 2H and 1T MoS2 on micropatterned SAMs to form conducting-semiconducting patterned MoS2 films.

Chemical Bath Deposition of Copper Sulfide on Functionalized SAMs: An Unusual Selectivity Mechanism.

We have investigated the chemical bath deposition (CBD) of CuS using thioacetamide on functionalized self-assembled monolayers (SAMs) using scanning electron and optical microscopies, X-ray photoelectron spectroscopy, and time-of-flight secondary ion mass spectrometry. For all SAMs studied, the amount of CuS deposited is strongly dependent on the bath pH and can be attributed to the interaction of the SAM terminal groups with the chalcogenide ions present in solution. For -CH3-terminated SAMs, there is a steady increase in the amount of CuS deposited with an increase in the bath pH because there is an increase in the concentration of chalcogenide ion. However, for -OH- and -COOH-terminated SAMs, we observe that the maximum amount of CuS is deposited at pH 10. We attribute this behavior to a competition between the repulsion of the chalcogenide ions by the negatively charged SAM terminal groups and an increase in the chalcogenide ion concentration with an increase in the bath pH. Using the interaction of the chalcogenide ions with the different SAM terminal functional groups, we demonstrate that CuS can be selectively deposited on the -CH3-terminated areas of patterned -OH/-CH3- and -COOH/-CH3-terminated SAMs.

Comparative implementation-effectiveness of three strategies to perform hearing screening among older adults in primary care clinics: study design and protocol.

BACKGROUND: The burden of hearing loss among older adults could be mitigated with appropriate care. This study compares implementation of three hearing screening strategies in primary care, and examines the reliability and validity of patient self-assessment, primary care providers (PCP) and diagnostic audiologists in the identification of 'red flag' conditions (those conditions that may require medical consultation and/or intervention). METHODS: Six primary care practices will implement one of three screening strategies (2 practices per strategy) with 660 patients (220 per strategy) ages 65-75 years with no history of hearing aid use or diagnosis of hearing loss. Strategies differ on the location and use of PCP encouragement to complete a telephone-based hearing screen (tele-HS). Group 1: instructions for tele-HS to complete at home and educational materials on warning signs and consequences of hearing loss. Group 2: PCP counseling/encouragement on importance of hearing screening, instructions to take the tele-HS from home, educational materials. Group 3: PCP counseling/encouragement, in-office tele-HS, and educational materials. Patients from all groups who fail the tele-HS will be referred for diagnostic audiological testing and medical evaluation, and complete a self-assessment of red flag conditions at this follow-up appointment. Due to the expected low incidence of ear disease in the PCP cohort, we will enroll a complementary population of patients (N = 500) from selected otolaryngology head and neck surgery clinics in a national practice-based research network to increase the likelihood of occurrence of medical conditions that might contraindicate hearing aid fitting. The primary outcome is the proportion of patients who complete the tele-HS within 2 months of the PCP appointment comparing Group 3 (PCP encouragement, in-office tele-HS, education) versus Groups 2 and 1 (education and tele-HS at home, with and without PCP encouragement, respectively). The several secondary outcomes include direct and indirect costs, patient, family and provider attitudes of hearing healthcare, and accuracy of red flag condition evaluations compared with expert medical assessment by an otolaryngology provider. DISCUSSION: Determining the relative effectiveness of three different strategies for hearing screening in primary care and the assessment accuracy of red flag conditions can each lead to practice and policy changes that will reduce individual, family and societal burden from hearing loss among older adults. TRIAL REGISTRATION: Clinicaltrials.gov: NCT02928107; 10/10/2016 protocol version 1.

An international survey on the clinical use of rigid and deformable image registration in radiotherapy.

OBJECTIVES: Rigid image registration (RIR) and deformable image registration (DIR) are widely used in radiotherapy. This project aims to capture current international approaches to image registration. METHODS: A survey was designed to identify variations in use, resources, implementation, and decision-making criteria for clinical image registration. This was distributed to radiotherapy centers internationally in 2018. RESULTS: There were 57 responses internationally, from the Americas (46%), Australia/New Zealand (32%), Europe (12%), and Asia (10%). Rigid image registration and DIR were used clinically for computed tomography (CT)-CT registration (96% and 51%, respectively), followed by CT-PET (81% and 47%), CT-CBCT (84% and 19%), CT-MR (93% and 19%), MR-MR (49% and 5%), and CT-US (9% and 0%). Respondent centers performed DIR using dedicated software (75%) and treatment planning systems (29%), with 84% having some form of DIR software. Centers have clinically implemented DIR for atlas-based segmentation (47%), multi-modality treatment planning (65%), and dose deformation (63%). The clinical use of DIR for multi-modality treatment planning and accounting for retreatments was considered to have the highest benefit-to-risk ratio (69% and 67%, respectively). CONCLUSIONS: This survey data provides useful insights on where, when, and how image registration has been implemented in radiotherapy centers around the world. DIR is mainly in clinical use for CT-CT (51%) and CT-PET (47%) for the head and neck (43-57% over all use cases) region. The highest benefit-risk ratio for clinical use of DIR was for multi-modality treatment planning and accounting for retreatments, which also had higher clinical use than for adaptive radiotherapy and atlas-based segmentation.

Law and Disorder: Special Stacking Units-Building the Intergrowth Ce6Co5Ge16.

A new structure type of composition Ce6Co5Ge16 was grown out of a molten Sn flux. Ce6Co5Ge16 crystallizes in the orthorhombic space group Cmcm, with highly anisotropic lattice parameters of a = 4.3293(5) Å, b = 55.438(8) Å, and c = 4.3104(4) Å. The resulting single crystals were characterized by X-ray diffraction, and the magnetic and transport properties are presented. The Sn-stabilized structure of Ce6Co5Ge16 is based on the stacking of disordered Ce cuboctahedra and is an intergrowth of existing structure types including AlB2, BaNiSn3, and AuCu3. The stacking of structural subunits has previously been shown to be significant in the fields of superconductivity, quantum materials, and optical materials. Herein, we present the synthesis, characterization, and complex magnetic behavior of Ce6Co5Ge16 at low temperature, including three distinct magnetic transitions.

Polytype control of MoS2 using chemical bath deposition.

Molybdenum disulfide (MoS2) has a wide range of applications from electronics to catalysis. While the properties of single-layer and multilayer MoS2 films are well understood, controlling the deposited MoS2 polytype remains a significant challenge. In this work, we employ chemical bath deposition, an aqueous deposition technique, to deposit large area MoS2 thin films at room temperature. Using Raman spectroscopy and x-ray photoelectron spectroscopy, we show that the deposited MoS2 polytype can be changed from semiconducting 2H MoS2 on hydrophobic -CH3 and -CO2C6F5 terminated self-assembled monolayers (SAMs) to semimetallic 1T MoS2 on hydrophilic -OH and -COOH terminated SAMs. The data suggest that the deposition of MoS2 polytypes is controlled by the substrate surface energy. High surface energy substrates stabilize 1T MoS2 films, while 2H MoS2 is deposited on lower surface energy substrates. This effect appears to be general enabling the deposition of different MoS2 polytypes on a wide range of substrates.

Effect of Ethanolamines on the Electroless Deposition of Copper on Functionalized Organic Surfaces.

Electroless deposition (ELD) is widely used in industry to deposit metals because it is inexpensive and compatible with organic materials. The deposition rate and deposited film properties critically depend on the reducing agent, complexing agent, and bath pH and temperature as well as bath additives. We have investigated the role of ethanolamine additives in the ELD of copper using the reducing agent dimethylamine borane on -CH3- and -OH-terminated self-assembled monolayers (SAMs) adsorbed on gold. Three additives were studied: ethanolamine (EOA), diethanolamine (DEOA), and triethanolamine (TEOA). Both the chemical identity and concentration of the ethanolamine significantly affect the deposition process. We show that the Cu deposition rate is faster on -CH3-terminated surfaces than on -OH-terminated SAMs because of the stronger interaction of the ethanolamines with the hydroxyl terminal group. In contrast to physical vapor deposition and other ELD processes, Cu deposits atop methyl-terminated SAMs using TEOA. However, using EOA and DEOA, copper penetrates through -CH3-terminated SAMs to the Au/S interface. For -OH-terminated SAMs, copper is observed to penetrate through the SAM for all ethanolamines investigated. The amount of copper penetration through the SAM to the Au/S interface increases with ethanolamine concentration. These effects are attributed to an adsorption-inhibition mechanism and differences in the chelation of Cu2+ in the deposition bath.

Conserved role of SIRT1 orthologs in fasting-dependent inhibition of the lipid/cholesterol regulator SREBP.

The sterol regulatory element-binding protein (SREBP) transcription factor family is a critical regulator of lipid and sterol homeostasis in eukaryotes. In mammals, SREBPs are highly active in the fed state to promote the expression of lipogenic and cholesterogenic genes and facilitate fat storage. During fasting, SREBP-dependent lipid/cholesterol synthesis is rapidly diminished in the mouse liver; however, the mechanism has remained incompletely understood. Moreover, the evolutionary conservation of fasting regulation of SREBP-dependent programs of gene expression and control of lipid homeostasis has been unclear. We demonstrate here a conserved role for orthologs of the NAD(+)-dependent deacetylase SIRT1 in metazoans in down-regulation of SREBP orthologs during fasting, resulting in inhibition of lipid synthesis and fat storage. Our data reveal that SIRT1 can directly deacetylate SREBP, and modulation of SIRT1 activity results in changes in SREBP ubiquitination, protein stability, and target gene expression. In addition, chemical activators of SIRT1 inhibit SREBP target gene expression in vitro and in vivo, correlating with decreased hepatic lipid and cholesterol levels and attenuated liver steatosis in diet-induced and genetically obese mice. We conclude that SIRT1 orthologs play a critical role in controlling SREBP-dependent gene regulation governing lipid/cholesterol homeostasis in metazoans in response to fasting cues. These findings may have important biomedical implications for the treatment of metabolic disorders associated with aberrant lipid/cholesterol homeostasis, including metabolic syndrome and atherosclerosis.

The circadian clock regulates inflammatory arthritis.

There is strong diurnal variation in the symptoms and severity of chronic inflammatory diseases, such as rheumatoid arthritis. In addition, disruption of the circadian clock is an aggravating factor associated with a range of human inflammatory diseases. To investigate mechanistic links between the biological clock and pathways underlying inflammatory arthritis, mice were administered collagen (or saline as a control) to induce arthritis. The treatment provoked an inflammatory response within the limbs, which showed robust daily variation in paw swelling and inflammatory cytokine expression. Inflammatory markers were significantly repressed during the dark phase. Further work demonstrated an active molecular clock within the inflamed limbs and highlighted the resident inflammatory cells, fibroblast-like synoviocytes (FLSs), as a potential source of the rhythmic inflammatory signal. Exposure of mice to constant light disrupted the clock in peripheral tissues, causing loss of the nighttime repression of local inflammation. Finally, the results show that the core clock proteins cryptochrome (CRY) 1 and 2 repressed inflammation within the FLSs, and provide novel evidence that a CRY activator has anti-inflammatory properties in human cells. We conclude that under chronic inflammatory conditions, the clock actively represses inflammatory pathways during the dark phase. This interaction has exciting potential as a therapeutic avenue for treatment of inflammatory disease.-Hand, L. E., Hopwood, T. W., Dickson, S. H., Walker, A. L., Loudon, A. S. I., Ray, D. W., Bechtold, D. A., Gibbs, J. E. The circadian clock regulates inflammatory arthritis.