Mapping of clonal lineages across developmental stages in human neural differentiation.
The cell lineages across developmental stages remain to be elucidated. Here, we developed single-cell split barcoding (SISBAR) that allows clonal tracking of single-cell transcriptomes across stages in an in vitro model of human ventral midbrain-hindbrain differentiation. We developed "potential-spective" and "origin-spective" analyses to investigate the cross-stage lineage relationships and mapped a multi-level clonal lineage landscape depicting the whole differentiation process. We uncovered many previously uncharacterized converging and diverging trajectories. Furthermore, we demonstrate that a transcriptome-defined cell type can arise from distinct lineages that leave molecular imprints on their progenies, and the multilineage fates of a progenitor cell-type represent the collective results of distinct rather than similar clonal fates of individual progenitors, each with distinct molecular signatures. Specifically, we uncovered a ventral midbrain progenitor cluster as the common clonal origin of midbrain dopaminergic (mDA) neurons, midbrain glutamatergic neurons, and vascular and leptomeningeal cells and identified a surface marker that can improve graft outcomes.


Constructing a representative sample of out-of-care HIV patients from a representative sample of in-care patients.
Individuals infected with HIV who are out of care are at a higher risk of HIV-related morbidity and mortality. It has been difficult to recruit a representative sample of out-of-care patients for epidemiological studies. Using a novel weighting method, we constructed a representative sample of out-of-care HIV patients from a representative sample of in-care patients. In-care patients were weighted based on the probability of receiving care during the study period and the probability of selection to participate in the study, and out-of-care patients were represented by those who were previously out of care and recently returned. The method can be used in other patient populations, if every patient in the population has a known, non-zero probability of receiving care and a known, non-zero probability of participating in the study.


Broadband Faraday isolator.
Driving on an analogy with the technique of composite pulses in quantum physics, we theoretically propose a broadband Faraday rotator and thus a broadband optical isolator, which is composed of sequences of ordinary Faraday rotators and achromatic quarter-wave plates rotated at the predetermined angles.


The conscious processing of emotion in depression disorder: a meta-analysis of neuroimaging studies.
Depression is generally accompanied by a disturbed conscious processing of emotion, which manifests as a negative bias to facial/voice emotion information and a decreased accuracy in emotion recognition tasks. Several studies have proved that abnormal brain activation was responsible for the deficit function of conscious emotion recognition in depression. However, the altered brain activation related to the conscious processing of emotion in depression was incongruent among studies. Therefore, we conducted an activation likelihood estimation (ALE) analysis to better understand the underlying neurophysiological mechanism of conscious processing of emotion in depression. Electronic databases were searched using the search terms "depression," "emotion recognition," and "neuroimaging" from inceptions to April 10th, 2023. We retrieved trials which explored the neuro-responses of depressive patients to explicit emotion recognition tasks. Two investigators independently performed literature selection, data extraction, and risk of bias assessment. The spatial consistency of brain activation in conscious facial expressions recognition was calculated using ALE. The robustness of the results was examined by Jackknife sensitivity analysis. We retrieved 11,365 articles in total, 28 of which were included. In the overall analysis, we found increased activity in the middle temporal gyrus, superior temporal gyrus, parahippocampal gyrus, and cuneus, and decreased activity in the superior temporal gyrus, inferior parietal lobule, insula, and superior frontal gyrus. In response to positive stimuli, depressive patients showed hyperactivity in the medial frontal gyrus, middle temporal gyrus, and insula (uncorrected p < 0.001). When receiving negative stimuli, a higher activation was found in the precentral gyrus, middle frontal gyrus, precuneus, and superior temporal gyrus (uncorrected p < 0.001). Among depressive patients, a broad spectrum of brain areas was involved in a deficit of conscious emotion processing. The activation of brain regions was different in response to positive or negative stimuli. Due to potential clinical heterogeneity, the findings should be treated with caution. https://inplasy.com/inplasy-2022-11-0057/, identifier: 2022110057.


Rapidly and slowly replicating human immunodeficiency virus type 1 isolates can be distinguished according to target-cell tropism in T-cell and monocyte cell lines.
Human immunodeficiency virus type 1 (HIV-1) isolates from various patients were divided into two major groups, rapid/high and slow/low, according to their replication properties in vitro. Rapid/high isolates grow well in cell lines and induce the formation of syncytia in peripheral blood mononuclear cells. In contrast, slow/low isolates do not replicate in cell lines and rarely induce syncytia in peripheral blood mononuclear cells. To understand the differences in replicative capacity of these isolates, a panel of indicator cell lines was used. These cell lines were generated for sensitive detection of HIV-1 isolates and show characteristics of T-lymphoid or monocytoid cells. As a result of infection, chloramphenicol acetyltransferase expression is activated. Rapid/high viruses activate chloramphenicol acetyltransferase expression in T-cell and monocytoid indicator cell lines, whereas slow/low isolates activate chloramphenicol acetyltransferase expression only in monocytoid cell lines. The block in infection of T-lymphoid cells by the slow/low isolates appears to occur early in the infection cycle, prior to the production of the virally encoded tat protein. HIV-1 isolates can thus be distinguished according to target-cell tropism. Monocyte-derived cells seem to be a more general target for the various HIV-1 isolates.


Testing the Use of Natural Language Processing Software and Content Analysis to Analyze Nursing Hand-off Text Data.
Natural language processing software programs are used primarily to mine both structured and unstructured data from the electronic health record and other healthcare databases. The mined data are used, for example, to identify vulnerable at-risk populations and predicting hospital associated infections and complications. Natural language processing programs are seldomly used in healthcare research to analyze the how providers are communicating essential patient information from one provider to another or how the language that is used impacts patient outcomes. In addition to analyzing how the message is being communicated, few studies have analyzed what is communicated during the exchange in terms of data, information, and knowledge. The analysis of the "how" and "what" of healthcare provider communication both written and verbal has the potential to decrease errors and improve patient outcomes. Here, we will discuss the feasibility of using an innovative within-methods triangulation data analysis to uncover the contextual and linguistic meaning of the nurse-to-nurse change-of-shift hand-off communication. The innovative within-methods triangulation data analysis uses a natural language processing software program and content analysis to analyze the nursing hand-off communication.


Kisspeptin decreases the adverse effects of human ovarian vitrification by regulating ROS-related apoptotic occurrences.
Kisspeptin is characterized as a neuropeptide with a pivotal function in female and male infertility, and its antioxidant properties have been demonstrated. In this study, the effects of kisspeptin on the improvement of the vitrification and thawing results of human ovarian tissues were investigated. In this work, 12 ovaries from patients who underwent hysterectomy were collected laparoscopically, and then 32 samples from each of their tissues were taken. Haematoxylin and eosin (H&E) staining was performed to check the normality of the ovarian tissue and, subsequently, the samples were allocated randomly into four groups, including: (1) fresh (control), (2) vitrification, (3) vitrified + 1 μM kisspeptin, and (4) vitrified + 10 μM kisspeptin groups. After vitrification, thawing, and tissue culture processes, H&E staining for tissue quality assessment, terminal deoxynucleotidyl transferase dUTP nick end labelling assay for apoptosis evaluation, and malondialdehyde (MDA), superoxide dismutase (SOD), and ferric reducing ability of plasma tests for oxidative stress appraisal were carried out. Our histological results showed incoherency of ovarian tissue morphology in the vitrification group compared with other groups. Other findings implicated increased apoptosis rate and MDA concentration and reduced SOD activity and total antioxidant capacity (TAC) in the vitrification group compared with the control group (P < 0.05). Moreover, decreased apoptosis rate and MDA concentration, and increased TAC and SOD function were observed in the vitrification with kisspeptin groups (1 μM and 10 μM) compared with the vitrified group (P < 0.05). Our reports express that kisspeptin is an effective agent to overcome the negative effects of vitrification by regulating reactive oxygen species-related apoptotic processes.


Mydriasis revealing vascular and osteodural compression of the oculomotor nerve: An observational study on five cases.
To describe a form of neurovascular compression of the third cranial nerve (CNIII) in idiopathic mydriasis, in which a neurovascular "conflict" exists between the oculomotor nerve, the posterior communicating artery and the clinoid process, using high-resolution magnetic resonance imaging (MRI) with fast imaging employing steady acquisition (FIESTA) sequences. An 18-month prospective, observational and monocentric case series report was performed. MRI was performed on 5 consecutive patients with idiopathic, unilateral, persistent and nonreactive mydriasis (pure intrinsic palsy of the CNIII). Patients with diplopia, ptosis or ophthalmoplegia were excluded. Cerebral MRI focused on the CNIII pathway from the mesencephalon to the cavernous sinus entry, particularly on the cisternal segment: image acquisition was performed on a 3 Tesla MRI; the protocol included fast imaging employing steady acquisition (FIESTA) and three-dimension time of flight (3D TOF) sequences. All patients presented a neurovascular compression point, involving the CNIII clamped between a tortuous posterior communicating artery (PCoA) and the posterior clinoid process at the entrance of the cavernous sinus. No cases occurred in the root entry zone. There was no compression on the contralateral side. No tumors or aneurysms were found. Thus, the mydriasis was caused by CNIII compression. MRI, including FIESTA sequences, revealed a new type of neurovascular conflict between the CNIII, PCoA and posterior clinoid process in patients with incomplete oculomotor palsy. Non-aneurysmal CNIII compression should be considered as a differential diagnosis in the work-up of idiopathic mydriasis. The role of MRI in the work-up of anisocoria should be considered.


On the micro-, meso-, and macroporous structures of polymer electrolyte membrane fuel cell catalyst layers.
In this work, N(2) adsorption was employed to investigate the effects of carbon support, platinum, and ionomer loading on the microstructure of polymer electrolyte membrane fuel cell catalyst layers (CLs). Brunauer-Emmett-Teller and t-plot analyses of adsorption isotherms and pore-size distributions were used to study the microstructure of carbon supports, platinum/carbon catalyst powders, and three-component platinum/carbon/ionomer CLs. Two types of carbon supports were chosen for the investigation: Ketjen Black and Vulcan XC-72. CLs with a range of Nafion ionomer loadings were studied in order to evaluate the effect of an ionomer on the CL microstructure. Regions of adsorption were differentiated into micropores associated with the carbon primary particles (<2 nm), mesopores ascribed to the void space inside agglomerates (2-20 nm), and meso- to macroporous space inside aggregates of agglomerates (>50 nm). Ketjen Black was found to possess a significant fraction of micropores, 25% of the total pore volume, in contrast to Vulcan XC-72, for which the corresponding fraction of micropores was 15% of the total pore volume. The microstructure of the carbon support was found to be a significant factor in the formation of the microstructure in the three-component CLs, serving as a rigid porous framework for distribution of platinum and the ionomer. It was found that platinum particle deposition on Ketjen Black occurs in, or at the mouth of, the support's micropores, thus affecting its effective microporosity, whereas platinum deposition on Vulcan XC-72 did not significantly affect the support's microstructure. The codeposition of ionomer in the CL strongly influenced its porosity, covering pores < 20 nm, which are ascribed to the pores within the primary carbon particles (pore sizes < 2 nm) and to the pores within agglomerates of the particles (pore sizes of 2-20 nm).


Expanding the scope of Mn(OAc)3-mediated cyclizations: synthesis of the tetracyclic core of tronocarpine.
Pyrroles, indoles, and surprisingly, indolines, when equipped with a pendant malonyl group on the nitrogen atom, were effective substrates in a Mn(III)-mediated oxidative cyclization reaction, yielding the 1,2-annulated products in good to excellent yields. When indole acetonitrile was used as a substrate this method provided a rapid synthesis of a tetracyclic tronocarpine subunit.


Enhancing national data to align with policy objectives: Aboriginal and Torres Strait Islander smoking prevalence at finer geographic levels.
Objectives The aim of the study was to assess the utility of national Aboriginal survey data in a regional geospatial analysis of daily smoking prevalence for Aboriginal and Torres Strait Islander Australians and discuss the appropriateness of this analysis for policy and program impact assessment. Methods Data from the last two Australian Bureau of Statistics (ABS) national surveys of Aboriginal and Torres Strait Islander people, the National Aboriginal and Torres Strait Islander Social Survey 2014-15 (n=7022 adults) and the National Aboriginal and Torres Strait Islander Health Survey 2012-13 (n=10896 adults), were used to map the prevalence of smoking by Indigenous regions. Results Daily smoking prevalence in 2014-15 at Indigenous regions ranges from 27.1% (95%CI 18.9-35.3) in the Toowoomba region in Queensland to 68.0% (95%CI 58.1-77.9) in the Katherine region in the Northern Territory. The confidence intervals are wide and there is no significant difference in daily smoking prevalence between the two time periods for any region. Conclusion There are significant limitations with analysing national survey data at finer geographical scales. Given the national program for Indigenous tobacco control is a regional model, evaluation requires finer geographical analysis of smoking prevalence to inform public health progress, policy and program effects. Options to improve the data currently collected include increasing national survey sample sizes, implementing a smoking status question in census surveys, investing in current cohort studies focused on this population or implementing localised surveys. What is known about the topic? The last geospatial analysis of Aboriginal and Torres Strait Islander smoking prevalence was undertaken in 1997. Current national survey data have not been analysed geospatially. What does this paper add? This paper provides new insights into the use of national survey data for understanding regional patterns and prevalence levels of smoking in Aboriginal and Torres Strait Islander populations. What are the implications for practitioners? The findings of the study suggest caution when interpreting prevalence maps and highlight the need for greater sample sizes in national survey data. The analysis is also an opportunity to assess the use of national survey data in evaluating the policy impact of programs targeted at a regional level.


Horner's Syndrome: An Uncommon Complication of Thyroidectomy and Selective Lateral Neck Dissection.
Horner's Syndrome is defined by myosis, enophthalmos, lack of sweating and eyelid ptosis, as well as vascular dilatation of one half of the face, caused by damage of the ipsilateral cervical sympathetic chain. It is known that Horner's syndrome is an unusual complication of thyroidectomy and selective lateral neck dissection. Its exact pathophysiology is not totally explained and its treatment remains conservative. A 27-year-old man developed one-sided partial eyelid ptosis, enophthalmos and myosis two hours after a total thyroid gland excision and a selective lateral neck dissection for papillary carcinoma. A clinical diagnosis of Horner's syndrome was formed. He was treated conservatively and presented with an incomplete recovery at a 2-month follow up. The present case report underlines the adjacent anatomical correlation between the thyroid gland, the celluloadipose tissue and the cervical sympathetic trunk throughout thyroidectomy and selective lateral neck dissection. Every surgeon should be familiar with the potential complications in order to preoperatively counsel patients, as well as avoid them during the surgical procedure.


Comparative flow DNA analysis of different cell suspensions in breast carcinoma.
This study compared three methods of dissociation of breast lesions for DNA flow cytometry. Eleven benign lesions and 66 cancers were dissociated using mechanical, Ficoll, or enzymatic methods. DNA flow analysis showed that the DNA index did not vary from one method of dissociation to another. All benign lesions were diploid and 67% of all cancers were aneuploid. Enzymatic dissociation gave a lower percentage of aneuploid cells with a diminution of the proportion of cells in the G2 + M phase (13.2% enzymatic against 17.6% Fi-coll); on the other hand, it provided cell populations of greater viability than the other methods (32.6% enzymatic, 17.2% Fi-coll; P less than 0.01). The mechanical and Ficoll suspensions did not differ significantly when they were analyzed on the basis of their DNA content and their cellular viability. When compared with mechanical preparation, Ficoll suspension showed a lower recovery of tumor cells, but this inconvenience was compensated for by a more homogeneous aspect where the contribution of aggregates and debris was clearly lessened. Therefore, this study led us to choose Ficoll suspension for subsequent flow analysis of breast tumors.


Man or machine? An experimental study of prehospital emergency amputation.
Prehospital emergency amputation is a rare procedure, which may be necessary to free a time-critical patient from entrapment. This study aimed to evaluate four techniques of cadaveric lower limb prehospital emergency amputation. A guillotine amputation of the distal femur was undertaken in fresh frozen self-donated cadavers. A prehospital doctor conducted a surgical amputation with Gigli saw or hacksaw for bone cuts and firefighters carried out the procedure using the reciprocating saw and Holmatro device. The primary outcome measures were time to full amputation and the number of attempts required. The secondary outcomes were observed quality of skin cut, soft tissue cut and CT assessment of the proximal bone. Observers also noted the potential risks to the rescuer or patient during the procedure. All techniques completed amputation within 91 s. The reciprocating saw was the quickest technique (22 s) but there was significant blood spattering and continuation of the cut to the surface under the leg. The Holmatro device took less than a minute. The quality of the proximal femur was acceptable with all methods, but 5 cm more proximal soft tissue damage was made by the Holmatro device. Emergency prehospital guillotine amputation of the distal femur can effectively be performed using scalpel and paramedic shears with bone cuts by the Gigli saw or fire service hacksaw. The reciprocating saw could be used to cut bone if no other equipment was available but carried some risks. The Holmatro cutting device is a viable option for a life-threatening entrapment where only firefighters can safely access the patient, but would not be a recommended primary technique for medical staff.


COX-2 expression in fibroblast aggregates as a functional indicator for the anti-inflammatory activity of leukemia patients' bone marrow-derived hematopoietic cells.
Reciprocal communication between hematopoietic cells and their surrounding bone marrow stroma is crucial for normal progression of hematopoiesis. This complex network of cell-to-cell signals in the microenvironment involves both cell contact-mediated and paracrine cues. In hematological malignancies the intricate balance is, however, disrupted to support cancer progression. In order to detect altered microenvironmental reactivity of a hematopoietic cell sample, cellular functional assays can be designed to measure the cells' capacity to modulate stromal stress reactions, such as inflammation.Recently, we showed that human leukemic cell lines of monocytic origin can actively participate in modulation of stromal inflammation. In order to further functionally evaluate the hematopoietic cells' capacity to modulate stromal inflammation, we utilized an in vitro model of nemosis-induced inflammation of fibroblasts in a three-dimensional culture setting. This process of stromal inflammation in fibroblast aggregates is consistent, requires both cell-contact and paracrine signals, and can be produced on a large scale to support dose-dependent analyses. To extend our previous observations, we evaluated the effect of a wide panel of leukemia cell lines on cyclooxygenase- 2 induction in fibroblast aggregates in co-culture. We also assessed the feasibility of the model to support clinical functional testing by utilizing the hematopoietic fraction of leukemia patients' bone marrow aspirates after immunophenotyping. Our results suggest that the stromal inflammation-modulating activity of these samples is differently modulated in cancer and in normal bone marrow. Moreover, differences in the samples' anti-inflammatory activity may reflect disease state.


A Bayesian phylogeographical analysis of type 1 porcine reproductive and respiratory syndrome virus (PRRSV).
Understanding viral transmission is an important factor for the effective prevention one of the most devastating swine diseases, porcine reproductive and respiratory syndrome. Focusing on molecular epidemiology of type 1 PRRSV, this study analysed a large ORF5 dataset collected worldwide from 1991 to 2012 using a coalescent-based Bayesian Markov chain Monte Carlo approach. The results suggested that the virus diversified into unique subpopulations in Russia & Belarus and Italy approximately 100 years ago. Previously unreported consecutive diffusions of the virus were identified, which showed that some countries, such as Spain and Germany, acted as distribution sources to some extent. This study also provided statistical evidence for the existence of an ORF5-based phylogeographical structure of type 1 PRRSV, in which the virus tended to cluster by geographical locations more tightly than expected by chance. In contrast to this tight geographical structure, the evolution of the ORF5 gene, based on mapping of non-synonymous/synonymous substitutions, was best described by a non-homogeneous process that could be implicated as a mechanism for viral immune evasion.


Electrophysiological Analysis of human Pluripotent Stem Cell-derived Cardiomyocytes (hPSC-CMs) Using Multi-electrode Arrays (MEAs).
Cardiomyocytes can now be derived with high efficiency from both human embryonic and human induced-Pluripotent Stem Cells (hPSC). hPSC-derived cardiomyocytes (hPSC-CMs) are increasingly recognized as having great value for modeling cardiovascular diseases in humans, especially arrhythmia syndromes. They have also demonstrated relevance as in vitro systems for predicting drug responses, which makes them potentially useful for drug-screening and discovery, safety pharmacology and perhaps eventually for personalized medicine. This would be facilitated by deriving hPSC-CMs from patients or susceptible individuals as hiPSCs. For all applications, however, precise measurement and analysis of hPSC-CM electrical properties are essential for identifying changes due to cardiac ion channel mutations and/or drugs that target ion channels and can cause sudden cardiac death. Compared with manual patch-clamp, multi-electrode array (MEA) devices offer the advantage of allowing medium- to high-throughput recordings. This protocol describes how to dissociate 2D cell cultures of hPSC-CMs to small aggregates and single cells and plate them on MEAs to record their spontaneous electrical activity as field potential. Methods for analyzing the recorded data to extract specific parameters, such as the QT and the RR intervals, are also described here. Changes in these parameters would be expected in hPSC-CMs carrying mutations responsible for cardiac arrhythmias and following addition of specific drugs, allowing detection of those that carry a cardiotoxic risk.


Effect of grazing on methane uptake from Eurasian steppe of China.
The effects of grazing on soil methane (CH4) uptake in steppe ecosystems are important for understanding carbon sequestration and cycling because the role of grassland soil for CH4 uptake can have major impacts at the global level. Here, a meta-analysis of 27 individual studies was carried out to assess the response patterns of soil CH4 uptake to grazing in steppe ecosystems of China. The weighted log response ratio was used to assess the effect size. We found that heavy grazing significantly depressed soil CH4 uptake by 36.47%, but light and moderate grazing had no significant effects in grassland ecosystem. The response of grassland soil CH4 uptake to grazing also was found to depend upon grazing intensity, grazing duration and climatic types. The increase in soil temperature and reduced aboveground biomass and soil moisture induced by heavy grazing may be the major regulators of the soil CH4 uptake. These findings imply that grazing effects on soil CH4 uptake are highly context-specific and that grazing in different grasslands might be managed differently to help mitigate greenhouse gas emissions.


Altered intrinsic regional brain activity in female asthmatics with or without depressive symptoms: A resting-state functional magnetic resonance imaging study.
Previous studies have suggested that asthma patients are more susceptible to anxiety or depression and have more specifically elevated depressive symptomology. These psychological factors are associated with anatomical brain changes. However, little is known about alterations in spontaneous brain activity in asthma patients with depressive symptoms. Here we hypothesized that asthma patients exhibit an altered regional spontaneous brain activity, which may contribute to their increased susceptibility to depression and poor perception of asthma symptoms. The purpose of this study was to examine spontaneous brain activity in female asthma patients using resting-state functional magnetic resonance imaging (rs-fMRI). Eleven asthmatics without depressive symptoms (ASs), 14 asthmatics with depressive symptoms (ADs), and 15 age- and education-matched healthy controls (HCs) completed rs-fMRI. The regional homogeneity (ReHo) value was calculated based on rs-fMRI to assess local signal synchrony strength and compared among the groups. Correlation analyses were conducted between both ReHo values and clinical parameters. Compared with HCs, ASs showed a significantly increased ReHo in the right insula; whereas ADs showed a significantly decreased ReHo in the right insula, which positively correlated with nocturnal symptom score in the Asthma Control Test (r = 0.562, P = 0.036). No significant correlation was observed between the total ACT scores and right insula activities (r = 0.263, P = 0.364). Decreased ReHo in the right insula may play an important role in depressive symptoms and abnormal asthma symptom perception.


Randomised controlled trial of advice on an egg exclusion diet in young children with atopic eczema and sensitivity to eggs.
The role of exclusion diets in the management of atopic eczema in young children is uncertain. This randomised controlled trial evaluates the effect of excluding egg from the diet in young children with atopic eczema and sensitivity to eggs. Fifty-five such children were randomised either to a 4-week regimen, in which mothers were given general advice on care of eczema and additional specific advice from a dietician about an egg exclusion diet (diet group), or to a control group in which general advice only was given. Both groups continued conventional topical treatment. Disease activity was assessed by estimates of the surface area affected by eczema and by an arbitrary severity score. Possible egg sensitivity was identified by RAST before randomisation and after the trial by double-blind placebo-controlled egg challenge. The mean reduction in surface area affected by eczema was significantly greater (p = 0.02) in the group receiving dietary advice (from 19.6% to 10.9% area affected) than in the control group (from 21.9% to 18.9%). A significant improvement also occurred in severity score (p = 0.04): from 33.9 to 24.0 units for the diet group compared with a decrease from 36.7 to 33.5 in the control group. The study suggests that advice on the dietary exclusion of eggs is useful as part of the overall management of young children with atopic eczema and sensitivity to eggs.


Detecting spontaneous deception in the brain.
Deception detection can be of great value during the juristic investigation. Although the neural signatures of deception have been widely documented, most prior studies were biased by difficulty levels. That is, deceptive behavior typically required more effort, making deception detection possibly effort detection. Furthermore, no study has examined the generalizability across instructed and spontaneous responses and across participants. To explore these issues, we used a dual-task paradigm, where the difficulty level was balanced between truth-telling and lying, and the instructed and spontaneous truth-telling and lying were collected independently. Using Multivoxel pattern analysis, we were able to decode truth-telling versus lying with a balanced difficulty level. Results showed that the angular gyrus (AG), inferior frontal gyrus (IFG), and postcentral gyrus could differentiate lying from truth-telling. Critically, linear classifiers trained to distinguish instructed truthful and deceptive responses could correctly differentiate spontaneous truthful and deceptive responses in AG and IFG with above-chance accuracy. In addition, with a leave-one-participant-out analysis, multivoxel neural patterns from AG could classify if the left-out participant was lying or not in a trial. These results indicate the commonality of neural responses subserved instructed and spontaneous deceptive behavior as well as the feasibility of cross-participant deception validation.


Prevalence of colorectal cancer screening among adults--Behavioral Risk Factor Surveillance System, United States, 2010.
Among cancers that affect both men and women, colorectal cancer is the second leading cause of cancer death. In 2007 (the most recent year for which data are available), >142,000 persons received a diagnosis for colorectal cancer and >53,000 persons died. Screening for colorectal cancer has been demonstrated to be effective in reducing the incidence of and mortality from the disease. In 2008, the U.S. Preventive Services Task Force (USPSTF) recommended that persons aged 50-75 years at average risk for colorectal cancer be screened by using one or more of the following methods: high-sensitivity fecal occult blood testing (FOBT) every year, sigmoidoscopy every 5 years with FOBT every 3 years, or colonoscopy every 10 years.


Whole blood viscosity determination in diabetes management: perspective in practice.
Antiplatelet and antioxidant nutritional therapies (ANT) are commonly used in diabetes management. Guidelines recommend identifying deficiencies of antioxidant vitamins and condition of no contraindication for nutritional and antiplatelet respectively. To determine whether the guidelines recommendations for diabetes patients to be assessed for (1) antioxidant vitamins' deficiencies and/or (2) whole blood viscosity (WBV) as indication of no antiplatelet contraindication. Laboratory records were audited. 10,342 de-identified glycaemic index (HbA1(c)) requests received in 2008 were sorted into three groups based on level of control. (1) Poor (n = 1962, HbA1(c) ≥ 8.1); (2) Good (n = 5616, HbA1(c) = 6.0 - 8.0) and (3) Excellent (n = 2764, HbA1(c) ≤ 5.9). All 57 cases with haematocrit and total protein results in the poor (n=30) and excellent (n=27) groups were selected for calculation and comparison of WBV levels. None of the two guidelines' recommendations are being followed as no case was requested for any antioxidant vitamin or WBV. Assessments of the latter show that WBV is statistically significantly lower (p < 0.05) in the group with excellent glycaemic control compared to the group with poor glycaemic control. Aspirin is one of the therapies in diabetes management. Its effect is modulated by WBV. ANT is alternative to aspirin and influences WBV. For patients that have full blood count and plasma protein results, WBV can be extrapolated at no extra cost to the health system. There is a need to raise awareness for the recommended guidelines for laboratory monitoring to be followed.


Platelets are associated with xenograft tumor growth and the clinical malignancy of ovarian cancer through an angiogenesis-dependent mechanism.
Platelets are known to facilitate tumor metastasis and thrombocytosis has been associated with an adverse prognosis in ovarian cancer. However, the role of platelets in primary tumour growth remains to be elucidated. The present study demonstrated that the expression levels of various markers in platelets, endothelial adherence and angiogenesis, including, platelet glycoprotein IIb (CD41), platelet endothelial cell adhesion molecule 1 (CD31), vascular endothelial growth factor (VEGF), lysyl oxidase, focal adhesion kinase and breast cancer anti‑estrogen resistance 1, were expressed at higher levels in patients with malignant carcinoma, compared with those with borderline cystadenoma and cystadenoma. In addition, the endothelial markers CD31 and VEGF were found to colocalize with the platelet marker CD41 in the malignant samples. Since mice transplanted with human ovarian cancer cells (SKOV3) demonstrated elevated tumor size and decreased survival rate when treated with thrombin or thrombopoietin (TPO), the platelets appeared to promote primary tumor growth. Depleting platelets using antibodies or by pretreating the cancer cells with hirudin significantly attenuated the transplanted tumor growth. The platelets contributed to late, but not early stages of tumor proliferation, as mice treated with platelet‑depleting antibody 1 day prior to and 11 days after tumor transplantation had the same tumor volumes. By contrast, tumor size in the early TPO‑injected group was increased significantly compared with the late TPO‑injected group. These findings suggested that the interplay between platelets and angiogenesis may contribute to ovarian cancer growth. Therefore, platelets and their associated signaling and adhesive molecules may represent potential therapeutic targets for ovarian cancer.


Biodegradable polyphosphoester micelles act as both background-free 31P magnetic resonance imaging agents and drug nanocarriers.
In vivo monitoring of polymers is crucial for drug delivery and tissue regeneration. Magnetic resonance imaging (MRI) is a whole-body imaging technique, and heteronuclear MRI allows quantitative imaging. However, MRI agents can result in environmental pollution and organ accumulation. To address this, we introduce biocompatible and biodegradable polyphosphoesters, as MRI-traceable polymers using the 31P centers in the polymer backbone. We overcome challenges in 31P MRI, including background interference and low sensitivity, by modifying the molecular environment of 31P, assembling polymers into colloids, and tailoring the polymers' microstructure to adjust MRI-relaxation times. Specifically, gradient-type polyphosphonate-copolymers demonstrate improved MRI-relaxation times compared to homo- and block copolymers, making them suitable for imaging. We validate background-free imaging and biodegradation in vivo using Manduca sexta. Furthermore, encapsulating the potent drug PROTAC allows using these amphiphilic copolymers to simultaneously deliver drugs, enabling theranostics. This first report paves the way for polyphosphoesters as background-free MRI-traceable polymers for theranostic applications.


Impact of subtrochanteric fractures in the geriatric population: better pre-fracture condition but poorer outcome than pertrochanteric fractures: evidence from the Spanish Hip Fracture Registry.
Clinical management in orthogeriatric units and outcome indicators are similar for extracapsular fragility hip fractures, without discriminating between subtrochanteric and pertrochanteric fractures. Geriatric patients, 75 years or older, with subtrochanteric fractures have worse clinical and functional outcomes than those with pertrochanteric fractures. Retrospective observational study of data prospectively collected by the Spanish Hip Fracture Registry including patients 75 years or older, admitted for extracapsular hip fractures from January 2017 to June 2019. Demographic and baseline status, pre-operative, post-operative and 30-day follow-up data were included. A total of 13,939 patients with extracapsular hip fractures were registered: 12,199 (87.5%) pertrochanteric and 1740 (12.5%) subtrochanteric. At admission, patients with subtrochanteric fractures were younger (86.5 ± 5.8 versus 87.1 ± 5.6 years old), had better pre-fracture mobility (3.7 ± 2.7 versus 3.9 ± 2.8) (1-to-10 scale, 1 being independent) and were more likely to be living at home; those with pertrochanteric fractures had worse cognitive function (Pfeiffer 3.3 ± 3.3 versus 3.8 ± 3.5). The subtrochanteric fracture group showed worse post-fracture mobility (7.3 ± 2.7 versus 6.7 ± 2.7) and greater deterioration of mobility (3.7 ± 3.0 versus 2.9 ± 2.7). Among individuals living at home at baseline, those with subtrochanteric fractures were more likely to remain in an assisted facility at 30-day follow-up. In-hospital mortality during acute admission was higher for the subtrochanteric group (5.6% versus 4.5%) (p = 0.028). To our knowledge, this is the first paper highlighting the differences between these two fracture groups in the geriatric population. Subtrochanteric fractures in the older population are a different and worse entity, with greater morbimortality and functional decline than pertrochanteric fractures. Despite being younger and fitter at admission, older patients with subtrochanteric fractures have a higher risk of remaining non-weight bearing and undergoing re-operation and institutionalization. Orthogeriatric units should be aware of this and manage subtrochanteric fractures accordingly. IV.


[The effect of prenatal stress on antioxidant glutathion-assosiated enzymes activity in subcellular fractions of rat's liver].
The activity of glutathione-associated antioxidant enzymes in subcellular fractions (cytosolic, mitochondrial, and cell nucleus fractions) was investigated in the liver of adult male Wistar rats born after prenatal stress was. Two groups of animals were studied in the experiment: (1) control group included - animals was born by intact mothers, and (2) prenatal stress group included animals whose mothers were subjected to immobilization stress in high-light conditions from the 15th to the 19th day of pregnancy. The activity of glutathione peroxidase (EC 188.8.131.52) in prenatally stressed animals decreased in the fractions of nuclei and mitochondria compared to the control group, while the activity of glutathione reductase (EC 220.127.116.11.) increased in the same subcellular fractions. The activity of glutathione transferase (EC 188.8.131.52) in prenatally stressed rats reduced in the cytosol and mitochondrial fractions as compared to control group. Redistribution of the antioxidant enzyme activity in the cytosol, the fraction of nuclei and the mitochondrial fraction of liver tissue may contribute to the formation of the pathological phenotype of prenatally stressed offspring.


[Risk factors of gout in Jinchang cohort: a Cox regression analysis].
Objective: To explore the incidence and risk factors of gout in Jinchang cohort and provide scientific evidence for the prevention and control of gout. Methods: People without gout detected by baseline survey in Jinchang cohort were selected as study subjects. All the subjects were followed up through questionnaire interview, physical examination as well as laboratory test from January 24, 2013 to November 24, 2015. Cox regression model was used to analyze the risk factors for gout in Jinchang cohort. In addition, log-linear model was used to analyze the interaction between risk factors. Results: A total of 33 153 subjects were followed up, and there were 277 newly diagnosed gout cases in the cohort. The overall incidence of gout was 0.8%. The incidence of gout in males was higher than that in the females, but the incidence of gout in males and females was similar after the age of 60 years. Cox regression analysis showed that age >40 years (at age 40 to 59 years: HR=2.982, 95%CI: 1.503-5.981; at age 60 to 91 years: HR=2.588, 95%CI: 1.107-6.049), alcohol abuse (HR=2.234, 95% CI: 1.128-4.427), obesity (HR=2.204, 95% CI: 1.216-3.997), diabetes (HR=2.725, 95% CI: 1.500-4.950) and high uric acid (HR=5.963, 95%CI: 3.577-9.943) were risk factors for gout, while weekly beans intake ≥0.25 kg (HR=0.528, 95%CI: 0.345-0.808) and regular physical exercise (HR=0.499, 95% CI: 0.286-0.869) were protective factors for gout. The analysis with log-linear model showed that there were two order effects between the risk factors. Conclusions: Age, beans intake, alcohol abuse, physical exercises, obesity, diabetes and high uric acid were important factors influencing the incidence of gout. It is important to have healthy lifestyle and dietary habits, receive regular health examination to prevent and control the incidence of gout in this cohort.


Self-assembled plasmonic nanoring cavity arrays for SERS and LSPR biosensing.
Self-assembled plasmonic nanoring cavity arrays are formed alongside the curvature of highly packed metallic nanosphere gratings. The sub-10-nm gap size is precisely tuned via atomic layer deposition and highly ordered arrays are produced over a cm-sized area. The resulting hybrid nanostructure boosts coupling efficiency of light into plasmons, and shows an improved SERS detection limit. These substrates are used for SERS detection of the biological analyte, adenine, followed by concurrent localized surface plasmon resonance sensing.


Classification of spontaneous isolated superior mesenteric artery dissection: correlation with multi-detector CT features and clinical presentation.
The purpose of the study is to propose a computed tomography (CT) classification of spontaneous isolated superior mesenteric artery dissection (SISMAD) correlated with clinical presentation METHODS: We retrospectively reviewed CT images of 40 patients with SISMAD at our institution from 2006 to 2015 and proposed a new classification: type I, patent false lumen with both entry and re-entry; type II, patent false lumen without re-entry; type III, completely or partially thrombosed false lumen; and type IV, thrombosed false lumen with ulcer-like projection. Additionally, we included a subtype (S) at each type when there was either a long segment of dissection and/or significant true lumen stenosis. CT features were statistically analyzed using Fisher's exact and Mann-Whitney test. The CT findings classified patients as type I (15%), type II (12.5%), type III (35%), and type IV (37.5%). Of the 40 patients, 25 (62.5%) were symptomatic. There was a significantly different proportion of each type between symptomatic and asymptomatic patients (p = 0.005). There were 25 patients with subtype (S); no type I or II, 12 type III, and 13 type IV. The symptomatic patients showed longer dissection tendency and more severe true lumen stenosis (78% vs. 53%, p = 0.000) compared with asymptomatic patients. The proposed multi-detector CT classification of SISMAD correlates with clinical presentation. This new classification could be helpful for treatment planning.


Pharmacokinetic and pharmacodynamic assessments of the dipeptidyl peptidase-4 inhibitor PHX1149: double-blind, placebo-controlled, single- and multiple-dose studies in healthy subjects.
PHX1149 is a dipeptidyl peptidase-4 (DPP4) inhibitor that is currently in clinical development for the treatment of type 2 diabetes mellitus. PHX1149 is a small (molecular weight = 241.16 Da), highly water-soluble (>2 g/mL), orally active molecule with a selectivity index of 15- to 319-fold relative to those of other members of the DPP family. The biochemical median inhibitory concentration of DPP4 is 2.5 nmol/L. The aim of these 2 double-blind, randomized, placebo-controlled studies was to examine the pharmacokinetic (PK) parameters and pharmacodynamic (PD) properties and tolerability of single and multiple ascending doses of PHX1149 in healthy human subjects. Healthy men and women aged 18 to 60 years were recruited to participate in a single- or a multiple-dose study in which sequential dose escalation paradigm was used. In the single-dose study, subjects were given a single oral dose of PHX1149 50 to 500 mg or placebo; in the multiple-dose study, subjects were given PHX1149 at doses from 50 to 400 mg or placebo QD for 13 days. There was no intrasubject dose escalation. Blood samples were collected from each subject at a series of time points ranging from 1 hour before to 24 hours after dosing on day 1 in the single- dose study and on days 1, 7, and 13 in the multiple-dose study. PK and PD analyses were performed in plasma samples to determine Cmax, Tmax, AUC0-t, AUC0-infinity, and DPP4 enzymatic activity. The drug accumulation index was also calculated for each dose of PHX1149 in the multiple-dose study. Adverse events (AEs) were monitored in both studies through physical examinations, including measurement of vital signs, and clinical laboratory testing. In both studies, electrocardiography was performed. The single- and multiple-dose studies enrolled 30 and 28 subjects, respectively, for a total enrollment in the 2 studies of 58 healthy adult subjects. The distribution of male and female subjects was 14 (47%) and 16 (53%), respectively, in the single- dose study and 16 (57%) and 12 (43%) in the multiple- dose study. In the single-dose study, 28 (93%) subjects were white; in the multidose study, all subjects were white. The mean (SD) ages in the 2 studies were 51 (10) and 51 (12) years, respectively; and mean (SD) body weights were 89.0 (10.8) and 81.1 (10.9) kg, respectively. PHX1149 exhibited dose-proportional increases in mean Cmax AUC0-t, and AUC0-infinity across the evaluated dose ranges. Tmax ranged from 2 to 4 hours, and t1/2 ranged from approximately 10 to 13 hours. No drug accumulation was observed. Plasma DPP4 inhibition at 24 hours was >or=50% in the multiple-dose study for doses of >or=100 mg. PHX1149 400 mg achieved approximately 90% 24-hour plasma DPP4 inhibition in the multiple-dose study. All AEs were characterized as mild, with the exception of 1 case of moderate edema, which occurred 17 days after the end of dosing in the multiple-dose study (50-mg dose group) and was considered unrelated to the study drug. Adverse events were experienced by 47% of all subjects studied in the single-dose study and 93% of subjects in the multiple-dose study. The rates of AEs were comparable between the study and placebo groups. The PK parameters and PD properties of PHX1149 were suitable (eg, tl/2, DPP4 inhibition) for once-daily dosing in this group of 58 healthy subjects. All doses were well tolerated.


[Basic and clinical studies on patients who have undergone autologous or allogeneic bone marrow transplantation].
Bone marrow transplantation (BMT) is now increasingly applied not only to hematologic disorders such as leukemias and aplastic anemia but also to some of solid tumors. We experienced ten cases of bone marrow harvest and six cases of autologous or allogeneic BMT during the period from June, 1986 to August, 1987. For autologous BMT cases, bone marrow cells were harvested and cryopreserved at -196 degrees C in liquid nitrogen tank and colony forming assays were examined to ascertain the colony forming ability of harvested bone marrow stem cells. Recovery of colony forming ability after cryopreservation in colony forming unit in culture and burst forming unit in erythrocyte is about 63 to 73% and well preserved. Among 6 cases undergone BMT, five cases are patients with advanced solid tumors including breast cancer, seminoma, lung cancer, malignant lymphoma and brain tumor and these 5 cases have undergone autologous BMT. Conditioning regimen for each cancer in autologous BMT differs based upon conventional chemotherapy regimen and two to four fold dose of conventionally used chemotherapy regimen were administered and after two or three days of high dose chemotherapy, cryopreserved bone marrow cells were thawed and infused. Peripheral white blood cells and platelets were recovered to more than 1000/microliters and 5 x 10(4)/microliters, respectively, within 21 days after bone marrow cell infusion. Disappearance or decrease in tumor size was observed in all cases except brain tumor even though those cases were advanced ones. After autologous BMT, recurrence occurred within three to five months in three cases.(ABSTRACT TRUNCATED AT 250 WORDS)


[Complications following implantation of the Simcoe lens of the posterior chamber].
After the introduction of phacoemulsification and ECCE at the Charlottenburg eye clinic of the Free University of Berlin, Simcoe posterior chamber lenses have been implanted there routinely since May 1982. Up to August 1983, 1124 posterior chamber lenses had been implanted, all of the Simcoe type. The advantages of posterior chamber lens implantation having been dealt with elsewhere, the authors point out the complications of the procedure in this paper. The complications seen were cyclitic reactions, including hypopyon in 6 patients. In one patient a rhegmatogenic retinal detachment was diagnosed 2.5 months after phacoemulsification and implantation of a Simcoe lens. Decentered lenses were found in 3 patients, in one of them after phacoemulsification of a radiogenic cataract with capsulotomy. In 2 patients the posterior capsule ruptured during insertion of the lens but the lens remained lodged in the sulcus, so that it did not have to be removed. Since March 1983 all Simcoe posterior chamber lenses have been fitted (in a total of 571 eyes) with loops angled 10 degrees forward, as suggested by the authors. Iris capture syndrome was found in 12 patients (2.2%) of a group in which 553 lenses without angled loops had been fitted. The condition was not found in any of the patients to whom lenses with angled loops had been fitted.


Unusual cases of resistance to minoxidil therapy.
Minoxidil was used to treat 112 patients with severe and refractory hypertension during a period of 8 years. The drug was highly effective and resistant cases were distinctly unusual. We reported here 4 such cases. In 2, the patients showed no response to large doses, even when minoxidil was combined with other drugs. In the third, a patient with severe gastrointestinal abnormalities could not retain the drug. No proof exists that if it had been given parenterally it would not have been effective. The last case is of a patient with obstructive cardiomyopathy (IHSS) who reponded well to minoxidil. Because of the vasodilator's profound effect on the cardiovascular system, changes in this patient's hemodynamics occurred which made fluid retention and cardiomegaly intolerable. Patients with severe obstructive cardiomyopathy should be considered for therapy with a strong vasodilator only with caution and with the awareness that fluid retention may be disproportionately large.


A pH-Stable Tb-MOF as Luminescence Sensor for Highly Sensitive Detection of Amino Acids through Diverse Sensing Mechanism.
A luminescent Tb-MOF with excellent stability and dual-emitting properties was constructed with an amide-functionalized tetracarboxylate ligand. Tb-MOFs were initially assembled on one-dimensional Tb3+ chains, then formed a two-dimensional double-decker layer through the synergistic linking of organic ligands and bridging formic acid anions, and further fabricated the final three-dimensional structure through the connection of the organic ligands. Powder X-ray diffraction experiments revealed that Tb-MOFs not only exhibited excellent stability in water but also maintained structural integrity in the pH range of 2-12. Importantly, this Tb-MOF provided the first example of a metal-organic framework (MOF)-based luminescence sensor that can simultaneously detect two acid amino acids (aspartic and glutamic acids) through a turn-off sensing mechanism and two basic amino acids (lysine and arginine acids) through unusual turn-on and turn-off-on sensing mechanisms. Moreover, high sensitivity, low detection limit, and excellent recyclability of this sensor endow Tb-MOFs with great potential as a highly efficient amino acid fluorescence sensor in chemical detection and biological environments.


Interleukin-1 receptor antagonist improves survival and preserves organ adenosine-5'-triphosphate after hemorrhagic shock.
This study was designed to determine the role of interleukin-1 (IL-1) in hemorrhagic shock death. Pentobarbital anesthetized C3H/HeN mice (n = 59) were prepared with a femoral arterial catheter and were randomized to treatment with an IL-1 receptor antagonist (IL-1ra, 10 mg/kg, n = 29) or an equal volume of phosphate-buffered saline solution (vehicle, n = 30) by subcutaneous bolus injection at 15 minutes before hemorrhage and again at 120 minutes. Continuous posthemorrhage delivery of IL-1ra or vehicle was performed in each group (1.5 mg IL-1ra in 30 microliters/day) through a subcutaneous osmotic pump. Rapid hemorrhage of 4 ml/100 gm weight was followed by normal saline resuscitation of 12 ml/100 gm 60 minutes later. Survival analysis by Wilcoxon rank sum analysis revealed a significantly improved 5-day survival in IL-1ra-treated mice (n = 15, 20%) as compared with vehicle-treated mice (n = 14, 6%, p < 0.001). To determine a possible mechanism of this survival advantage, the remaining mice in each treatment group were killed at 30 minutes to obtain blood and tissue samples from the heart, liver, and kidney for measurement of adenosine-5'-triphosphate (ATP). No difference in hematocrit, circulating neutrophils, or levels of glucose, lactate, or tumor necrosis factor was identified between groups to explain the improved outcome. IL-1ra prevented hemorrhage-induced ATP depletion observed in vital organs of vehicle-treated mice. The data implicate IL-1 in shock-induced ATP depletion and suggest IL-1ra may improve hemorrhagic shock survival by preventing ATP depletion in vital organs.


Identification and functional characterization of Leishmania donovani secretory peroxidase: delineating its role in NRAMP1 regulation.
Leishmania silently evades host immune system and establish in the hostile environment of host macrophage phagolysosomes. For differentiation, growth and division parasite acquires divalent cations especially iron from the host nutritive pool. Natural resistance associated with macrophage protein1 (NRAMP1), a cation transporter that effluxes out divalent cations specifically iron from phagosomal milieu to the cytosol, to create ions deprived status for pathogenic microorganisms. The mechanisms of NRAMP1 regulation are largely unknown in leishmanial infections. In the present study, we identified a secretory Leishmania donovani peroxidase (Prx) that showed peroxidoxin like peroxidase activity and significantly reduced H(2)O(2), O(2).(-) and NO levels in LPS activated macrophages. Further, we also observed down regulated Nramp1 expression and concomitantly declined labile iron pool in activated macrophages treated with identified peroxidase. Prx also decreased levels of TNF-α, IFN-γ and IL-12 in LPS activated macrophages. These observations indicate a bifunctional protective role of secretory Prx; first it reduces redox activation of macrophages, and secondly it allows iron access to Leishmania by down regulating NRAMP1 expression.


Accurate theoretical prediction of vibrational frequencies in an inhomogeneous dynamic environment: a case study of a glutamate molecule in water solution and in a protein-bound form.
We propose a hierarchical approach to model vibrational frequencies of a ligand in a strongly fluctuating inhomogeneous environment such as a liquid solution or when bound to a macromolecule, e.g., a protein. Vibrational frequencies typically measured experimentally are ensemble averaged quantities which result (in part) from the influence of the strongly fluctuating solvent. Solvent fluctuations can be sampled effectively by a classical molecular simulation, which in our model serves as the first, low level of the hierarchy. At the second high level of the hierarchy a small subset of system coordinates is used to construct a patch of the potential surface (ab initio) relevant to the vibration in question. This subset of coordinates is under the influence of an instantaneous external force exerted by the environment. The force is calculated at the lower level of the hierarchy. The proposed methodology is applied to model vibrational frequencies of a glutamate in water and when bound to the Glutamate receptor protein and its mutant. Our results are in close agreement with the experimental values and frequency shifts measured by the Jayaraman group by the Fourier transform infrared spectroscopy [Q. Cheng et al., Biochem. 41, 1602 (2002)]. Our methodology proved useful in successfully reproducing vibrational frequencies of a ligand in such a soft, flexible, and strongly inhomogeneous protein as the Glutamate receptor.


The key role of differential broad H3K4me3 and H3K4ac domains in breast cancer.
Epigenetic processes are radically altered in cancer cells. The altered epigenetic events may include histone post-translational modifications (PTMs), DNA modifications, and/or alterations in the levels and modifications of chromatin modifying enzymes and chromatin remodelers. With changes in gene programming are changes in the genomic distribution of histone PTMs. Genes that are poised or transcriptionally active have histone H3 trimethylated lysine 4 (H3K4me3) located at the transcription start site and at the 5' end of the gene. However, a small population of genes that are involved in cell identity or cancer cell properties have a broad H3K4me3 domain that may stretch for several kilobases through the coding region of the gene. Each cancer cell type appears to mark a select set of cancer-related genes in this manner. In this study, we determined which genes were differentially marked with the broad H3K4me3 domain in normal-like (MCF10A), luminal-type breast cancer (MCF7), and triple-negative breast cancer (MDA-MB-231) cells. We also determined whether histone H3 acetylated lysine 4 (H3K4ac), also a mark of active promoters, had a broad domain configuration. We applied two peak callers (MACS2, PeakRanger) to analyze H3K4me3 and H3K4ac chromatin immunoprecipitation sequencing (ChIP-Seq) data. We identified genes with a broad H3K4me3 and/or H3K4ac domain specific to each cell line and show that the genes have critical roles in the breast cancer subtypes. Furthermore, we show that H3K4ac marks enhancers. The identified genes with the broad H3K4me3/H3K4ac domain have been targeted in clinical and pre-clinical studies including therapeutic treatments of breast cancer.


Synthesis of Daidzein and Thiophene Containing Benzoxazine Resin and Its Thermoset and Carbon Material.
In this work, a novel bio-based high-performance bisbenzoxazine resin was synthesized from daidzein, 2-thiophenemethylamine and paraformaldehyde. The chemical structure was confirmed using nuclear magnetic resonance spectroscopy (NMR) and Fourier-transform infrared spectroscopy (FT-IR). The polymerization process was systematically studied using differential scanning calorimetry (DSC) and in situ FT-IR spectra. It can be polymerized through multiple polymerization behaviors under the synergistic reaction of thiophene rings with benzopyrone rather than a single polymerization mechanism of traditional benzoxazines, as reported. In addition, thermogravimetric analysis (TGA) and a microscale combustion calorimeter (MCC) were used to study the thermal stability and flame retardancy of the resulting polybenzoxazine. The thermosetting material showed a high carbon residue rate of 62.8% and a low heat release capacity (HRC) value of 33 J/gK without adding any flame retardants. Based on its outstanding capability of carbon formation, this newly obtained benzoxazine resin was carbonized and activated to obtain a porous carbon material doped with both sulfur and nitrogen. The CO2 absorption of the carbon material at 0 °C and 25 °C at 1 bar was 3.64 mmol/g and 3.26 mmol/g, respectively. The above excellent comprehensive properties prove its potential applications in many advanced fields.


SorLA in Interleukin-6 Signaling and Turnover.
Interleukin-6 (IL-6) is a multifunctional cytokine with important functions in various physiologic processes. Mice lacking IL-6 exhibit multiple phenotypic abnormalities, such as an inadequate immune and acute-phase response, and elevated levels of circulating IL-6 have been found to accompany several pathological conditions. IL-6 binds the nonsignaling IL-6 receptor (IL-6R), which is expressed as a transmembrane, as well as a secreted circulating protein, before it engages homodimeric gp130 for signaling. Complex formation between IL-6 and the membrane-bound IL-6 receptor gives rise to classic cis signaling, whereas complex formation between IL-6 and the soluble IL-6R results in trans signaling. Here, we report that the endocytic receptor SorLA targets IL-6 and IL-6R. We present evidence that SorLA mediates efficient cellular uptake of both IL-6 and the circulating IL-6R in astrocytes. We further show that SorLA interacts with the membrane-bound IL-6R at the cell surface and thereby downregulates IL-6 cis signaling. Finally, we find that the SorLA ectodomain, released from the cell membrane upon enzymatic cleavage of full-length SorLA, may act as an IL-6 carrier protein that stabilizes IL-6 and its capacity for trans signaling.


Vocally disruptive behaviors management in older people with dementia.
Although shouting is a common psycho-behavioral symptom in geriatric institutions, the question of its assessment and treatment remains seldom studied and has rarely been the subject of specific recommendations. The combination of the focus group method and brainstorming has emerged as a methodology both relevant and feasible in geriatric facility to identify the coping strategies used by professionals and generalize guidelines for clinical observation and vocally disruptive behaviors management (shouting). The standardized gathering of professional experiences in nursing homes and their analysis with reference to results of the literature enabled the development of an analytical and clinical decision making diagram that can be an operational tool to cope with the occurrence of shouting in older people with dementia. Five types of triggers/aggravating shoutings emerged: 1) physical or moral pain and emotional reactions, 2) presence of sensory loss, 3) social isolation, under-stimulation or hyper sensitivity to stimulation and care, 4) reminiscences and 5) re-emergence of painful memories and loss of language skills. These factors have been associated with five methods of intervention : 1) pharmacological treatments, 2) animations, such as listening to music, physical activity and workshops using therapeutic mediation, 3) family or animal support and use of interventions to provide relaxation or stimulation, 4) interventions to deal with sensory deficits and 5) interventions modifying the environment.


Glutamate-induced neuronal death in primary cultures of cerebellar granule cells: protection by synthetic derivatives of endogenous sphingolipids.
The delayed neuronal death induced by a brief (15 min) application of glutamate to primary cultures of cerebellar granule cells can be prevented by pretreating the cultures with the natural ganglioside monosialoglycosylceramide (GM1), the semisynthetic GM1 with N-acetyl sphingosine (LIGA4), GM1 with N-dichloroacetyl sphingosine (LIGA20) and d-eritro 1,3-dihydroxy-2-dichloroacetylamide-4-trans-octadecene (PKS3). The semisynthetic lipids LIGA4, LIGA20 and PKS3 are more potent than the parent natural compounds. The rank order of potency for the protection against glutamate-induced neuronal death is: LIGA20 greater than or equal to LIGA4 greater than PKS3 greater than GM1; the corresponding EC50 values are 4.5 microM for LIGA20, 5 microM for LIGA4, 30 microM for PKS3 and 55 microM for GM1. The effect of the semisynthetic lipids is faster (maximal protection after a 5-min preincubation) and lasts longer (up to 24 hr) than that of the natural compound GM1. The protection from glutamate-induced neuronal death by the semisynthetic sphingolipids persists after thorough washout of free sphingolipid from the incubation medium. Therefore, LIGA4, LIGA20 and PKS3 are potent and efficacious antagonists of glutamate-induced neuronal death with a good separation between the doses needed for pharmacological action and the intrinsic neurotoxic activity. The natural (GM1) and semisynthetic (LIGA4, LIGA20 and PKS3) sphingolipids block neuronal death without affecting the function of glutamate-operated cationic channels. The protective action of sphingolipids appears to be associated with their insertion into membranes where they inhibit specific second messenger-mediated responses triggered by persistent stimulation of glutamate receptors.(ABSTRACT TRUNCATED AT 250 WORDS)


The PIK3CA gene is mutated with high frequency in human breast cancers.
The phosphatidylinositol 3-kinases (PI3Ks) are known regulators of cellular growth and proliferation. It has recently been reported that somatic mutations within the PI3K subunit p110alpha (PIK3CA) are present in human colorectal and other cancers. Here we show that thirteen of fifty-three breast cancers (25%) contain somatic mutations in PIK3CA, with the majority of mutations located in the kinase domain. These results demonstrate that PIK3CA is the most mutated oncogene in breast cancer and support a role for PIK3CA in epithelial carcinogenesis.


Synthesis and antimuscarinic properties of quinuclidin-3-yl 1,2,3,4-tetrahydroisoquinoline-2-carboxylate derivatives as novel muscarinic receptor antagonists.
In the course of continuing efforts to develop potent and bladder-selective muscarinic M3 receptor antagonists, quinuclidin-3-yl 1-aryl-1,2,3,4-tetrahydroisoquinoline-2-carboxylate derivatives and related compounds were designed as conformationally restricted analogues of quinuclidin-3-yl benzhydrylcarbamate (8). Binding assays with rat muscarinic receptor subtypes revealed that the quinuclidin-3-yl 1-aryl-1,2,3,4-tetrahydroisoquinoline-2-carboxylate derivatives showed high affinities for the M3 receptor, and selectivity for the M3 receptor over the M2 receptor. Of these derivatives, (+)-(1S,3'R)-quinuclidin-3'-yl 1-phenyl-1,2,3,4-tetrahydroisoquinoline-2-carboxylate monohydrochloride (9b) exhibited almost the same inhibitory activity against bladder contraction to that of oxybutynin (1), and more than 10-fold selectivity for bladder contraction versus salivary secretion, demonstrating that 9b may be useful for the treatment of symptoms associated with overactive bladder without having side effects such as dry mouth.


Enrichment and characterization of hydrocarbon-degrading bacteria from petroleum refinery waste as potent bioaugmentation agent for in situ bioremediation.
Intrinsic biodegradation potential of bacteria from petroleum refinery waste was investigated through isolation of cultivable strains and their characterization. Pseudomonas and Bacillus spp. populated the normal cultivable taxa while prolonged enrichment with hydrocarbons and crude oil yielded hydrocarbonoclastic bacteria of genera Burkholderia, Enterobacter, Kocuria, Pandoraea, etc. Strains isolated through enrichment showed assemblages of superior metabolic properties: utilization of aliphatic (C6-C22) and polyaromatic compounds, anaerobic growth with multiple terminal electron acceptors and higher biosurfactant production. Biodegradation of dodecane was studied thoroughly by GC-MS along with detection of gene encoding alkane hydroxylase (alkB). Microcosms bioaugmented with Enterobacter, Pandoraea and Burkholderia strains showed efficient biodegradation (98% TPH removal) well fitted in first order kinetic model with low rate constants and decreased half-life. This study proves that catabolically efficient bacteria resides naturally in complex petroleum refinery wastes and those can be useful for bioaugmentation based bioremediation.


Correction: Controversy matters: Impacts of topic and solution controversy on the perceived credibility of a scientist who advocates.
[This corrects the article DOI: 10.1371/journal.pone.0187511.].


Three-dimensional power Doppler assessment of uterine vascularization in women with primary dysmenorrhea.
The aim of this study was to assess myometrial vascularization with 3-dimensional (3D) power Doppler angiography (PDA) in women with different grades of primary dysmenorrhea at the moment of maximum menstrual pain in an effort to improve the pathophysiologic knowledge of one of the most common gynecologic conditions. This was a cross-sectional study involving 70 voluntary women that studied or worked at the Clinica Universitaria de Navarra between January 2006 and January 2008. All women underwent transvaginal sonographic 3D PDA on the day of maximum pain after the onset of menstruation or during the first 24 to 48 hours of the new cycle if no pain was present. Three groups were defined according to a visual analog scale: no pain to mild dysmenorrhea, moderate dysmenorrhea, and severe dysmenorrhea. Vascularity assessment was done on the basis of 3D vascularity indices: the vascularization index (VI), flow index (FI), and vascularization-flow index (VFI). The mean VI and VFI for the inner 5 mm of the myometrium and the total myometrium were significantly higher in the women with severe dysmenorrhea than in those with no pain to mild dysmenorrhea (P < .05). The VI, FI, and VFI in the women with moderate dysmenorrhea did not differ significantly from those in the women with severe dysmenorrhea. This study evaluated the use of 3D PDA for assessing uterine and specifically myometrial vascularization. Our data indicate that women with severe dysmenorrhea have increased myometrial vascularization during the early menstrual phase compared with women without pain.


Dietary behaviors associated with total fat and saturated fat intake.
To estimate percentages of US adults who have adopted behaviors promoted by dietary guidance about how to reduce fat intake, and to assess relationships between these behaviors and intake of energy from total and saturated fat. Relationships were examined between intake of total and saturated fat from two 24-hour recalls in the US Department of Agriculture's 1994-1996 Continuing Survey of Food Intakes by Individuals and responses to 19 fat-related behavior questions on the follow-up Diet and Health Knowledge Survey (DHKS). Data are from a national sample of 5,649 individuals 20 years of age and older. Multiple regression models are used to identify dietary behaviors, demographic factors, and personal characteristics that are determinants of fat intake. In this study, the percentage of US adults who consistently followed the low-fat behaviors ranged from 8% to 70%. The most highly adopted behaviors (45% or more of adults) included trimming fat from meat, removing skin from chicken, and eating chips infrequently. The least highly adopted behaviors (15% or less of adults) included eating baked or boiled potatoes without added fat, avoiding butter or margarine on breads, eating low-fat instead of regular cheeses, and having fruit for dessert when dessert is eaten. Together, the 19 fat-related behavior questions on the DHKS formed a statistically significant predictor for total fat and saturated fat intake, expressed as a percent of energy (P<.0001). Key behaviors in terms of their predicted effect on lowering both total and saturated fat intake were never adding fat to baked or boiled potatoes, not eating red meats, eating less than 3 eggs per week, and never eating chicken fried. Predicted effects of these key behaviors in terms of lowering fat intake as a percentage of energy were > or = 1.5 percentage points for total fat and > or = 0.5 percentage point for saturated fat. Results have applications for designing brief fat assessment instruments and for identifying key nutrition education messages that promote important fat-lowering behaviors.


Resolving the interactions between population density and air pollution emissions controls in the San Joaquin Valley, USA.
The effectiveness of emissions control programs designed to reduce concentrations of airborne particulate matter with an aerodynamic diameter < 2.5 microm (PM2.5) in California's San Joaquin Valley was studied in the year 2030 under three growth scenarios: low, medium, and high population density. Base-case inventories for each choice of population density were created using a coupled emissions modeling system that simultaneously considered interactions between land use and transportation, area source, and point source emissions. The ambient PM2.5 response to each combination of population density and emissions control was evaluated using a regional chemical transport model over a 3-week winter stagnation episode. Comparisons between scenarios were based on regional average and population-weighted PM2.5 concentrations. In the absence of any emissions control program, population-weighted concentrations of PM2.5 in the future San Joaquin Valley are lowest undergrowth scenarios that emphasize low population density. A complete ban on wood burning and a 90% reduction in emissions from food cooking operations and diesel engines must occur before medium- to high-density growth scenarios result in lower population-weighted concentrations of PM2.5. These trends partly reflect the fact that existing downtown urban cores that naturally act as anchor points for new high-density growth in the San Joaquin Valley are located close to major transportation corridors for goods movement. Adding growth buffers around transportation corridors had little impact in the current analysis, since the 8-km resolution of the chemical transport model already provided an artificial buffer around major emissions sources. Assuming that future emissions controls will greatly reduce or eliminate emissions from residential wood burning, food cooking, and diesel engines, the 2030 growth scenario using "as-planned" (medium) population density achieves the lowest population-weighted average PM2.5 concentration in the future San Joaquin Valley during a severe winter stagnation event. The San Joaquin Valley is one of the most heavily polluted air basins in the United States that are projected to experience strong population growth in the coming decades. The best plan to improve air quality in the region combines medium- or high-density population growth with rigorous emissions controls. In the absences of controls, high-density growth leads to increased population exposure to PM2.5 compared with low-density growth scenarios (urban sprawl).


Local versus Global Perceptual Scope, Empathic Concern, and Helping Preferences in Multiple-Victim Situations.
Previous research on the one-among-others effect has shown that inducing empathic concern towards a victim presented alongside with a small number of other victims enhances (a) the perception of this set of victims as separate and different individuals (instead of as a group), and (b) the preference to help them individually (rather than collectively). We propose that inducing a local (vs. global) perceptual scope increases (vs. lessens) these two outcomes. In this work, participants first reported their perception of an ad that showed a victim depicted as one-among-others and, afterwards, were unexpectedly asked to indicate their preference for giving the victims either "individualized", "collective", or "equal" assistance. In Experiment 1 (N = 48), we manipulated the participants' local (vs. global) perceptual scope and allowed empathy concern to occur naturally. In Experiment 2 (N = 213), we manipulated both the perceptual scope and empathy concern. Overall, results showed that the combined presence of local scope and empathic concern increased the awareness of others (η p 2 = .203 and .047, 95% CI = [0.05, 0.35] and [0.03, 0.13], ps < .03) and the preference for individualized assistance (zs = 2.08 and 2.74, ps < .02). Lastly, we discuss the theoretical and practical implications of perceiving a set of victims as individuals (rather than as a group) in need.


Tumbling and anomalous alignment of optically levitated anisotropic microparticles in chiral hollow-core photonic crystal fiber.
The complex tumbling motion of spinning nonspherical objects is a topic of enduring interest, both in popular culture and in advanced scientific research. Here, we report all-optical control of the spin, precession, and nutation of vaterite microparticles levitated by counterpropagating circularly polarized laser beams guided in chiral hollow-core fiber. The circularly polarized light causes the anisotropic particles to spin about the fiber axis, while, regulated by minimization of free energy, dipole forces tend to align the extraordinary optical axis of positive uniaxial particles into the plane of rotating electric field. The end result is that, accompanied by oscillatory nutation, the optical axis reaches a stable tilt angle with respect to the plane of the electric field. The results reveal new possibilities for manipulating optical alignment through rotational degrees of freedom, with applications in the control of micromotors and microgyroscopes, laser alignment of polyatomic molecules, and study of rotational cell mechanics.


[Comparative evaluation of reamberin and mafusol on acute toxic liver damage models].
Comparative evaluation of the infusion of reamberin and mafusol has been carried out on the model of toxic liver damage caused by ammonium chloride. Reamberin contributed to more rapid normalization of indices due to an increase in the substrate reserve for energy metabolism. In a group of animals with alcohol intoxication, only the treatment with Reamberin allowed the system of antioxidant protection (reduced glutathione, thiol groups) and functional activity of the liver to be to normalized by the end of experiments on a level of the control group (intact animals).


Developmental toxicity evaluation of triclopyr butoxyethyl ester and triclopyr triethylamine salt in the CD rat.
Triclopyr (3,5,6-trichloro-2-pyridyloxyacetic acid) is an herbicide used extensively in the control of woody plants and broadleaf weeds, and is often formulated as a triethylamine salt (T-TEA) or butoxyethyl ester (T-BEE). This study evaluated the developmental toxicity of T-TEA or T-BEE in time-mated CD rats gavaged on gestation days 6-15 with 0, 30, 100 or 300 mg/kg body weight(bw)/day. The doses of each compound were equimolar and equivalent to 22, 76, 216 mg/kg bw/day of triclopyr, based on prior studies indicating rapid cleavage of the salt or ester and equivalent pharmacokinetics for the active ingredient. T-TEA caused maternal toxicity, evidenced by the death of one high-dose dam, reduced body weight gain, increased relative liver and kidney weights (300 mg/kg bw/day), reduced feed consumption, and increased water consumption (100 and 300 mg/kg bw/day). Developmental effects were limited to slightly decreased fetal body weight and reduced skeletal ossification at the high dose level. T-BEE caused similar, albeit slightly more severe, maternal toxicity, with three maternal deaths at 300 mg/kg bw/day, and slight maternal effects at 30 mg/kg bw/day. Due to an equivocal increase in malformations, which were mainly clustered in litters from three high dose dams with marked maternal toxicity, the T-BEE study was repeated using 30 dams/group, investigator-blind fetal evaluations, and an additional dose group (5 mg/kg bw/day). In the repeat study, the only reproducible fetal effect was an increased incidence of 14th thoracolumbar rib at 300 mg/kg bw/day. Overall analysis of the two T-BEE studies suggested that the fetal malformations unique to the initial study likely reflected a combination of spontaneous events, exacerbated by marked maternal toxicity. The combined weight of evidence from these developmental toxicity studies, coupled with their known pharmacokinetic equivalence, indicates that T-BEE and T-TEA are not selectively toxic to the fetus. The respective maternal toxicity no-observed effect levels (NOEL) for T-BEE and T-TEA were 5 and 30 mg/kg bw/day, while the NOEL for developmental toxicity was 100 mg/kg bw/day for both compounds.


Mode conversion coefficients in graded-index fibers with various fiber-coating schemes: measurements.
Mode conversion coefficients in graded-index fibers with various fiber-coating schemes are measured. The experiment proved that graded-index and step-index fibers agree in the order of magnitude of parameters representing random bends along the fiber axis. It is found that mode conversion coefficients are largely concerned with the structure of the coating. The results show that mode conversion characteristics are affected by structure of the coating and refractive-index depression at the center of the fiber core. The combination of a relatively hard jacket and a thick isolation layer made of soft material is found to be effective in reducing the mode coupling among samples investigated.


Investigating Pregnancy Outcomes After Abnormal Cell-Free DNA Test Results.
Cell-free DNA (cfDNA) testing has increased sensitivity and specificity compared to other prenatal screening methods, but invasive diagnostic testing (IDT) is recommended for confirmation. We performed a retrospective chart review of 39 women with abnormal cfDNA results between March 2012 and September 2015 at an urban academic hospital to evaluate patient choice and pregnancy outcomes. We analyzed data using descriptive statistics, Fisher's exact tests, and Wilcoxon rank-sum tests. Median maternal age was 36.0 years [interquartile range (IQR) 31, 39]; 64.1% of women (25/39) were advanced maternal age and 69.2% (27/39) had abnormal ultrasounds. Median gestational age at time of cfDNA testing was 18 3/7 weeks [IQR 12 2/7, 20 5/7]. cfDNA results included trisomy 21 (89.7%, 35/39), trisomy 18 (7.7%, 3/39), and both trisomy 21/monosomy X (2.6%, 1/39). Of 39 women, 22 (56.4%) continued and 10 (25.6%) terminated the pregnancy; six (15.4%) had fetal demises, and one was lost to follow-up. Of women continuing their pregnancies, 54.6% (12/22) declined further genetic counseling, and 77.3% (17/22) declined IDT. Only 14 women pursued IDT; not pursuing IDT was associated with continuing the pregnancy (Fisher's exact test, p = .001). All women terminating their pregnancy (90.0%, 9/10) pursued IDT or had major anomalies on ultrasound, suggesting that women considering termination undergo more confirmatory tests or already have high suspicion for an abnormal pregnancy.


Designing humans: A human rights approach.
Advances in genomic technologies such as CRISPR-Cas9, mitochondrial replacement techniques, and in vitro gametogenesis may soon give us more precise and efficient tools to have children with certain traits such as beauty, intelligence, and athleticism. In this paper, I propose a new approach to the ethics of reproductive genetic engineering, a human rights approach. This approach relies on two claims that have certain, independent plausibility: (a) human beings have equal moral status, and (b) human beings have human rights to the fundamental conditions for pursuing a good life. I first argue that the human rights approach gives us a lower bound of when reproductive genetic engineering would be permissible. I then compare this approach with other approaches such as the libertarian, perfectionist, and life worth living approaches. Against these approaches, I argue that the human rights approach offers a novel, and more plausible, way of assessing the ethics of reproductive genetic engineering.


[Influence of termolabile enterotoxin of Enterobacter cloacae on phagocytic activity of mice peritoneal macrophages].
Influence of termolabile enterotoxin (LT-enterotoxin) of Enterobacter cloacae on functional activity of mice peritoneal macrophages was studied and following combinations were used: LT-enterotoxin-producing E. cloacae, its isogenic pair--LT-enterotoxin non-producing E. cloacae, supernatantof broth culture containing LT-enterotoxin, and physiological salt solution (in control group). Data showing decrease in phagocytic and lysosomal activity, disorder in functions of hexosemonophosphate shunt enzymes in peritoneal phagocytes were obtained.


Sarcopenia and body mass index predict sunitinib-induced early dose-limiting toxicities in renal cancer patients.
Little is known on factors predicting sunitinib toxicity. Recently, the condition of low muscle mass, named sarcopenia, was identified as a significant predictor of toxicity in metastatic renal cell cancer (mRCC) patients treated with sorafenib. We investigated whether sarcopenia could predict early dose-limiting toxicities (DLTs) occurrence in mRCC patients treated with sunitinib. Consecutive mRCC patients treated with sunitinib were retrospectively reviewed. A DLT was defined as any toxicity leading to dose reduction or treatment discontinuation. Body composition was evaluated using CT scan obtained within 1 month before treatment initiation. Among 61 patients eligible for analysis, 52.5% were sarcopenic and 32.8% had both sarcopenia and a body mass index (BMI)<25 kg m(-2). Eighteen patients (29.5%) experienced a DLT during the first cycle. Sarcopenic patients with a BMI<25 kg m(-2) experienced more DLTs (P=0.01; odds ratio=4.1; 95% CI: (1.3-13.3)), more cumulative grade 2 or 3 toxicities (P=0.008), more grade 3 toxicities (P=0.04) and more acute vascular toxicities (P=0.009). Patients with sarcopenia and a BMI<25 kg m(-2) experienced significantly more DLTs during the first cycle of treatment.


Evidence of stereospecificity in the in vivo methylation of [14C](+/-)-nicotine in the guinea pig.
In vivo metabolism of [14C]nicotine to N-methylnicotinium ion in the guinea pig appears to be a stereospecific biotransformation, involving only the R-(+)-isomer. The detection and quantitation of urinary radiolabeled nicotine metabolites after ip injection of either [N-14CH3](+/-)-nicotine or [2'-14C](+/-)-nicotine, was carried out on an HPLC cation-exchange analytical system. Utilizing the recently discovered phenomenon of differential enantiomeric association, the stereo-chemistry of the methylation pathway was determined. Significant differences in the tissue distribution of 14C label from the [N-14CH3]-vs. [2'-14C]nicotine-treated animals were observed 24 hr after nicotine administration. An unidentified metabolite with high affinity on cation-exchange chromatography, was detected as a metabolite of [2'-14C](+/-)-nicotine, but was not observed as a metabolite of [N-14CH3](+/-)-nicotine.


Trade secrets in life science and pharmaceutical companies.
Trade secret protection arises under state common law and state statutes. In general, a trade secret is information that is not generally known to the public and is maintained as a secret, and it provides a competitive advantage or economic benefit to the trade secret holder. Trade secrets can be worth tens or hundreds of millions of dollars, and damage awards in trade secret litigation have been high; often, there is a lot at stake. Obtaining a trade secret through "improper means" is misappropriation. If the alleged trade secret, however, was developed independently, known publicly, or not maintained as a secret, then those defenses may successfully overcome a claim for trade secret misappropriation. With today's interconnectedness in the biotechnology and pharmaceutical fields, more collaborations, joint ventures, and outsourcing arrangements among firms, and increased mobility of employees' careers, life science companies need to not only understand how to protect their trade secrets, but also know how to defend against a claim for trade secret theft.


Hyperpolarization-activated, cyclic nucleotide-gated, cation non-selective channel subunit expression pattern of guinea-pig spiral ganglion cells.
Although the hyperpolarization-activated non-specific cationic current (I(h)) plays important roles in determining the membrane characteristics of the spiral ganglion cells (SGCs), neither the exact types of the hyperpolarization-activated, cyclic nucleotide-gated, cation non-selective channel (HCN) subunits contributing to the molecular assembly of the relevant channels, nor their distribution pattern presented by the SGCs is known. In the present work immunolabeling and Western blot analysis were performed to describe the presence and distribution of all four known HCN subunits in the guinea-pig spiral ganglion. Besides determining the expression of the HCN1-HCN4 subunits by both type I and type II SGCs, the presence of possible apico-basal gradients in the expression patterns was also sought. The results indicate that both type I and type II SGCs express all four HCN subunits. The intensity of the immunolabeling of the cell surface membrane was generally strong, but it showed pronounced cell-to-cell variability. The Western blot experiments in combination with densitometry revealed that the amount of the HCN1 and HCN3 proteins was more significant in the apical than in the basal third of the guinea-pig cochlea. These findings not only imply potential heteromeric HCN channel formation of the spiral ganglion neurons, but they also offer a possible explanation of the previously reported heterogeneity of I(h) recorded in functional studies.


A novel biosensor based on a bio-barcode for the detection of Mycobacterium tuberculosis.
Tuberculosis (TB), the second (after COVID-19) deadliest infectious killer, is a chronic infectious disease caused by infection with Mycobacterium tuberculosis (M.T.), where early diagnosis and management are the key to containing the condition. Here, we report a novel biosensor for the detection of M.T. DNA based on magnetic separation, urease catalysis and silicon nanowire field effect transistor (SiNW FET) detection. M.T. DNA is sequence-specifically captured by magnetic nanoparticles and urease-labelled silica nanoparticles simultaneously to form a sandwich complex and urea is catalyzed into ammonium carbonate by urease modified on a sandwich complex. By using SiNW FET, the detection of M.T. DNA is realized indirectly by the detection of ammonium carbonate. The limit of detection (LOD) was determined to be 78.541 fM. The specificity of the biosensor was confirmed by detecting a panel of bacterial species. The utility of the biosensor was demonstrated in real-sample analysis and the recovery study of M.T. DNA was done in the genomic DNA extracted from cultured Mycobacterium tuberculosis. The biosensor holds promise to become a rapid, sensitive and accurate method for clinical diagnosis.


Secondary artisan phakic intraocular lens for correction of progressive high myopia in a pseudophakic child.
An 8-week-old infant underwent unilateral cataract extraction and posterior chamber intraocular lens implantation for total cataract in the left eye. After surgery, a residual progressive myopic error was observed, ranging from -4.5 diopters (D) 6 months after the operation to -14.0 D at the age of 3 years. Because of parental noncompliance for contact lens and spectacles use, secondary implantation of Artisan phakic IOL of -14.0 D power was performed. No intra- or postoperative complications were observed. Nine months after this second operation, myopia diminished to -3.25 D.


22q11 deletion syndrome and forensic research: can we go there?
Chromosome 22q11 deletion syndrome (22q11DS) encompasses velocardiofacial syndrome (VCFS), DiGeorge syndrome (DGS), and conotruncal anomaly face syndrome (CTAFS). The disorder may represent the interface between genetics and brain-behavior relationships. As there is a strong relationship between the genetic syndrome and schizophrenia, individuals with the disorder are likely to be disproportionately represented in the criminal justice system. The purpose of this article is to review the 22q11DS in the context of forensic research. The existing literature regarding the syndrome and its relationship to schizophrenia is reviewed. A study design is presented to determine the prevalence of the syndrome in correctional facilities compared with expected community prevalence rates. Finally, a brief history of genetic research in correctional facilities is reviewed as a potential model to determine the feasibility of research involving 22q11DS.


[Asthmatic exacerbation in pregnant woman].
The physiological changes in the pregnant woman expose her to a risk of faster respiratory decompensation. Asthma affects 2-13% of pregnancies. It is therefore important to ensure regular monitoring to allow good control of asthma to reduce the risk of exacerbations. Finally, the background treatment, such as exacerbations, must be identical to the treatment of other patients.


Ferromagnetic ligand holes in cobalt perovskite electrocatalysts as an essential factor for high activity towards oxygen evolution.
The definition of the interplay between chemical composition, electro-magnetic configuration and catalytic activity requires a rational study of the orbital physics behind active materials. Apart from Coulomb forces, quantum spin exchange interactions (QSEI) are part of the potentials that differentiate the activity of magnetic oxides, strongly correlated electrocatalysts, in electron transfer reactions. Ferromagnetic (FM) cobalt oxides can show low overpotentials for the oxygen evolution reaction (OER) and the La1-XSrXCoO3-δ (0 ≤ X ≤ 1) family of perovskites is good ground to gain understanding of the electronic interactions in strongly correlated catalysts. In this case, Sr-doping raises the OER activity and the conductivity and increases FM spin moments. The efficiency of electrocatalysts based on Earth-abundant 3d-transition metals correlates with the interrelated factors: mild-bonding energies, the reduction of the electronic repulsions because of the QSEI in the open-shells, and enhanced spin delocalization in FM ordering. The reason for the outstanding OER activity of SrCoO3-δ is the accumulation of FM holes in the 3d-2p bonds, including the ligand orbitals, thus facilitating spin-selected charge transport and production of triplet O2 moieties from the oxidation of diamagnetic precursors. Spin-polarized oxygen atoms in the lattice can participate in O-O coupling and release of O2 in a Mars-Van Krevelen mechanistic fashion. We show that the stabilizing FM QSEI decrease the adsorption and activation energies during oxygen evolution and spin-dependent potentials are one of the factors that govern the catalytic activity of magnetic compositions: spintro-catalysis.


Significance of reductive metabolism in human intestine and quantitative prediction of intestinal first-pass metabolism by cytosolic reductive enzymes.
The number of new drug candidates that are cleared via non-cytochrome P450 (P450) enzymes has increased. However, unlike oxidation by P450, the roles of reductive enzymes are less understood. The metabolism in intestine is especially not well known. The purposes of this study were to investigate the significance of reductive metabolism in human intestine, and to establish a quantitative prediction method of intestinal first-pass metabolism by cytosolic reductive enzymes, using haloperidol, mebendazole, and ziprasidone. First, we estimated the metabolic activities for these compounds in intestine and liver using subcellular fractions. Metabolic activities were detected in human intestinal cytosol (HIC) for all three compounds, and the intrinsic clearance values were higher than those in human liver cytosol for haloperidol and mebendazole. These metabolic activities in HIC were NADPH- and/or NADH-dependent. Furthermore, the metabolic activities for all three compounds in HIC were largely inhibited by menadione, which has been used as a carbonyl reductase (CBR)-selective chemical inhibitor. Therefore, considering subcellular location, cofactor requirement, and chemical inhibition, these compounds might be metabolized by CBRs in human intestine. Subsequently, we tried to quantitatively predict intestinal availability (F(g)) for these compounds using human intestinal S9 (HIS9). Our prediction model using apparent permeability of parallel artificial membrane permeability assay and metabolic activities in HIS9 could predict F(g) in humans for the three compounds well. In conclusion, CBRs might have higher metabolic activities in human intestine than in human liver. Furthermore, our prediction method of human F(g) using HIS9 is applicable to substrates of cytosolic reductive enzymes.