Enhanced prediction of Src homology 2 (SH2) domain binding potentials using a fluorescence polarization-derived c-Met, c-Kit, ErbB, and androgen receptor interactome.

Many human diseases are associated with aberrant regulation of phosphoprotein signaling networks. Src homology 2 (SH2) domains represent the major class of protein domains in metazoans that interact with proteins phosphorylated on the amino acid residue tyrosine. Although current SH2 domain prediction algorithms perform well at predicting the sequences of phosphorylated peptides that are likely to result in the highest possible interaction affinity in the context of random peptide library screens, these algorithms do poorly at predicting the interaction potential of SH2 domains with physiologically derived protein sequences. We employed a high throughput interaction assay system to empirically determine the affinity between 93 human SH2 domains and phosphopeptides abstracted from several receptor tyrosine kinases and signaling proteins. The resulting interaction experiments revealed over 1000 novel peptide-protein interactions and provided a glimpse into the common and specific interaction potentials of c-Met, c-Kit, GAB1, and the human androgen receptor. We used these data to build a permutation-based logistic regression classifier that performed considerably better than existing algorithms for predicting the interaction potential of several SH2 domains.

EMGD-FE: an open source graphical user interface for estimating isometric muscle forces in the lower limb using an EMG-driven model.

BACKGROUND: This paper describes the "EMG Driven Force Estimator (EMGD-FE)", a Matlab® graphical user interface (GUI) application that estimates skeletal muscle forces from electromyography (EMG) signals. Muscle forces are obtained by numerically integrating a system of ordinary differential equations (ODEs) that simulates Hill-type muscle dynamics and that utilises EMG signals as input. In the current version, the GUI can estimate the forces of lower limb muscles executing isometric contractions. Muscles from other parts of the body can be tested as well, although no default values for model parameters are provided. To achieve accurate evaluations, EMG collection is performed simultaneously with torque measurement from a dynamometer. The computer application guides the user, step-by-step, to pre-process the raw EMG signals, create inputs for the muscle model, numerically integrate the ODEs and analyse the results. RESULTS: An example of the application's functions is presented using the quadriceps femoris muscle. Individual muscle force estimations for the four components as well the knee isometric torque are shown. CONCLUSIONS: The proposed GUI can estimate individual muscle forces from EMG signals of skeletal muscles. The estimation accuracy depends on several factors, including signal collection and modelling hypothesis issues.

Data-driven decarbonisation pathways for reducing life cycle GHG emissions from food waste in the hospitality and food service sectors.

The Hospitality and Food Service (HaFS) sectors are notoriously known for their contribution to the food waste problem. Hence, there is an urgent need to devise strategies to reduce food waste in the HaFS sectors and to decarbonise their operation to help fight hunger, achieve food security, improve nutrition and mitigate climate change. This study proposes three streams to decarbonise the staff cafeteria operation in an integrated resort in Macau. These include upstream optimisation to reduce unserved food waste, midstream education to raise awareness amongst staff about the impact of food choices on the climate and health, and finally downstream recognition to reduce edible plate waste using a state-of-the-art computer vision system. Technology can be an effective medium to facilitate desired behavioural change through nudging, much like how speed cameras can cause people to slow down and help save lives. The holistic and data-driven approach taken revealed great potential for organisations or institutions that offer catering services to reduce their food waste and associated carbon footprint whilst educating individuals about the intricate link between food, climate and well-being.

Model Pruning Enables Efficient Federated Learning on Edge Devices.

Federated learning (FL) allows model training from local data collected by edge/mobile devices while preserving data privacy, which has wide applicability to image and vision applications. A challenge is that client devices in FL usually have much more limited computation and communication resources compared to servers in a data center. To overcome this challenge, we propose PruneFL -a novel FL approach with adaptive and distributed parameter pruning, which adapts the model size during FL to reduce both communication and computation overhead and minimize the overall training time, while maintaining a similar accuracy as the original model. PruneFL includes initial pruning at a selected client and further pruning as part of the FL process. The model size is adapted during this process, which includes maximizing the approximate empirical risk reduction divided by the time of one FL round. Our experiments with various datasets on edge devices (e.g., Raspberry Pi) show that: 1) we significantly reduce the training time compared to conventional FL and various other pruning-based methods and 2) the pruned model with automatically determined size converges to an accuracy that is very similar to the original model, and it is also a lottery ticket of the original model.

Targeted protein-omic methods are bridging the gap between proteomic and hypothesis-driven protein analysis approaches.

While proteomic methods have illuminated many areas of biological protein space, many fundamental questions remain with regard to systems-level relationships between mRNAs, proteins and cell behaviors. While mass spectrometric methods offer a panoramic picture of the relative expression and modification of large numbers of proteins, they are neither optimal for the analysis of predefined targets across large numbers of samples nor for assessing differences in proteins between individual cells or cell compartments. Conversely, traditional antibody-based methods are effective at sensitively analyzing small numbers of proteins across small numbers of conditions, and can be used to analyze relative differences in protein abundance and modification between cells and cell compartments. However, traditional antibody-based approaches are not optimal for analyzing large numbers of protein abundances and modifications across many samples. In this article, we will review recent advances in methodologies and philosophies behind several microarray-based, intermediate-level, 'protein-omic' methods, including a focus on reverse-phase lysate arrays and micro-western arrays, which have been helpful for bridging gaps between large- and small-scale protein analysis approaches and have provided insight into the roles that protein systems play in several biological processes.

Topical application of adipose tissue-derived mesenchymal stem cells (ADMSCs) reduced cerebral edema in experimental traumatic brain injury (TBI)-a preliminary study.

BACKGROUND: Our previous studies showed that topical application of mesenchymal stem cells (MSCs) improved functional recovery in rat traumatic brain injury (TBI) model, and hypoxic precondition further enhanced the therapeutic effects of MSCs. There was no previous study on the attenuation of cerebral edema by MSCs. We investigated whether topical application of normoxic and hypoxic MSCs could reduce cerebral edema in an experimental TBI model. METHODS: Two million normoxic (N = 24) and hypoxic (N = 24) MSCs were applied topically to exposed the cerebral cortex in a controlled cortical impact (CCI) model. The MSCs were fixed in position with fibrin glue. No treatment was given to control animals (TBI only: n = 24). After surgery, four animals in each group were sacrificed daily (day 1 to day 6) for edema evaluation. Normal animals without TBI were used as reference (n = 4). The expressions of GFAP, AQP4, and MMP9 were also investigated by immunofluorescence staining and RT-PCR at day 3. RESULTS: The edema peaked within 3 days after TBI. Compared with the control, hypoxic MSCs reduced brain water content significantly (p < 0.05). Both hypoxic and normoxic MSCs downregulated the expression of MMP9 and normalized AQP4 distribution to astrocyte end feet. CONCLUSION: Our preliminary study showed that topical application of hypoxic MSCs suppressed both vasogenic and cytotoxic edema formation.

The extracytoplasmic function sigma factor σVreI is active during infection and contributes to phosphate starvation-induced virulence of Pseudomonas aeruginosa.

The extracytoplasmic function sigma factor σVreI of the human pathogen Pseudomonas aeruginosa promotes transcription of potential virulence determinants, including secretion systems and secreted proteins. Its activity is modulated by the VreR anti-σ factor that inhibits the binding of σVreI to the RNA polymerase in the absence of a (still unknown) inducing signal. The vreI-vreR genes are expressed under inorganic phosphate (Pi) starvation, a physiological condition often encountered in the host that increases P. aeruginosa pathogenicity. However, whether or not σVreI is active in vivo during infection and contributes to the Pi starvation-induced virulence of this pathogen has not been analyzed yet. Using zebrafish embryos and a human alveolar basal epithelial cell line as P. aeruginosa hosts, we demonstrate in this work that σVreI is active during infection and that lack of σVreI considerably reduces the Pi starvation-induced virulence of this pathogen. Surprisingly, lack of the σVreI inhibitor, the VreR anti-σ factor, also diminishes the virulence of P. aeruginosa. By transcriptomic analyses we show that VreR modulates gene expression not only in a σVreI-dependent but also in a σVreI-independent manner. This includes potential virulence determinants and transcriptional regulators that could be responsible for the reduced virulence of the ΔvreR mutant.

CSN5 inhibition triggers inflammatory signaling and Rho/ROCK-dependent loss of endothelial integrity.

RhoGTPases regulate cytoskeletal dynamics, migration and cell-cell adhesion in endothelial cells. Besides regulation at the level of guanine nucleotide binding, they also undergo post-translational modifications, for example ubiquitination. RhoGTPases are ubiquitinated by Cullin RING ligases which are in turn regulated by neddylation. Previously we showed that inhibition of Cullin RING ligase activity by the neddylation inhibitor MLN4924 is detrimental for endothelial barrier function, due to accumulation of RhoB and the consequent induction of contractility. Here we analyzed the effect of pharmacological activation of Cullin RING ligases on endothelial barrier integrity in vitro and in vivo. CSN5i-3 induced endothelial barrier disruption and increased macromolecule leakage in vitro and in vivo. Mechanistically, CSN5i-3 strongly induced the expression and activation of RhoB and to lesser extent of RhoA in endothelial cells, which enhanced cell contraction. Elevated expression of RhoGTPases was a consequence of activation of the NF-κB pathway. In line with this notion, CSN5i-3 treatment decreased IκBα expression and increased NF-κB-mediated ICAM-1 expression and consequent adhesion of neutrophils to endothelial cells. This study shows that sustained neddylation of Cullin RING-ligases leads to activation the NF-κB pathway in endothelial cells, elevated expression of RhoGTPases, Rho/ROCK-dependent activation of MLC and disruption of the endothelial barrier.

Interferon Regulatory Factor 6 Is Necessary for Salivary Glands and Pancreas Development.

Interferon regulatory factor 6 ( IRF6) acts as a tumor suppressor and controls cell differentiation in ectodermal and craniofacial tissues by regulating expression of target genes. Haploinsufficiency of IRF6 causes Van der Woude and popliteal pterygium syndrome, 2 syndromic forms of cleft lip and palate. Around 85% of patients with Van der Woude express pits on the lower lip that continuously or intermittently drain saliva, and patients with the common cleft lip and palate have a higher prevalence of dental caries and gingivitis. This study aims to identify the role of IRF6 in development of exocrine glands, specifically the major salivary glands. Our transgenic mouse model that expresses LacZ reporter under the control of the human IRF6 enhancer element showed high expression of IRF6 in major and minor salivary glands and ducts. Immunostaining data also confirmed the endogenous expression of IRF6 in the developing ductal, serous, and mucous acinar cells of salivary glands. As such, we hypothesized that Irf6 is important for proper development of salivary glands and potentially other exocrine glands. Loss of Irf6 in mice causes an increase in the proliferation level of salivary cells, disorganized branching morphogenesis, and a lack of differentiated mucous acinar cells in submandibular and sublingual glands. Expression and localization of the acinar differentiation marker MIST1 were altered in Irf6-null salivary gland and pancreas. The RNA-Seq analysis demonstrated that 168 genes are differentially expressed and confer functions associated with transmembrane transporter activity, spliceosome, and transcriptional regulation. Furthermore, expression of genes involved in the EGF pathway-that is, Ereg, Ltbp4, Matn1, Matn3, and Tpo-was decreased at embryonic day 14.5, while levels of apoptotic proteins were elevated at postnatal day 0. In conclusion, our data report a novel role of Irf6 in exocrine gland development and support a rationale for performing exocrine functional tests for patients with IRF6-damaging mutations.

Tissue distribution of human alpha1-microglobulin.

Human alpha(1)-microglobulin was isolated from the urine of patients with tubular proteinuria, and its molecular weight was established by sodium dodecyl sulfate-polyacrylamide gel electrophoresis at 33,000 daltons. The carbohydrate content was 21.7%. Anti-alpha(1)-microglobulin serum was prepared and observed to react monospecifically in gel diffusion to purified alpha(1)-microglobulin, as well as to normal human serum and urine. Sera from the domestic chicken, mouse, rat, rabbit, dog, calf, cow, goat, sheep, and horse, however, did not react to anti-alpha(1)-microglobulin serum in immunodiffusion. The lymphocyte culture supernate was found to contain alpha(1)-microglobulin. Both thymus-derived(T)- and bone marrow-derived(B)-lymphocyte culture media clearly displayed a specific precipitin line against anti-alpha(1)-microglobulin serum when tested with the Ouchterlony immunodiffusion method. The tissue distribution of alpha(1)-microglobulin was studied under immunofluorescence, and a positive staining was recognized on the lymphocyte surface. Identical staining patterns were noted on both T and B lymphocytes, though B lymphocytes took a more intense stain. It would thus seem quite possible that lymphocytes are the primary source of alpha(1)-microglobulin and that this is filtered through the glomerular basement membrane and partly reabsorbed by the renal tubules. This, then, would suggest the possibility that alpha(1)-microglobulin shares some immunological role in vivo with lymphocytes and(or) is one of the membrane proteins of lymphocytes.

Treatment of profuse epistaxis in patients irradiated for nasopharyngeal carcinoma.

BACKGROUND: Profuse epistaxis in patients with nasopharyngeal carcinoma (NPC) previously treated with radiotherapy (RT) can be life threatening. Surgical means to prevent rebleeding may at times be difficult and unsuccessful. We aim to investigate the characteristics of this group of patients and our experience of endovascular embolization technique in the management of epistaxis in this group of patients. METHODS: A retrospective review of all nasopharyngeal carcinoma patients presented with profuse epistaxis during follow up after radiotherapy was carried out in a regional neurosurgical centre in Hong Kong. Seventeen patients were included for the analysis within the recent 6-year period. The age of patients was 55.5 +/- 8.358 years (mean +/- standard deviation). The sex ratio was 5:1 (M : F). Diagnostic catheter angiography was carried out in all 17 patients. Endovascular embolization was carried out in 11 patients with the joint decision of the otolaryngologist and neurointerventionist in charge . RESULTS: Four patients underwent main trunk occlusion for internal carotid pseudoaneurysm. Seven patients underwent embolization of branches of external carotid artery. One patient required another session of external carotid artery embolization 1 month later. There was one inpatient death because of pneumonia and hepatic encephalopathy. With our protocol, there were only two patients (11.7%) with delayed rebleed at 2 and 5 months, respectively. Both patients had advanced diseases and died. CONCLUSION: In irradiated patients with nasopharyngeal carcinoma presenting with profuse epistaxis, angiography had a high yield of pseudoaneurysm or hypervascularity and these lesions could be safely managed through endovascular embolization.

Interactome and reciprocal activation of pathways in topical mesenchymal stem cells and the recipient cerebral cortex following traumatic brain injury.

In this study, GFP-MSCs were topically applied to the surface of cerebral cortex within 1 hour of experimental TBI. No treatment was given to the control group. Three days after topical application, the MSCs homed to the injured parenchyma and improved the neurological function. Topical MSCs triggered earlier astrocytosis and reactive microglia. TBI penumbra and hippocampus had higher cellular proliferation. Apoptosis was suppressed at hippocampus at 1 week and reduced neuronal damaged was found in the penumbral at day 14 apoptosis. Proteolytic neuronal injury biomarkers (alphaII-spectrin breakdown products, SBDPs) and glial cell injury biomarker, glial fibrillary acidic protein (GFAP)-breakdown product (GBDPs) in injured cortex were also attenuated by MSCs. In the penumbra, six genes related to axongenesis (Erbb2); growth factors (Artn, Ptn); cytokine (IL3); cell cycle (Hdac4); and notch signaling (Hes1) were up-regulated three days after MSC transplant. Transcriptome analysis demonstrated that 7,943 genes were differentially expressed and 94 signaling pathways were activated in the topical MSCs transplanted onto the cortex of brain injured rats with TBI. In conclusion, topical application offers a direct and efficient delivery of MSCs to the brain.

Stent restenosis in a Chinese population.

BACKGROUND: Stents are now widely used in Hong Kong and China and there is a clinical impression that restenosis is less common because of the lower prevalence of coronary artery disease and associated risk factors in the Chinese. However, there are no published data on angiographic stent restenosis rates in Chinese patients. METHOD: In a prospective study of 114 consecutive Chinese patients who underwent coronary stenting, quantitative coronary analyses were made at the time of stent implantation and subsequently at 6 months post-stenting (n = 97). RESULTS: At 6 months, restenosis (> or = 50% diameter stenosis in the dilated segment) was present in 42 (43.3%) of the 97 patients and 54 (33.5%) of the total 161 lesions stented. Vessel reference diameter (VRD) of < 3 mm and stented length of > or = 18 mm were associated with higher restenosis rates (36% and 38%). Compared to those without, those with restenosis had a greater residual stenosis of 16.53+/-11.54% and smaller final minimal luminal diameter (MLD) of 2.41+/-0.49 mm, (p < 0.01 and p < 0.008 respectively). Standard coronary risk factors were not associated with a higher rate of restenosis. Lesion morphology was significantly associated with restenosis. CONCLUSION: Coronary stenting in Hong Kong Chinese patients is associated with a restenosis rate comparable to that demonstrated in previously published trials from populations in the West.

Bone density and body composition on the Pacific rim: a comparison between Japan-born and U.S.-born Japanese-American women.

Bone mineral density (BMD) of total body, spine, and proximal femur and the percentage of body fat in 151 U.S.-born Japanese-American women and 137 Japan-born immigrant Japanese-American women living in San Diego, California were measured using dual-energy x-ray absorptiometry. These data were compared with unpublished data from Japanese women obtained in previous studies in Hamamatsu, Japan. The age-adjusted BMD for the spinal level, femoral neck, Ward's triangle, trochanter, and total body, respectively, of U.S.-born Japanese-American women were 10.2, 9.8, 9.9, 9.2, and 2.7% higher than those of native Japanese women. The U.S.-born Japanese-American women had significantly higher body fat than immigrant Japanese-American women. Furthermore, the immigrant women had higher BMD and higher body fat than their native Japanese counterparts; however, no significant total-body BMD differences were found among the three groups after age, height, and weight were adjusted. The U.S.-born Japanese-American women had BMD values equivalent to those of white normals at the spine and femur. Significant life-style differences between U.S.-born and immigrant Japanese-American women were noted. Weight, exercise, early menarche, and years of lifetime estrogen exposure correlated positively with BMD. The significant negative correlates of BMD were age, smoking, and percentage of body fat. Our study presents data suggesting that immigration to the United States has produced a higher BMD in Japanese-American women that is attributable to changes in life-style and diet.

Human alpha 1-microglobulin levels in various body fluids.

alpha 1-Microglobulin levels in serum and urine were estimated by using single radial immunodiffusion, resulting in the following mean values: umbilical cord blood serum, 40.6 mg/l; normal adult serum, 44.2 mg/l; and normal urine, 5.7 mg/24 h urine volume. Slightly higher levels of serum alpha 1-microglobulin were found in infants and the aged. Serum and urine alpha 1-microglobulin levels in patients with renal failure, however, were greatly increased, mean levels being 231.5 mg/l and 100.7 mg/24 h urine volume, respectively. Serum alpha 1-microglobulin levels in these patients correlated well with both serum creatinine and beta 2-microglobulin levels. Serum alpha 1-microglobulin level did not correlate positively with serum levels of other plasma proteins, such as alpha 1-antitrypsin, haptoglobin, complement, etc. Ouchterlony immunodiffusion also revealed the presence of alpha 1-microglobulin in synovial fluid, ascites, pleural effusion, amniotic fluid, cyst fluid, and cerebrospinal fluid. The levels of alpha 1-microglobulin in these fluids were measured by single radial immunodiffusion, except that its level in cerebrospinal fluid was measured by radioimmunoassay. Mean alpha 1-microglobulin concentration was 20.8 mg/l in synovial fluid, 28.7 mg/l in ascites, 21.5 mg/l in pleural effusion, 2.7 mg/l in amniotic fluid, 8.2 mg/l in cyst fluid, and 42.3 ng/ml in cerebrospinal fluid.

Severe antecollis during antipsychotics treatment: a report of three cases.

1. The authors report on three patients with severe antecollis that developed after chronic treatment with antipsychotics. These patients had been treated with neuroleptics for their delusions and hallucinations. Antecollis is a rare form of tardive dystonia that has drawn little attention. To our knowledge, there have been no reports on this disorder. 2. The patients developed the symptom after receiving a number of antipsychotics for 4 months to 14 years. Neither discontinuation of antipsychotics nor administration of anticholinergic agents affected the symptom. 3. Although spontaneous improvement of dystonia was obtained after several months without any specific treatment in one patient, the symptom persisted for several years in another. The last patient could not be followed after discharge from our hospital since she and her family did not come to the hospital. 4. Severe antecollis may cause disturbances in various functions, such as vision, speaking and swallowing. Forward bending of the neck may cause inspiratory obstruction. Severe antecollis may not be unusual and psychiatrists should be aware of this symptom in routine clinical practice.

Posterior capsule rupture by blunt ocular trauma.

A patient with posterior lens capsule rupture caused by blunt trauma and in whom the anterior capsule and the remainder of the eyeball structure was intact had phacoemulsification and aspiration of the crystalline lens with implantation of a posterior chamber intraocular lens. Further rupture of the capsule was prevented by the fibrosis, which tightened the margin of the ruptured capsule. This case shows that blunt trauma can rupture the posterior lens capsule, leaving the anterior capsule intact.

Recanalization of chronic total occlusion after conventional guidewire failure: guided by optical coherent reflectometry and facilitated by radiofrequency energy ablation.

The success rate of percutaneous recanalization of chronic total occlusion remains low. The Safe-Cross wire, which utilizes the principle of optical coherent reflectometry for guidance and has the ability to deliver radiofrequency energy for tissue ablation, was evaluated in 21 patients. This wire was used only after conventional guidewire failure, except in 4 patients who had failed an interventional procedure 3 months to 2 years previously. Conventional guidewires were successful in 9, and the Safe-Cross wire was successful in 10 of the remaining 12, including those 4 with a failed previous attempt. The total success rate was 90% (19/21 patients). Technological improvement in the steerability of the Safe-Cross wire may help to improve the success rate further.