Medicaid and state budgets: clearing storm, foggy forecast.
This issue brief examines the recent history and trends in state budgets and considers how those trends have influenced the role of the Medicaid program. The paper offers several indicators for predicting the future of states' fiscal standing, cautioning that, although the "stormy" period from 2001 to 2003 is over, states face many challenges in he near future. This issue brief also poses several questions regarding the appropriate rules of state and federal governments in administering the Medicaid program. These questions become particularly important as the population ages and states increasingly take the lead in developing solutions for covering the uninsured.


Patient Perception of Route of Rectal Administration of Live Biotherapeutic Product for Recurrent Clostridioides difficile Infection.
CDI is a recurrent disease that is treated with antibiotics, but patients commonly experience repeat infections with significant impacts on hospital budgets and patient health quality. Standard of care management includes the antibiotics, vancomycin and fidaxomicin, which frequently provide clinical response, but do not avoid recurrence of Clostridioides difficile infection (rCDI). These recurrent infections occur due to dysbiosis of the colonic microbiota. One adjunctive therapeutic approach is to restore the deficient gastrointestinal flora using fecal microbiota transplantation (FMT) or live biotherapeutic products (LBP) when given after standard of care antimicrobials, which have been successful in reducing repeat infections with success rates up to 88%. FMT or LBP can be given by various routes. Two groups of subjects aged ≥18 years with at least one previous CDI episode within the previous 36 months completed self-administered online surveys to assess the acceptability of an LBP administered rectally. Group 1 consisted of LBP-recipients who had received RBL (REBYOTA) rectally as part of the Phase III PUNCH CD3 clinical trial. Group 2 consisted of LBP-naïve subjects who volunteered to participate and had experienced CDI within the prior 36 months but had no history of receiving FMT or LBP therapy. LBP-recipients considered rectal administration easy (96%) and quick (94%), while 98% of respondents considered the lack of need for bowel preparation appealing. Most LBP-recipients (96%) wished they had earlier access to RBL. Most LBP-naïve subjects (87%) were likely or somewhat likely to consider a rectally administered treatment and 80% preferred a treatment option that does not require bowel preparation. Many of these subjects (76%) expressed interest in finding out about new treatment options for rCDI. LBP-recipients and LBP-naïve subjects alike felt that rectal delivery of microbiome therapy is not only acceptable but highly interesting as a treatment avenue.


Mediastinal and thoracic complications of necrotizing fasciitis of the head and neck.
Mediastinal and thoracic extension of head and neck infections are rare but occur even in the modern antibiotic era. Early intervention is paramount to successful clinical outcome. 111Indium-labeled white blood cell (WBC) scan, a new imaging modality, appears to play a role in complementing computed tomographic (CT) findings, demonstrating early extension of disease, and following therapeutic efficacy. Together, the CT scan and WBC scan aid in directing early intervention and extent of surgery in this disease of high-potential mortality. We report 3 cases of deep head and neck infection complicated by mediastinal extension, including mediastinitis, pericardial effusion, and tamponade, empyema, and respiratory failure. Early surgical intervention included neck drainage, tracheostomy, thoracotomy, and pericardiotomy. While usually associated with greater than 50% mortality, all of the patients in this series survived. Based on our experience, we recommend prompt aggressive surgical debridement in treating mediastinal complications resulting from head and neck infections.


Study of TALP and TRIS citrate medium on caprine sperm capacitation and subsequent in vitro embryo production.
The aim of the present investigation was to compare Tyrode's albumin lactate pyruvate (TALP) medium and TRIS citrate medium for capacitation of caprine sperm. In experiment 1 capacitation was assessed by chlortetracycline assay and in experiment 2 with in vitro fertilization and embryo development. In experiment 2, cumulus oocyte complexes (COCs) recovered by slicing the caprine ovaries were matured in maturation medium for 27 h in humidified atmosphere at 38.5°C with 5% CO2. After 27 h of culture a total of 2480 in vitro matured oocytes were selected and randomly divided into two groups. Group 1 (n=1124) matured oocytes were fertilized by the spermatozoa capacitated in TALP medium and in group 2 (n=1356) matured oocytes were fertilized by the spermatozoa capacitated in TRIS citrate medium. The results of experiment 1 indicated a comparatively more number of sperms with Chlortetracycline (CTC) Pattern B in TRIS citrate than TALP medium (55.32 ± 0.91% vs 47.96 ± 0.20%). In experiment 2, the cleavage rate and blastocyst production were higher following capacitation of spermatozoa in TRIS citrate than TALP medium. In conclusion, TRIS citrate can be used as an alternative and effective media for sperm capacitation to get higher cleavage rate and blastocyst production in goat.


Life cycle air quality impacts of conventional and alternative light-duty transportation in the United States.
Commonly considered strategies for reducing the environmental impact of light-duty transportation include using alternative fuels and improving vehicle fuel economy. We evaluate the air quality-related human health impacts of 10 such options, including the use of liquid biofuels, diesel, and compressed natural gas (CNG) in internal combustion engines; the use of electricity from a range of conventional and renewable sources to power electric vehicles (EVs); and the use of hybrid EV technology. Our approach combines spatially, temporally, and chemically detailed life cycle emission inventories; comprehensive, fine-scale state-of-the-science chemical transport modeling; and exposure, concentration-response, and economic health impact modeling for ozone (O3) and fine particulate matter (PM2.5). We find that powering vehicles with corn ethanol or with coal-based or "grid average" electricity increases monetized environmental health impacts by 80% or more relative to using conventional gasoline. Conversely, EVs powered by low-emitting electricity from natural gas, wind, water, or solar power reduce environmental health impacts by 50% or more. Consideration of potential climate change impacts alongside the human health outcomes described here further reinforces the environmental preferability of EVs powered by low-emitting electricity relative to gasoline vehicles.


Growth-incompetent monomers of human calcitonin lead to a noncanonical direct relationship between peptide concentration and aggregation lag time.
The role of the peptide hormone calcitonin in skeletal protection has led to its use as a therapeutic for osteoporosis. However, calcitonin aggregation into amyloid fibrils limits its therapeutic efficacy, necessitating a modification of calcitonin's aggregation kinetics. Here, we report a direct relationship between human calcitonin (hCT) concentration and aggregation lag time. This kinetic trend was contrary to the conventional understanding of amyloid aggregation and persisted over a range of aggregation conditions, as confirmed by thioflavin-T kinetics assays, CD spectroscopy, and transmission EM. Dynamic light scattering, 1H NMR experiments, and seeded thioflavin-T assay results indicated that differences in initial peptide species contribute to this trend more than variations in the primary nucleus formation rate. On the basis of kinetics modeling results, we propose a mechanism whereby a structural conversion of hCT monomers is needed before incorporation into the fibril. Our kinetic mechanism recapitulates the experimentally observed relationship between peptide concentration and lag time and represents a novel mechanism in amyloid aggregation. Interestingly, hCT at low pH and salmon calcitonin (sCT) exhibited the canonical inverse relationship between concentration and lag time. Comparative studies of hCT and sCT with molecular dynamics simulations and CD indicated an increased α-helical structure in sCT and low-pH hCT monomers compared with neutral-pH hCT, suggesting that α-helical monomers represent a growth-competent species, whereas unstructured random coil monomers represent a growth-incompetent species. Our finding that initial monomer concentration is positively correlated with lag time in hCT aggregation could help inform future efforts for improving therapeutic applications of CT.


Relation of frontal eye field activity to saccade initiation during a countermanding task.
The countermanding (or stop signal) task probes the control of the initiation of a movement by measuring subjects' ability to withhold a movement in various degrees of preparation in response to an infrequent stop signal. Previous research found that saccades are initiated when the activity of movement-related neurons reaches a threshold, and saccades are withheld if the growth of activity is interrupted. To extend and evaluate this relationship of frontal eye field (FEF) activity to saccade initiation, two new analyses were performed. First, we fit a neurometric function that describes the proportion of trials with a stop signal in which neural activity exceeded a criterion discharge rate as a function of stop signal delay, to the inhibition function that describes the probability of producing a saccade as a function of stop signal delay. The activity of movement-related but not visual neurons provided the best correspondence between neurometric and inhibition functions. Second, we determined the criterion discharge rate that optimally discriminated between the distributions of discharge rates measured on trials when saccades were produced or withheld. Differential activity of movement-related but not visual neurons could distinguish whether a saccade occurred. The threshold discharge rates determined for individual neurons through these two methods agreed. To investigate how reliably movement-related activity predicted movement initiation; the analyses were carried out with samples of activity from increasing numbers of trials from the same or from different neurons. The reliability of both measures of initiation threshold improved with number of trials and neurons to an asymptote of between 10 and 20 movement-related neurons. Combining the activity of visual neurons did not improve the reliability of predicting saccade initiation. These results demonstrate how the activity of a population of movement-related but not visual neurons in the FEF contributes to the control of saccade initiation. The results also validate these analytical procedures for identifying signals that control saccade initiation in other brain structures.


A quantitative comparison of soft tissue compressive viscoelastic model accuracy.
Viscoelastic models are generally considered a good option for modeling biological tissue due to tissue time-dependency. However, although various forms of viscoelastic models have been developed, only a few have shown a good balance between model mathematical simplicity and experimental fit accuracy. Starting from a basic Standard Linear Solid (SLS) model, a systematic modification of the viscoelastic model leading to a more accurate tissue model is presented. A five-element model family, with a Double Maxwell-arm Wiechert (DMW) representative model, is selected for its mathematical simplicity and mathematical loading accuracy. This DMW model is then used to fit experimental data collected from stress relaxation indentation tests performed on fresh porcine liver and spleen. The results show that this DMW model provides a closer fit with the experimental liver (SLS R(2)=0.731, DMW R(2)=0.991) and spleen (SLS R(2)=0.720, DMW R(2)=0.981) data, compared to an SLS model, while maintaining appreciable mathematical simplicity by using only five model elements, compared to seven-element models. Thus, any model from this five-element model family can be used as a base compressive model for complex soft tissue with an approximate 35% improved model fit over SLS. Finally, model element parameters for in vitro fresh porcine liver and spleen are determined from the associated indentation tests.


Value of true whole-body FDG-PET/CT scanning protocol in oncology: optimization of its use based on primary diagnosis.
No standardized field of view (FOV) currently exists for whole-body (WB) positron emission tomography/computed tomography (PET/CT). Limited WB PET/CT FOV can exclude portions of the head, upper, and lower extremities, because there is little perceived clinical benefit to be gained from imaging these areas. To determine how often utilizing WB PET/CT changes the clinical stage and management compared to each of the limited WB FOVs used for PET/CT. We retrospectively identified 556 oncologic patients (804 PET/CT studies) who underwent staging or restaging PET/CT between November 2010 and November 2011. Abnormal hypermetabolic areas that were suspicious for malignancy in areas that are outside of some of the limited fields of view including in the brain, scalp, and calvarium (above the orbital ridge), in the proximal upper extremity (distal to the humeral neck), distal upper extremity (beyond the elbow), proximal lower extremity (distal to the lesser trochanter), and distal lower extremity (beyond the knees) were recorded. A total of 8.5% (47/556) of patients had abnormal findings outside the most limited FOV (skull base to upper thighs) used in PET/CT. More patients had abnormal hypermetabolic lesions in the lower extremity (5.9%) than in the upper extremity (2.3%). Similarly, more patients had abnormal lesions in the proximal (6.5%) compared to the distal (1.4%) upper and lower extremities. The stage was only changed in one patient (0.2%), however new lesions noted in the brain changed management in six patients (1.1%). Melanoma, lymphoma, multiple myeloma, sarcomas and stage IV lung, breast, prostate, bladder, testicular, and renal cancer were more likely to have findings outside the most limited FOV (skull base to upper thighs). WB FOV detects additional sites of disease compared to the limited WB FOV, and although these lesions rarely change stage, some of these lesions may change clinical management.


[Predictors of major mental disorders].
Predictors of several major mental disorders include strong genetic linkage that is modified by biological, psychological and social factors. Insight into the biological mechanisms underlying these interactions is growing. Several candidate genes have been identified but their predictive value is still limited for predictions in the single individual. Comorbidities are common, including combinations of different mental disorders and/or combinations of mental and physical disorders. The combination of a mental and physical disorder often indicates a worse outcome for the physical disorder.


Fast and high-yield microreactor syntheses of ortho-substituted [(18)F]fluoroarenes from reactions of [(18)F]fluoride ion with diaryliodonium salts.
A microreactor was applied to produce ortho-substituted [(18)F]fluoroarenes from the reactions of cyclotron-produced [(18)F]fluoride ion (t(1/2) = 109.7 min) with diaryliodonium salts. The microreactor provided a very convenient means for running sequential reactions rapidly with small amounts of reagents under well-controlled conditions, thereby allowing reaction kinetics to be followed and Arrhenius activation energies (E(a)) to be measured. Prepared symmetrical iodonium chlorides (Ar(2)I(+)Cl(-)) rapidly (<4 min) gave moderate (Ar = 2-MeOC(6)H(4), 51%) to high (Ar = Ph or 2-MeC(6)H(4), 85%) decay-corrected radiochemical yields (RCYs) of a single radioactive product (Ar(18)F). Reaction velocity with respect to Ar group was 2-MeOC(6)H(4) < Ph < 2-MeC(6)H(4). Activation energies were in the range 18-28 kcal/mol. Prepared unsymmetrical salts (e.g., 2-RC(6)H(4)I(+)2'-R'C(6)H(4)X(-); X = Cl or OTs) also rapidly gave two products (2-RC(6)H(4)(18)F and 2-R'C(6)H(4)(18)F) in generally high total RCYs (79-93%). Selectivity for product [(18)F]fluoroarene was controlled by the nature of the ortho substituents. The power of ortho substituents to impart an ortho-effect was in the following order:, 2,6-di-Me > 2,4,6-tri-Me > Br > Me > Et approximately (i)Pr >> H > OMe. For (2-methyphenyl)(phenyl)iodonium chloride, the time-course of reaction product selectivity was constant and consistent with the operation of the Curtin-Hammett principle. These results will aid in the design of diaryliodonium salt precursors to (18)F-labeled tracers for molecular imaging.


Multiple sclerosis and motherhood choice: an observational study in Portuguese women patients.
INTRODUCTION. Multiple sclerosis (MS) is a disabling disease occurring mainly in women of childbearing age. MS may interfere with family planning and motherhood decision. AIM. To study the influence of MS diagnosis and course of the disease on motherhood decision. PATIENTS AND METHODS. The cohort of 35 to 45-year-old female patients diagnosed with MS for at least ten years was selected from six Portuguese MS centers. A structured questionnaire was applied to all patients in consecutive consultation days. Clinical records were reviewed to characterize and collect information about the disease and pregnancies. RESULTS. One hundred women were included; mean age at MS diagnosis was 26.3 ± 5.0 years; 90% of the participants presented with a relapsing-remitting MS; 57% had no pregnancies after the diagnosis. MS type and number of relapses were not significantly different between women with or without pregnancies after the diagnosis (p = 0.39 and p = 0.50, respectively). Seventy-seven percent of the patients did not have the intended number of pregnancies. Main reasons given were fear of future disability and the possibility of having relapses. Forty-three women considered that pregnancy might worsen MS. CONCLUSION. In our population, motherhood choice was unrelated to the MS type and the number of relapses. However, a relevant number of women had fewer pregnancies than those intended before MS diagnosis and believed that pregnancy could worsen the disease. An effort to better inform the patients should be made to minimize the impact of MS diagnosis on motherhood decision.


4th Seah Cheng Siang Memorial Lecture. Primary gastrointestinal lymphoma in Hong Kong.
Many primary gastrointestinal lymphomas (PGL) are treatable and carry a good prognosis, particularly of localized and of "low grade" malignancy. In general, the stomach is the most commonly involved site followed by the small and then large intestines. The incidence of gastric lymphoma may be on the rise, and the response of lymphoma arising from gastric Mucosa Associated Lymphoid Tissue (MALT) to treatment of the co-existing Helicobacter pylori infection has added a new dimension to the study of PGL. Most PGLs are histologically aggressive and those involving the intestines tend to present late. In a series of 425 adult Chinese patients with PGL seen in Hong Kong between 1975 and 1993, there were 230 males and 195 females with a median age of 53 years. Sites of involvement were the oesophagus in 3, the stomach in 238, small intestines in 131 and large intestines in 53. The majority were of diffuse large cell, small cell, mixed or immunoblastic histology (Working Formulation) and 90% were of B cell origin. At presentation 70.6% had stage II, IV disease (Manchester Classification) and 64.7% had B symptoms. The most common presenting clinical features were abdominal pain, gastrointestinal bleeding, anorexia, vomiting and weight loss. Perforation occurred in 76 patients. Surgery was carried out in 318 (74.8%), radiotherapy in 161 (37.9%) and all patients with advanced diseases received chemotherapy, with or without radiotherapy. The overall 5-year survival was 75% in patients with low grade histology and 70% in those with clinical stage I and II disease.(ABSTRACT TRUNCATED AT 250 WORDS)


Fine-scale genetic mapping of a hybrid sterility factor between Drosophila simulans and D. mauritiana: the varied and elusive functions of "speciation genes".
Hybrid male sterility (HMS) is a usual outcome of hybridization between closely related animal species. It arises because interactions between alleles that are functional within one species may be disrupted in hybrids. The identification of genes leading to hybrid sterility is of great interest for understanding the evolutionary process of speciation. In the current work we used marked P-element insertions as dominant markers to efficiently locate one genetic factor causing a severe reduction in fertility in hybrid males of Drosophila simulans and D. mauritiana. Our mapping effort identified a region of 9 kb on chromosome 3, containing three complete and one partial coding sequences. Within this region, two annotated genes are suggested as candidates for the HMS factor, based on the comparative molecular characterization and public-source information. Gene Taf1 is partially contained in the region, but yet shows high polymorphism with four fixed non-synonymous substitutions between the two species. Its molecular functions involve sequence-specific DNA binding and transcription factor activity. Gene agt is a small, intronless gene, whose molecular function is annotated as methylated-DNA-protein-cysteine S-methyltransferase activity. High polymorphism and one fixed non-synonymous substitution suggest this is a fast evolving gene. The gene trees of both genes perfectly separate D. simulans and D. mauritiana into monophyletic groups. Analysis of gene expression using microarray revealed trends that were similar to those previously found in comparisons between whole-genome hybrids and parental species. The identification following confirmation of the HMS candidate gene will add another case study leading to understanding the evolutionary process of hybrid incompatibility.


Pure mesenchymal neoplasms of the uterine corpus: selected problems.
The first part of this review includes a discussion of some issues in decision analysis as it applies to uterine mesenchymal tumors, as well as a discussion of some of the morphologic features and histochemical techniques that may be used to determine whether a mesenchymal tumor is demonstrating smooth muscle or endometrial stromal differentiation. Also included in the first part are caveats that the pathologist should observe before interpreting mesenchymal tumors of the uterus. The second part of the paper is devoted to morphologic diagnostic criteria and differential diagnosis.


Dynamic regulation of LINC complex composition and function across tissues and contexts.
The concept of mechanotransduction to the nucleus through a direct force transmission mechanism has fascinated cell biologists for decades. Central to such a mechanism is the linker of nucleoskeleton and cytoskeleton (LINC) complex, which spans the nuclear envelope to couple the cytoplasmic cytoskeleton to the nuclear lamina. In reality, there is not one LINC complex identity, but instead, a family of protein configurations of varied composition that exert both shared and unique functions. Regulated expression of LINC complex components, splice variants, and mechanoresponsive protein turnover mechanisms together shape the complement of LINC complex forms present in a given cell type. Disrupting specific gene(s) encoding LINC complex components therefore gives rise to a range of organismal defects. Moreover, evidence suggests that the mechanical environment remodels LINC complexes, providing a feedback mechanism by which cellular context influences the integration of the nucleus into the cytoskeleton. In particular, evidence for crosstalk between the nuclear and cytoplasmic intermediate filament networks communicated through the LINC complex represents an emerging theme in this active area of ongoing investigation.


XIAP and survivin as therapeutic targets for radiation sensitization in preclinical models of lung cancer.
Survivin and XIAP are members of inhibitors of apoptosis (IAPs) family. They are upregulated in various malignancies. Inactivation of these molecules has resulted in chemosensitization. The purpose of this study was to determine whether inhibition of survivin, XIAP, or both enhances radiotherapy in a lung cancer model. Transient transfection of H460 cells with antisense oligonucleotides (ASOs) against either molecule has specifically reduced their expression, by Western analysis. Results from 3-(4,5-methylthiazol-2-yl)-2,5-diphenyl-tetrazolium bromide and clonogenic assays suggest that inhibition of survivin or XIAP greatly decreased cell survival following irradiation. A significantly increased number of apoptotic cells were detected when H460 cells were treated with either antisurvivin, anti-XIAP or both ASOs (P=0.03, 0.0003 and 0.01, respectively) plus irradiation. H460 xenografts that were treated with ASOs plus radiotherapy demonstrated growth delay beyond 15 days. Growth delay in the groups of combined treatment was greater than that in other groups. However, treatment with ASOs alone did not affect tumor growth delay in mice, but decreased the survival of H460 cells in culture. Antisense treatment did not cause any mortality or weight loss during the 32 days of study. These data suggest that inhibition of survivin or XIAP radiosensitizes H460 lung cancer cells by upregulating apoptosis and downregulating cell survival. Combination of radiotherapy and inhibition of survivin and XIAP through the antisense approach results in improved tumor control by radiotherapy in a mouse model of lung cancer.


A systematic review of the outcomes of osteoporotic fracture patients after hospital discharge: morbidity, subsequent fractures, and mortality.
Osteoporotic fracture is the main complication of osteoporosis. The current management is to discharge patients as early as possible so they can get back to their daily activities. Once discharged, there are three main issues relating to morbidity, mortality, and risk of a subsequent fracture that need to be addressed and discussed. Therefore, the aim of this systematic review was to summarize and evaluate the evidence from published literature, to determine the outcome of osteoporotic fracture patients after their hospital discharge. The MEDLINE and Cumulative Index to Nursing and Allied Health Literature (CINAHL) databases were searched, using the terms "osteoporosis", "fracture", "osteoporotic fracture", "hip fracture", and "vertebral fracture". We included only human studies published in English between 2004 and 2014. The reference lists of included studies were thoroughly reviewed in search for other relevant studies. A total of 18 studies met the selection criteria. Most were observational and cohort studies. Out of all the studies, five studies looked into the morbidity, six studies looked into the risk of subsequent fractures, and seven studies looked into mortality. Vertebral fracture caused the greatest health burden, but hip fracture patients were the main users of informal care after hospital discharge. There was an increased risk of a subsequent fracture after a primary fracture compared with the control group, a cohort comparison, or the general population. Osteoporotic fractures, especially hip fractures, are associated with higher mortality rate despite the advances in the management of osteoporotic fracture cases. There is strong evidence to show that after hospital discharge, osteoporotic fracture patients are faced with higher morbidity, subsequent fractures, and mortality.


[Development of artificial disc nucleus materials (semicrystalline polyvinyl alcohol hydrogel elastomers)].
For the purpose of developing of disc nucleus replacement (semicrystalline PVA hydrogel elastomers) and explorating the possibility of clinical application, in this study,the aqueous PVA solution froze at -20 degrees C for 6-12 h, and then thawed at room temperature for 1-2 h. The same process was repeated 1-3 times. After the specimen was dehydrated in vacuum, a kind of artificial disc nucleus materials (semicrystalline PVA hydrogel elastomers ) was formed. DSC and mechanical tests were conducted to investigate the influence of aqueous PVA solution concentration, of dehydrating in vacuum, and of gamma-ray irradiating upon the degree of crystallity and mechanical properties of PVA hydrogel elastomers.


Evaluation of the likelihood of a selective CHK1 inhibitor (LY2603618) to inhibit CYP2D6 with desipramine as a probe substrate in cancer patients.
LY2603618 is a selective inhibitor of deoxyribonucleic acid damage checkpoint kinase 1 (CHK1) and has been in development for the enhancement of chemotherapeutic agents. The study described was to assess the potential interaction between LY2603618 and cytochrome P450 isoform 2D6 (CYP2D6) substrate desipramine in patients with cancer. Before clinical investigation, in silico simulations (using Simcyp®) were conducted. An open-label, two-period, fixed-sequence study was planned in 30 patients with advanced or metastatic cancers, in which a 50 mg oral dose of desipramine was administered alone and in combination with 275 mg of LY2603618 (i.v. infusion). An interim analysis was planned after 15 patients completed both periods. Ratios of geometric least squares means (LSMs) of primary pharmacokinetic (PK) parameters and 90% repeated confidence intervals (RCIs) between desipramine plus LY2603618 and desipramine alone were calculated. Lack of an interaction was declared if the 90% RCI fell between 0.8 and 1.25. The LSM ratios (90% RCI) for areas under the plasma concentration-time curve from time zero to tlast (AUC[0-tlast]) and to infinity (AUC[0-∞]) and maximum plasma concentration (Cmax) were 1.14 (1.04, 1.25), 1.09 (0.99, 1.21) and 1.16 (1.05, 1.29). In silico simulations were predictive of clinical results. Single doses of 275 mg LY2603618 administered with 50 mg desipramine were generally well tolerated. In conclusion, no clinically significant interaction was observed between LY2603618 and desipramine in patients with cancer. In silico predictions of clinical results demonstrated that mechanistic and physiologically based PK approaches may inform clinical study design in cancer patients.


Effect of a hospitalist-run postdischarge clinic on outcomes.
New post-discharge strategies to reduce adverse events are needed. To determine whether follow-up in a hospitalist-run post-discharge clinic (PDC) decreases post-discharge adverse events when compared to follow-up in a primary care clinic (PCP) or urgent care clinic (UC). Retrospective cohort study using propensity scoring in multivariate analysis. Consecutive Veterans discharged home after a nonscheduled admission seen in PDC, UC, or PCP within 30 days of discharge. Recently discharged patients are seen by housestaff who cared for them during the index admission and staffed with a rotating hospitalist in PDC; UC and PCP patients are seen by housestaff or attending ambulatory physicians. The primary outcome was a composite of hospital readmissions, Emergency Department visits, and mortality 30 days after discharge. 5085 patients met criteria; 538 followed up in PDC (10.6%), 1848 with their PCP (36.3%), and 2699 in UC (53.1%). Patients following up in PDC were older and had a higher comorbidity burden. ICU exposure was similar between groups. Patients seen in PDC had shorter length of stay (LOS) (PDC, 3.8 days, UC, 5.0 days, PCP, 6.2 days; p = 0.04) and time to first post-discharge visit (PDC, 5.0 days, UC, 9.4 days, PCP, 13.7 days; p < 0.01). There were no differences between groups in the primary outcome in unadjusted or propensity-adjusted multivariate analysis. Patients seen in a hospitalist-run PDC had similar 30-day post-discharge adverse outcome rates despite a 2.4-day shorter LOS compared to patients seen by their PCP. Prospective testing of PDCs is warranted.


Clinical significance of TP53 mutations in adult T-cell leukemia/lymphoma.
Adult T-cell leukaemia/lymphoma (ATL) patients have a poor prognosis. Here, we investigated the impact of TP53 gene mutations on prognosis of ATL treated in different ways. Among 177 patients, we identified 47 single nucleotide variants or insertion-deletions (SNVs/indels) of the TP53 gene in 37 individuals. TP53 copy number variations (CNVs) were observed in 38 patients. Altogether, 67 of 177 patients harboured TP53 SNVs/indels or TP53 CNVs, and were categorized as having TP53 mutations. In the entire cohort, median survival of patients with and without TP53 mutations was 1·0 and 6·7 years respectively (P < 0·001). After allogeneic haematopoietic stem cell transplantation (HSCT), median survival of patients with (n = 16) and without (n = 29) TP53 mutations was 0·4 years and not reached respectively (P = 0·001). For patients receiving mogamulizumab without allogeneic HSCT, the median survival from the first dose of antibody in patients with TP53 mutations (n = 27) was only 0·9 years, but 5·1 years in those without (n = 42; P < 0·001). Thus, TP53 mutations are associated with unfavourable prognosis of ATL, regardless of treatment strategy. The establishment of alternative modalities to overcome the adverse impact of TP53 mutations in patients with ATL is required.


A review of factors influencing measurements of decadal variations in metal contamination in San Francisco Bay, California.
This review summarizes some of the principal results of systematic measurements of trace metal concentrations throughout San Francisco Bay that began in 1989, and that have yielded insights on the factors controlling temporal and spatial variations of those concentrations on seasonal to decadal time scales. Pronounced seasonal variation in some metal concentrations is associated with gradients in the system's hydrology and the diagenetic remobilization of metals from benthic sediments. Additional temporal variation is associated with interannual differences in hydrologic flushing (e.g., ENSO cycles) and episodic storm events. While intra- and inter-annual variabilities complicate assessments of long-term variations in metal concentrations, recent analyses using stable lead isotopic composition distributions and time-series models have deconvoluted decadal changes in lead and silver concentrations in the estuary. Decadal variations in concentrations of other contaminant metals (e.g., mercury) are now being characterized, as well as projections of future concentrations of other metals of concern (e.g., copper). These historic assessments and projections of trace metal variations attest to the importance of long-term, systematic monitoring programs to quantify past and future impacts on water quality in San Francisco Bay and other complex estuarine systems.


NH4Cl activates AE2 anion exchanger in Xenopus oocytes at acidic pHi.
In the course of experiments to define regulation by intracellular pH (pHi) of the AE2 anion exchanger expressed in Xenopus oocytes, we discovered an unexpected regulation of AE2 by NH4+. Intracellular acidification produced by extracellular acidification or produced by equimolar substitution of NaCl with sodium acetate each inhibited AE2 activity. In contrast, intracellular acidification by equimolar substitution of NaCl with NH4Cl activated AE2-associated, trans-anion-dependent, 4,4'-diisothiocyanostilbene-2,2'-disulfonic acid-sensitive 36Cl- influx and efflux. Regulation by NH4+ was isoform specific, since neither erythroid nor kidney AE1 was activated. AE2 activation was maximal at <5 mM NH4Cl; was not mimicked by extracellular KCl, chloroquine, or polyamines; and was insensitive to amiloride, bumetanide, barium, and gadolinium. Whether NH4Cl acts directly on AE2 or on another target remains to be determined. Activation of AE2 by NH4+ may serve to sustain Cl-/HCO3- exchange activity in the presence of acidic pH in renal medulla, colon, abscesses, and other AE2-expressing acidic locales exposed to elevated NH4+ concentration.


How lac repressor recognizes lac operator.
Nucleotide analogs were substituted for unmodified nucleotides at specific sites in the lac operator sequence by a combination of chemical and enzymatic procedures. The nitrocellulose filter assay was used to study the interactions of these modified operators with wild-type (SQ) and tight-binding (QX86) lac repressors. These studies implicate directly the 5 methyl of thymine and the 2 amino of guanine as important operator-repressor contact sites. Furthermore, when these findings are combined with published results from other laboratories, a model for the lac operator-lac repressor interaction can be derived. Two important postulates follow from this model. (i) The repressor interacts at specific and defined sites with the N7 of guanine, the 5 methyl of thymine, the 2 amino of guanine, and the central major groove of the operator. (ii) The repressor binds to one side of the operator.


Red Blood Cell-Derived Extracellular Vesicles Display Endogenous Antiviral Effects and Enhance the Efficacy of Antiviral Oligonucleotide Therapy.
The COVID-19 pandemic has resulted in a large number of fatalities and, at present, lacks a readily available curative treatment for patients. Here, we demonstrate that unmodified red blood cell-derived extracellular vesicles (RBCEVs) can inhibit SARS-CoV-2 infection in a phosphatidylserine (PS) dependent manner. Using T cell immunoglobulin mucin domain-1 (TIM-1) as an example, we demonstrate that PS receptors on cells can significantly increase the adsorption and infection of authentic and pseudotyped SARS-CoV-2 viruses. RBCEVs competitively inhibit this interaction and block TIM-1-mediated viral entry into cells. We further extend the therapeutic efficacy of this antiviral treatment by loading antisense oligonucleotides (ASOs) designed to target conserved regions of key SARS-CoV-2 genes into RBCEVs. We establish that ASO-loaded RBCEVs are efficiently taken up by cells in vitro and in vivo to suppress SARS-CoV-2 replication. Our findings indicate that this RBCEV-based SARS-CoV-2 therapeutic displays promise as a potential treatment capable of inhibiting SARS-CoV-2 entry and replication.


Adverse drug reactions in hospitalized psychiatric patients.
Reducing adverse drug reactions (ADRs) is a critical element in providing safe medication use to hospitalized patients. There is an abundance of literature describing ADRs and preventable ADRs (pADRs) in hospitalized patients; however, little has been published specific to psychiatric inpatients. Further knowledge of the most common pADRs in hospitalized psychiatric patients will allow targeted patient safety initiatives to be developed. To determine the most frequent ADRs and pADRs in a psychiatric hospital, with emphasis on identifying factors for prevention. Three years of ADRs at a psychiatric hospital were analyzed and evaluated according to type of medication, preventability, severity, and factors associated with preventability. From July 1, 2006, to June 30, 2009, 93 ADRs were reported; 19 (20.4%) were classified as preventable. Psychiatric medications accounted for 45 (48.4%) of the ADRs and nonpsychiatric medications were associated with 48 (51.6%). Cardiovascular agents (n = 17) and antiepileptics (n = 17) were responsible for most ADRs. Of the 19 pADRs, lithium was the drug reported most frequently, followed by phenytoin and anxiolytics. Nine (47%) of the pADRs were severe and required a medical transfer for management; 3 of the 9 were lithium toxicity. The most common preventability factor involved drug interactions. A pharmacy intervention involving staff education to reduce lithium pADRs is presented. Awareness of the most frequent drug classes associated with ADRs and pADRs in a psychiatric hospital allows opportunity for education, medication management system changes, and improved patient safety. Lithium, followed by phenytoin and anxiolytics, were the most common drugs associated with pADRs. A drug-drug interaction was the most frequent factor associated with pADRs.


A new in vitro model to study endothelial injury.
Endothelial dysfunction or "endothelialitis" is a prominent feature in several disease states ranging from atherosclerosis to transplant rejection. This dysfunction is also caused by drugs such as cyclosporin A (CyA) and leads to allograft vasculopathy and eventual graft loss. Despite the frequency and importance of this injury, there is no model to study the morphological effects of endothelial injury and dysfunction in vitro. We utilized a model in which mouse endothelial cells (SVEC 4-10) can be induced to form capillary tubes by culturing on a laminin-rich matrix (Matrigel). In this morphological model of endothelial cell function, we studied the effect of varying doses of CyA on two parameters of tube formation: initiation of tube formation and disruption of mature capillary tubes. As a positive control we used IFN-gamma, which inhibited capillary tube formation. We developed this assay in 96-well culture plates to test several samples simultaneously. The assay could be adapted to a 96-well format by optimizing the cell density. Endothelial dysfunction was seen when the endothelial cells were incubated with cyclosporin A, which affected both morphological parameters of tube formation. At higher doses (2-20 microg/ml) CyA both inhibited capillary tube formation and disrupted mature capillary tubes. At lower doses CyA only inhibited the initiation of tube formation; it did not disrupt mature capillary tubes. IL-2 (400-1000 pg/ml) and IFN-gamma (10-400 pg/ml) inhibited initiation of tube formation but did not disrupt mature capillary tubes. None of these agents, including high doses of CyA, impaired endothelial cell viability. CyA-induced endothelial dysfunction can be modeled in vitro by this novel morphological assay of capillary tube formation. This assay can discern mild and severe degrees of endothelial dysfunction. The different effects of low and high levels of CyA on capillary tube formation imply that similar dysfunction in vivo may be responsible for allograft vasculopathy caused by CyA. This novel model can also be utilized to study other forms of vasculitis.


Fluoride and silver ion concentrations and pH in silver diamine fluoride solutions from Argentina.
The aim of this study was to measure the fluoride (F) and silver (Ag) ion concentration and the pH, over time, of 2 solutions of 38% silver diamine fluoride (SDF) produced in Argentina. The brand Fluorsilver® was established as Group 1 (G1) (Densell), and the brand FAgamin® (Tedequim) as Group 2 (G2), each with two different lots. The following were determined at time 0 (t0) and 30 days after opening (t30): a) fluoride concentration (w/v) by visible spectrophotometry b) Ag content (w/v) by atomic absorption spectrophotometry c) pH. Results: The data in the freshly opened bottles were for G1 lot1/lot2: a) 0.96/1, b) 8.3/7.8, c).11.5/11.3; G2 lot1/lot2: a) 11.5/9.9, b) 39/39, c) 7/6,9; and after 30 days, G1 lot1/lot2: a) 0.85/0.81, b) 7.2/8.2, c) 11.3/11.6; G2 lot1/lot2: a) 9.35/8.43, b) 38/38, c) 7.6/7.6. Conclusion In relation to the expected values (5.0-5.9% fluoride and 24.4-28.8% silver), the average concentration of fluoride and silver ions was lower for G1, but higher for G2. The pH was alkaline for G1 and neutral for G2. Over the 30 days, the content of fluoride and silver tended to decrease.


Limb salvage following iatrogenic arterial injury: complications of cardiac support using intra-aortic balloon pumps.
This is a unique case report describing complex limb salvage in a patient who experienced acute limb ischaemia due to a complication of intra-aortic balloon pump (IABP) counterpulsation. This case focuses on a patient who had an IABP counterpulsation device inserted following myocardial infarction, requiring urgent coronary artery bypass grafting for acute coronary syndrome. Postoperatively, the IABP could not be removed, with consequent iliac thrombosis and acute limb ischaemia. Emergency femoral-to-femoral crossover bypass was performed using a polytetrafluoroethylene graft. A portion of the IABP balloon tip was entrapped and retained, however, and became the focus of delayed septicaemia, resulting in graft infection and wound breakdown 6 weeks later. Explantation of the residual balloon tip, ligation of the right external iliac artery and redo femoral-femoral crossover using the great saphenous vein were successfully performed.


Effects of aerobic exercise on non-high-density lipoprotein cholesterol in children and adolescents: a meta-analysis of randomized controlled trials.
The authors used the meta-analytic approach to examine the effects of aerobic exercise on non-high-density lipoprotein cholesterol (non-HDL-C) in children and adolescents. Thirteen non-HDL-C outcomes in 404 males and females (221 exercise, 183 control) were available for pooling. Random-effects modeling yielded a nonstatistically significant exercise minus control group reduction of 0.61% in non-HDL-C (X +/- SEM, -0.7 +/- 2.4 mg/dL, 95% confidence interval [CI], -5.4 to 5.0 mg/dL). A statistically significant decrease of 7% was found for percent body fat (X +/- SEM, -2.1 +/- 0.5%, 95% CI, -3.0 to -1.2%) as well as an 8% increase in aerobic capacity (X +/- SEM, 3.4 +/- 1.0 mL/kg/min, 95% CI, 1.4-5.3 mL/kg/min), both secondary outcomes of the study. It was concluded that aerobic exercise does not reduce non-HDL-C but does improve percent body fat and aerobic capacity in children and adolescents. However, a need exists for additional studies on this topic.


Fabrication of defective graphene oxide for efficient hydrogen production and enhanced 4-nitro-phenol reduction.
Hydrogen has been considered as one of the most promising alternative energy source to solve the future energy demands due to its high energy capacity and emission-free character. The generation of hydrogen from non-fossil sources is necessary for the sustainable development of human life on this planet. The hydrolysis of sodium borohydride can quickly produce a large amount of hydrogenin situand on-demand in the presence of the catalyst, which can be used as an alternative energy source. So, it is crucial to fabricate the highly efficient, robust, and economical catalyst for the production of hydrogen via hydrolysis of sodium borohydride. Herein, a facile and efficient approach for the synthesis of metal-functionalized reduced graphene oxide for the production of hydrogen at room temperature was used. Moreover, the synthesized catalyst has also been tested in the field of environmental catalysis for the reduction of toxic 4-nitrophenol to valuable 4-aminophenol in the presence of sodium borohydride. The enhanced activity of prepared metal-functionalized reduced graphene oxide is ascribed to a strong affinity between Fe-NXand reduced graphene oxide which facilitates electron transfer as well as synergistic effect. Overall, this work presents a crucial procedure for green chemistry reactions when a carbonaceous material is selected as a catalyst.


[Nonplatelet Effects of Ticagrelor].
This review summarizes current knowledge concerning "nonplatelet effects of P2Y12 receptor antagonist ticagrelor. We show the experimental and clinical evidence that ticagrelor increases plasma concentration of adenosine as a potential mechanism of additive effects of ticagrelor. In addition, we sought to compare the clinical profile of ticagrelor with pharmacological effects of adenosine and discuss from this point of view the effects of ticagrelor on vascular tone, cardiac electrophysiology, ischemia/reperfusion injury, immunity and inflammatory reactions, peripheral nerves.


Could the Novel Oral Anticoagulants Be Used for Coronary Artery Aneurysm?
Coronary artery aneurysms (CAAs) are uncommon in coronary angiography, and left main coronary artery aneurysms are rare. There is no consensus for the treatment of CAAs. A young patient with left coronary artery aneurysm diagnosed by coronary angiography and with recurrent acute myocardial infarction was treated with rivaroxaban and aspirin. The patient had no angina for 6 months. Novel oral anticoagulants combined with antiplatelet agents may be appropriate for the treatment of CAAs.


Bound states for magic state distillation in fault-tolerant quantum computation.
Magic state distillation is an important primitive in fault-tolerant quantum computation. The magic states are pure nonstabilizer states which can be distilled from certain mixed nonstabilizer states via Clifford group operations alone. Because of the Gottesman-Knill theorem, mixtures of Pauli eigenstates are not expected to be magic state distillable, but it has been an open question whether all mixed states outside this set may be distilled. In this Letter we show that, when resources are finitely limited, nondistillable states exist outside the stabilizer octahedron. In analogy with the bound entangled states, which arise in entanglement theory, we call such states bound states for magic state distillation.


Technical challenges and clinical outcomes of using a closed-loop glycemic control system in the hospital.
According to large randomized trials, results suggest that maintaining normoglycemia postoperatively through tight glycemic control (TGC) and intensive insulin therapy (IIT) can improve surgical outcomes as well as reduce mortality and morbidity in critically ill patients. However, trials examining the effects of TGC have had conflicting results. Systematic reviews and meta-analyses have also led to differing conclusions. The main reason these clinical trials and meta-analyses show negative results for TGC is the high incidence of hypoglycemia induced by IIT. This could not be prevented because there is no reliable technique that can avoid this condition during IIT. The development of accurate, continuous blood glucose monitoring devices and closed-loop systems for computer-assisted blood glucose control in the intensive care unit (ICU) will probably help avoid hypoglycemia in these situations. The STG closed-loop glycemic control system was introduced to our department to be used and evaluated for strict serum glucose control with no hypoglycemic episodes during IIT in the surgical ICU, to reduce the workload of ICU nurses, and to decrease incidents related to the management of blood glucose levels according to manual conventional venous infusion insulin therapy. The goal of our team was to use the STG closed-loop glycemic control system for perioperative TGC in surgical patients to solve the complications of IIT and reduce risk of hypoglycemia. The challenge at our hospital demonstrated that the STG closed-loop glycemic control system can be expected to achieve TGC with no occurrence of hypoglycemia induced by IIT after surgery.


Biomedical risk assessment as an aid for smoking cessation.
A possible strategy for increasing smoking cessation rates could be to provide smokers who have contact with healthcare systems with feedback on the biomedical or potential future effects of smoking, e.g. measurement of exhaled carbon monoxide (CO), lung function, or genetic susceptibility to lung cancer. We reviewed systematically data on smoking cessation rates from controlled trials that used biomedical risk assessment and feedback. To determine the efficacy of biomedical risk assessment provided in addition to various levels of counselling, as a contributing aid to smoking cessation. We systematically searched he Cochrane Collaboration Tobacco Addiction Group Specialized Register, Cochrane Central Register of Controlled Trials (CENTRAL), MEDLINE (1966 to 2004), and EMBASE (1980 to 2004). We combined methodological terms with terms related to smoking cessation counselling and biomedical measurements. Inclusion criteria were: a randomized controlled trial design; subjects participating in smoking cessation interventions; interventions based on a biomedical test to increase motivation to quit; control groups receiving all other components of intervention; an outcome of smoking cessation rate at least six months after the start of the intervention. Two assessors independently conducted data extraction on each paper, with disagreements resolved by consensus. From 4049 retrieved references, we selected 170 for full text assessment. We retained eight trials for data extraction and analysis. One of the eight used CO alone and CO + Genetic Susceptibility as two different intervention groups, giving rise to three possible comparisons. Three of the trials isolated the effect of exhaled CO on smoking cessation rates resulting in the following odds ratios (ORs) and 95% confidence intervals (95% CI): 0.73 (0.38 to 1.39), 0.93 (0.62 to 1.41), and 1.18 (0.84 to 1.64). Combining CO measurement with genetic susceptibility gave an OR of 0.58 (0.29 to 1.19). Exhaled CO measurement and spirometry were used together in three trials, resulting in the following ORs (95% CI): 0.6 (0.25 to 1.46), 2.45 (0.73 to 8.25), and 3.50 (0.88 to 13.92). Spirometry results alone were used in one other trial with an OR of 1.21 (0.60 to 2.42). Two trials used other motivational feedback measures, with an OR of 0.80 (0.39 to 1.65) for genetic susceptibility to lung cancer alone, and 3.15 (1.06 to 9.31) for ultrasonography of carotid and femoral arteries performed in light smokers (average 10 to 12 cigarettes a day). Due to the scarcity of evidence of sufficient quality, we can make no definitive statements about the effectiveness of biomedical risk assessment as an aid for smoking cessation. Current evidence of lower quality does not however support the hypothesis that biomedical risk assessment increases smoking cessation in comparison with standard treatment. Only two studies were similar enough in term of recruitment, setting, and intervention to allow pooling of data and meta-analysis.


Influences of El Niño on assemblages of mesopelagic fish larvae along the Pacific coast of Baja California Sur.
Seasonal assemblages of mesopelagic fish larvae and changes related with environmental factors (plankton biomass, sea surface temperature anomaly, upwelling, and the multivariate El Niño index) were investigated. From 1982 to 1987, 16 oceanographic cruises were carried out along the Pacific coast of Baja California Sur, Mexico. Larvae of 42 mesopelagic fish taxa were collected. Larval abundance was highly variable during the studied period, but summer months coincided with higher abundance (>200 larvae under 10 m2). Larval assemblages were dominated by three of the most common species of tropical (Vinciguerria lucetia, Diogenichthys laternatus) and subtropical affinity (Triphoturus mexicanus). A group of species of tropical affinity (Diplophos proximus, Diaphus pacificus, Benthosema panamense) was useful for distinguishing the 1982-84 El Niño event, and an assemblage of larvae of temperate affinity (Symbolophorus californiensis, Melamphaes lugubris, Bathylagus ochotensis, Leuroglossus stilbius, Protomyctophum crockeri) characterized 'normal' years (mid-1984 to mid-1987).


The Effect of Tinnitus on Listening Effort in Normal-Hearing Young Adults: A Preliminary Study.
The objective of this study was to investigate the effect of chronic tinnitus on listening effort. Thirteen normal-hearing young adults with chronic tinnitus were matched with a control group for age, gender, hearing thresholds, and educational level. A dual-task paradigm was used to evaluate listening effort in different listening conditions. A primary speech-recognition task and a secondary memory task were performed both separately and simultaneously. Furthermore, subjective listening effort was questioned for various listening situations. The Tinnitus Handicap Inventory was used to control for tinnitus handicap. Listening effort significantly increased in the tinnitus group across listening conditions. There was no significant difference in listening effort between listening conditions, nor was there an interaction between groups and listening conditions. Subjective listening effort did not significantly differ between both groups. This study is a first exploration of listening effort in normal-hearing participants with chronic tinnitus showing that listening effort is increased as compared with a control group. There is a need to further investigate the cognitive functions important for speech understanding and their possible relation with the presence of tinnitus and listening effort.


Maximal Respiratory Pressure Reference Equations in Healthy Adults and Cut-off Points for Defining Respiratory Muscle Weakness.
Maximal inspiratory and expiratory pressures (PImax/PEmax) reference equations obtained in healthy people are needed to correctly interpret respiratory muscle strength. Currently, no clear cut-off points defining respiratory muscle weakness are available. We aimed to establish sex-specific reference equations for PImax/PEmax in a large sample of healthy adults and to objectively determine cut-off points for respiratory muscle weakness. A multicentre cross-sectional study was conducted across 14 Spanish centres. Healthy non-smoking volunteers aged 18-80 years stratified by sex and age were recruited. PImax/PEmax were assessed using uniform methodology according to international standards. Multiple linear regressions were used to obtain reference equations. Cut-off points for respiratory muscle weakness were established by using T-scores. The final sample consisted of 610 subjects (314 females; 48 [standard deviation, SD: 17] years). Reference equations for PImax/PEmax included body mass index and a squared term of the age as independent variables for both sexes (p<0.01). Cut-off points for respiratory muscle weakness based on T-scores ≥2.5 SD below the peak mean value achieved at a young age were: 62 and 83cmH2O for PImax and 81 and 109cmH2O for PEmax in females and males, respectively. These reference values, based on the largest dataset collected in a European population to date using uniform methodology, help identify cut-off points for respiratory muscle weakness in females and males. These data will help to better identify the presence of respiratory muscle weakness and to determine indications for interventions to improve respiratory muscle function.


Colloidal gels assembled via a temporary interfacial scaffold.
The liquid-liquid phase separation of a binary solvent can be arrested by colloidal particles trapped at the interface [K. Stratford, Science 309, 2198 (2005)]. We show experimentally that the colloidal network so formed can remain stable after fully remixing the liquids, creating a new type of gel in which colloids in a single-phase solvent have locally planar coordination. We argue that this structure is likely maintained by primary-minimum Derjaguin-Landau-Verweg-Overbeek bonding of our charged colloids, created under strong compression by capillary forces. We present simulation evidence that the combination of a short-ranged attraction with a repulsive barrier can strongly stabilize such locally planar gels.


Molecular phylogenetics of swimming crabs (Portunoidea Rafinesque, 1815) supports a revised family-level classification and suggests a single derived origin of symbiotic taxa.
Portunoidea is a diverse lineage of ecologically and economically important marine crabs comprising 8 families and 14 subfamilies. Closely related portunid subfamilies Caphyrinae and Thalamitinae constitute some of this group's greatest morphological and taxonomic diversity, and are the only known lineages to include symbiotic taxa. Emergence of symbiosis in decapods remains poorly studied and portunoid crabs provide an interesting, but often overlooked example. Yet the paucity of molecular phylogenetic data available for Portunoidea makes it challenging to investigate the evolution and systematics of the group. Phylogenetic analyses, though limited, suggest that many putative portunoid taxa are para- or polyphyletic. Here I augment existing molecular data-significantly increasing taxon sampling of Caphyrinae, Thalamitinae, and several disparate portunoid lineages-to investigate the phylogenetic origin of symbiosis within Portunoidea and reevaluate higher- and lower-level portunoid classifications. Phylogenetic analyses were carried out on sequences of H3, 28S rRNA, 16S rRNA, and CO1 for up to 168 portunoid taxa; this included, for the first time, molecular data from the genera Atoportunus, Brusinia, Caphyra, Coelocarcinus, Gonioinfradens, Raymanninus, and Thalamonyx. Results support the placement of all symbiotic taxa (Caphyra, Lissocarcinus, and two Thalamita) in a single clade derived within the thalamitine genus Thalamita. Caphyrina Paulson, 1875, nom. trans. is recognized here as a subtribe within the subfamily Thalamitinae. Results also support the following taxonomic actions: Cronius is reclassified as a thalamitine genus; Thalamonyx is reestablished as a valid genus; Goniosupradens is raised to the generic rank; and three new genera (Zygita gen. nov., Thranita gen. nov., and Trierarchus gen. nov.) are described to accommodate some Thalamita s.l. taxa rendered paraphyletic by Caphyrina. A new diagnosis of Thalamitinae is provided. Results also support a more conservative classification of Portunoidea comprising three instead of eight extant families: Geryonidae (Geryonidae + Ovalipidae; new diagnosis provided), Carcinidae (Carcinidae + Pirimelidae + Polybiidae + Thiidae + Coelocarcinus; new diagnosis provided) and Portunidae. Finally, 16s rRNA data suggests family Brusiniidae might not be a portunoid lineage.


The identification of a novel natural activator of p300 histone acetyltranferase provides new insights into the modulation mechanism of this enzyme.
Many severe human pathologies are related to alterations of the fine balance between histone acetylation and deacetylation; because not all such diseases involve hypoacetylation, but also hyperacetylation, compounds able to enhance or repress the activities of histone acetyltransferases (HATs) could be promising therapeutic agents. We evaluated in vitro and in cell the ability of eleven natural polyisoprenylated benzophenone derivatives to modulate the HAT activity of p300/CBP, an enzyme that plays a pivotal role in a variety of cellular processes. Some of the tested compounds bound efficiently to the p300/CBP protein: in particular, guttiferone A, guttiferone E and clusianone inhibit its HAT activity, whereas nemorosone showed a surprising ability to activate the enzyme. The ability of nemorosone to penetrate cell membranes and modulate histone acetylation into the cell together with its high affinity for the p300/CBP enzyme made this compound a suitable lead for the design of optimized anticancer drugs. Besides, the studies performed at a cellular and molecular level on both the inhibitors and the activator provided new insights into the modulation mechanism of p300/CBP by small molecules.


Methanol production from CO(2) by resting cells of the methanotrophic bacterium Methylosinus trichosporium IMV 3011.
Methanol production from carbon dioxide was successfully achieved using resting cells of Methylosinus trichosporium IMV 3011 as biocatalysts. Carbon dioxide was reduced to methanol and extracellular methanol accumulation has been found in the carbon dioxide incubations. However, resting cells of methanotrophs have a finite or intrinsic methanol production capacity due to a limiting supply of intracellular reducing equivalent. It has been found that the catabolism of stored Poly-beta -Hydroxybutyrate (PHB) can provide intracellular reducing equivalents to improve the intrinsic methanol production capacity. The initial nitrogen and copper concentration in the culture medium were studied for the accumulation of PHB by M. trichosporium IMV 3011, to expand its potential uses in methanol production from carbon dioxide reduction. It appeared that the total methanol production capacity was increased with increasing PHB content in cells. Resting cells containing 38.6% PHB exhibited the highest total methanol production capacity. But higher PHB accumulation adversely affected the total methanol production capacity. The effects of methanol production process on the survival and recovery of M. trichosporium IMV 3011 were examined. The results showed that the methanol production from carbon dioxide reduction was not detrimental to the viability of methanotrophs.


Transcription of mouse Sp2 yields alternatively spliced and sub-genomic mRNAs in a tissue- and cell-type-specific fashion.
The Sp-family of transcription factors is comprised by nine members, Sp1-9, that share a highly conserved DNA-binding domain. Sp2 is a poorly characterized member of this transcription factor family that is widely expressed in murine and human cell lines yet exhibits little DNA-binding or trans-activation activity in these settings. As a prelude to the generation of a "knock-out" mouse strain, we isolated a mouse Sp2 cDNA and performed a detailed analysis of Sp2 transcription in embryonic and adult mouse tissues. We report that (1) the 5' untranslated region of Sp2 is subject to alternative splicing, (2) Sp2 transcription is regulated by at least two promoters that differ in their cell-type specificity, (3) one Sp2 promoter is highly active in nine mammalian cell lines and strains and is regulated by at least five discrete stimulatory and inhibitory elements, (4) a variety of sub-genomic messages are synthesized from the Sp2 locus in a tissue- and cell-type-specific fashion and these transcripts have the capacity to encode a novel partial-Sp2 protein, and (5) RNA in situ hybridization assays indicate that Sp2 is widely expressed during mouse embryogenesis, particularly in the embryonic brain, and robust Sp2 expression occurs in neurogenic regions of the post-natal and adult brain.


Reactions of 2,4-hexadiyne-1,6-diol with [H2Os3(CO)9(PR3)] clusters. Cyclization of the diyne and reversible exchange of the phosphine ligands between different positions of the "Os3C3" framework.
Reactions between unsaturated [H(2)Os(3)(CO)(9)(PR(3))] clusters (PR(3)= PPh(3), P(4-CF(3)-C(6)H(4))(3), PEt(3)) and 2,4-hexadiyne-1,6-diol have been studied. It was found that the diyne ligand easily reacts with all these complexes to give [HOs(3)(CO)8(PR3)-[mu3, eta1:eta3:eta1)-(CH(3)-C-C=CH-CH=C-O)]] complexes (V, VI and VII, respectively) containing the "Os3C3" pentagonal pyramid cluster framework. This structural pattern is formed through the diyne cyclization, dissociation of a CO ligand and eventual coordination of the cyclized organic moiety to the osmium triangle in the [mu3, eta1:eta3:eta1) manner. In the case of the PEt(3) substituted cluster the second hydride transfer onto the organic fragment occurs to afford the nonhydride [Os(3)(CO)(8)(PR3)[mu3), eta1:eta2:eta1)-(CH(3)-CH-C=CH-CH=C-O)]] cluster, VIII, containing distorted pentagonal pyramid framework with a broken Os-C bond. Heating V, VI of VII and in hexane solutions results in formation of the regioisomers (Va, VIa and VIIa) with the phosphine ligand located at adjacent osmium atoms across the Os-Os bond bridged by the coordinated organic fragment. The most probable mechanism of the isomerization includes reversible phosphine migration between these metal centres. Solid-state structure of V, Va, VI, VIIa and VIII have been established by single crystal X-ray diffraction. A general mechanistic scheme for the diyne ligand cyclization and cluster framework transformations is suggested and discussed.


Feasibility of paramedic treatment and referral of minor illnesses and injuries.
Approximately 40% of Hennepin County Medical Center's (HCMC's) ambulance runs are for minor medical conditions as defined by billing criteria ["ALS minor," i.e., no advanced life support (ALS) procedures done in the field]. Current metropolitan guidelines mandate that all such patients must be transported to a hospital unless they refuse this service. It has been proposed that some patients with minor medical conditions could be better served by treatment in the field by paramedics and referred to a clinic or hospital for early follow-up care. It is proposed that this approach would save costs and improve paramedic availability for patients with more serious conditions. To evaluate the feasibility and safety of implementing such a program by identifying high-volume, low-complexity groupings of cases. Such high-volume, low-complexity cases would serve as the topics for curriculum development for paramedic training in field treatment and referral. Data were obtained from ambulance run sheets and emergency department (ED) records for all patients transported by the HCMC ambulance service in 1996 who were covered by the Metropolitan Health Plan (MHP) and who were categorized for billing purposes as "ALS minor" transports. The data included demographic information, vital signs, presenting problem, diagnoses in the ED, and procedures, laboratory studies, or x-rays done in the ED. Patients were classified as "potentially treatable" in the field if they were treated and discharged from the ED without undergoing any procedures or diagnostic studies. Patients who required more extensive evaluation in the ED, or who were admitted, were classified as likely too "complex" to be treated at the scene and then referred for early follow-up. The data were analyzed to find the most common presenting problems and the numbers, characteristics, and dispositions of "potentially treatable" and "complex" patients in each group. This information was used to determine what, if any, types of patients could potentially be treated safely and effectively according to this scheme. The study group comprised 1,103 patients, representing 127 different presenting medical problems. There were 523 (47%) "potentially treatable" patients and 580 (53%) "complex" patients. The 127 medical problems were grouped and the 15 most common presenting problem groups were identified. Within these groups there was no single medical problem with high volume. Each of these 15 most common problem groups contained a substantial proportion of "complex" patients, ranging from 24% to 100%. None of the 15 most frequently encountered problem groups consisted of a high enough proportion of "potentially treatable" cases to serve as a high-volume, low-complexity category for paramedic treatment in the field with early follow-up. Without any identified high-volume, low-complexity categories, a treatment and referral program as proposed in this article would require a substantial investment in development of appropriate criteria and in training paramedics to apply the criteria for numerous clinical entities. This would limit any cost saving, and require great care to avoid compromising patient safety accompanied by substantial professional liability exposure.


Desensitizing effect of a stabilized stannous fluoride/Sodium hexametaphosphate dentifrice.
Stannous fluoride (0.4%) has been incorporated into oral hygiene products to reduce dentinal hypersensitivity since the 1960s. The present study was designed to assess the desensitizing efficacy of a stabilized 0.454% stannous fluoride/sodium hexametaphosphate dentifrice compared to a sodium fluoride control dentifrice. This was a double-blind, parallel-group, randomized clinical trial conducted according to the American Dental Association Guidelines for the Acceptance of Products for the Treatment of Dentinal Hypersensitivity. Seventy-seven subjects who met the entrance criteria were stratified based on age, gender, and air-sensitivity scores and randomly assigned to either the stabilized stannous fluoride/sodium hexametaphosphate dentifrice or the sodium fluoride control dentifrice. Subjects were instructed to brush twice daily for 8 weeks. Oral soft tissue examination and efficacy assessments including tactile (Yeaple probe) and thermal (Schiff Air Index) sensitivity were made at baseline, week 4, and week 8. The mean sensitivity score based on the Schiff Air Index for the experimental group was statistically significantly lower than that of the sodium fluoride control group, at both weeks 4 and 8 (P < .0001). The mean sensitivity score based on the Yeaple Probe Index for the stannous fluoride/sodium hexametaphosphate group was statistically significantly higher, indicating a reduction in sensitivity, than that of the sodium fluoride control group, at both weeks 4 and 8 (P < .0001). The results demonstrate that the stabilized stannous fluoride/sodium hexametaphosphate dentifrice provides clinically and statistically significant reductions in dentinal hypersensitivity when compared to the sodium fluoride control dentifrice.


Robust Bifunctional Lanthanide Cluster Based Metal-Organic Frameworks (MOFs) for Tandem Deacetalization-Knoevenagel Reaction.
A series of 12-connected lanthanide cluster based metal-organic frameworks (MOFs) have been constructed by [Ln6(μ3-OH)8(COO-)12] secondary building units (SBUs) and 2-aminobenzenedicarboxylate (BDC-NH2) ligands. These obtained materials exhibit high chemical stability and generic thermal stability, especially in acidic and basic conditions. They also present commendable CO2 adsorption capacity, and Yb-BDC-NH2 was further confirmed by a breakthrough experiment under both dry and wet conditions. Moreover, these materials possess both Lewis acid and Brønsted base sites that can catalyze one-pot tandem deacetalization-Knoevenagel condensation reactions.


Posttraumatic stress in school-age children and adolescents: medical providers' role from diagnosis to optimal management.
Millions of children and adolescents each year are exposed to potentially traumatic events (PTEs), placing them at risk for posttraumatic stress (PTS) disorder symptoms. Medical providers play an important role in the identification and treatment of PTS, as they are typically the initial point of contact for families in the wake of a PTE or during a PTE if it is medically related (eg, injury/illness). This paper offers a review of the literature focused on clinical characteristics of PTS, the assessment and diagnosis of PTS, and current effective treatments for PTS in school-age children and adolescents. The clinical presentation of PTS is often complex as symptoms may closely resemble other internalizing and externalizing disorders. A number of screening and evaluation tools are available for medical providers to assist them in the accurate diagnosis of PTS. Treatment options are available for youth at minimal risk of PTS as well as for those with more intensive needs. Additional training regarding trauma-informed medical care may benefit medical providers. By taking a trauma-informed approach, rooted in a solid understanding of the clinical presentation of PTS in children and adolescents, medical providers can ensure PTS does not go undetected, minimize the traumatic aspects of medical care, and better promote health and well-being.


Reliability of human retina organoid generation from hiPSC-derived neuroepithelial cysts.
The possible applications for human retinal organoids (HROs) derived from human induced pluripotent stem cells (hiPSC) rely on the robustness and transferability of the methodology for their generation. Standardized strategies and parameters to effectively assess, compare, and optimize organoid protocols are starting to be established, but are not yet complete. To advance this, we explored the efficiency and reliability of a differentiation method, called CYST protocol, that facilitates retina generation by forming neuroepithelial cysts from hiPSC clusters. Here, we tested seven different hiPSC lines which reproducibly generated HROs. Histological and ultrastructural analyses indicate that HRO differentiation and maturation are regulated. The different hiPSC lines appeared to be a larger source of variance than experimental rounds. Although previous reports have shown that HROs in several other protocols contain a rather low number of cones, HROs from the CYST protocol are consistently richer in cones and with a comparable ratio of cones, rods, and Müller glia. To provide further insight into HRO cell composition, we studied single cell RNA sequencing data and applied CaSTLe, a transfer learning approach. Additionally, we devised a potential strategy to systematically evaluate different organoid protocols side-by-side through parallel differentiation from the same hiPSC batches: In an explorative study, the CYST protocol was compared to a conceptually different protocol based on the formation of cell aggregates from single hiPSCs. Comparing four hiPSC lines showed that both protocols reproduced key characteristics of retinal epithelial structure and cell composition, but the CYST protocol provided a higher HRO yield. So far, our data suggest that CYST-derived HROs remained stable up to at least day 200, while single hiPSC-derived HROs showed spontaneous pathologic changes by day 200. Overall, our data provide insights into the efficiency, reproducibility, and stability of the CYST protocol for generating HROs, which will be useful for further optimizing organoid systems, as well as for basic and translational research applications.


Sustainable and cost-effective teenage breast awareness campaigns: Insights from a Nigerian high school intervention study.
With limited government-sponsored breast screening programmes in developing countries, breast awareness remains the only realistic survival hope for millions. Poor levels of knowledge and preventive practices remain in these countries, and early enlightenment to empower teenage high school girls has been advocated for, recently. This study evaluates ways to ensure sustainability for such an approach. A 6-month longitudinal, interventional cohort study of 432 high school female students in South-eastern Nigeria. The efficacies of a video-assisted face-to-face intervention, as well as the use of printed handouts, were evaluated. A total of 317 (73.4%) and 301 (69.7%) valid responses were received from the pre-intervention (16.8 ± 1.5 years) and post-intervention (17.2 ± 1.6 years) surveys, respectively. Logistic regression revealed that participants who were "engaged" with the campaigns, either through symposium attendance or by reading handouts, showed significant improvements on most aspects of knowledge regarding the cancer's early symptoms and risk factors, as well as breast self-examination (BSE). However, the monthly practice of BSE was not significantly increased (Attendees: OR = 1.44, P = 0.18; Handout-readers: OR = 1.52; P = 0.17). Also, when "engagement" to the respective empowerment activities was disregarded, a chi-squared analysis comparing the pre-intervention and post-intervention groups showed significant improvements on specific knowledge regarding risk factors and early symptoms of breast cancer, as well as BSE techniques and regular monthly practice: χ2 (1, N = 596) = 46.703, P < 0.001. Across multiple parameters, the impact of exclusive face-to-face participation was not different to that from the reading of handouts. Face-to-face and handout were both effective and of similar impact. However, sustained impact on monthly BSE is doubtful. To surmount this, strategies to ensure ongoing engagements are vital. Perhaps adjusting existing high school curricula to allow repeated yearly teachings on breast cancer and BSE, along with in-built-in evaluation systems like examinations and quizzes, are ways of ensuring engagement.


Speciation and subsequent secondary contact in two edaphic endemic primroses driven by Pleistocene climatic oscillation.
Climatic perturbation during the Pleistocene era has played a major role in plant evolutionary history by altering species distribution range. However, the relative roles of climatic and geographic factors in the distribution dynamics remain poorly understood; in particular, the edaphic endemics. In this paper, we examine the evolutionary history of two ultramafic primroses, Primula hidakana and Primula takedana. These species are ecologically and morphologically distinct with disjunct distributions on Hokkaido Island, Japan. Primula hidakana is found on various rocks in southern Hokkaido and P. takedana in serpentine areas in northern Hokkaido. We performed population genetics analyses on nuclear and chloroplast data sets and tested alternative phylogenetic models of divergence using approximate Bayesian computation (ABC) analyses. Nuclear microsatellite loci clearly distinguished the two sister taxa. In contrast, chloroplast sequence variations were shared between P. takedana and P. hidakana. ABC analyses based on nuclear data supported a secondary contact scenario involving asymmetrical gene flow from P. hidakana to P. takedana. Paleodistribution modeling also supported the divergence model, and predicted their latitudinal range shifts leading to past secondary contact. Our findings highlight the importance of the distribution dynamics during the Pleistocene climatic oscillations in the evolution of serpentine plants, and demonstrate that tight species cohesion between serpentine and nonserpentine sister taxa has been maintained despite past interspecific gene flow across soil boundaries.


Disruption of mammalian SWI/SNF and polycomb complexes in human sarcomas: mechanisms and therapeutic opportunities.
Soft-tissue sarcomas are increasingly characterized and subclassified by genetic abnormalities that represent underlying drivers of their pathology. Hallmark tumor suppressor gene mutations and pathognomonic gene fusions collectively account for approximately one-third of all sarcomas. These genetic abnormalities most often result in global transcriptional misregulation via disruption of protein regulatory complexes which govern chromatin architecture. Specifically, alterations to mammalian SWI/SNF (mSWI/SNF or BAF) ATP-dependent chromatin remodeling complexes and polycomb repressive complexes cause disease-specific changes in chromatin architecture and gene expression across a number of sarcoma subtypes. Understanding the functions of chromatin regulatory complexes and the mechanisms underpinning their roles in oncogenesis will be required for the design and development of new therapeutic strategies in sarcomas. Copyright © 2018 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.


Diagnostic imaging of herpes simplex virus encephalitis using a radiolabeled antiviral drug: autoradiographic assessment in an animal model.
To develop a new approach to the diagnosis of herpes simplex encephalitis, we used a radiolabeled antiviral drug, 2'-fluoro-5-methyl-1-beta-D-arabinosyluracil labeled with carbon 14 ([14C]FMAU), as a probe for selectively imaging brain infection in a rat model by quantitative autoradiography. A high correlation was found between focal infection, as defined by immunoperoxidase viral antigen staining, and increased regional [14C]FMAU uptake in brain sections. Two potential sources of false-positive imaging were defined: high concentrations of drug in the choroid plexus because of its higher permeability compared with brain, and drug sequestration by proliferating uninfected cell populations. Our results support the soundness of the proposed strategy of using a labeled antiviral drug that is selectively phosphorylated by herpes simplex virus type 1 thymidine kinase in conjunction with scanning methods for human diagnosis, and also define some of the factors that must be taken into account when planning clinical application.


'Are We One Body?' Body Boundaries in Telesomatic Experiences.
This paper explores the embodiedness of body boundaries in the telesomatic experiences of 20 adult twins. Respondents were recruited through snowball sampling resulting in 16 in-depth face-to-face interviews. Interviews were analysed using an immersion-crystallization approach within a meaning-centred interpretive framework. Respondents often experienced trouble making subject-object distinctions between themselves and their co-twins that often resulted in them posing the question, 'Are we (myself and my co-twin) one body?' Their experiences suggest that, sometimes symptoms of one illness are experienced as shared between two people, and their experiences highlight the ethical nature of individualism in western cultures as twins frequently do not view a greater level of attachment to their co-twins as pathological but as something special. We suggest that controversy regarding the ontological status of parapsychological phenomena has resulted in anthropologists being slow to consider these and similar experiences in western cultures as topics worthy of research.


Nitric oxide reactivity of Cu(II) complexes of tetra- and pentadentate ligands: structural influence in deciding the reduction pathway.
Four Cu(II) complexes, 1, 2, 3 and 4, are synthesized with ligands, L1, L2, L3 and L4 [L1 = N1,N2-bis((pyridin-2-yl)methyl)ethane-1,2-diamine; L2 = N1,N3-bis((pyridin-2-yl)methyl)propane-1,3-diamine; L3 = N1,N1,N2-tris((pyridin-2-yl)methyl)ethane-1,2-diamine; L4 = N1-((1-methyl-1H-imidazol-2-yl)methyl)-N1,N2-bis((pyridin-2-yl)methyl)ethane-1,2-diamine], respectively, as their perchlorate salts. The complexes were characterized by various spectroscopic techniques as well as single crystal X-ray structure determination. Nitric oxide reactivities of the complexes were studied in acetonitrile as well as methanol solvent. It has been found that the ligand frameworks have a considerable effect in controlling the mechanism of the reduction of a Cu(II) center by nitric oxide. The flexibility of the ligand/s for a Cu(II) complex to attain a trigonal bipyramidal geometry after NO coordination is found to be the most important parameter in dictating the pathway for their interaction. In the present study, all the four compounds, because of structural constraints, were found to follow a deprotonation pathway for the reduction of a Cu(II) center by nitric oxide rather than [Cu(II)-NO] intermediate formation. All the ligands were found to yield an N-nitrosoamine product along with the reduction of Cu(II) centers by nitric oxide.


Ante-partum haemorrhage: an update.
Ante-partum haemorrhage is an important cause of maternal and fetal morbidity and mortality, despite modern improvement in obstetric practice and transfusion service. It is defined as any vaginal bleeding from the 20th week of gestation till delivery. The initial management of ante-partum haemorrhage should concentrate on resuscitation and accurate diagnosis. The most important causes are placenta praevia and abruption accounting for more than half the cases. The numbers of cases of placenta praevia and placenta accreta are increasing with the increasing caesarean section rate. In many cases, it is not possible to make a definite diagnosis, despite all the investigations. Development of ultrasound especially transvaginal scan has helped in the definitive diagnosis and management of placenta praevia. Every unit should have a clear protocol for the management of massive haemorrhage, which should be regularly updated and rehearsed.


[Development of a first-class undergraduate major in bioengineering facing the emerging engineering direction of biomedicine].
In the "Tutorial for outline of the healthy China 2030 plan", biomedicine was listed as a key planning and development area. Shanghai government also lists biomedicine as an emerging pillar industry. The rapid development of biomedicine industry put higher requirement for talents. Taking the idea of cross integration, mutually beneficial development, inheritance and innovation, the School of Biotechnology of East China University of Science and Technology organically integrates bioengineering and pharmaceutical majors to develop a new undergraduate engineering program of biomedicine, which specially reforms the talent training practice from the aspects of developing a "trinity teaching" standard system, a "three integration, three convergence" curriculum system, and a "three comprehensive education" innovative talent training system. We put forward the trinity of "value guidance, knowledge system, technology and non-technical core competence literacy" to foster emerging biomedicine engineering talents, and developed a comprehensive innovative talents training mode featured by "covering class-in and class-out, covering every student, and covering ideology and curriculum". Moreover, we established effective connections between courses and training goals, between general education courses and professional courses, and between top-notch talent training systems and training programs. Based on the achievements of teaching reform of the emerging engineering program "intelligent bio-manufacturing", the experience we obtained may provide ideas for development of the first-class bioengineering major in China.


Copper-Targeting Approaches in Alzheimer's Disease: How To Improve the Fallouts Obtained from in Vitro Studies.
According to the amyloid cascade hypothesis, metal ions, mainly Cu and Zn ions, bound to the amyloid-β (Aβ) peptides are implicated in Alzheimer's disease (AD), a widespread neurodegenerative disease. They indeed impact the aggregation pathways of Aβ and are involved in the catalytic generation of reactive oxygen species (ROS) that participate in oxidative stress, while Aβ aggregation and oxidative stress are regarded as two key events in AD etiology. Cu ions due to their redox ability have been considered to be the main potential therapeutic targets in AD. A considerable number of ligands have been developed in order to modulate the toxicity associated with Cu in this context, via disruption of the Aβ-Cu interaction. Among them, small synthetic ligands and small peptide scaffolds have been designed and studied for their ability to remove Cu from Aβ. Some of those ligands are able to prevent Cu(Aβ)-induced ROS production and can modify the aggregation pathways of Aβ in vitro and in cellulo. Examples of such ligands are gathered in this Viewpoint, as a function of their structures and discussed with respect to their properties against Cu(Aβ) deleterious fallouts. Nevertheless, the beneficial activities of the most promising ligands detected in vitro and in cellulo have not been transposed to human yet. Some parameters that might explain this apparent contradiction and key concepts to consider for the design of "more" efficient ligands are thus reported and discussed. En passant, this Viewpoint sheds light on the difficulties in comparing the results from one study to another that hamper significant advances in the field.


The effect of alternating current iontophoresis on rats with the chronic constriction injury to the infraorbital nerve.
This study aimed to examine the effect of AC iontophoresis on rats with the chronic constriction injury (CCI) to the infraorbital nerve by animal experiments. CCI model rats were divided into four groups, namely, rats that received general anesthesia for 60 min except AC IOP (CCI: n = 5), AC IOP with 0.9% physiological saline for 60 min (CCI + saline AC IOP: n = 5), AC IOP with 4% lidocaine hydrochloride for 60 min (CCI + lidocaine AC IOP: n = 5), and attachment of two electrodes soaked with 4% lidocaine hydrochloride to the facial skin for 60 min (CCI + attach lidocaine: n = 5). In the CCI + lidocaine AC IOP group, an elevated withdrawal threshold was observed after AC IOP, and the duration of efficacy was longer compared with that in the CCI + saline AC IOP and CCI + attached lidocaine groups. A significant decrease in the number of Fos-like immunoreactive (LI) cells was observed in the CCI + lidocaine AC IOP group compared with that in the CCI group. These findings suggest that the effect of CCI + lidocaine AC IOP group may be caused by active permeation of lidocaine into the facial skin and electrical stimulation of the trigeminal nucleus.


Predictors and long-term health outcomes of eating disorders.
Anorexia and bulimia nervosa may have long-term effects on overall and reproductive health. We studied predictors of self-reported eating disorders and associations with later health events. We estimated odds ratios (ORs) for these associations in 47,759 participants from the Sister Study. Two percent (n = 967) of participants reported a history of an eating disorder. Risk factors included being non-Hispanic white, having well-educated parents, recent birth cohort (OR = 2.16, 95% confidence interval [CI]: 2.01-2.32 per decade), and having a sister with an eating disorder (OR = 3.68, CI: 1.92-7.02). As adults, women who had experienced eating disorders were more likely to smoke, to be underweight, to have had depression, to have had a later first birth, to have experienced bleeding or nausea during pregnancy, or to have had a miscarriage or induced abortion. In this descriptive analysis, we identified predictors of and possible long-term health consequences of eating disorders. Eating disorders may have become more common over time. Interventions should focus on prevention and mitigation of long-term adverse health effects.


Spatial Distribution of the Pepper Blight (Phytophthora capsici) Suppressive Microbiome in the Rhizosphere.
The properties of plant rhizosphere are dynamic and heterogeneous, serving as different habitat filters for or against certain microorganisms. Herein, we studied the spatial distribution of bacterial communities in the rhizosphere of pepper plants treated with a disease-suppressive or non-suppressive soil. The bacterial richness was significantly (p < 0.05) higher in plants treated with the disease-suppressive soil than in those treated with the non-suppressive soil. Bacterial richness and evenness greatly differed between root parts, with decrease from the upper taproot to the upper fibrous root, the lower taproot, and the lower fibrous root. As expected, the bacterial community in the rhizosphere differed between suppressive and non-suppressive soil. However, the spatial variation (36%) of the bacterial community in the rhizosphere was much greater than that explained by soils (10%). Taxa such as subgroups of Acidobacteria, Nitrosospira, and Nitrospira were known to be selectively enriched in the upper taproot. In vitro Bacillus antagonists against Phytophthora capsici were also preferentially colonized in the taproot, while the genera such as Clostridium, Rhizobium, Azotobacter, Hydrogenophaga, and Magnetospirillum were enriched in the lower taproot or fibrous root. In conclusion, the spatial distribution of bacterial taxa and antagonists in the rhizosphere of pepper sheds light on our understanding of microbial ecology in the rhizosphere.


On methionine restriction, suppression of mitochondrial dysfunction and aging.
Rats and mice, when subjected to methionine restriction (MetR), may live longer with beneficial changes to their mitochondria. Most explanations of these observations have centered on MetR somehow suppressing the effects of oxygen free radicals. It is suggested here that MetR's effects on protein metabolism should also be considered when attempting to explain its apparent anti-aging actions. Methionine is the initiating amino acid in mRNA translation. It is proposed that MetR decreases the protein biosynthesis rate due to methionine limitation, which correspondingly decreases generation of ribosomal-mediated error proteins, which then lowers the total abnormal protein load that cellular proteases and chaperone proteins (mitochondrial and cytoplasmic) must deal with. This will increase protease availability for elimination of proteins damaged postsynthetically and help delay abnormal protein accumulation, the major molecular symptom of aging. The slowed rate of protein synthesis may also alter protein folding, which could also alter polypeptide susceptibility to oxidative attack. MetR will also increase lysosomal proteolysis, including autophagy of dysfunctional mitochondria, and promote mitogenesis. MetR may decrease synthesis of S-adenosyl-methionine (SAM), which could decrease spontaneous O(6)-methylguanine formation in DNA. However decreased SAM may compromise repair of protein isoaspartate residues by protein-isoaspartate methyltransferase (PIMT). Changes in SAM levels may also affect gene silencing. All the above may help explain, at least in part, the beneficial effects of MetR.


Structure function analysis of interleukin 7: requirement for an aromatic ring at position 143 of helix D.
The residues located at the carboxyl terminus of helix D in interleukin-7 (IL-7) have previously been targeted as important for recruitment and binding to the gamma chain component of the IL-7 receptor (IL-7R). In this study, Trp 143 of helix D was mutated to His, Phe, Tyr and Pro and these mutants, along with a W143A mutant previously described, were studied to determine the effects on activation of DNA synthesis and binding affinity to IL-7R positive 2E8 cells. The W143F and W143Y mutants were similar to wild type IL-7 in their binding properties and retained 85% and 74% of their activating properties, respectively. In contrast, the W143H mutant possessed a lower binding affinity and a corresponding decrease in activation, the W143A mutant possessed an over 100-fold decreased binding affinity and some residual activation activity and the W143P mutant possessed a greatly decreased binding affinity and did not activate. These results strongly suggest an aromatic residue is required at position 143 for IL-7R binding and subsequent signal transduction.