Circularly permuted LOV2 as a modular photoswitch for optogenetic engineering.
Plant-based photosensors, such as the light-oxygen-voltage sensing domain 2 (LOV2) from oat phototropin 1, can be modularly wired into cell signaling networks to remotely control protein activity and physiological processes. However, the applicability of LOV2 is hampered by the limited choice of available caging surfaces and its preference to accommodate the effector domains downstream of the C-terminal Jα helix. Here, we engineered a set of LOV2 circular permutants (cpLOV2) with additional caging capabilities, thereby expanding the repertoire of genetically encoded photoswitches to accelerate the design of optogenetic devices. We demonstrate the use of cpLOV2-based optogenetic tools to reversibly gate ion channels, antagonize CRISPR-Cas9-mediated genome engineering, control protein subcellular localization, reprogram transcriptional outputs, elicit cell suicide and generate photoactivatable chimeric antigen receptor T cells for inducible tumor cell killing. Our approach is widely applicable for engineering other photoreceptors to meet the growing need of optogenetic tools tailored for biomedical and biotechnological applications.


Targeting neurotrophin receptors in the central nervous system.
Neurotrophic factors, and in particular the neurotrophins, restore the function of damaged neurons and prevent apoptosis in adults. The potential therapeutic property of the neurotrophins is however, complicated by the peptidergic structure of these trophic factors, which impairs their penetration into the brain parenchyma, and therefore makes their pharmaco-therapeutic properties difficult to evaluate. In this article we will focus on the neurotrophin Brain-derived neurotrophic factor (BDNF) and its receptors to address various therapeutic strategies that may overcome this problem. We will call this strategy "small molecule approach" because it relies on increasing the function of endogenous neurotrophins by pharmacological compounds that induce synthesis and release of neurotrophins in relevant brain areas or by small synthetic molecules that bind and activate specific neurotrophin receptors. The ability of small molecules to mimic BDNF has a potential therapeutic importance in preventing neuronal damage in several chronic neurodegenerative diseases including Parkinson's Disease, Alzheimer's Disease, and AIDS dementia.


Framing advance care planning in Parkinson disease: Patient and care partner perspectives.
Advance care planning (ACP) is a core quality measure in caring for individuals with Parkinson disease (PD) and there are no best practice standards for how to incorporate ACP into PD care. This study describes patient and care partner perspectives on ACP to inform a patient- and care partner-centered framework for clinical care. This is a qualitative descriptive study of 30 patients with PD and 30 care partners within a multisite, randomized clinical trial of neuropalliative care compared to standard care. Participants were individually interviewed about perspectives on ACP, including prior and current experiences, barriers to ACP, and suggestions for integration into care. Interviews were analyzed using theme analysis to identify key themes. Four themes illustrate how patients and care partners perceive ACP as part of clinical care: (1) personal definitions of ACP vary in the context of PD; (2) patient, relationship, and health care system barriers exist to engaging in ACP; (3) care partners play an active role in ACP; (4) a palliative care approach positively influences ACP. Taken together, the themes support clinician initiation of ACP discussions and interdisciplinary approaches to help patients and care partners overcome barriers to ACP. ACP in PD may be influenced by patient and care partner perceptions and misperceptions, symptoms of PD (e.g., apathy, cognitive dysfunction, disease severity), and models of clinical care. Optimal engagement of patients with PD and care partners in ACP should proactively address misperceptions of ACP and utilize clinic teams and workflow routines to incorporate ACP into regular care.


Tractography-Pathology Correlations in Traumatic Brain Injury: A TRACK-TBI Study.
Diffusion tractography magnetic resonance imaging (MRI) can infer changes in network connectivity in patients with traumatic brain injury (TBI), but the pathological substrates of disconnected tracts have not been well defined because of a lack of high-resolution imaging with histopathological validation. We developed an ex vivo MRI protocol to analyze tract terminations at 750-μm isotropic resolution, followed by histopathological evaluation of white matter pathology, and applied these methods to a 60-year-old man who died 26 days after TBI. Analysis of 74 cerebral hemispheric white matter regions revealed a heterogeneous distribution of tract disruptions. Associated histopathology identified variable white matter injury with patchy deposition of amyloid precursor protein (APP), loss of neurofilament-positive axonal processes, myelin dissolution, astrogliosis, microgliosis, and perivascular hemosiderin-laden macrophages. Multiple linear regression revealed that tract disruption strongly correlated with the density of APP-positive axonal swellings and neurofilament loss. Ex vivo diffusion MRI can detect tract disruptions in the human brain that reflect axonal injury.


Immune sensitization in the skin is enhanced by antigen-independent effects of IgE.
Contact sensitivity responses require both effective immune sensitization following cutaneous exposure to chemical haptens and antigen-specific elicitation of inflammation upon subsequent hapten challenge. We report that antigen-independent effects of IgE antibodies can promote immune sensitization to haptens in the skin. Contact sensitivity was markedly impaired in IgE(-/-) mice but was restored by either transfer of sensitized cells from wild-type mice or administration of hapten-irrelevant IgE before sensitization. Moreover, IgE(-/-) mice exhibited impairment in the reduction of dendritic cell numbers in the epidermis after hapten exposure. Monomeric IgE has been reported to influence mast cell function. We observed diminished contact sensitivity in mice lacking FcepsilonRI or mast cells, and mRNA for several mast cell-associated genes was reduced in IgE(-/-) versus wild-type skin after hapten exposure. We speculate that levels of IgE normally present in mice favor immune sensitization via antigen-independent but FcepsilonRI-dependent effects on mast cells.


Polarization periodicity in the B(1) columnar phase determined by resonant x-ray scattering.
We report structural results that evidence the polarization distribution of the blocks in the columnar phase of an achiral bent-core liquid crystal. The study was performed using resonant x-ray diffraction at the sulfur K edge on oriented samples aligned on substrates. The extra periodicity is revealed through the violation of the systematic extinction rule of the structural symmetry group along the experimentally accessible diffraction direction. Further data obtained from the polarization analysis of a resonant reflection give information concerning the transition mechanism between B(1) and B(2) phases.


Early highly aggressive MS successfully treated by hematopoietic stem cell transplantation.
During the last 15 years, high-dose chemotherapy with autologous hematopoietic stem cell transplantation (HSCT) has globally been performed for severe multiple sclerosis (MS). Most patients have been in progressive phase with long disease duration. As a rule, treatment effect has been minor or moderate. Since 2004, we have performed HSCT in nine young patients with "malignant" relapsing-remitting MS. Criteria for treatment were short duration of disease; very frequent, severe relapses; recent improvement periods indicating potential for recovery after strong immunosuppression. Median age at treatment was 27 (range 9-34) years, MS duration 26 (4-100) months, and annualized relapse rate 10 (4-12). Median Disability Status Scale (extended disability status scale, EDSS) at HSCT was 7.0 (3.5-8.0). Median follow-up time April 2008 is 29 (23-47) months. Median EDSS improvement is 3.5 (1.0-7.0), clearly surpassing most previous reports. One patient relapsed mildly with rapid recovery 7 months after HSCT. All patients are otherwise stable, median EDSS being 2.0 (0-6.0). Before HSCT, 61 relapses occurred in 82 patient months; during follow-up, one relapse in 289 patient months. This small series of patients with "malignant" relapsing-remitting MS suggests HSCT to be an effective treatment option for this relatively rare disease course. It further suggests that future criteria for HSCT in MS should be close to the present ones.


Greenhouse gas emissions and the Australian diet--comparing dietary recommendations with average intakes.
Nutrition guidelines now consider the environmental impact of food choices as well as maintaining health. In Australia there is insufficient data quantifying the environmental impact of diets, limiting our ability to make evidence-based recommendations. This paper used an environmentally extended input-output model of the economy to estimate greenhouse gas emissions (GHGe) for different food sectors. These data were augmented with food intake estimates from the 1995 Australian National Nutrition Survey. The GHGe of the average Australian diet was 14.5 kg carbon dioxide equivalents (CO2e) per person per day. The recommended dietary patterns in the Australian Dietary Guidelines are nutrient rich and have the lowest GHGe (~25% lower than the average diet). Food groups that made the greatest contribution to diet-related GHGe were red meat (8.0 kg CO2e per person per day) and energy-dense, nutrient poor "non-core" foods (3.9 kg CO2e). Non-core foods accounted for 27% of the diet-related emissions. A reduction in non-core foods and consuming the recommended serves of core foods are strategies which may achieve benefits for population health and the environment. These data will enable comparisons between changes in dietary intake and GHGe over time, and provide a reference point for diets which meet population nutrient requirements and have the lowest GHGe.


Second generation cephalosporin antibiotic prophylaxis and Clostridium difficile infection in hip and knee arthroplasty.
Introduction The use of broad spectrum cephalosporin antibiotics has been discouraged by the Department of Health in England because of the link to increased Clostridium difficile infection rates. The aim of this study was to evaluate whether a local protocol that included the use of second generation cephalosporin (cefuroxime) antibiotics as a prophylactic agent was associated with increased risk of C difficile in elective hip and knee arthroplasty patients. Methods A retrospective intention-to-treat study was conducted. An infection control database of all cases of C difficile infection both in hospital and in the community was reviewed and cross-referenced against surgical records. A positive correlation was identified when a C difficile positive sample was documented within eight weeks of arthroplasty surgery. Results Only 1 case (0.02%) of C difficile positive diarrhoea was identified that correlated to the 8-week postoperative period following 4,488 arthroplasty procedures. Conclusions The use of cephalosporin antibiotic prophylaxis in the elective hip and knee arthroplasty setting does not appear to be associated with increased C difficile infection rates, achieving surgical site infection rates that are comparable with the national average.


LAMPs: Shedding light on cancer biology.
Lysosomes are important cytoplasmic organelles whose critical functions in cells are increasingly being understood. In particular, despite the long-standing accepted concept about the role of lysosomes as cellular machineries solely assigned to degradation, it has been demonstrated that they play active roles in homeostasis and even in cancer biology. Indeed, it is now well documented that during the process of cellular transformation and cancer progression lysosomes are changing localization, composition, and volume and, through the release of their enzymes, lysosomes can also enhance cancer aggressiveness. LAMPs (lysosome associated membrane proteins) represent a family of glycosylated proteins present predominantly on the membrane of lysosomes whose expression can vary among different tissues, suggesting a separation of functions. In this review we focus on the functions and roles of the different LAMP family members, with a particular emphasis on cancer progression and metastatic spread. LAMP proteins are involved in many different aspects of cell biology and can influence cellular processes such as phagocytosis, autophagy, lipid transport, and aging. Interestingly, for all the five members identified so far (LAMP1, LAMP2, LAMP3, CD68/Macrosialin/LAMP4, and BAD-LAMP/LAMP5), a role in cancer has been suggested. While this is well documented for LAMP1 and LAMP2, the involvement of the other three proteins in cancer progression and aggressiveness has recently been proposed and remains to be elucidated. Here we present different examples about how LAMP proteins can influence and support tumor growth and metastatic spread, emphasizing the impact of each single member of the family.


Auricular point acupressure for chronic low back pain: a feasibility study for 1-week treatment.
Objectives. The objective of this one-group, repeated-measures design was to explore the acceptance of auricular point acupressure (APA) to reduce chronic low back pain (CLBP) and estimate minimum clinically important differences (MCIDs) for pain intensity change. Methods. Subjects received 7-day APA treatment. After appropriate acupoints were identified, vaccaria seeds were carefully taped onto each selected auricular point for 7-day. The Brief Pain Inventory Short Form (BPI) was used to collect outcome data. Results. A total of 74 subjects participated in the study. Ten subjects dropped out and the retention rate was 87%. Subjects reported a 46% reduction in BPI worst pain, and over 50% reduction in BPI average pain, overall pain severity and pain interference by the end of study, and 62.5% subjects also reported less pain medication use. The MCIDs for the subscale of BPI ranged from .70 to 1.86 points. The percentage improvement of MCIDs from baseline was between 14.5-24.9%. Discussion. APA appears to be highly acceptable to patients with CLBP. A sham group is needed in order to differentiate the true effects of APA from the possible psychological effects of more frequent visits by the auricular therapist and patients' expectation of the APA treatment.


miR-196a ameliorates phenotypes of Huntington disease in cell, transgenic mouse, and induced pluripotent stem cell models.
Huntington disease (HD) is a dominantly inherited neurodegenerative disorder characterized by dysregulation of various genes. Recently, microRNAs (miRNAs) have been reported to be involved in this dysregulation, suggesting that manipulation of appropriate miRNA regulation may have a therapeutic benefit. Here, we report the beneficial effects of miR-196a (miR196a) on HD in cell, transgenic mouse models, and human induced pluripotent stem cells derived from one individual with HD (HD-iPSCs). In the in vitro results, a reduction of mutant HTT and pathological aggregates, accompanying the overexpression of miR-196a, was observed in HD models of human embryonic kidney cells and mouse neuroblastoma cells. In the in vivo model, HD transgenic mice overexpressing miR-196a revealed the suppression of mutant HTT in the brain and also showed improvements in neuropathological progression, such as decreases of nuclear, intranuclear, and neuropil aggregates and late-stage behavioral phenotypes. Most importantly, miR-196a also decreased HTT expression and pathological aggregates when HD-iPSCs were differentiated into the neuronal stage. Mechanisms of miR-196a in HD might be through the alteration of ubiquitin-proteasome systems, gliosis, cAMP response element-binding protein pathway, and several neuronal regulatory pathways in vivo. Taken together, these results show that manipulating miR-196a provides beneficial effects in HD, suggesting the potential therapeutical role of miR-196a in HD.


[Helicobacter pylori].
Ever since 1983 when Marshall & Warren succeeded in cultivating Helicobacter pylori (HP) (previously known as Campylobacter pylori) a high incidence thereof has been demonstrated in patients with ulcers and non-ulcerous dyspepsia. Helicobacter pylori is easily diagnosed via microscopy, cultivation and serological tests. The bacterium may be treated with antibiotics or the ulcer drug bismuth subcitrate (De-Nol). The pathogenetic role of HP is not clear. Some studies have shown a lower recurrence rate of duodenal ulcers after treatment addressed to Helicobacter pylori with the ulcer drug De-Nol, which suggests that HP plays a role in the onset of recurrence in cases of ulcus duodeni.


Why do kids eat healthful food? Perceived benefits of and barriers to healthful eating and physical activity among children and adolescents.
The goal was to have children and adolescents identify and rank the major perceived benefits of and barriers to healthful eating and physical activity and to suggest strategies for overcoming barriers. Semistructured, in-depth focus groups were undertaken using standardized questions and prompts. Students in grades 2 through 11(ages 7 through 17; N=213) from 34 randomly selected schools participated in 38 focus groups. Major benefits of healthful eating included improvements to cognitive and physical performance, fitness, endurance, psychological benefits, physical sensation (feeling good physically), and production of energy. Barriers included convenience, taste, and social factors. Benefits of physical activity included social benefits, enhancement of psychological status, physical sensation, and sports performance. Barriers included a preference for indoor activities, lack of energy and motivation, time constraints, and social factors. Suggested strategies for overcoming barriers included support from parents and school staff, better planning, time management, self-motivation, education, restructuring the physical environment, and greater variety of physical activities.


On the origin of biological construction, with a focus on multicellularity.
Biology is marked by a hierarchical organization: all life consists of cells; in some cases, these cells assemble into groups, such as endosymbionts or multicellular organisms; in turn, multicellular organisms sometimes assemble into yet other groups, such as primate societies or ant colonies. The construction of new organizational layers results from hierarchical evolutionary transitions, in which biological units (e.g., cells) form groups that evolve into new units of biological organization (e.g., multicellular organisms). Despite considerable advances, there is no bottom-up, dynamical account of how, starting from the solitary ancestor, the first groups originate and subsequently evolve the organizing principles that qualify them as new units. Guided by six central questions, we propose an integrative bottom-up approach for studying the dynamics underlying hierarchical evolutionary transitions, which builds on and synthesizes existing knowledge. This approach highlights the crucial role of the ecology and development of the solitary ancestor in the emergence and subsequent evolution of groups, and it stresses the paramount importance of the life cycle: only by evaluating groups in the context of their life cycle can we unravel the evolutionary trajectory of hierarchical transitions. These insights also provide a starting point for understanding the types of subsequent organizational complexity. The central research questions outlined here naturally link existing research programs on biological construction (e.g., on cooperation, multilevel selection, self-organization, and development) and thereby help integrate knowledge stemming from diverse fields of biology.


dCTP pyrophosphohydrase exhibits nucleic accumulation in multiple carcinomas.
Nucleoside triphosphate pyrophosphohydrolase (NTP-PPase) functions as one of the mechanisms to guarantee the fidelity of DNA replication through the cleavage of non-canonical nucleotides into di- or monophosphates. Human NTP-PPase is poorly understood and investigated. In the present study, by using tissue microassays with the paired cancer and adjacent regions, we found that with the prevalent expression of dCTP pyrophosphohydrase (DCTPP1) in the cytosol and nucleus in tumors investigated, DCTPP1 was inclined to accumulate in the nucleus of cancer cells compared to the paired adjacent tissue cells in multiple carcinoma including lung, breast, liver, cervical, gastric and esophagus cancer. More significantly, the higher DCTPP1 expression in the nucleus of lung, gastric and esophagus cancer cells was associated with histological subtypes. The nucleic accumulation of DCTPP1 was apparently observed as well when cancer cell line MCF-7 was treated with H2O2 in vitro. Considering the roles of DCTPP1 on restricting the concentration of non-canonical nucleotides in the nucleotide pool, accumulation of DCTPP1 in the nucleus of cancer cells might suffice for maintaining the proper DNA replication in order to fulfill the requirement for the survival and proliferation of tumor cells.


A survey of successful FFARACS candidates in Australasia.
As of October 1985, 37 candidates have passed the final examination in intensive care for the Diploma of Fellow of the Faculty of Anaesthetists, Royal Australasian College of Surgeons (FFARACS). In September 1984, 23 of these successful candidates responded to a questionnaire seeking information on their educational experiences during training and the nature of their work since the examination. At that time, six were staff specialists in anesthetic practice, one was involved in full-time intensive care research, one was the director of an accident and emergency center, and the remaining 15 were full-time staff specialists or senior registrars in intensive care. The responses to the questions on training indicated that more intensive care and medical experience were considered desirable. Most felt that their training and the examination were useful in determining long-term employment, satisfactory performance in intensive care, and personal job satisfaction.


Self-Propelled Detachment upon Coalescence of Surface Bubbles.
The removal of microbubbles from substrates is crucial for the efficiency of many catalytic and electrochemical gas evolution reactions in liquids. The current work investigates the coalescence and detachment of bubbles generated from catalytic decomposition of hydrogen peroxide. Self-propelled detachment, induced by the coalescence of two bubbles, is observed at sizes much smaller than those determined by buoyancy. Upon coalescence, the released surface energy is partly dissipated by the bubble oscillations, working against viscous drag. The remaining energy is converted to the kinetic energy of the out-of-plane jumping motion of the merged bubble. The critical ratio of the parent bubble sizes for the jumping to occur is theoretically derived from an energy balance argument and found to be in agreement with the experimental results. The present results provide both physical insight for the bubble interactions and practical strategies for applications in chemical engineering and renewable energy technologies like electrolysis.


Intravascular Large B Cell Lymphoma Presenting as Fever of Unknown Origin and Diagnosed by Random Skin Biopsies: A Case Report and Literature Review.
BACKGROUND Intravascular lymphoma (IVL) is a rare lymphoproliferative disorder characterized by the proliferation of large B lymphoma cells within the lumen of small-caliber blood vessels. Clinical features are nonspecific, presenting as a systemic disease with fever and may be life-threatening. Antemortem diagnosis is difficult but may be made with biopsies of affected tissues or with random skin biopsies. CASE REPORT We report the case of a 66-year-old white woman presenting with fever of unknown origin (FUO) who developed neurologic, pulmonary, and hematologic manifestations. The diagnosis of intravascular large B cell lymphoma (IVLBCL) was made by random skin biopsies. She received treatment with steroids, rituximab, cyclophosphamide, vincristine, and doxorubicin (R-CHOP). Her disease evolution was unfavorable and she died after her first cycle of chemotherapy. CONCLUSIONS Our case illustrates that IVL can present as FUO and should be considered in the differential diagnosis of this syndrome, especially in patients with neurologic compromise and persistently elevated serum lactate dehydrogenase. In this case, the diagnosis was made with cutaneous biopsies of visibly unaffected skin. As in our patient, the course of IVL is usually fatal within a few months.


General Approach to Peripheral Nerve Disorders.
This article provides a conceptual framework for the evaluation of patients with suspected polyneuropathy to enhance the clinician's ability to localize and confirm peripheral nervous system pathology and, when possible, identify an etiologic diagnosis through use of rational clinical and judicious testing strategies. Although these strategies are largely time-honored, recent insights pertaining to the pathophysiology of certain immune-mediated neuropathies and to evolving genetic testing strategies may modify the way that select causes of neuropathy are conceptualized, evaluated, and managed. The strategies suggested in this article are intended to facilitate accurate bedside diagnosis in patients with suspected polyneuropathy and allow efficient and judicious use of supplementary testing and application of rational treatment when indicated.


dbPTM in 2022: an updated database for exploring regulatory networks and functional associations of protein post-translational modifications.
Protein post-translational modifications (PTMs) play an important role in different cellular processes. In view of the importance of PTMs in cellular functions and the massive data accumulated by the rapid development of mass spectrometry (MS)-based proteomics, this paper presents an update of dbPTM with over 2 777 000 PTM substrate sites obtained from existing databases and manual curation of literature, of which more than 2 235 000 entries are experimentally verified. This update has manually curated over 42 new modification types that were not included in the previous version. Due to the increasing number of studies on the mechanism of PTMs in the past few years, a great deal of upstream regulatory proteins of PTM substrate sites have been revealed. The updated dbPTM thus collates regulatory information from databases and literature, and merges them into a protein-protein interaction network. To enhance the understanding of the association between PTMs and molecular functions/cellular processes, the functional annotations of PTMs are curated and integrated into the database. In addition, the existing PTM-related resources, including annotation databases and prediction tools are also renewed. Overall, in this update, we would like to provide users with the most abundant data and comprehensive annotations on PTMs of proteins. The updated dbPTM is now freely accessible at https://awi.cuhk.edu.cn/dbPTM/.


Sameness and difference: metaphor and politics in the constitution of addiction, social exclusion and gender in Australian and Swedish drug policy.
Like any other discourse, drug policy is imagined and articulated through metaphors. In this article, we explore the metaphors and meanings at work in the current national drug policies of Australia and Sweden. Australia's approach to welfare is usually characterised as liberal-welfarist, emphasising individual difference and 'freedom'. Sweden's approach is usually characterised as social-democratic, universalistic and paternalistic, with an emphasis on social rights, equity and sameness. How do these models of citizenship--difference versus sameness--play out in national drug policies? What are the risks and benefits of these models and the claims they allow? In the textual analysis presented here, we focus on metaphors and meanings relating to the themes of addiction, social exclusion and gender. We choose metaphor as our major analytical tool because we think that the risks and benefits of adopting different models of citizenship in drug policy need to be understood to operate at many levels and with a high degree of subtlety and abstraction. In the cases of addiction and social exclusion, a complicated picture emerges. In Australia, drug users are offered two options: sameness (and reintegration into society) or difference (and re-connection). In Sweden, drug users are excluded from society but not because they are fundamentally different from non-users. Because drug users are understood to be suffering from a temporary and curable personal affliction, the goal is to return them to sameness through care and treatment. With respect to gender, although differently expressed in the two national contexts and differently shaped by national imaginaries, both national policies adopt similar approaches: the unequal treatment of women transcends differences in national setting. Accounts of drug policy usually focus on the degree to which drug policy is, or should be, 'evidence-based', or on the complex political negotiations involving diverse stakeholders and interests. We suggest here another, complementary, perspective: that national imaginaries (i.e. culturally specific metaphors, symbols and beliefs, and national ideologies) shape drug policy in subtle but crucial ways.


Identifying the critical oncogenic mechanism of LDHA based on a prognostic model of T-cell synthetic drivers.
Despite its early success, immunotherapy focused on removing T-cell inhibition does not achieve the desired effect in most patients. New strategies that target antigen-driven T-cell activation are needed to improve immunotherapy outcomes. However, a comprehensive analysis of synthetic drivers of T-cells is greatly lacking in lung adenocarcinoma (LUAD) and other types of tumors. We comprehensively evaluated the patterns of LUAD patients based on T -cell synthetic drivers by unsupervised clustering analysis. A risk model was constructed using Lasso Cox regression analysis. The predicted survival and immunotherapy efficacy of the model was validated by independent cohorts. Finally, single-cell sequencing analysis, and a series of in vitro experiments were conducted to explore the role of lactate dehydrogenase A (LDHA) in the malignant progression of LUAD. Patients in the high-risk group were characterized by survival disadvantage, a "cold" immune phenotype, and by not having benefitted from immunotherapy. LDHA was shown to promote LUAD cell proliferation, cell cycle, invasion, and migration. Secondly, we found that LDHA induced NF-κB pathway activation, tyrosine kinase inhibitor resistance and immunosuppressant microenvironment. Finally, LDHA was found to be highly expressed in fibroblasts, which may be involved in promoting TKI resistance and mediating the immune escape. This study revealed that the T-cell synthetic driver-associated prognostic model developed herein significantly predicted prognosis and immunotherapy efficacy in LUAD. We further investigated the role of LDHA in the malignant phenotype of tumor cells and tumor microenvironment remodeling, providing a promising and novel therapeutic strategy for LUAD.


Emerging Microfluidic Tools for Simultaneous Exosomes and Cargo Biosensing in Liquid Biopsy: New Integrated Miniaturized FFF-Assisted Approach for Colon Cancer Diagnosis.
The early-stage diagnosis of cancer is a crucial clinical need. The inadequacies of surgery tissue biopsy have prompted a transition to a less invasive profiling of molecular biomarkers from biofluids, known as liquid biopsy. Exosomes are phospholipid bilayer vesicles present in many biofluids with a biologically active cargo, being responsible for cell-to-cell communication in biological systems. An increase in their excretion and changes in their cargo are potential diagnostic biomarkers for an array of diseases, including cancer, and they constitute a promising analyte for liquid biopsy. The number of exosomes released, the morphological properties, the membrane composition, and their content are highly related to the physiological and pathological states. The main analytical challenge to establishing liquid biopsy in clinical practice is the development of biosensors able to detect intact exosomes concentration and simultaneously analyze specific membrane biomarkers and those contained in their cargo. Before analysis, exosomes also need to be isolated from biological fluids. Microfluidic systems can address several issues present in conventional methods (i.e., ultracentrifugation, size-exclusion chromatography, ultrafiltration, and immunoaffinity capture), which are time-consuming and require a relatively high amount of sample; in addition, they can be easily integrated with biosensing systems. A critical review of emerging microfluidic-based devices for integrated biosensing approaches and following the major analytical need for accurate diagnostics is presented here. The design of a new miniaturized biosensing system is also reported. A device based on hollow-fiber flow field-flow fractionation followed by luminescence-based immunoassay is applied to isolate intact exosomes and characterize their cargo as a proof of concept for colon cancer diagnosis.


Enhanced detection of explosives by turn-on resonance Raman upon host-guest complexation in solution and the solid state.
The recognition of nitroaromatic explosives by a tetrakis-tetrathiafulvalene-calix[4]pyrrole receptor (TTF-C[4]P) yields a "turn on" and fingerprinting response in the resonance Raman scattering observed in solution and the solid state. Intensity changes in nitro vibrations with analyte complexation occur via a mechanism of resonance between the 785 nm laser line and the strongly absorbing charge-transfer chromophore arising from the complex between electron-donating TTF-C[4]P and electron-accepting nitroaromatic explosives. The addition of chloride forms the Cl-·TTF-C[4]P complex resetting the system for reuse.


Polarizing genetic information in the egg: RNA localization in the frog oocyte.
RNA localization is a powerful strategy used by cells to localize proteins to subcellular domains and to control protein synthesis regionally. In germ cells, RNA targeting has profound implications for development, setting up polarities in genetic information that drive cell fate during embryogenesis. The frog oocyte offers a useful system for studying the mechanism of RNA localization. Here, we discuss critically the process of RNA localization during frog oogenesis. Three major pathways have been identified that are temporally and spatially separated in oogenesis. Each pathway uses a different mechanism to effect RNA localization. In some cases, localization elements within the 3' untranslated region have been identified and have provided unique insights into the localization process. This important field is still in its infancy, however, and much remains to be learned.


Effect of milk-based carbohydrate-protein supplement timing on the attenuation of exercise-induced muscle damage.
Exercise-induced muscle damage (EIMD) leads to decrements in muscle performance and increases in intramuscular enzymes measured in the plasma, and to delayed onset of muscle soreness (DOMS), partly due to the activation of degradative pathways. It has been shown that milk-based carbohydrate-protein (CHO-P) can limit changes in markers of EIMD, possibly by attenuating protein degradation and (or) increasing protein synthesis. However, the timing of supplementation has received limited attention, and this may alter the response. This study examined the effects of acute milk-based CHO-P supplementation timing on the attenuation of EIMD. Four independent matched groups of 8 healthy males consumed milk-based CHO-P before (PRE), immediately after (POST), or 24 h after (TWENTY-FOUR) muscle-damaging exercise. Active DOMS, isokinetic muscle performance, reactive strength index (RSI), and creatine kinase (CK) were assessed immediately before and 24, 48, and 72 h after EIMD. POST and TWENTY-FOUR demonstrated a benefit in limiting changes in active DOMS, peak torque, and RSI over 48 h, compared with PRE. PRE showed a possible benefit in reducing increases in CK over 48 h and limiting changes in other variables over 72 h. Consuming milk-based CHO-P after muscle-damaging exercise is more beneficial in attenuating decreases in muscle performance and increases in active DOMS at 48 h than ingestion prior to exercise.


Discovery of synergistic material-topography combinations to achieve immunomodulatory osteoinductive biomaterials using a novel in vitro screening method: The ChemoTopoChip.
Human mesenchymal stem cells (hMSCs) are widely represented in regenerative medicine clinical strategies due to their compatibility with autologous implantation. Effective bone regeneration involves crosstalk between macrophages and hMSCs, with macrophages playing a key role in the recruitment and differentiation of hMSCs. However, engineered biomaterials able to simultaneously direct hMSC fate and modulate macrophage phenotype have not yet been identified. A novel combinatorial chemistry-topography screening platform, the ChemoTopoChip, is used here to identify materials suitable for bone regeneration by screening 1008 combinations in each experiment for human immortalized mesenchymal stem cell (hiMSCs) and human macrophage response. The osteoinduction achieved in hiMSCs cultured on the "hit" materials in basal media is comparable to that seen when cells are cultured in osteogenic media, illustrating that these materials offer a materials-induced alternative to osteo-inductive supplements in bone-regeneration. Some of these same chemistry-microtopography combinations also exhibit immunomodulatory stimuli, polarizing macrophages towards a pro-healing phenotype. Maximum control of cell response is achieved when both chemistry and topography are recruited to instruct the required cell phenotype, combining synergistically. The large combinatorial library allows us for the first time to probe the relative cell-instructive roles of microtopography and material chemistry which we find to provide similar ranges of cell modulation for both cues. Machine learning is used to generate structure-activity relationships that identify key chemical and topographical features enhancing the response of both cell types, providing a basis for a better understanding of cell response to micro topographically patterned polymers.


[A statistical wavelength selection method of infrared spectra used in exhaust gas detection].
In order to extract the quantitative features of the rare pollution components from noisy atmospheric infrared spectra and thus create calibration models, a wavelength selection method based on statistic theory is proposed in this paper. In this method, an objective function is defined based on the estimation of spectral noise level at every wavelength position. Because the size of the wavelength subset is also included in the function, the model size will not become too big during the minimization of the error of the calibration model. To test the performance of this method, the wavelength subsets of measured spectra with background noises were selected and the calibration models were then created using neural network technique for three pollution gases, respectively. The test showed that the sizes of the selected wavelength subsets accorded with the calculated results. The subset sizes were less than 2% of the total wavelength points. Meantime, the spectral noises were also restrained markedly in the calibration model because of the wavelength selection. The experimental results proved the validity of the wavelength selection method.


Formation and purification of tailored liposomes for drug delivery using a module-based micro continuous-flow system.
Liposomes are lipid based bilayer vesicles that can encapsulate, deliver and release low-soluble drugs and small molecules to a specific target site in the body. They are currently exploited in several nanomedicine formulations. However, their development and application is still limited by expensive and time-consuming process development and production methods. Therefore, to exploit these systems more effectively and support the rapid translation of new liposomal nanomedicines from bench to bedside, new cost-effective and scalable production methods are needed. We present a continuous process flow system for the preparation, modification and purification of liposomes which offers lab-on-chip scale production. The system was evaluated for a range of small vesicles (below 300 nm) varying in lipid composition, size and charge; it offers effective and rapid nanomedicine purification with high lipid recovery (> 98%) combined with effective removal of non-entrapped drug (propofol >95% reduction of non-entrapped drug present) or protein (ovalbumin >90% reduction of OVA present) and organic solvent (ethanol >95% reduction) in less than 4 minutes. The key advantages of using this bench-top, rapid, process development tool are the flexible operating conditions, interchangeable membranes and scalable high-throughput yields, thereby offering simultaneous manufacturing and purification of nanoparticles with tailored surface attributes.


Analysis and classification of RNA tertiary structures.
There is a fast growing interest in noncoding RNA transcripts. These transcripts are not translated into proteins, but play essential roles in many cellular and pathological processes. Recent efforts toward comprehension of their function has led to a substantial increase in both the number and the size of solved RNA structures. With the aim of addressing questions relating to RNA structural diversity, we examined RNA conservation at three structural levels: primary, secondary, and tertiary structure. Additionally, we developed an automated method for classifying RNA structures based on spatial (three-dimensional [3D]) similarity. Applying the method to all solved RNA structures resulted in a classified database of RNA tertiary structures (DARTS). DARTS embodies 1333 solved RNA structures classified into 94 clusters. The classification is hierarchical, reflecting the structural relationship between and within clusters. We also developed an application for searching DARTS with a new structure. The search is fast and its performance was successfully tested on all solved RNA structures since the creation of DARTS. A user-friendly interface for both the database and the search application is available online. We show intracluster and intercluster similarities in DARTS and demonstrate the usefulness of the search application. The analysis reveals the current structural repertoire of RNA and exposes common global folds and local tertiary motifs. Further study of these conserved substructures may suggest possible RNA domains and building blocks. This should be beneficial for structure prediction and for gaining insights into structure-function relationships.


Use of situational judgment tests for assessing non-cognitive attributes of final year dental students.
Situational judgment tests (SJT) have been previously used in the admission process of medical and dental undergraduate programs, but their utilization as an assessment tool is fairly new. The objective of this study was to explore essential non-cognitive attributes of dental graduates. We also aimed to assess the attributes of final year dental students utilizing SJT and later collected participants' reactions on the test. A mixed-method exploratory sequential study was conducted. One-on-one and group discussions were done with subject matter experts (SMEs) to explore the essential attributes of fresh dental graduates. Based on the thematic analysis, 10 SJT items per domain were constructed by one group of SMEs and expert validated by a different group of SMEs and vice versa. The final dental-SJT was piloted online on final year dental students and their perceptions were collected using a five-point Likert scale questionnaire. Descriptive statistics and Cronbach's alpha were calculated for the test. The consultation with SMEs generated three main themes, namely, Conventional skills, Tribal skills, and Occupational skills. The 70-item dental-SJT piloted on 150 final year dental students revealed data were normally distributed. The internal reliability of test was good (0.738). Students scored highest in "management skills" (>70%) and lowest in "professional ethics" (56%) and "diverse experiences" (58%). The overall student perception about the test was good. SJT is an effective tool to assess non-cognitive attributes of dental students. It has an overall positive perception about perceived predictive validity, perceived fairness, face and content validity.


Chemical bonding of fullerene and fluorinated fullerene on bare and hydrogenated diamond.
We investigate the interface between a C(60) fullerite film, C(60)F(36), and diamond (100) by using core-level photoemission spectroscopy, cyclic voltammetry (CV), and high-resolution electron energy loss spectroscopy (HREELS). We show that C(60) can be covalently bonded to reconstructed C(100)-2x1 and that the bonded interface is sufficiently robust to exhibit characteristic C(60) redox peaks in solution. The bare diamond surface can be passivated against oxidation and hydrogenation by covalently bound C(60). However, C(60)F(36) is not as stable as C(60) and desorbs below 300 degrees C (the latter species being stable up to 500 degrees C on the diamond surface). Neither C(60) fullerite nor C(60)F(36) form reactive interfaces on the hydrogenated surface-they both desorb below 300 degrees C. The surface transfer doping process of hydrogenated diamond by C(60)F(36) is the most evident one among all the adsorbate systems studied (with a coverage-dependent band bending induced by C(60)F(36)).


Robot-assisted laparoscopic nephrectomy and contralateral ureteral reimplantation in children.
Robot-assisted laparoscopic surgery (RALS) has expanded the role for minimally invasive surgery within pediatrics. RALS may be particularly beneficial for the treatment of children with a refluxing nonfunctioning renal moiety and contralateral vesicoureteral reflux. In this report, we describe a single RALS procedure, which includes both nephrectomy or partial nephrectomy, and contralateral extravesical ureteral reimplantation (EVUR). A retrospective review was performed of four patients who underwent RALS nephrectomy/partial nephrectomy and concurrent EVUR in one setting. Procedures were performed by a single surgeon using a robot-assisted laparoscopic approach. Four ports were used in a transperitoneal approach with patient positioning changed without moving the robotic system between the nephrectomy and reimplant. We described the technique and assessed its safety and efficacy. All cases were treated with the single RALS approach. Mean patient age was 2.3 years. Three patients underwent a nephrectomy and one a lower pole partial nephrectomy. The mean estimated blood loss was 16 mL, mean operative time was 291 minutes, and mean length of stay was 2.3 days. There was one case of postoperative ureteral obstruction that was treated with 3 weeks of ureteral stenting without further sequela. Overall, the mean follow-up time was 21 months and follow-up renal ultrasonographs and radionuclide cystograms were normal in all patients. A single RALS procedure that combines nephrectomy/partial nephrectomy and EVUR offers a novel approach to a clinical dilemma that often requires two operations. In this small series, RALS was safe and efficacious. We recommend routine Double-J stenting for the solitary reimplanted ureter.


Storage density limitation of a volume-type hologram memory: theory.
The maximum storage density of a volume-type hologram memory obtainable with a prescribed signal-to-noise ratio is discussed. In the theoretical analysis, a microscopic particle model of a phase hologram is considered; the refractive index variation is assumed to be caused by the density variation of bleached silver particles distributed spatially at random. The signal and noise intensities are derived from the analysis based upon this model. The theoretical limit of the storage density and the optimum hologram thickness are then derived in terms of the signal-to-noise ratio. The maximum storage density is finally given as a function of the average scattering cross section of the particles, the light wavelength, and the prescribed signal-to-noise ratio. Some practical cases are also discussed on the basis of measured material parameters.


Israeli Defense Forces Medical Corps humanitarian mission for Kosovo's refugees.
In April 1999, during the crisis in Kosovo, the Israeli government launched a medical, field hospital in order to provide humanitarian aid to the Albanian refugees that fled from their homes in Kosovo. This facility was set up by the Medical Corps of the Israeli Defense Forces, in a refugee camp located in Northern Macedonia. During the 16 days during which the hospital functioned, the medical staff treated 1,560 patients and hospitalized >100. The field hospital served as a referral center for all of the other primary clinics that were hastily erected in the camp and its surroundings. This communication elaborates on the various aspects of the humanitarian medical aid that were provided by this medical facility and the conclusions that learned from such a mission.


Overexpression of protein kinase C alpha-subtype in Swiss/3T3 fibroblasts causes loss of both high and low affinity receptor numbers for epidermal growth factor.
The full length cDNA coding for the alpha form of protein kinase C (PKC) was introduced into Swiss/3T3 cells using a retroviral expression system. This has enabled the generation of a series of cell lines stably expressing high levels of PKC alpha enzyme, as well as the appropriate control cell lines, carrying an integrated vector but lacking PKC alpha cDNA insert. PKC alpha-overexpressing cell lines did not display a transformed morphology nor were they capable of growth in soft agar. However, these cells exhibited enhanced growth rates especially under low serum conditions. Using Scatchard plot analysis of 125I-epidermal growth factor (EGF) binding to its receptor on the surface of PKC alpha-overproducing cells revealed reduction in EGF receptor numbers when compared to control cells, without change in affinities of remaining receptors. These data indicated that reduced receptor numbers for EGF were among the phenotypic changes occurring in these cells underlying their diminished dependence on external factors for growth. Furthermore, we provide evidence that reduced EGF receptor numbers found on the cell surface of PKC alpha-overproducing cells resulted from the decreased biosynthesis of EGF receptor molecules, which correlated also with lower levels of mRNA transcripts coding for the EGF receptor found in these cells. Hence, our studies imply that PKC alpha is involved in a cellular mechanism regulating the expression of EGF receptor molecules in Swiss/3T3 cells. Thus, deregulation of PKC alpha, i.e. by increasing its expression levels in specific cells may affect, in turn the expression of cell surface receptors including the EGF receptor. Similar molecular mechanisms may be involved in initial stages of neoplasia and tumor promotion.


TGF-β signaling promotes tumor vasculature by enhancing the pericyte-endothelium association.
The breast cancer microenvironment promotes tumor vascularization through the complex interactions involving tumor-associated fibroblasts (TAFs). Emerging data indicate that TAFs increase production and signaling by TGF-β cytokines, while the role of TGF-β signaling in the regulation of tumor blood vessels is not fully understood. The current study presents evidence that TAFs enhance the organization of tumor blood capillaries, and TGF-β signaling plays an important role in this response. Tumor vascularization was studied in xenograft models of breast carcinoma cells, alone and in combination with fibroblasts. TGF-β signaling in breast cancer cells was modulated by expression of kinase-inactive TGFBR1-K232R (dnTGFBR1) or constitutive-active TGFBR1-T204D (caTGFBR1) receptor mutants. The architecture of tumor blood capillaries was assessed by immune-histochemical analysis of endothelium and pericytes. The role of TGF-β-Smad signaling in fibronectin expression was examined using adenoviral transduction of signaling components. Our studies revealed that TAFs significantly increase the lumen size of blood microvessels. Inactivation of TGF-β signaling in tumor cells by dnTGFBR1 reduced the microvessel density and lumen sizes, decreasing tumor growth. In contrast, caTGFBR1-tumors exhibited greater vessel density and lumen sizes. Tumors with inactive dnTGFBR1 showed lower amounts of TAFs, while caTGFBR1 increased amounts of TAFs compared to the control. Inspection of pericytes and endothelial cells in tumor vasculature revealed that TAFs enhanced vessel coverage by pericytes, vascular cells supporting capillaries. This effect was impaired in dnTGFBR1-tumors, whereas active caTGFBR1 enhanced the association of pericytes with endothelium. Accordingly, dnTGFBR1-tumors exhibited the presence of hemorrhages, a sign of fragile blood vessels. Biochemical analysis showed that TGFBR1-SMAD signaling up-regulates fibronectin, a prominent regulator of endothelium-pericyte interactions. The current study indicates that tumor-fibroblast crosstalk enhances tumor vascularization by increasing the pericyte-endothelium association via a mechanism involving the TGFβ-fibronectin axis. The tumor-fibroblast model represents a useful system for dissecting the complex interactions governing tumor angiogenesis and developing new approaches to therapeutic targeting tumor vasculature.


Overview of the SAMPL6 pKa challenge: evaluating small molecule microscopic and macroscopic pKa predictions.
The prediction of acid dissociation constants (pKa) is a prerequisite for predicting many other properties of a small molecule, such as its protein-ligand binding affinity, distribution coefficient (log D), membrane permeability, and solubility. The prediction of each of these properties requires knowledge of the relevant protonation states and solution free energy penalties of each state. The SAMPL6 pKa Challenge was the first time that a separate challenge was conducted for evaluating pKa predictions as part of the Statistical Assessment of Modeling of Proteins and Ligands (SAMPL) exercises. This challenge was motivated by significant inaccuracies observed in prior physical property prediction challenges, such as the SAMPL5 log D Challenge, caused by protonation state and pKa prediction issues. The goal of the pKa challenge was to assess the performance of contemporary pKa prediction methods for drug-like molecules. The challenge set was composed of 24 small molecules that resembled fragments of kinase inhibitors, a number of which were multiprotic. Eleven research groups contributed blind predictions for a total of 37 pKa distinct prediction methods. In addition to blinded submissions, four widely used pKa prediction methods were included in the analysis as reference methods. Collecting both microscopic and macroscopic pKa predictions allowed in-depth evaluation of pKa prediction performance. This article highlights deficiencies of typical pKa prediction evaluation approaches when the distinction between microscopic and macroscopic pKas is ignored; in particular, we suggest more stringent evaluation criteria for microscopic and macroscopic pKa predictions guided by the available experimental data. Top-performing submissions for macroscopic pKa predictions achieved RMSE of 0.7-1.0 pKa units and included both quantum chemical and empirical approaches, where the total number of extra or missing macroscopic pKas predicted by these submissions were fewer than 8 for 24 molecules. A large number of submissions had RMSE spanning 1-3 pKa units. Molecules with sulfur-containing heterocycles or iodo and bromo groups were less accurately predicted on average considering all methods evaluated. For a subset of molecules, we utilized experimentally-determined microstates based on NMR to evaluate the dominant tautomer predictions for each macroscopic state. Prediction of dominant tautomers was a major source of error for microscopic pKa predictions, especially errors in charged tautomers. The degree of inaccuracy in pKa predictions observed in this challenge is detrimental to the protein-ligand binding affinity predictions due to errors in dominant protonation state predictions and the calculation of free energy corrections for multiple protonation states. Underestimation of ligand pKa by 1 unit can lead to errors in binding free energy errors up to 1.2 kcal/mol. The SAMPL6 pKa Challenge demonstrated the need for improving pKa prediction methods for drug-like molecules, especially for challenging moieties and multiprotic molecules.


Characteristics of lipase-catalyzed hydrolysis of olive oil in AOT-isooctane reversed micelles.
Candida rugosa lipase solubilized in organic solvents in the presence of both surfactant and water could catalyze the hydrolysis of triglycerides, and kinetic analysis of the lipase-catalyzed reaction was found to be possible in this system. Among eight organic solvents tested, isooctane was most effective for the hydrolysis of olive oil in reversed micelles. Temperature effect, pH profile, K(m,app) and V(max,app) were determined. Among various chemical compounds, Cu(2+), Hg(2+), and Fe(3+) inhibited lipase severely. But the enzyme activity was restorable partially by adding histidine or glycine to the system containing these metal ions. The enzyme activity was dependent on R (molar ratio of water to surfactant) and maximum activity was obtained at R = 10.5. Upon addition of glycerol to the reversed micelles, lipase activity was affected in a different fashion depending on the R values. Stability of the lipase in reversed micelles was also dependent on R, and it was most stable at R = 5.5.


Safety and immunogenicity of TETRActHIB (a vaccine combining DTP vaccine and Haemophilus influenzae type B conjugate vaccine) administered to infants at 6, 10 and 14 weeks of age.
The safety and immunogenicity of TETRActHIB (a vaccine combining diphtheria and tetanus toxoids-pertussis vaccine (DTP) with Haemophilus influenzae type b (Hib) conjugate vaccine (polyribosyl ribitol phosphate conjugated to tetanus protein) (PRP-T)) was assessed in 131 Cape Town infants immunized at 6, 10 and 14 weeks of age. Serological responses to all component antigens were measured before the first dose and at 18 weeks of age. In addition, anti-PRP antibodies were measured at 9 and 18 months of age to determine long-term immunogenicity. The vaccine was well tolerated by infants and no significant side-effects were reported. Responses to Hib at 18 weeks of age were good in that most infants achieved a level of anti-PRP antibodies > or = 0.15 microgram/ml, indicative of short-term protection, and 70% achieved a level > or = 1 microgram/ml, indicative of long-term protection. The proportions of children with protective levels > or = 0.15 microgram/ml and > or = 1 microgram/ml were similar at 9 and 18 months of age, i.e. approximately 75% and 45%, respectively. Responses to tetanus and diphtheria toxoids were excellent and all infants achieved protective serological levels. Responses to pertussis were moderate in that approximately 65% achieved 'protective' serum levels of pertussis agglutinins, i.e. titres > or = 320. In conclusion, this study has shown that the DTP/PRP-T vaccine is safe, immunogenic and well tolerated in infants immunised at 6, 10 and 14 weeks of age. TETRActHIB is therefore suitable for inclusion in the World Health Organisation Expanded Programme on Immunisation (WHO EPI) schedule.


Alzheimer's Toxic Amyloid Beta Oligomers: Unwelcome Visitors to the Na/K ATPase alpha3 Docking Station.
Toxic amyloid beta oligomers (AβOs) are known to accumulate in Alzheimer's disease (AD) and in animal models of AD. Their structure is heterogeneous, and they are found in both intracellular and extracellular milieu. When given to CNS cultures or injected ICV into non-human primates and other non-transgenic animals, AβOs have been found to cause impaired synaptic plasticity, loss of memory function, tau hyperphosphorylation and tangle formation, synapse elimination, oxidative and ER stress, inflammatory microglial activation, and selective nerve cell death. Memory loss and pathology in transgenic models are prevented by AβO antibodies, while Aducanumab, an antibody that targets AβOs as well as fibrillar Aβ, has provided cognitive benefit to humans in early clinical trials. AβOs have now been investigated in more than 3000 studies and are widely thought to be the major toxic form of Aβ. Although much has been learned about the downstream mechanisms of AβO action, a major gap concerns the earliest steps: How do AβOs initially interact with surface membranes to generate neuron-damaging transmembrane events? Findings from Ohnishi et al (PNAS 2005) combined with new results presented here are consistent with the hypothesis that AβOs act as neurotoxins because they attach to particular membrane protein docks containing Na/K ATPase-α3, where they inhibit ATPase activity and pathologically restructure dock composition and topology in a manner leading to excessive Ca++ build-up. Better understanding of the mechanism that makes attachment of AβOs to vulnerable neurons a neurotoxic phenomenon should open the door to therapeutics and diagnostics targeting the first step of a complex pathway that leads to neural damage and dementia.


Models of experimentally derived competitive effects predict biogeographical differences in the abundance of invasive and native plant species.
Mono-dominance by invasive species provides opportunities to explore determinants of plant distributions and abundance; however, linking mechanistic results from small scale experiments to patterns in nature is difficult. We used experimentally derived competitive effects of an invader in North America, Acroptilon repens, on species with which it co-occurs in its native range of Uzbekistan and on species with which it occurs in its non-native ranges in North America, in individual-based models. We found that competitive effects yielded relative abundances of Acroptilon and other species in models that were qualitatively similar to those observed in the field in the two ranges. In its non-native range, Acroptilon can occur in nearly pure monocultures at local scales, whereas such nearly pure stands of Acroptilon appear to be much less common in its native range. Experimentally derived competitive effects of Acroptilon on other species predicted Acroptilon to be 4-9 times more proportionally abundant than natives in the North American models, but proportionally equal to or less than the abundance of natives in the Eurasian models. Our results suggest a novel way to integrate complex combinations of interactions simultaneously, and that biogeographical differences in the competitive effects of an invader correspond well with biogeographical differences in abundance and impact.


JAK/STAT inhibition with ruxolitinib enhances oncolytic virotherapy in non-small cell lung cancer models.
The concept of using viruses to treat cancer has now shown proof of concept in several recent clinical trials, leading to the first FDA approval of virotherapy for melanoma last year. Vesicular stomatitis virus (VSV) is a promising oncolytic virus that has inhibitory effects on a number of cancer types including non-small cell lung cancer. One of the major mechanisms of resistance to VSV infection is the type I interferon (IFN) response, leading to the development of VSV expressing IFNβ which will lead to resistance of viral replication in normal cells which have intact IFN signaling but allow replication in cancer cells with defective IFNβ signaling. However, some cancer cells have intact or partially intact IFN signaling pathways leading to resistance to virotherapy. Here we utilized JAK/STAT inhibitor, ruxolitinib, in combination with VSV-IFNβ to see if inhibition of JAK/STAT signaling will enhance VSV-IFNβ therapy for lung cancer. We used five human and two murine NSCLC cell lines in vitro, and the combination treatment was assayed for cytotoxicity. We performed western blots on treated cells to see the effects of ruxolitinib on JAK/STAT signaling and PDL-1 expression in treated cells. Finally, the combination of VSV-IFNβ and ruxolitinib was tested in an immune competent murine model of NSCLC. Ruxolitinib enhanced virotherapy in resistant and sensitive NSCLC cells. The addition of ruxolitinib inhibited STAT1 phosphorylation and to a lesser extent STAT3 phosphorylation. Ruxolitinib treatment prevented NSCLC cells from enhancing PDL-1 expression in response to virotherapy. Combination ruxolitinib and VSV-IFNβ therapy resulted in a trend toward improved survival of mice without substantially effecting PDL-1 levels or levels of immune infiltration into the tumor. These results support further clinical evaluation of the combination of JAK/STAT inhibition with virotherapy.


Strategies for achieving whole-practice engagement and buy-in to the patient-centered medical home.
The current model of primary care in the United States limits physicians' ability to offer high-quality care. The patient-centered medical home (PCMH) shows promise in addressing provision of high-quality care, but achieving a PCMH practice model often requires comprehensive organizational change. Guided by Solberg's conceptual framework for practice improvement, which argues for shared prioritization of improvement and change, we describe strategies for obtaining organizational buy-in to and whole-staff engagement of PCMH transformation and practice improvement. Semistructured interviews with 136 individuals and 7 focus groups involving 48 individuals were conducted in 20 small- to mid-sized medical practices in Pennsylvania during the first regional rollout of a statewide PCMH initiative. For this study, we analyzed interview transcripts, monthly narrative reports, and observer notes from site visits to identify discourse pertaining to organizational buy-in and strategies for securing buy-in from personnel. Using a consensual qualitative research approach, data were reduced, synthesized, and managed using qualitative data management and analysis software. We identified 13 distinct strategies used to obtain practice buy-in, reflecting 3 overarching lessons that facilitate practice buy-in: (1) effective communication and internal PCMH campaigns, (2) effective resource utilization, and (3) creation of a team environment. Our study provides a list of strategies useful for facilitating PCMH transformation in primary care. These strategies can be investigated empirically in future research, used to guide medical practices undergoing or considering PCMH transformation, and used to inform health care policy makers. Our study findings also extend Solberg's conceptual framework for practice improvement to include buy-in as a necessary condition across all elements of the change process.


Total hip replacement with a cementless acetabular component and a cemented femoral component in patients younger than fifty years of age.
We have been using hybrid total hip arthroplasty (a cementless acetabular component and a cemented stem) in young patients. The purpose of this study was to determine the prevalence of aseptic loosening, polyethylene wear, and osteolysis after the use of this technique. We studied a prospective consecutive series of sixty-four primary hybrid total hip replacements in fifty-five patients younger than fifty years old. There were forty-three men and twelve women; the average age at the time of the index operation was 43.4 years. The average duration of follow-up was 9.4 years. We used a cementless acetabular component without screw-holes and a cemented femoral component with a 22-mm head in all hips. Clinical follow-up with use of Harris hip ratings and radiographic follow-up were performed at six weeks; at three, six, and twelve months; and yearly thereafter. The sequential annual linear and volumetric wear rates were measured, and bone-remodeling and osteolysis were assessed. The mean preoperative Harris hip score was 44 points, which increased to 95 points at the time of final follow-up. No hip had aseptic loosening. One hip (2%) was revised because of late infection. The average linear wear (and standard deviation) was 0.96 +/- 0.066 mm, with an average annual rate of 0.096 +/- 0.013 mm. The average volumetric wear was 364.7 +/- 25.2 mm (3), with an average annual rate of 43.4 +/- 3.5 mm (3). Six hips (9%) had an osteolytic lesion of <1 cm in diameter in the calcar femorale (zone 7). Our results show that a hybrid arthroplasty with a cementless acetabular component and a smooth cemented femoral component (Ra, 0.6 mm) is effective for primary total hip replacement in young patients. Although there was no aseptic loosening and a low prevalence of osteolysis at the latest follow-up evaluation, the high rates of linear and volumetric wear of the polyethylene liner in these young patients remain a concern.


Novel protein-disulfide isomerases from the early-diverging protist Giardia lamblia.
Protein-disulfide isomerase is essential for formation and reshuffling of disulfide bonds during nascent protein folding in the endoplasmic reticulum. The two thioredoxin-like active sites catalyze a variety of thiol-disulfide exchange reactions. We have characterized three novel protein-disulfide isomerases from the primitive eukaryote Giardia lamblia. Unlike other protein-disulfide isomerases, the giardial enzymes have only one active site. The active-site sequence motif in the giardial proteins (CGHC) is characteristic of eukaryotic protein-disulfide isomerases, and not other members of the thioredoxin superfamily that have one active site, such as thioredoxin and Dsb proteins from Gram-negative bacteria. The three giardial proteins have very different amino acid sequences and molecular masses (26, 50, and 13 kDa). All three enzymes were capable of rearranging disulfide bonds, and giardial protein-disulfide isomerase-2 also displayed oxidant and reductant activities. Surprisingly, the three giardial proteins also had Ca(2+)-dependent transglutaminase activity. This is the first report of protein-disulfide isomerases with a single active site that have diverse roles in protein cross-linking. This study may provide clues to the evolution of key functions of the endoplasmic reticulum in eukaryotic cells, protein disulfide formation, and isomerization.


One site is enough: a theoretical investigation of iron-catalyzed dehydrogenation of formic Acid.
Dehydrogenation of HCO2H: The reaction mechanism for the dehydrogenation of formic acid catalyzed by a highly active and selective iron complex has been studied by DFT. The most favorable pathway shows the hydride in Fe-H complexes acting as a spectator ligand throughout the catalytic cycle. This result opens up the Fe complex for modification in order to achieve more efficient and selective catalysts.


Gene modification therapies: views of parents of people with Down syndrome.
In considering gene modification technologies, the priorities of patient communities must be a central consideration. The purpose of this study is to assess views of families with Down syndrome (DS) regarding potential genome-based interventions. We constructed an anonymous online survey for family members of people with DS. Participants were asked to agree or disagree with scenarios describing hypothetical interventions to silence or significantly alter the physical and cognitive effects of a trisomy 21, and also with scenarios depicting currently available physical interventions. All 532 respondents were parents of people with DS. For each of the five scenarios, over half said they would approve the intervention or would advise their children with DS to do so. Responses to hypothetical prenatal and pediatric cognitive interventions were significantly affected by participants' assessments of the impact of DS on their children's and their families' lives, while physical and adult cognitive scenarios were not. Future interventions to address genetic conditions will impact patient communities and cannot succeed without their input and support. While many parents of people with DS indicated approval for hypothetical genetic therapies, these results indicate a need for continuing dialogue about benefits and drawbacks of gene modification technologies.


Critical DNA damage recognition functions of XPC-hHR23B and XPA-RPA in nucleotide excision repair.
It has been reported that 80-90% of human cancers may result, in part, from DNA damage. Cell survival depends critically on the stability of our DNA and exquisitely sensitive DNA repair mechanisms have developed as a result. In humans, nucleotide excision repair (NER) protects the DNA against the mutagenic effects of carcinogens and ultraviolet (UV) radiation from sun exposure. By preventing mutations from forming in the DNA, the repair machinery ultimately protects us from developing cancers. DNA damage recognition is the rate-limiting step in repair, and although many details of NER have been elucidated, the mechanisms by which DNA damage is recognized remain to be fully determined. Two primary protein complexes have been proposed as the damaged DNA recognition factor in NER: xeroderma pigmentosum protein A-replication protein A (XPA-RPA) and xeroderma pigmentosum protein C-human homolog of RAD23B (XPC-hHR23B). Here we compare the evidence that supports damage detection by these protein complexes and propose a model for DNA damage recognition in NER based on the current understanding of the roles these proteins may play in the processing of DNA lesions.


Role of Region-Specific Brain Decellularized Extracellular Matrix on In Vitro Neuronal Maturation.
Recent advancements in tissue engineering suggest that biomaterials, such as decellularized extracellular matrix (ECM), could serve to potentiate the localization and efficacy of regenerative therapies in the central nervous system. Still, what factors and which mechanisms are required from these ECM-based biomaterials to exert their effect are not entirely understood. In this study, we use the brain as a novel model to test the effects of particular biochemical and structural properties by evaluating, for the first time, three different sections of the brain (i.e., cortex, cerebellum, and remaining areas) side-by-side and their corresponding decellularized counterparts using mechanical (4-day) and chemical (1-day) decellularization protocols. The three different brain subregions had considerably different initial conditions in terms of cell number and growth factor content, and some of these differences were maintained after decellularization. Decellularized ECM from both protocols was used as a substrate or as soluble factor, in both cases showing good cell attachment and growth capabilities. Interestingly, the 1-day protocol was capable of promoting greater differentiation than the 4-day protocol, probably due to its capacity to remove a similar amount of cell nuclei, while better conserving the biochemical and structural components of the cerebral ECM. Still, some limitations of this study include the need to evaluate the response in other biologically relevant cell types, as well as a more detailed characterization of the components in the decellularized ECM of the different brain subregions. In conclusion, our results show differences in neuronal maturation depending on the region of the brain used to produce the scaffolds. Complex organs such as the brain have subregions with very different initial cellular and biochemical conditions that should be considered for decellularization to minimize exposure to immunogenic components, while retaining bioactive factors conducive to regeneration. [Figure: see text] Impact statement The present study offers new knowledge about the production of decellularized extracellular matrix scaffolds from specific regions of the porcine brain, with a direct comparison of their effect on in vitro neuronal maturation. Our results show differences in neuronal maturation depending on the region of the brain used to produce the scaffolds, suggesting that it is necessary to consider the initial cellular content of the source tissue and its bioactive capacity for the production of an effective regenerative therapy for stroke.


[Induction of the phenobarbital form of cytochrome P-450 by chemically unrelated compounds].
The induction of the phenobarbital form of cytochrome P-450 by xenobiotics (phenobarbital, PB, hexachlorobenzene, HCB; hexachlorocyclohexane. HCCH, and aroclor 1016, Ar) was studied. It was demonstrated that administration of these compounds to animals is accompanied by an increase in the total cytochrome P-450, NADPH-cytochrome P-450 reductase, benzphetamine-N-demethylase and aldrin-epoxidase activities. Using monospecific antibodies against the cytochrome P-450 form isolated from PB-induced microsomes (PB-cytochrome P-450), a double immunodiffusion test revealed immunological identity of cytochrome P-450 forms induced by phenobarbital and other xenobiotics. The content of this form determined by rocket immunoelectrophoresis increased markedly and made up to 20-40% of the total cytochrome P-450 content. Antibodies against PB-cytochrome P-450 inhibited by 50-70% the benzphetamine-N-demethylase and aldrin-epoxidase activities, whereas the antibodies to methylcholanthrene-induced cytochrome P-450 were fairly ineffective. It was concluded that the chemically unrelated compounds induce in liver microsomes a cytochrome P-450 form, whose immunological properties and substrate specificity are close to the PB-form of cytochrome P-450.


Quantitative assessment of regional left ventricular motion using endocardial landmarks.
In this study the hypothesis is tested that the motion pattern of small anatomic landmarks, recognizable at the left ventricular endocardial border in the contrast angiocardiogram, reflects the motion of the endocardial wall. To verify this, minute metal markers were inserted in the endocardium of eight pigs with a novel retrograde transvascular approach. Marker motion was subsequently recorded with roentgen cinematography and compared with the motion of the landmarks on the endocardial contours detected from the contrast ventriculogram with an automated contour detection system. Linear regression analysis of the directions of the systolic metal marker and endocardial landmark pathways yielded a correlation coefficient of 0.86 and a standard error of the estimate of 10.3 degrees. Landmark pathways were also measured in 23 normal human left ventriculograms. Normal left ventricular endocardial wall motion during systole, as observed in the 30 degrees right anterior oblique view, is characterized by a dominant inward transverse motion of the opposite anterior and inferoposterior walls and a descent of the base toward the apex. The apex itself is almost stationary. On the basis of these observations, a widely applicable model for the assessment of left ventricular wall motion is described in mathematical terms.


Induction of growth alterations in factor-dependent hematopoietic progenitor cell lines by cocultivation with irradiated bone marrow stromal cell lines.
We studied the production of hemopoietins by x-irradiated plateau-phase cultures of cloned marrow stromal cell lines derived from C3H/HeJ marrow, termed D2XRII and clone 11. The production of CSF in agar overlay of control or 10,000 rad irradiated stromal cultures was quantitated by induction of colonies in: overlaid fresh marrow, IL-3-dependent cell line 32D cl 3, or GM-CSF/IL-3-dependent cell lines FDCP-1 or bg/bg cl 1. Conditioned media were tested for CSF by bioassay using fresh marrow cells, for M-CSF (CSF-1) by RIA, and for IL-3 and GM-CSF by microwell proliferation assay with 32D cl 3 and FDCP-1 cells, respectively. X-irradiation to doses that decreased CSF-1 to 40% of control levels (greater than 5,000 rad) resulted in a 30-fold increase in growth of FDCP-1 or bg/bg cl 1 cells in liquid co-culture or agar culture overlay with no detectable growth of 32D cl 3. The frequency of subculture of nonautocrine, factor independent (FI) variant clonal lines of FDCP-1 or bg/bg cl 1 cells was increased over 1000-fold by 15 weeks cocultivation with irradiated stromal cell cultures. FI subclonal lines formed tumors in syngeneic mice and contained no detectable poly A messenger RNA for GM-CSF or IL-3, and no elevation in c-myc, c-abl, c-src, or erb-B onc gene-specific messenger RNA compared to parent factor-dependent lines. These data indicate that x-irradiated plateau phase marrow stromal cells produce increased levels of cell contact-mediated biologically active hemopoietin(s) other than M-CSF, GM-CSF, or IL-3 and induce nonautocrine factor-independent malignant cell lines in vitro.


Changes in health status for persons with wrist or hand impairments receiving occupational therapy or physical therapy.
The purpose of this study was to describe changes of health status as perceived by clients with hand or wrist impairments who received rehabilitation in acute, orthopedic outpatient facilities from occupational therapy or physical therapy personnel. One thousand three hundred ninety-nine adults with wrist (n = 692) or hand (n = 707) impairments who were treated between July 1996 and June 1997 were selected from the Focus On Therapeutic Outcomes, Inc. (FOTO) national rehabilitation database. Each client completed a health status questionnaire on intake and discharge. Data consisted of number of outpatient visits, duration of treatment episode, and health status scores for six functional scales. Measures of intensity, global health status, global utilization, and client satisfaction were calculated. Outcomes were evaluated across occupational therapists and physical therapists. Clients perceived improvement (p < .05) in their health status over the course of therapy. Number of visits and measures of health status and client satisfaction were similar across type of therapist. Episode duration was longer (p < .05) and intensity was less (p < .05) for clients seen by occupational therapists. Clients receiving rehabilitation in acute orthopedic outpatient centers perceived improvement in their functional abilities and health and well-being (global health status and individual functional scales) over the time during which treatment was provided. Results confirm the responsiveness of the outcomes instrument to clinical change in the clients' perception of their health status over the course of therapy and support the use of health status as a measure of clinical outcome.


Carotenoid biosynthesis in Rhodopseudomonas spheroides. S-adenosylmethionine as the methylating agent in the biosynthesis of spheroidene and spheroidenone.
[methyl-(14)C]Methionine and S-adenosyl[methyl-(14)C]methionine were incorporated into the methoxycarotenoids spheroidene and spheroidenone by Rhodopseudomonas spheroides. The incorporation was greatly enhanced in the presence of lysozyme. On degradation of labelled spheroidene by hydriodic acid, the (14)C label was recovered in methyl iodide. Degradation of spheroidenone by reduction and allylic dehydration and demethylation of the reduction product gave a mixture of unlabelled carotenoid hydrocarbons, including 3,4-didehydrolycopene and 3,4-didehydro-7',8'-dihydrolycopene. The label from [methyl-(14)C]methionine and S-adenosyl[methyl-(14)C]methionine was located specifically in the methoxy group of spheroidene and spheroidenone. The biosynthesis of methoxycarotenoids in Rps. spheroides involves methylation of the tertiary hydroxyl groups of intermediates with S-adenosylmethionine.


Training in the implementation of prolonged exposure therapy: provider correlates of treatment outcome.
The authors examined the degree to which provider characteristics, such as profession, treatment orientation, prior experience in treating posttraumatic stress disorder (PTSD), prior experience with prolonged exposure (PE) therapy, and attitudes about PE, were related to the clinical outcomes of veterans receiving care from clinicians participating in the national Department of Veterans Affairs (VA) PE Training Program. Positive patient outcomes were achieved by providers of every profession, theoretical orientation, level of clinical experience treating PTSD, and prior PE training experience. With 1,105 providers and 32 predictors (13 provider variables), power was at least 90% power to detect an effect of β = .15. Profession was the only provider characteristic significantly related to outcomes, but the mean effect (a 2 point difference on the PTSD Checklist) was too small to be clinically meaningful. The results support the intensive training model used in the VA PE training program and demonstrate that clinicians of varying backgrounds can be trained using interactive training workshops followed by case consultation to deliver PE effectively.


Efficacy and safety of phenobarbital for benign convulsions with mild gastroenteritis: A prospective randomized controlled study.
previous studies have shown that phenobarbital (PB) is a effective and safe drug in the treatment of benign convulsions with mild gastroenteritis (CwG), but there is a lack of large sample prospective randomized controlled study of different doses. This study was a prospective randomized controlled study on the efficacy and safety of different doses of phenobarbital for CwG. There has been no similar study. One hundred twenty CwG cases were included in this study. All of them were hospitalized in the Department of Neurology of Jiangxi Provincial Children's Hospital from January 2019 to August 2021. They were randomly divided into 10 mg/kg single dose group (Group A, n = 60) and 5 mg/kg single dose group (Group B, n = 60). The criteria for judging the efficacy of PB in our study were there was no convulsion in the course of acute gastroenteritis within 2 weeks after using PB. The effective rate was 93.33% in group A and 80.00% in group B. There was significant difference between the 2 groups (P < .05). Drowsiness was the most frequent adverse reaction. 14 cases in group A and 7 cases in group B had drowsiness. There was no significant difference between the 2 groups in the incidence of adverse events such as somnolence, ataxia, abnormal liver function, anemia, abnormal leukocyte, respiratory depression, cognitive impairment, rash, abnormal platelet and abnormal renal function (P > .05). All side reaction were transient. it is suggested that PB 10 mg/kg intravenously should be used as soon as possible for CwG, which has high effectiveness and safety.


Fluorophotometry. I. Technique.
A radiometer and photomultiplier assembly was used to measure light intensities under several artificial conditions to assess the efficacy of the fluorophotometer and the technique of ocular fluorophotometer and the technique of ocular fluorophotometry. Using an artificial eye and a cat eye that had undergone vitrectomy, we found that scatter of light from the retinal surface may contribute to the fluorescence recorded.


Cigarette smoking induces overexpression of a fat-depleting gene AZGP1 in the human.
Smokers weigh less and have less body fat than nonsmokers. Increased body fat and weight gain are observed following smoking cessation. To assess a possible molecular mechanism underlying the inverse association between smoking and body weight, we hypothesized that smoking may induce the expression of a fat-depleting gene in the airway epithelium, the cell population that takes the brunt of the stress of cigarette smoke. To assess whether smoking up-regulates expression in the airway epithelium of genes associated with weight loss, microarray analysis was used to evaluate genes associated with fat depletion in large airway epithelial samples obtained by fiberoptic bronchoscopy from healthy smokers and healthy nonsmokers. As a candidate gene we further evaluated the expression of alpha(2)-zinc-glycoprotein 1 (AZGP1), a soluble protein that stimulates lipolysis, induces a reduction in body fat in mice, is associated with the cachexia related to cancer, and is known to be expressed in secretory cells of lung epithelium. AZGP1 protein expression was assessed by Western analysis and localization in the large airway epithelium by immunohistochemistry. Both microarray and TaqMan analysis demonstrated that AZGP1 messenger RNA levels were higher in the large airway epithelium of healthy smokers compared to healthy nonsmokers (p < 0.05, all comparisons). Western analysis of airway biopsy specimens from smokers compared with those from nonsmokers demonstrated up-regulation of AZGP1 at the protein level, and immunohistochemical analysis demonstrated up-regulation of AZGP1 in secretory as well as neuroendocrine cells of smokers. In the context that AZGP1 is involved in lipolysis and fat loss, its overexpression in the airway epithelium of chronic smokers may represent one mechanism for the weight difference in smokers vs nonsmokers.


Trajectories of prolonged grief one to six years after a natural disaster.
The long-term trajectories of prolonged grief are poorly understood. The aims were to examine the course of grief among bereaved disaster survivors up to six years post loss and factors predicting worse bereavement outcome. A third aim was to explore differences in grief indicators between trajectories. Bereaved Swedish tourists who survived the 2004 Indian Ocean tsunamis responded to surveys including the Inventory of Complicated Grief 1 to 6 years after the disaster. Latent growth mixture modeling was used to identify longitudinal trajectories of grief. Multinomial logistic regression analysis was used to examine predictors of class membership. Three trajectories were identified: resilient (41% of the sample), recovering (48%), and chronic (11%). The strongest predictor of chronic grief was the loss of one's child. When examining grief indicators, the chronic trajectory was characterized by not accepting the loss, while yearning was common in all trajectories. This study highlights the importance of considering how traumatically bereaved individuals can be affected by loss for several years after a disaster, especially after losing one's child. An inability to accept the loss, more so than yearning, appears to characterize bereaved survivors at risk of a chronic trajectory of grief.


Audiovisual processing in children with and without autism spectrum disorders.
Fifteen children with autism spectrum disorders (ASD) and twenty-one children without ASD completed six perceptual tasks designed to characterize the nature of the audiovisual processing difficulties experienced by children with ASD. Children with ASD scored significantly lower than children without ASD on audiovisual tasks involving human faces and voices, but scored similarly to children without ASD on audiovisual tasks involving nonhuman stimuli (bouncing balls). Results suggest that children with ASD may use visual information for speech differently from children without ASD. Exploratory results support an inverse association between audiovisual speech processing capacities and social impairment in children with ASD.


Body build and its relationship to pressure distribution in the seated wheelchair patient.
The clinical evaluation of wheelchair cushions used to relieve pressure of patients with severe physical disability has become a major concern for the rehabilitation team. This paper describes the effects of body build, based on height, weight, sex, and age of the subjects studied, on the location, magnitude and gradient of the pressure exerted by patients seated in wheelchairs. It was found that thin patients had higher pressures over bony prominences and greater frequency of the maximum pressure occurring in a bony location than did average-weight or obese subjects.


Bioorthogonal Strategy for Bioprocessing of Specific-Site-Functionalized Enveloped Influenza-Virus-Like Particles.
Virus-like particles (VLPs) constitute a promising platform in vaccine development and targeted drug delivery. To date, most applications use simple nonenveloped VLPs as human papillomavirus or hepatitis B vaccines, even though the envelope is known to be critical to retain the native protein folding and biological function. Here, we present tagged enveloped VLPs (TagE-VLPs) as a valuable strategy for the downstream processing and monitoring of the in vivo production of specific-site-functionalized enveloped influenza VLPs. This two-step procedure allows bioorthogonal functionalization of azide-tagged nascent influenza type A hemagglutinin proteins in the envelope of VLPs through a strain-promoted [3 + 2] alkyne-azide cycloaddition reaction. Importantly, labeling does not influence VLP production and allows for construction of functionalized VLPs without deleterious effects on their biological function. Refined discrimination and separation between VLP and baculovirus, the major impurity of the process, is achieved when this technique is combined with flow cytometry analysis, as demonstrated by atomic force microscopy. TagE-VLPs is a versatile tool broadly applicable to the production, monitoring, and purification of functionalized enveloped VLPs for vaccine design trial runs, targeted drug delivery, and molecular imaging.


Effects of oriented surface dipole on photoconversion efficiency in an alkane/lipid-hybrid-bilayer-based photovoltaic model system.
When a phospholipid monolayer containing a zinc-coordinated porphyrin species formed atop a self-assembled monolayer of heptadecafluoro-1-decanethiol (CF3(CF2)7(CH2)2SH) is subjected to photoelectrochemical current generation, a significant modulation effect is observed. Compared with devices that contain similar photoactive lipid monolayers but formed on 1-dodecanethiol SAMs, these fluorinated hybrid bilayers produce a >60% increase in cathodic currents and a similar decrease in anodic currents. Photovoltages recorded from these hybrid bilayers are found to vary in the same fashion. The modulation of photovoltaic responses in these hybrid-bilayer-based devices is explained by the opposite surface dipoles associated with the thiols employed in this study, which in one case (fluorothiol) increase and in another (alkanethiol) decrease the work function of the underlying gold substrates. A similar trend of photovoltage/photocurrent modulation is also observed if fullerene is used as the photoagent in these devices. Our results reveal the intricacy of orientated surface dipole in influencing the photovoltaic processes, and its subtle interplay with other factors related to the photoagents, such as their location and orientation within the organic matrix.


Synostosis of the first and second ribs in six horses.
CASE DESCRIPTION Over a 2-year period, 6 horses (4 Selle Français, 1 Hanoverian, and 1 Thoroughbred) were referred for evaluation of forelimb lameness. All horses had radiographic evidence of synostosis of the first and second ribs (SFSR). CLINICAL FINDINGS For 1 horse, the SFSR was considered the probable cause of the lameness (grade 3/5), with a shortening of the cranial phase of the stride in the affected limb. For 3 horses, it was considered a possible cause of the lameness (grade 1/5) for the same reason. For 2 horses, SFSR was considered an incidental finding unassociated with any clinical signs. The 4 horses with lameness suspected as attributable to SFSR had a moderate to severe amount of irregularly marginated new bone formation at the site of the SFSR, with a cranial displacement of the first rib, compared with findings for the 2 horses in which the SFSR was considered incidental. A likely congenital abnormality of the first rib was first suspected on nuclear scintigraphy in the 1 horse for which it was performed or on radiography of the caudal cervical portion of the vertebral column (3 horses) or shoulder joint (2 horses). TREATMENT AND OUTCOME The horse in which SFSR was considered the probable cause of the lameness was retired to the field and remained chronically lame. Two of the 3 horses in which SFSR was considered a possible cause of lameness received an IV infusion of tiludronate disodium and mesotherapy over the caudal cervical and cranial thoracic regions; both returned to competition but with poor results. One of the 2 horses with subclinical SFSR never developed lameness on the affected side. No follow-up information was available for the other 2 horses. CLINICAL RELEVANCE SFSR can be an incidental finding in horses, with or without clinical manifestations. This abnormality should be considered as a differential diagnosis for horses with forelimb lameness and associated shortening of the cranial phase of the stride that fails to improve with diagnostic analgesic techniques.


Establishing a universal protocol for deep vein thrombosis following orthopedic surgery: total knee arthroplasty.
The incidence of deep vein thrombosis (DVT) after total knee replacement surgery is reported to occur in 84% of all unprotected patients and may be as high as 68% in patients who receive DVT prophylaxis. Moreover, controversy exists as to which pharmacologic or mechanical agent is most effective. Although the scientific literature provides some answers, many issues of DVT prophylaxis are not completely addressed, especially with regard to the duration of prophylaxis. The most recent report from the American College of Chest Physicians Consensus Conference on Antithrombotic Therapy reconfirms the recommendations offered from previous consensus groups on the importance of establishing and applying a universal protocol for the prevention of DVT in orthopedic surgery.