Contrasting physiological responses of ozone-tolerant Phaseolus vulgaris and Nicotiana tobaccum varieties to ozone and nitric acid.
Ozone (O3) and nitric acid (HNO3) are synthesized by the same atmospheric photochemical processes and are almost always co-pollutants. Effects of O3 on plants have been well-elucidated, yet less is known about the effects of HNO3 on plants. We investigated the physiological effects of experimental O3 and HNO3 fumigation on Phaseolus vulgaris (snap bean) and Nicotiana tobaccum (tobacco) varieties with known sensitivity to O3, but unknown responses to HNO3. Responses were measured as leaf absorptance, aboveground plant biomass, and photosynthetic CO2-response curve parameters. Our results demonstrate that O3 reduced absorptance, stomatal conductance and plant biomass in both species, and maximum photosynthetic rate in P. vulgaris, whereas the main effect of HNO3 was an increase in mesophyll conductance. Overall, the results suggest that HNO3 affects mesophyll conductance through increased nitrogen absorbed by leaves during HNO3 deposition which in turn increases photosynthetic demand for CO2, or that damage to epicuticular waxes on leaves increased diffusion of CO2 to sites of carboxylation.


The incidence of stroke among pregnant women in Rochester, Minn, 1955 through 1979.
This study defines the incidence of ischemic and hemorrhagic cerebrovascular disorders among pregnant women in Rochester, Minn, from 1955 through 1979. Of the 26,099 live births during this period, only one instance of cerebral infarction (5.1 cerebral infarctions per 100,000 person-years of observation) and no instances of transient ischemic attack or intracranial hemorrhage were identified in pregnant women. These data suggest that the occurrence rates of cerebrovascular events during pregnancy may be much lower than has previously been reported.


Activation of STAT3 is a key event in TLR4 signaling-mediated melanoma progression.
Malignant melanoma is aggressive and has a high mortality rate. Toll-like receptor 4 (TLR4) has been linked to melanoma growth, angiogenesis and metastasis. However, signal transduction mediated by TLR4 for driving melanoma progression is not fully understood. Signal transducer and activator of transcription 3 (STAT3) has been identified as a major oncogene in melanoma progression. We found: that TLR4 expression positively correlates with activation/phosphorylation of STAT3 in human melanoma samples; that TLR4 ligands activate STAT3 through MYD88 and TRIF in melanoma cells; and that intratumoral activation of TLR4 increases STAT3 activation in the tumor and promotes tumor growth, angiogenesis, epithelial-mesenchymal transition (EMT) and the formation of an immunosuppressive tumor microenvironment in mice. Further, we found that the effects mediated by activating TLR4 are weakened by suppressing STAT3 function with a dominant negative STAT3 variant in melanoma. Collectively, our work identifies STAT3 activation as a key event in TLR4 signaling-mediated melanoma progression, shedding new light on the pathophysiology of melanoma.


Falls and outcomes amongst old people in rural dwellings.
Falls are the leading cause of injury deaths among people 65 years and older. This study gives an insight into the prevalence of falls among older people and how they occur in a rural setting in Nigeria. A community based survey of 210 consenting old people aged 65 years and above selected using a multi-stage sampling technique was done. Study instrument was a semi-structured interviewer administered questionnaire and visual acuity was tested using Snellens chart. Incidence of falls was 21.4%. Of those who had falls, 86.7% were walking while 11.1% were either sitting or running when it occurred. The nature of the fall was tripping in 44.4%, slipping in 35.6% and hitting an object in 17.8% of cases. Consequences of falls included pain 48.9%, bruises 22.2%, lacerations 13.3% and fractures 11.1%. Females had more falls than males; 23.8% vs 19.0%, p = 0.40. Major injuries resulting from falls also occurred more frequently amongst females than males; 30.7% vs. 15.0%, p = 0.3. History of diabetes and alcohol use increased the odds of falling (OR 4.1, 95% CI 1.0 - 16.0; OR 2.2, 95% CI 1.0 - 4.6 respectively). Being in a monogamous marriage and having normal sight were protective of having falls (OR 0.4, 95% CI 0.2 - 0.9; OR 0.4, 95% CI 0.2 - 0.9 respectively). Falls often occur from tripping and slipping while females are more likely to have major injuries. Risk factors for falls were alcohol use and diabetes while having normal sight and being monogamous were protective. Prevention should aim at a life course approach to addressing these intrinsic and extrinsic factors.


Modifications to the Aesop's Fable paradigm change New Caledonian crow performances.
While humans are able to understand much about causality, it is unclear to what extent non-human animals can do the same. The Aesop's Fable paradigm requires an animal to drop stones into a water-filled tube to bring a floating food reward within reach. Rook, Eurasian jay, and New Caledonian crow performances are similar to those of children under seven years of age when solving this task. However, we know very little about the cognition underpinning these birds' performances. Here, we address several limitations of previous Aesop's Fable studies to gain insight into the causal cognition of New Caledonian crows. Our results provide the first evidence that any non-human animal can solve the U-tube task and can discriminate between water-filled tubes of different volumes. However, our results do not provide support for the hypothesis that these crows can infer the presence of a hidden causal mechanism. They also call into question previous object-discrimination performances. The methodologies outlined here should allow for more powerful comparisons between humans and other animal species and thus help us to determine which aspects of causal cognition are distinct to humans.


DNA methyltransferase 3 beta mediates the methylation of the microRNA-34a promoter and enhances chondrocyte viability in osteoarthritis.
Osteoarthritis (OA) is characterized by destruction of articular cartilage with an imbalance between synthesis and degradation of extracellular matrix (ECM). In the current study, we explored the role of microRNA-34a (miR-34a) and the behind epigenetic mechanism in the degradation of ECM in OA. Using miRNA-based microarray analysis, we found that miR-34a was overexpressed in cartilage tissues of OA patients relative to patients with acute traumatic amputations. Moreover, its expression was positively correlated with the ECM degradation and inflammation. Mechanistically, miR-34a targeted MCL1, and possible target genes of miR-34a were enriched in the PI3K/AKT pathway. Furthermore, DNMT3B inhibited miR-34a by promoting miR-34a methylation. Functional experiments using CCK-8, flow cytometry, Safranin O staining, RT-qPCR, ELISA, Western blot, and HE staining revealed that miR-34a inhibitor suppressed ECM degradation and inflammatory response of chondrocytes and cartilage tissues. By contrast, downregulation of DNMT3B and MCL1 reversed the repressive effects of miR-34a inhibitor in vitro and in vivo. Altogether, our findings establish that silencing of miR-34a by DNMT3B could effectively reduce chondrocyte ECM degradation and inflammatory response in mice by targeting MCL1 and mediating the downstream PI3K/AKT pathway. This present study revealed that miR-34a knockdown might develop a novel intervention for OA treatment.


Crystal structures of HLA-A*0201 complexed with Melan-A/MART-1(26(27L)-35) peptidomimetics reveal conformational heterogeneity and highlight degeneracy of T cell recognition.
There is growing interest in using tumor associated antigens presented by class I major histocompatibility complex (MHC-I) proteins as cancer vaccines. As native peptides are poorly stable in biological fluids, researchers have sought to engineer synthetic peptidomimetics with greater biostability. Here, we demonstrate that antigenic peptidomimetics of the Melan-A/MART-1(26(27L)-35) melanoma antigen adopt strikingly different conformations when bound to MHC-I, highlighting the degeneracy of T cell recognition and revealing the challenges associated with mimicking native peptide conformation.


Identification of a promoter component involved in positioning the 5' termini of simian virus 40 early mRNAs.
The 5' termini of the principal early mRNAs produced in cells transformed by wild-type simian virus 40 lie 21-25 nucleotides downstream from an A-T-T-T-A-T sequence on the DNA template. The 5' termini of early mRNAs produced by five origin-defective mutants containing deletions downstream from the A-T-T-T-A-T sequence and one viable mutant dl892 with a deletion starting 15 nucleotides upstream from this sequence were determined by a method involving synthesis, separation, and determination of the sequences of DNAs complementary to 5' termini. Mutant dl892 produced early mRNAs with the same principal 5' termini as wild-type virus; the origin-defective mutants produced mRNAs with principal 5' termini shifted downstream by a distance equivalent to the length of the deleted DNA segment. These data suggest that a DNA sequence of 29 nucleotides, which includes the A-T-T-T-A-T sequence, contains a component(s) of a promoter for early transcription. This component functions in positioning the 5' ends of the principal early mRNAs 21-25 nucleotides downstream from the A-T-T-T-A-T sequence and acts independently of these downstream sequences.


Endothelial cells in the bone marrow of patients with multiple myeloma.
Endothelial cells (EC) were extracted through a lectin-based method from bone marrow of 57 patients with active multiple myeloma (MM) and compared with their healthy quiescent counterpart, human umbilical vein EC (HUVEC). MMECs exhibit specific antigens that indicate ongoing angiogenesis and embryo vasculogenesis; solid intercellular connections, hence stability of MM neovessels; and frequent interactions with plasma cells, hence tumor dissemination. They show heterogeneous antigen expression, hence existence of subsets. Their main genetic markers are indicative of a vascular phase. They show intrinsic angiogenic ability, because they rapidly form a capillary network in vitro, and extrinsic ability, because they generate numerous new vessels in vivo. They vividly secrete growth and invasive factors for plasma cells. They signal through kinases mandatory for development of neovascularization. Ultrastructurally, they are abnormal and show metabolic activation, like tumor ECs. Thalidomide heavily interferes with their functions. Vasculogenesis and angiogenesis might contribute to the MM vascular tree and progression, in the form of growth, invasion, and dissemination. In view of the heterogeneity of the antigenic phenotype of MMECs, a mixture (or a sequence) of antiangiogenic agents coupled with thalidomide would seem plausible for the biologic management of MM.


Second year scepticism: pre-qualifying health and social care students' midpoint self-assessment, attitudes and perceptions concerning interprofessional learning and working.
A study in an English Faculty of Health and Social Care explores the effects of a pre-qualifying interprofessional curriculum incorporating interprofessional modules in each year of study. The study design involves collecting data on entry to the Faculty, after completion of the second interprofessional module, on qualification and after 9 months qualified practice. At each point, students complete questionnaires concerning communication and teamwork skills and interprofessional learning and working. This paper presents results from 723 students at the second data collection point. Although most students were positive about their communication and teamwork skills, they were less positive than on entry to the Faculty. Similarly there was a negative shift in students' attitudes to interprofessional learning and interprofessional interaction. Nevertheless, most students were positive about their own interprofessional relationships. Mature students' responses were more positive than those of younger students. The emergence of differences in responses based on a professional programme suggests that interprofessional education may not necessarily influence professional socialization. Demographic and professional variables affecting students' responses in their second year of study demonstrate the complexity of student learning. The planned follow-up of the students will show whether variables affecting interim data have a long-term effect on attitudes.


[Obtention and characterization of a diploid cell line of human kidney].
A new diploid cell line of human embrionary kidney was obtained by serial subcultures (Mag) starting from a primary culture. It was prepared by applying the explant technique instead of the classical enzymatic digestion with trypsin. The stabilization process of the diploid line after the "secondary culture" was attained between the passes 6 and 7. 3 culture media were tested during the process. Only the MEM was completely satisfactory. The biological characteristics of the new line were as follows: fibroblastic morphology, Eagle MEM culture mean with 10% of SBF, split from 1:2 to 1:3, normal human carotype, postfreezing viability of 60%, pollutant-free and non-tumorigenic. The cryopreserved Mag subcultures 11-13 were studied from the point of view of their usefulness for the diagnosis of different viral groups.


Predictive factors for acne flare during isotretinoin treatment.
Flare of acne is common at the beginning of isotretinoin treatment. However, severe flare is rare. Multiple comedones, male gender and young age are reported as promoting factors. However, detailed information is still limited. Our aim was to investigate the incidence, types and course of acne flare and the predictive factors for its occurrence. 244 patients were enrolled. Acne grade was defined according to global acne grading system (GAGS) score. Flare was classified according to the increase in number of inflammatory nodules and treatment requirements of the patients. Risk factors (age, sex, duration of acne, basal acne grade, baseline numbers of comedones, papule-pustules, nodules, hyperandrogenism, and presence of sinuses) were investigated. 161 patients completed the study. 79 patients (32%) had facial and/or truncal flare. Flare was mild in 18% (n = 44), moderate in 10% (n = 24), and severe in 4.5% (n = 11) of the patients. For severe flare, male sex, severe acne, GAGS cut-off score greater than 28, presence of more than 44 facial comedones and 2 facial nodules and presence of truncal nodules were found to be predictive. Recognizing predictive factors for severe flare may help to take early precautions and to prevent severe flares which may result with permanent scars.


Anaphylaxis: recognition and management.
Anaphylaxis is a severe, life-threatening, systemic allergic reaction that is almost always unanticipated and may lead to death by airway obstruction or vascular collapse. Anaphylaxis occurs as the result of an allergen response, usually immunoglobulin E-mediated, which leads to mast cell and basophil activation and a combination of dermatologic, respiratory, cardiovascular, gastrointestinal, and neurologic symptoms. Dermatologic and respiratory symptoms are most common, occurring in 90 and 70 percent of episodes, respectively. The three most common triggers are food, insect stings, and medications. The diagnosis of anaphylaxis is typically made when symptoms occur within one hour of exposure to a specific antigen. Confirmatory testing using serum histamine and tryptase levels is difficult, because blood samples must be drawn with strict time considerations. Allergen skin testing and in vitro assay for serum immunoglobulin E of specific allergens do not reliably predict who will develop anaphylaxis. Administration of intramuscular epinephrine at the onset of anaphylaxis, before respiratory failure or cardiovascular compromise, is essential. Histamine H(1) receptor antagonists and corticosteroids may be useful adjuncts. All patients at risk of recurrent anaphylaxis should be educated about the appropriate use of prescription epinephrine autoinjectors.


[Application of anocutaneous flap in surgical treatment of complex fistulas-in-ano].
The author makes an assessment of results of treatment of recurrent pararectal fistulas of extrasphincteric pararectal fistulas with liquidation of internal opening of the fistula using a combination of bringing down the mucous-muscular coat of the rectum and transfer of the anocutaneous island flap on the feeding pedicle from the subcutaneous fat. After operation the superficial inflammation of the wound of the perianal area was noted in 9 patients, primary wound healing at the place of connection of the cutaneous and mucous-muscular flap was observed in 28 patients. Recurrent fistula was noted in 2 patients, one of them having Crohn's disease. The holding function of the rectum sphincter apparatus after operation was saved.


Determinants of energy utilization in the activated myocardium.
This is a review of work dealing with the effect of pressure overload and thryotoxic hypertrophy of rabbit hearts on the production of total activity related (TA) and initial (I) heats during isometric contraction. Pressure overload hypertrophy is produced by constricting the pulmonary artery with a spiral monel metal clip. Thyrotoxic hypertrophy is produced by 14 daily i.m. injections of 0.2 mg L-thyroxine per kilogram. Heat output is measured with Hill-type planar vacuum deposited bismuth and antimony thermopiles, and force is measured with a capacitance strain gauge. The pressure overload results in a depressed velocity of unloaded shortening, a depressed rate of isometric force development, and an increased time-to-peak tension. These changes are associated with a decreased myosin ATPase, a heart with no V1 myosin isoenzyme, and an increase in the economy of isometric force development (integral of Pdt/TA, integral of Pdt/I). The thyrotoxic hearts exhibit an increased velocity of shortening and rate of force development, and a decrease in time-to-peak tension. These changes are associated with an increase in myosin ATPase activity, a heart with increase in the V1 isoenzyme composition (88% V1), and a decrease in the economy of isometric force development (integral of Pdt/TA, integral of Pdt/I). The changes in the two types of hypertrophied hearts are interpreted in terms of altered cross-bridge cycling rates and changes in cross-bridge tension time integral as well as excitation contraction coupling phenomena. In the thyrotoxic hearts there is an increase in the economy of the recovery processes. Both types of hypertrophy are considered to be adaptive and involve the coordinated restructuring of the excitation-contraction, contractile, and recovery systems.


Lymphomas expressing ALK fusion protein(s) other than NPM-ALK.
The tumor cells in ALK-positive lymphoma ("ALKoma") usually express the product of the NPM-ALK chimeric gene, generated by the t(2;5) chromosomal translocation. However, 10% to 20% of ALK-positive lymphomas express ALK fusion protein(s) other than NPM-ALK, and in this report, we describe the immunohistologic and clinicopathologic features of 15 such cases. The absence of the NPM-ALK fusion gene was confirmed by reverse transcriptase-polymerase chain reaction (RT-PCR) in 8 cases and by fluorescence in situ hybridization (FISH) analysis in a further 2 cases. In each case, ALK staining was restricted to the cytoplasm and the N-terminus of NPM to the nucleus (contrasting with lymphomas expressing NPM-ALK in which cytoplasmic as well as nuclear labeling is seen). However, in the course of screening 53 ALK-positive lymphomas, 2 biopsies were found that had a "cytoplasm-only" ALK staining pattern but that nevertheless were shown to carry the (2;5) (by NPM staining and RT-PCR). The 15 cases resembled typical NPM-ALK-positive lymphomas in that all were of T or null phenotype, usually occurred in young male patients, and frequently presented with advanced disease associated with systemic symptoms and extranodal involvement. Moreover, their prognosis was excellent and indistinguishable from that of classical t(2;5)-positive tumors, but was clearly different from that of ALK-negative anaplastic large-cell lymphomas. These results suggest that lymphomas carrying variants of the NPM-ALK fusion protein can be detected by immunostaining for ALK and NPM and also that they can be grouped with classical t(2;5)-positive tumors as a single entity (ALK-positive lymphoma or "ALKoma") that shows a better prognosis than ALK-negative anaplastic large-cell lymphoma.


The alpha-helix and the organization and gating of channels.
The structures of an increasing number of channels and other alpha-helical membrane proteins have been determined recently, including the KcsA potassium channel, the MscL mechanosensitive channel, and the AQP1 and GlpF members of the aquaporin family. In this chapter, the orientation and packing characteristics of bilayer-spanning helices are surveyed in integral membrane proteins. In the case of channels, alpha-helices create the sealed barrier that separates the hydrocarbon region of the bilayer from the permeation pathway for solutes. The helices surrounding the permeation pathway tend to be rather steeply tilted relative to the membrane normal and are consistently arranged in a right-handed bundle. The helical framework further provides a supporting scaffold for nonmembrane-spanning structures associated with channel selectivity. Although structural details remain scarce, the conformational changes associated with gating transitions between closed and open states of channels are reviewed, emphasizing the potential roles of helix-helix interactions in this process.


On semiparametric accelerated failure time models with time-varying covariates: A maximum penalised likelihood estimation.
The accelerated failure time (AFT) model offers an important and useful alternative to the conventional Cox proportional hazards model, particularly when the proportional hazards assumption for a Cox model is violated. Since an AFT model is basically a log-linear model, meaningful interpretations of covariate effects on failure times can be made directly. However, estimation of a semiparametric AFT model imposes computational challenges even when it only has time-fixed covariates, and the situation becomes much more complicated when time-varying covariates are included. In this paper, we propose a penalised likelihood approach to estimate the semiparametric AFT model with right-censored failure time, where both time-fixed and time-varying covariates are permitted. We adopt the Gaussian basis functions to construct a smooth approximation to the nonparametric baseline hazard. This model fitting method requires a constrained optimisation approach. A comprehensive simulation study is conducted to demonstrate the performance of the proposed method. An application of our method to a motor neuron disease data set is provided.


Seroprevalence of Toxoplasma gondii in dogs in Shandong, Henan, and Heilongjiang Provinces, and in the Xinjiang Uygur Autonomous Region, People's Republic of China.
Seroprevalence of Toxoplasma gondii infection was determined in sera of 632 dogs (551 pets, 81 strays) from Shandong, Henan, and Heilongjiang Provinces, and in the Xinjiang Uygur Autonomous Region, People's Republic of China (PRC), using the indirect hemagglutination assay (cutoff titer 1:64 or higher); 11.1% were seropositive. The seroprevalence in stray dogs and in ≥3-yr-old dogs was significantly higher (P < 0.05) than that in household dogs and in <3-yr-old dogs. There were no significant differences in terms of gender, breed, or locality (P ≥ 0.05). The results indicate that T. gondii infections are common in dogs in PRC.


Random C-peptide in the classification of diabetes.
To clarify whether random C-peptide is a valuable test in the classification of diabetes. All C-peptide measurements conducted in the diabetic population of Skaraborg (280,539 inhabitants and 3.2% diabetes) between 1995 and 1998 (3,115 samples) were considered, but only patients with well-defined diabetes type (1,449 samples from 1,093 patients) were analyzed for the correlation between diabetes type and C-peptide concentration. Serum C-peptide was measured after fasting over night (fCP), after glucagon stimulation (gCP), and randomly (rCP) without considering previous meals at an ordinary visit to the diabetic clinic (rCP). Receiver Operating Characteristic (ROC) curves were constructed to illustrate the power of the different C-peptide protocols and to determine the optimal cut-off values. Although all three tests had high discriminative power, the ROC curves demonstrated that rCP was superior to fCP and gCP in discriminating type 1 from type 2 diabetes. The optimal cut-off value for rCP was 0.50 nmol/L, for fCP 0.42 nmol/L, and for gCP 0.60 nmol/L. rCP is more powerful than fCP and gCP in distinguishing type 1 from type 2 diabetes and can therefore be recommended as a classification tool, particularly in outpatients.


[The determination of erythrocyte deformability using a filtration method].
Red cell deformability was assessed in donors, patients with chronic renal insufficiency, and with thermal injuries by filtration through special filters. Filtration of donor red cells decreased their count but insignificantly; in patients with chronic renal insufficiency this characteristic was lowered, particularly so before hemoperfusion, whereas after hemoperfusion red cell deformability improved. Changes of red cell deformability in patients with thermal injuries is an objective criterion reflecting the status of the erythron peripheral component in connection with the severity of injury and course of its healing.


Inflammation and oxidative stress in viper bite: an insight within and beyond.
Though systemic and local manifestations of snakebite are considered serious, the relevance of oxidative stress in viper bite pathology is largely denied. However, over the past decade, studies have provided substantial evidence for the presence of persistent oxidative stress in viper bite victims. This review aims at highlighting the disturbances in redox homeostasis soon after viper envenomation and its implications in the pathomechanism of secondary/long term complications including thrombocytopenia, hypopituitarism, infertility, renal abnormalities and persistent local tissue degradation. Both enzymatic and non-enzymatic components of viper venom play a pivotal role in bringing redox turbulence in victims. Venom-induced hemorrhage and necrosis with subsequent release of damage associated molecular pattern (DAMPs) molecules also contribute to sustained oxidative stress and inflammation. Studies have demonstrated that along with anti-venom therapy an antioxidant treatment during the early stages of viper bite and also long term treatment could help to reduce the occurrence of secondary/long term complications. Further, proper knowledge regarding the pathophysiology will allow for exploration of new avenues in the treatment of viper bite.


Mannich-type reactions in the gas-phase: the addition of enol silanes to cyclic N-acyliminium ions.
The intrinsic gas-phase reactivity of cyclic N-acyliminium ions in Mannich-type reactions with the parent enol silane, vinyloxytrimethylsilane, has been investigated by double- and triple-stage pentaquadrupole mass spectrometric experiments. Remarkably distinct reactivities are observed for cyclic N-acyliminium ions bearing either endocyclic or exocyclic carbonyl groups. NH-Acyliminium ions with endocyclic carbonyl groups locked in s-trans forms participate in a novel tandem N-acyliminium ion reaction: the nascent adduct formed by simple addition is unstable and rearranges by intramolecular trimethylsilyl cation shift to the ring nitrogen, and an acetaldehyde enol molecule is eliminated. An NSi(CH(3))(3)-acyliminium ion is formed, and this intermediate ion reacts with a second molecule of vinyloxytrimethylsilane by simple addition to form a stable acyclic adduct. N-Acyl and N,N-diacyliminium ions with endocyclic carbonyl groups, for which the s-cis conformation is favored, react distinctively by mono polar [4(+) + 2] cycloaddition yielding stable, ressonance-stabilized cycloadducts. Product ions were isolated via mass-selection and structurally characterized by triple-stage mass spectrometric experiments. B3LYP/6-311G(d,p) calculations corroborate the proposed reaction mechanisms.


Do two current canine parvovirus type 2 and 2b vaccines provide protection against the new type 2c variant?
Three groups (n=9 or 10) of 12-week-old canine parvovirus type 2 (CPV-2) antibody-negative puppies were vaccinated: one group with a product containing modified-live CPV-2b (Galaxy DA2PPv; Schering-Plough Animal Health), one group with a product containing modified-live CPV-2 (Continuum DAP, Intervet), and one group (controls) with sterile saline. All puppies receiving CPV-2 and CPV-2b vaccines developed antibody as determined by the hemagglutination inhibition assay. All groups of puppies were challenged with a combination of virulent CPV-2b and CPV-2c 5 weeks after vaccination. All puppies in the CPV-2 and CPV-2b vaccinated groups were protected from disease, whereas all control group puppies developed disease and 50% died or were euthanized. This study demonstrated that the CPV-2 and CPV-2b vaccine components of the Continuum DAP and Galaxy DA2PPv products, respectively, provided protection against the CPV-2b virus and also provided complete protection against the new CPV-2c variant.


Aversive Foraging Conditions Modulate Downstream Social Food Sharing.
Eusocial insects divide their labour so that individuals working inside the nest are affected by external conditions through a cascade of social interactions. Honey bees (Apis mellifera) transfer food and information via mouth-to-mouth social feeding, ie trophallaxis, a process known to be modulated by the rate of food flow at feeders and familiarity of food's scent. Little is understood about how aversive foraging conditions such as predation and con-specific competition affect trophallaxis. We hypothesized that aversive conditions have an impact on food transfer inside the colony. Here we explore the effect of foragers' aversive experience on downstream trophallaxis in a cage paradigm. Each cage contained one group of bees that was separated from feeders by mesh and allowed to feed only through trophallaxis, and another group that had access to feeders and self-specialized to either forage or distribute food. Our results show that aversive foraging conditions increase non-foragers' trophallaxis with bees restricted from feeder access when food is scented, and have the opposite effect when food is unscented. We discuss potential behavioural mechanisms and implications for the impact of aversive conditions such as malaise inducing toxins, predation, and con-specific competition.


[Laboratorial alteration preceding staphylococcal infection clinical manifestations after intestinal transplantation].
Hospital-acquired infection, often with Staphylococcus aureus, is an important complication in intestinal transplant. A 2-year-old girl underwent small bowel transplantation owing to a small bowel volvulus. On the first postoperative day, lymphocyte phenotypes, serum immunoglobulins and chemotactic and phagocytic activity of neutrophils were assessed in peripheral blood. A decrease in the ingestion phase of phagocytosis by neutrophils was identified, in comparison with the results of 20 healthy children. On the second day, the patient had low fever and, on the third, abdominal pain. In view of this, she underwent a laparotomy that revealed purulent ascites due to Staphylococcus aureus. Specific treatment resulted in rapid regression of the infectious condition and good evolution of the patient. A decrease in the ingestion stage of phagocytosis by neutrophils preceded staphylococcal purulent ascites clinical manifestations, and immunologic assessment contributed to early diagnosis and treatment of the infection. We believe evaluation of neutrophilic activity is important in patients undergoing intestinal transplantation in order for possible hospital-acquired infections to be early diagnosed.


Sociodemographic and Clinical Characteristics of Geriatric Patients with Psoriasis Receiving Narrowband Ultraviolet B Phototherapy.
Although the demographic and clinical characteristics of patients with psoriasis have been evaluated in many countries, studies specifically on geriatric patients remain scarce and none have focused on those receiving phototherapy. This study describes the sociodemographic and clinical characteristics of geriatric patients with psoriasis in Indonesia, specifically those who received narrowband ultraviolet B (NB-UVB) phototherapy. This retrospective study using data obtained from phototherapy and medical records of psoriasis patients who received phototherapy in 2014-2019 was conducted at the Dermatovenereology Clinic of Dr. Cipto Mangunkusumo National General Hospital. Among 24 geriatric patients with psoriasis who received NB-UVB phototherapy, the median age of onset was 61 years (range, 36-74 years). Regarding comorbidities, 15 patients (62.5%) had dyslipidemia, 15 patients (62.5%) had hypertension, 11 patients (45.8%) had obesity, 9 patients (37.5%) had periodontitis/gingivitis, 9 patients (37.5%) had type 2 diabetes mellitus, and 6 patients (25.0%) had hyperuricemia. Some comorbidities have been associated with psoriasis, including metabolic syndrome and periodontitis. The data from this study could help physicians in evaluating and making appropriate clinical decisions when managing psoriasis patients in the geriatric population.


Spontaneous testicular regression in collared lemmings (Dicrostonyx groenlandicus) exposed to prolonged long photoperiod.
Reproductive maturation and attainment of maximal gonadal size in collared lemmings (Dicrostonyx groenlandicus) is facilitated by transfer from a short photoperiod (8 h light: 16 h dark) to a long photoperiod (22 h light:2 h dark). However, reproductive maturation in lemmings born in 22 h light:2 h dark is impeded by exposure to the natal photoperiod of 22 h light:2 h dark. Data from adult lemmings suggest that prolonged exposure to a long photoperiod of 20 h light:4 h dark results in gonadal regression. The present experiments were conducted to test the hypothesis that adult lemmings exposed to a prolonged long photoperiod undergo testicular regression. Male collared lemmings were transferred at weaning (19 days of age) from the natal photoperiod of 8 h light:16 h dark to one of two long photoperiods: 22 h light:2 h dark or 24 h light:0 h dark (constant light). Gonadal mass was maximal in both groups 10 weeks after weaning. However, 20 weeks after weaning, gonadal mass in both groups was low (relative to that at 10 weeks), suggesting that regression had occurred. When testes mass was maximal 10 weeks after weaning, animals were transferred in groups from 22 h light:2 h dark to one of several shorter photoperiods: 20 h light:4 h dark, 18 h light:6 h dark, 16 h light:8 h dark, or 8 h light:16 h dark. Testes mass 20 weeks after weaning was greatest, that is, not different from maximal, in animals from the 20 h light:4 h dark and 18 h light:6 h dark groups, intermediate in animals from the 16 h light:8 h dark group, and low in animals from the 8 h light:16 h dark group. These observations indicate that transfer from 22 h light:2 h dark to a slightly shorter photoperiod permits maintenance of gonadal size, but transfer to a short photoperiod causes testicular regression. Body weight, bifid claw width and pelage colour did not change during spontaneous gonadal regression in animals housed in a long photoperiod for 20 weeks. These results suggest that prolonged exposure to an unchanging long photoperiod causes spontaneous testicular regression, and that photoperiod regulates reproductive and somatic parameters independently.


Pharmacological evaluation of mild analgesics.
1 The analgesic, anti-inflammatory, antipyretic and ulcerogenic properties of the non-steroidal agents, acetylsalicylic acid, paracetamol, ibuprofen, propyphenazone and aminophenazone are compared. 2 The results show that ibuprofen has the most potent effect on all four parameters followed in descending order of potency by aminophenazone, propyphenazone, paracetamol and acetylsalicylic acid. 3 The inflamed paw technique and the adjuvant arthritis model, both in the rat and involving pathological (chronic) pain, are the most successful methods of predicting analgesic activity in man. The short-lasting oedema caused by injecting naphthoylheparamine into the rat paw is the most useful method of predicting clinical anti-inflammatory activity.


Increasing voluntary medical male circumcision uptake among adult men in Tanzania.
We evaluated a demand-creation intervention to increase voluntary medical male circumcision (VMMC) uptake among men aged 20-34 years in Tanzania, to maximise short-term impact on HIV incidence. A cluster randomized controlled trial stratified by region was conducted in 20 outreach sites in Njombe and Tabora regions. The sites were randomized 1 : 1 to receive either a demand-creation intervention package in addition to standard VMMC outreach, or standard VMMC outreach alone. The intervention package included enhanced public address messages, peer promotion by recently circumcised men, facility setup to increase privacy, and engagement of female partners in demand creation. The primary outcome was the proportion of VMMC clients aged 20-34 years. Overall, 6251 and 3968 VMMC clients were enrolled in intervention and control clusters, respectively. The proportion of clients aged 20-34 years was slightly greater in the intervention than control arm [17.7 vs. 13.0%; prevalence ratio = 1.36; 95% confidence intervals (CI):0.9-2.0]. In Njombe region, the proportion of clients aged 20-34 years was similar between arms but a significant two-fold difference was seen in Tabora region (P value for effect modification = 0.006). The mean number of men aged 20-34 years (mean difference per cluster = 97; 95% CI:40-154), and of all ages (mean difference per cluster = 227, 95% CI:33-420) were greater in the intervention than control arm. The intervention was associated with a significant increase in the proportion of clients aged 20-34 years in Tabora but not in Njombe. The intervention may be sensitive to regional factors in VMMC programme scale-up, including saturation.


Monitoring COVID-19 contagion growth.
We present a statistical model that can be employed to monitor the time evolution of the COVID-19 contagion curve and the associated reproduction rate. The model is a Poisson autoregression of the daily new observed cases and dynamically adapt its estimates to explain the evolution of contagion in terms of a short-term and long-term dependence of case counts, allowing for a comparative evaluation of health policy measures. We have applied the model to 2020 data from the countries most hit by the virus. Our empirical findings show that the proposed model describes the evolution of contagion dynamics and determines whether contagion growth can be affected by health policies. Based on our findings, we can draw two health policy conclusions that can be useful for all countries in the world. First, policy measures aimed at reducing contagion are very useful when contagion is at its peak to reduce the reproduction rate. Second, the contagion curve should be accurately monitored over time to apply policy measures that are cost-effective.


Single cell RNA sequencing identifies early diversity of sensory neurons forming via bi-potential intermediates.
Somatic sensation is defined by the existence of a diversity of primary sensory neurons with unique biological features and response profiles to external and internal stimuli. However, there is no coherent picture about how this diversity of cell states is transcriptionally generated. Here, we use deep single cell analysis to resolve fate splits and molecular biasing processes during sensory neurogenesis in mice. Our results identify a complex series of successive and specific transcriptional changes in post-mitotic neurons that delineate hierarchical regulatory states leading to the generation of the main sensory neuron classes. In addition, our analysis identifies previously undetected early gene modules expressed long before fate determination although being clearly associated with defined sensory subtypes. Overall, the early diversity of sensory neurons is generated through successive bi-potential intermediates in which synchronization of relevant gene modules and concurrent repression of competing fate programs precede cell fate stabilization and final commitment.


Clinical outcome prediction in aneurysmal subarachnoid hemorrhage - Alterations in brain-body interface.
Brain-body associations are essential in influencing outcome in patients with ruptured brain aneurysms. Thus far, there is scarce literature on such important relationships. The multicenter Tirilazad database (3551 patients) was used to create this clinical outcome prediction model in order to elucidate significant brain-body associations. Traditional binary logistic regression models were used. Binary logistic regression main effects model included four statistically significant single prognostic variables, namely, neurological grade, age, stroke, and time to surgery. Logistic regression models demonstrated the significance of hypertension and liver disease in development of brain swelling, as well as the negative consequences of seizures in patients with a history of myocardial infarction and post-admission fever worsening neurological outcome. Using the aforementioned results generated from binary logistic regression models, we can identify potential patients who are in the high risk group of neurological deterioration. Specific therapies can be tailored to prevent these detriments, including treatment of hypertension, seizures, early detection and treatment of myocardial infarction, and prevention of hepatic encephalopathy.


Identifying reliable ions for the statistical differentiation of structurally similar fentanyl analogs.
Definitive identification of fentanyl analogs based on mass spectral comparison is challenging given the high degree of structural and, hence, spectral similarity. To address this, a statistical method was previously developed in which two electron-ionization (EI) mass spectra are compared using the unequal variance t-test. Normalized intensities of corresponding ions are compared, testing the null hypothesis (H0 ) that the difference in intensity is equal to zero. If H0 is accepted at all m/z values, the two spectra are statistically equivalent at the specified confidence level. If H0 is not accepted at any m/z value, then there is a significant difference in intensity at that m/z value between the two spectra. In this work, the statistical comparison method is applied to distinguish EI spectra of valeryl fentanyl, isovaleryl fentanyl, and pivaloyl fentanyl. Spectra of the three analogs were collected over a 9-month period and at different concentrations. At the 99.9% confidence level, the spectra of corresponding isomers were statistically associated. Spectra of different isomers were statistically distinct, and ions responsible for discrimination were identified in each comparison. To account for inherent instrument variations, discriminating ions for each pairwise comparison were ranked based on the magnitude of the calculated t-statistic (tcalc ) value. For a given comparison, ions with higher tcalc values are those with the greatest difference in intensity between the two spectra and, therefore, are considered more reliable for discrimination. Using these methods, objective discrimination among the spectra was achieved and ions considered most reliable for discrimination of these isomers were identified.


Programming complex shapes in thin nematic elastomer and glass sheets.
Nematic elastomers and glasses are solids that display spontaneous distortion under external stimuli. Recent advances in the synthesis of sheets with controlled heterogeneities have enabled their actuation into nontrivial shapes with unprecedented energy density. Thus, these have emerged as powerful candidates for soft actuators. To further this potential, we introduce the key metric constraint which governs shape-changing actuation in these sheets. We then highlight the richness of shapes amenable to this constraint through two broad classes of examples which we term nonisometric origami and lifted surfaces. Finally, we comment on the derivation of the metric constraint, which arises from energy minimization in the interplay of stretching, bending, and heterogeneity in these sheets.


Minimally invasive treatment for obstructive tumors of the left colon: endoluminal self-expanding metal stent and laparoscopic colectomy. Preliminary results.
Obstruction of the left colon may be the first manifestation of colorectal cancer. Resection of the colonic segment involved and the construction of an end colostomy (Hartman's procedure) is the most frequent treatment. Alternatives to the placement of a stoma are subtotal colectomy or intraoperative lavage of the colon and primary anastomosis, but their application depends on intraoperative findings and the availability of a skilled surgeon. The use of an expandable stent (SEMS) can enhance the feasibility of laparoscopic colectomy, avoiding the need for a colostomy and offering the advantages of a combination of two minimally invasive procedures. Between 1997 and 2004, an SEMS was placed in 11 cases of left colonic obstruction due to cancer, the obstruction being successfully resolved in each case. Seven patients were approached by laparoscopy to attempt the definitive colectomy. We evaluated the location and pathological characteristics of the tumor, effectiveness and complications of SEMS insertion, time interval between the insertion of SEMS and laparoscopic surgery, and postoperative data. The tumors were situated in the recto-sigma (1 case), sigma (3 cases) and descending colon (3 cases). Immediate relief of the obstruction was achieved in all cases after SEMS insertion of the stent, and oral diet was started at 24 h. The 7 patients were operated on an average of 8 days (range 6-14) after insertion of the stent. Conversion to open surgery was necessary in one case for reasons not related to the stent. Preliminary results of the combination of SEMS and elective laparoscopic surgery demonstrate that the procedure is feasible and that it presents all the clinical advantages of a minimally invasive approach. The procedure is a valid alternative to traditional major urgent surgery.


Hierarchy of elements regulating synthesis of ribosomal proteins in Saccharomyces cerevisiae.
Saccharomyces cerevisiae cells respond to a heat shock by temporarily slowing the synthesis of ribosomal proteins (C. Gorenstein and J. R. Warner, Proc. Natl. Acad. Sci. U.S.A. 73:1574-1551, 1976). When cultures growing oxidatively on ethanol as the sole carbon source were shifted from 23 to 36 degrees C, the synthesis of ribosomal proteins was coordinately inhibited twice as rapidly and 45% more severely than in comparable cultures growing fermentatively on glucose. Within 15 min, the relative rates of synthesis of at least 30 ribosomal proteins declined to less than one-sixth their initial values, whereas the overall rate of protein synthesis increased at least threefold. We suggest that this is due primarily to controls at the level of synthesis of messenger ribonucleic acid for ribosomal proteins but may also involve changes in messenger ribonucleic acid stability. In contrast, a nutritional shift-up causes a stimulation of the synthesis of ribosomal proteins. Experiments designed to determine the hierarchy of stimuli affecting the synthesis of these proteins demonstrated that temperature shock was dominant to glucose stimulation. When a culture growing on ethanol was shifted from 23 to 36 degrees C and glucose was added shortly afterward, the decline in ribosomal protein synthesis continued unabated. However, in wild-type cells ribosomal protein synthesis began to recover within 15 min. In mutants temperature sensitive for ribosome synthesis, e.g., rna2, there was no recovery in the synthesis of most ribosomal proteins, suggesting that the product of rna2 is essential for the production of these proteins under all vegetative conditions.


Defining exceptional cognition in older adults: A systematic review of cognitive super-ageing.
A consistent approach to defining cognitive super-ageing is needed to increase the value of research insights that may be gained from studying this population including ageing well and preventing and treating neurodegenerative conditions. This review aims to evaluate the existing definitions of 'super-ageing' with a focus on cognition. A systematic literature search was conducted across PubMed, Embase, Web of Science, Scopus, PsycINFO and Google Scholar from inception to 24 July 2023. Of 44 English language studies that defined super-ageing from a cognitive perspective in older adults (60-97 years), most (n = 33) were based on preserved verbal episodic memory performance comparable to that of younger adult in age range 16-65 years. Eleven studies defined super-agers as the top cognitive performers for their age group based upon standard deviations or percentiles above the population mean. Only nine studies included longitudinal cognitive performance in their definitions. Equivalent cognitive abilities to younger adults, exceptional cognition for age and a lack of cognitive deterioration over time are all meaningful constructs and may provide different insights into cognitive ageing. Using these criteria in combination or individually to define super-agers, with a clear rationale for which elements have been selected, could be fit for purpose depending on the research question. However, major discrepancies including the age range of super-agers and comparator groups and the choice of cognitive domains assessed should be addressed to reach some consensus in the field.


Construction of biologically functional bacterial plasmids in vitro.
The construction of new plasmid DNA species by in vitro joining of restriction endonuclease-generated fragments of separate plasmids is described. Newly constructed plasmids that are inserted into Escherichia coli by transformation are shown to be biologically functional replicons that possess genetic properties and nucleotide base sequences from both of the parent DNA molecules. Functional plasmids can be obtained by reassociation of endonuclease-generated fragments of larger replicons, as well as by joining of plasmid DNA molecules of entirely different origins.


Does bereavement-related major depression differ from major depression associated with other stressful life events?
Of the stressful life events influencing risk for major depression, DSM-III and DSM-IV assign a special status to bereavement. A depressive episode that is bereavement-related and has clinical features and course characteristic of normal grief is not diagnosed as major depression. This study evaluates the empirical validity of this exclusion criterion. To determine the similarities of bereavement-related depression and depression related to other stressful life events, the authors identified and compared cases on a range of validators in a large-population-based sample of twins. The authors evaluated whether cases of bereavement-related depression that also met DSM criteria for "normal grief" were qualitatively distinct from other depressive cases. Eighty-two individuals with confirmed bereavement-related depression and 224 with confirmed depression related to other stressful life events were identified. The two groups did not differ in age at onset of major depression, number of prior episodes, duration of index episode, number of endorsed "A criteria," risk for future episodes, pattern of comorbidity, levels of extraversion, risk for major depression in their co-twin, or the proportion meeting criteria for "normal grief." However, individuals with bereavement-related depression were slightly older, and more likely to be female, and had lower levels of neuroticism, treatment-seeking, and guilt and higher levels of fatigue and loss of interest. Interaction analyses failed to find unique features of people whose illness met criteria for both bereavement-related depression and normal grief compared to those whose illness was related to other life stressors. The similarities between bereavement-related depression and depression related to other stressful life events substantially outweigh their differences. These results question the validity of the bereavement exclusion for the diagnosis of major depression.


Chronically administered retinoic acid has trophic effects in the rat small intestine and promotes adaptation in a resection model of short bowel syndrome.
Following the loss of functional small bowel surface area, the intestine undergoes a compensatory adaptive response. The observation that adaptation is inhibited in vitamin A-deficient rats following submassive intestinal resection suggested that vitamin A is required for this response and raised the possibility that exogenous vitamin A could augment adaptation. Therefore, to directly assess whether chronically administered retinoic acid could stimulate gut adaptation in a model of short bowel syndrome and to address the mechanisms of any such effects, Sprague-Dawley rats were implanted with controlled release retinoic acid or control pellets and then subjected to mid-small bowel or sham resections. At 2 wk postoperation, changes in gut morphology, crypt cell proliferation and apoptosis, enterocyte migration, the extracellular matrix, and gene expression were assessed. Retinoic acid had significant trophic effects in resected and sham-resected rats. Retinoic acid markedly inhibited apoptosis and stimulated crypt cell proliferation and enterocyte migration postresection. Data presented indicate that these proadaptive effects of retinoic acid may be mediated via changes in the extracellular matrix (e.g., by increasing collagen IV synthesis, decreasing E-cadherin expression, and reducing integrin beta(3) levels), via affects on Hedgehog signaling (e.g., by reducing expression of the Hedgehog receptors Ptch and Ptch2 and the Gli1 transcription factor), by increasing expression of Reg1 and Pap1, and by modulation of retinoid and peroxisome proliferator-activated receptor signaling pathways. These studies are the first to demonstrate that retinoic acid can significantly enhance intestinal adaptation and suggest it may be beneficial in patients with short bowel syndrome.


[Role of structural polymorphism of the angiotensin-converting enzyme gene in the development of myocardial infarction].
Genotyping of angiotensin-converting enzyme (ACE) using polymerase chain reaction was conducted in 184 males with acute macrofocal infarction versus 72 males free of arterial hypertension and ischemic heart disease (controls). The age of the patients ranged from 30 to 70 years. Normotensive patients who survived myocardial infarction at the age under 60 had significantly more frequent genotype DD (in the system I/D-polymorphism of ACE gene) than controls or hypertensive patients. The involvement of genotype DD in the onset of myocardial infarction in normotensives was observed at the middle, presenile and senile age. A significant association was found between hereditary IHD loading and carriage of DD genotype in normotensive patients with myocardial infarction.


Distribution and estrogen regulation of membrane progesterone receptor-β in the female rat brain.
Although several studies have reported the localization of membrane progesterone (P(4)) receptors (mPR) in various tissues, few have attempted to describe the distribution and regulation of these receptors in the brain. In the present study, we investigated expression of two mPR subtypes, mPRα and mPRβ, within regions of the brain, known to express estradiol (E(2))-dependent [preoptic area (POA) and hypothalamus] and independent (cortex) classical progestin receptors. Saturation binding and Scatchard analyses on plasma membranes prepared from rat cortex, hypothalamus, and POA demonstrated high-affinity, specific P(4)-binding sites characteristic of mPR. Using quantitative RT-PCR, we found that mPRβ mRNA was expressed at higher levels than mPRα, indicating that mPRβ may be the primary mPR subtype in the rat brain. We also mapped the distribution of mPRβ protein using immunohistochemistry. The mPRβ-immunoreactive neurons were highly expressed in select nuclei of the hypothalamus (paraventricular nucleus, ventromedial hypothalamus, and arcuate nucleus), forebrain (medial septum and horizontal diagonal band), and midbrain (oculomotor and red nuclei) and throughout many areas of the cortex and thalamus. Treatment of ovariectomized female rats with E(2) benzoate increased mPRβ immunoreactivity within the medial septum but not the medial POA, horizontal diagonal band, or oculomotor nucleus. Together, these findings demonstrate a wide distribution of mPRβ in the rodent brain that may contribute to functions affecting behavioral, endocrine, motor, and sensory systems. Furthermore, E(2) regulation of mPRβ indicates a mechanism through which estrogens can regulate P(4) function within discrete brain regions to potentially impact behavior.


Comorbidity Burden and Adverse Outcomes After Transcatheter Aortic Valve Replacement.
Background Transcatheter aortic valve replacement (TAVR) has become the preferred treatment for symptomatic patients with aortic stenosis and elevated procedural risk. Many deaths following TAVR are because of noncardiac causes and comorbid disease burden may be a major determinant of postprocedure outcomes. The prevalence of comorbid conditions and associations with outcomes after TAVR has not been studied. Methods and Results This was a retrospective single-center study of patients treated with TAVR from January 2015 to October 2018. The association between 21 chronic conditions and short- and medium-term outcomes was assessed. A total of 341 patients underwent TAVR and had 1-year follow-up. The mean age was 81.4 (SD 8.0) years with a mean Society of Thoracic Surgeons predicted risk of mortality score of 6.7% (SD 4.8). Two hundred twenty (65%) patients had ≥4 chronic conditions present at the time of TAVR. There was modest correlation between Society of Thoracic Surgeons predicted risk of mortality and comorbid disease burden (r=0.32, P<0.001). After adjusting for Society of Thoracic Surgeons predicted risk of mortality, age, and vascular access, each additional comorbid condition was associated with increased rates of 30-day rehospitalizations (odds ratio, 1.21; 95% CI, 1.02-1.44), a composite of 30-day rehospitalization and 30-day mortality (odds ratio, 1.20; 95% CI, 1.02-1.42), and 1-year mortality (odds ratio, 1.29; 95% CI, 1.05-1.59). Conclusions Comorbid disease burden is associated with worse clinical outcomes in high-risk patients treated with TAVR. The risks associated with comorbid disease burden are not adequately captured by standard risk assessment. A systematic assessment of comorbid conditions may improve risk stratification efforts.


A chemical analog of curcumin as an improved inhibitor of amyloid Abeta oligomerization.
Amyloid-like plaques are characteristic lesions defining the neuropathology of Alzheimer's disease (AD). The size and density of these plaques are closely associated with cognitive decline. To combat this disease, the few therapies that are available rely on drugs that increase neurotransmission; however, this approach has had limited success as it has simply slowed an imminent decline and failed to target the root cause of AD. Amyloid-like deposits result from aggregation of the Aβ peptide, and thus, reducing amyloid burden by preventing Aβ aggregation represents an attractive approach to improve the therapeutic arsenal for AD. Recent studies have shown that the natural product curcumin is capable of crossing the blood-brain barrier in the CNS in sufficient quantities so as to reduce amyloid plaque burden. Based upon this bioactivity, we hypothesized that curcumin presents molecular features that make it an excellent lead compound for the development of more effective inhibitors of Aβ aggregation. To explore this hypothesis, we screened a library of curcumin analogs and identified structural features that contribute to the anti-oligomerization activity of curcumin and its analogs. First, at least one enone group in the spacer between aryl rings is necessary for measureable anti-Aβ aggregation activity. Second, an unsaturated carbon spacer between aryl rings is essential for inhibitory activity, as none of the saturated carbon spacers showed any margin of improvement over that of native curcumin. Third, methoxyl and hydroxyl substitutions in the meta- and para-positions on the aryl rings appear necessary for some measure of improved inhibitory activity. The best lead inhibitors have either their meta- and para-substituted methoxyl and hydroxyl groups reversed from that of curcumin or methoxyl or hydroxyl groups placed in both positions. The simple substitution of the para-hydroxy group on curcumin with a methoxy substitution improved inhibitor function by 6-7-fold over that measured for curcumin.


[Management of prostate cancer in the elderly man].
In Switzerland and in most developed countries, the incidence of prostate cancer (PCa) is increasing, especially in older men. More than half of PCa are diagnosed over 70 years. The elderly population can be very heterogeneous and their management is a real challenge for all physicians. Older patients with PCa should be managed according to their individual health status, which is driven mainly by the severity of associated comorbid conditions, and not by patient's age. A complete assessment of their health status with validated measurement tools, like the G8 questionnaire (Geriatric 8) and the CISR-G (Cumulative Illness Rating Score-Geriatrics), is necessary to ensure a personalized treatment. This optimal assessment depends on the quality of collaboration between urologists, geriatricians, general practicians and other specialists, which can be accomplished for example in a prostate cancer center.


Computed tomography imaging of acute neck inflammatory processes.
Early diagnosis and management of neck infections and inflammatory processes is a common challenge for emergency and ear, neck and throat physicians, as well as radiologists. Emergency neck infections are diverse in their presentation, ranging from a transient enlargement of a lymph node to a rapidly spreading necrotizing fasciitis. Symptoms and signs, with the clinical history, usually suggest the diagnosis. But complex neck anatomy and sometimes limited physical examination can obscure and delay diagnosis, thus the need for an appropriate imaging exam and correct interpretation. In this pictorial review, we will consider common neck acute inflammatory processes that may be encountered in the emergency room and discuss some of their salient imaging findings.


May 2003: 57-year-old-woman with acute loss of strength in her right upper extremity and slurred speech.
The May 2003 COM. A 57-year-old woman presented with slurring of her speech and right arm weakness. Her past medical history included idiopathic hypertrophic subendocardial stenosis (IHSS), arthritis, asthma, congestive heart failure, hypertension and NIDDM. Neurological examination showed persistent word finding difficulty but her motor and sensory function had essentially returned to normal. Extensive laboratory studies were unrevealing. Imaging studies showed a meningeal lesion over the left posterior parietal lobe and the findings suggested an infectious or inflammatory process. A biopsy of the involved dura and meninges was performed and revealed leptomeningeal Rosai-Dorfman disease. Emperipolesis was noted. The finding of emperipolesis is characteristic of Rosai-Dorfman disease of the leptomeninges, but in 30% of cases, this feature will not be identified. Large pale histiocytes of Rosai-Dorfman disease are immunoreactive for S-100 protein and KP1, but negative for CD1a. The differential diagnosis of a chronic inflammatory infiltrate containing numerous, large histiocytes includes granulomatous diseases such as Wegener graulomatosis and sarcoid, Hodgkin disease, and Langerhans histiocytosis. CNS Rosai-Dorfman most commonly involves patients between 20- and 40-years-old, with a slight male predominance. Approximately 75% of cases are intracranial, whereas 20% involve the spine. Over 90% of CNS Rosai-Dorfman cases involve the leptomeninges and are seen by neuroimaging as a dural-based, contrast-enhancing masses that often elicit vasogenic edema in the underlying brain. Thus, clinically and radiologically, the disease is thought to represent meningioma. Leptomeningeal Rosai-Dorfman disease is considered a benign condition and in most cases surgical resection is the treatment of choice. Although the number of cases in the literature is small, disease progression following surgical resection is uncommon. Little is known regarding the pathogenesis of Rosai-Dorfman disease. Most have suggested that it represents either an autoimmune disease or a reaction to an infectious agent that has yet to be discovered. Currently it is best considered a benign, idiopathic histiocytosis.


Ecology, histopathology, and microbial ecology of a white-band disease outbreak in the threatened staghorn coral Acropora cervicornis.
This study is a multi-pronged description of a temperature-induced outbreak of white-band disease (WBD) that occurred in Acropora cervicornis off northern Miami Beach, Florida (USA), from July to October 2014. We describe the ecology of the disease and examine diseased corals using both histopathology and next-generation bacterial 16S gene sequencing, making it possible to better understand the effect this disease has on the coral holobiont, and to address some of the seeming contradictions among previous studies of WBD that employed either a purely histological or molecular approach. The outbreak began in July 2014, as sea surface temperatures reached 29°C, and peaked in mid-September, a month after the sea surface temperature maximum. The microscopic anatomy of apparently healthy portions of colonies displaying active disease signs appeared normal except for some tissue atrophy and dissociation of mesenterial filaments deep within the branch. Structural changes were more pronounced in visibly diseased fragments, with atrophy, necrosis, and lysing of surface and basal body wall and polyp structures at the tissue-loss margin. The only bacteria evident microscopically in both diseased and apparently healthy tissues with Giemsa staining was a Rickettsiales-like organism (RLO) occupying mucocytes. Sequencing also identified bacteria belonging to the order Rickettsiales in all fragments. When compared to apparently healthy fragments, diseased fragments had more diverse bacterial communities made up of many previously suggested potential primary pathogens and secondary (opportunistic) colonizers. Interactions between elevated seawater temperatures, the coral host, and pathogenic members of the diseased microbiome all contribute to the coral displaying signs of WBD.


Confined-space synthesis of single crystal TiO₂ nanowires in atmospheric vessel at low temperature: a generalized approach.
Extensive efforts have been devoted to develop innovative synthesis strategies for nanomaterials in order to exploit the true potential of nanotechnology. However, most approaches require high temperature or high pressure to favor crystallization. Here we highlight an unconventional approach for the confined-space synthesis of the single crystal TiO₂ nanowires in the atmospheric vessel at low temperature by cleverly manipulating the unique physical properties of straight-chain saturated fatty acids. Our method also applys to icosane due to its straight-chain saturated hydrocarbon structure and similar physical properties to the saturated fatty acids. Interestingly, we also found that the unsaturated fatty acids can facilitate the crystal growth, but their bent chains lead to the formation of TiO₂ particle aggregates. In addition, we demonstrate the growth of TiO₂ nanowires on arbitrary substrates, which are of great importance for their wider applications. We thus anticipate our presented method to be a possible starting point for non-classical crystallization strategies and be easily adapted for the fabrication of all other inorganic materials.


Association between Depression and C-Reactive Protein.
Objective. Depression has been associated with increased cardiovascular disease risk, and a depression-related elevation of high sensitivity C-reactive protein (hs-CRP) has been proposed as a possible mechanism. The objective of this paper is to examine association between depression and high sensitivity C-reactive protein (hs-CRP). Methods. Subjects consisted of 508 healthy adults (mean age 48.5 years; 49% women, 88% white) residing in central Massachusetts. Data were collected at baseline and at quarterly intervals over a one-year period per individual. Multivariable linear mixed models were used to assess the association for the entire sample and by gender. Results. The mean Beck Depression Inventory score was 5.8 (standard deviation (SD) 5.4; median 4.3), and average serum hs-CRP was 1.8 mg/L (SD 1.7; median 1.2). Results from the multivariable linear mixed models show that individuals with higher depression scores have higher levels of hs-CRP. Analyses by gender show persistence of an independent association among women, but not among men. Body mass index (BMI = weight(kg)/height(m)(2)) appears to be a partial mediator of this relationship. Conclusion. Depression score was correlated to hs-CRP levels in women. Further studies are required to elucidate the biological mechanisms underlying these associations and their implications.


MAPK1 is required for establishing the pattern of cell proliferation and for cell survival during lens development.
The mitogen-activated protein kinases (MAPKs; also known as ERKs) are key intracellular signaling molecules that are ubiquitously expressed in tissues and were assumed to be functionally equivalent. Here, we use the mouse lens as a model system to investigate whether MAPK1 plays a specific role during development. MAPK3 is known to be dispensable for lens development. We demonstrate that, although MAPK1 is uniformly expressed in the lens epithelium, its deletion significantly reduces cell proliferation in the peripheral region, an area referred to as the lens germinative zone in which most active cell division occurs during normal lens development. By contrast, cell proliferation in the central region is minimally affected by MAPK1 deletion. Cell cycle regulators, including cyclin D1 and survivin, are downregulated in the germinative zone of the MAPK1-deficient lens. Interestingly, loss of MAPK1 subsequently induces upregulation of phosphorylated MAPK3 (pMAPK3) levels in the lens epithelium; however, this increase in pMAPK3 is not sufficient to restore cell proliferation in the germinative zone. Additionally, MAPK1 plays an essential role in epithelial cell survival but is dispensable for fiber cell differentiation during lens development. Our data indicate that MAPK1/3 control cell proliferation in the lens epithelium in a spatially defined manner; MAPK1 plays a unique role in establishing the highly mitotic zone in the peripheral region, whereas the two MAPKs share a redundant role in controlling cell proliferation in the central region of the lens epithelium.


HERC2 targets the iron regulator FBXL5 for degradation and modulates iron metabolism.
FBXL5 (F-box and leucine-rich repeat protein 5) is the F-box protein subunit of, and therefore responsible for substrate recognition by, the SCF(FBXL5) ubiquitin-ligase complex, which targets iron regulatory protein 2 (IRP2) for proteasomal degradation. IRP2 plays a central role in the maintenance of cellular iron homeostasis in mammals through posttranscriptional regulation of proteins that contribute to control of the intracellular iron concentration. The FBXL5-IRP2 axis is integral to control of iron metabolism in vivo, given that mice lacking FBXL5 die during early embryogenesis as a result of unrestrained IRP2 activity and oxidative stress attributable to excessive iron accumulation. Despite its pivotal role in the control of iron homeostasis, however, little is known of the upstream regulation of FBXL5 activity. We now show that FBXL5 undergoes constitutive ubiquitin-dependent degradation at the steady state. With the use of a proteomics approach to the discovery of proteins that regulate the stability of FBXL5, we identified the large HECT-type ubiquitin ligase HERC2 (HECT and RLD domain containing E3 ubiquitin protein ligase 2) as an FBXL5-associated protein. Inhibition of the HERC2-FBXL5 interaction or depletion of endogenous HERC2 by RNA interference resulted in the stabilization of FBXL5 and a consequent increase in its abundance. Such accumulation of FBXL5 in turn led to a decrease in the intracellular content of ferrous iron. Our results thus suggest that HERC2 regulates the basal turnover of FBXL5, and that this ubiquitin-dependent degradation pathway contributes to the control of mammalian iron metabolism.


Filtration, diffusion, and molecular sieving through porous cellulose membranes.
1. A study has been made of the diffusion and filtration of a graded series of molecules (including tritium-labelled water, urea, glucose, antipyrine, sucrose, raffinose, and hemoglobin) in aqueous solution through porous cellulose membranes of three degrees of porosity. 2. Experimental results were in close agreement with predictions based on the membrane pore theory of Pappenheimer et al. (1,2). Restriction to molecular diffusion is a function of pore radius and molecular radius described by equation (11) in the text. Molecular sieving during ultrafiltration is a function of total pore area per unit path length, pore radius, molecular radius, and filtration rate given by equations (16) and (19). 3. Estimates of average pore radius made by means of this theory were considerably larger than estimates made by the method of Elford and Ferry (3) (Table II). Sources of error in the latter method are discussed and a new method of membrane calibration is proposed in which the total cross-sectional area of the pores is measured by direct diffusion of isotope-labelled water. 4. Steady-state osmotic pressures of solutions of sucrose and raffinose measured during molecular sieving through cellulose membranes were found to be close to the "ideal" osmotic pressures calculated by van't Hoff's law. Thus the present experimental data support the methods used by Pappenheimer et al. in their studies on living capillary walls as well as their theory of membrane pore permeability.


Enantioselective effects of chiral prothioconazole and its metabolites: Oxidative stress in HepG2 cells and lysozyme activity.
Chiral pesticides may exhibit enantioselectivity in terms of bioconcentration, environmental fate, and reproductive toxicity. Here, chiral prothioconazole and its metabolites were selected to thoroughly investigate their enantioselective toxicity and mechanisms at the molecular and cellular levels. Multispectral techniques revealed that the interaction between chiral PTC/PTCD and lysozyme resulted in the formation of a complex, leading to a change in the conformation of lysozyme. Meanwhile, the effect of different conformations of PTC/PTCD on the conformation of lysozyme differed, and its metabolites were able to exert a greater effect on lysozyme compared to prothioconazole. Moreover, the S-configuration of PTCD interacted most strongly with lysozyme. This conclusion was further verified by DFT calculations and molecular docking as well. Furthermore, the oxidative stress indicators within HepG2 cells were also affected by chiral prothioconazole and its metabolites. Specifically, S-PTCD induced more substantial perturbation of the normal oxidative stress processes in HepG2 cells, and the magnitude of the perturbation varied significantly among different configurations (P > 0.05). Overall, chiral prothioconazole and its metabolites exhibit enantioselective effects on lysozyme conformation and oxidative stress processes in HepG2 cells. This work provides a scientific basis for a more comprehensive risk assessment of the environmental behaviors and effects caused by chiral pesticides, as well as for the screening of highly efficient and less biotoxic enantiomeric monomers.


Search filters can find some but not all knowledge translation articles in MEDLINE: an analytic survey.
Advances from health research are not well applied giving rise to over- and underuse of resources and inferior care. Knowledge translation (KT), actions and processes of getting research findings used in practice, can improve research application. The KT literature is difficult to find because of nonstandardized terminology, rapid evolution of the field, and it is spread across several domains. We created multiple search filters to retrieve KT articles from MEDLINE. Analytic survey using articles from 12 journals tagged as having KT content and also as describing a KT application or containing a KT theory. Of 2,594 articles, 579 were KT articles of which 201 were about KT applications and 152 about KT theory. Search filter sensitivity (retrieval efficiency) maximized at 83%-94% with specificity (no retrieval of irrelevant material) approximately 50%. Filter performances were enhanced with multiple terms, but these filters often had reduced specificity. Performance was higher for KT applications and KT theory articles. These filters can select KT material although many irrelevant articles also will be retrieved. KT search filters were developed and tested, with good sensitivity but suboptimal specificity. Further research must improve their performance.


The participation of community pharmacists in the case management of malaria in Enugu metropolis, Nigeria: a cross-sectional survey.
Nigeria accounts for approximately 25% of the global malaria burden. Malaria is a major cause of morbidity and mortality, especially in children and pregnant women. Pharmacists play vital roles in the fight against malaria. However, in Nigeria, the role of the community pharmacist in managing cases of malaria has received very little research attention. This study aimed to evaluate the level of participation of community pharmacists in the management of malaria cases in Enugu metropolis and to explore factors associated with such participation. A cross-sectional survey was conducted among community pharmacists in Enugu metropolis using a modified and re-validated 16-item self-administered questionnaire. The questionnaire was distributed to participants in selected pharmacies for completion. Descriptive statistics and the chi-square test were used for statistical analysis. Out of the 103 participants, more than half (55.3%) were male. More than half of the pharmacists satisfactorily provided preventive (57.3%), pharmaceutical (62.1%), and curative (51.1%) services for patients with malaria. Overall, 57% of the pharmacists satisfactorily participated in the management of malaria cases. The number of years of practice was significantly associated with the pharmacists level of involvement in preventive (P=0.003) and curative (P=0.018) services. However, the provision of pharmaceutical care services for malaria patients was significantly associated with the sex of the respondents (P=0.023). Our results suggest that more than half of the community pharmacists in Enugu metropolis were satisfactorily involved in the management of malaria cases. However, the number of years of practice and sex were factors associated with the extent of pharmacist involvement in the management of malaria cases.


Genetic and phenotypic analysis of the genes of the elbow-no-ocelli region of chromosome 2L of Drosophila melanogaster.
The elbow locus is found to be two genes elA and elB, each of which has a distinct phenotype when mutant. Mutations of the elA gene have a strong phenotype where the wing is markedly disrupted. Mutations of elB are weak, mainly affecting the alula and the wing bristles. The two genes are dominant enhancers of each other. Homozygous deletion of the complete elbow region results in lethality. Situated between the elbow genes is the pupal gene and a locus which when deleted causes a crippled leg phenotype. This locus may be a control region for elbow. Immediately adjacent on the proximal side of elA is the no-ocelli locus. The phenotypes of noc alleles vary from extreme, where the ocelli and associated bristles are absent, to weak where these structures are disrupted. The various noc phenotypes are associated with genetically distinct gene regions, mutations of which act as enhancers of each other. Alleles of el and noc show partial failure of complementation, heterozygotes having weak el or weak noc phenotypes. Alleles of both these genes interact with the antimorphic noc allele Sco.


The context of delusional experiences in the daily life of patients with schizophrenia.
Global characteristics and psychosocial risk factors related to delusions have been identified. The present study extends these findings to the level of everyday functioning, identifying characteristics of delusional moments (DMs) and contextual risk and protective factors for delusional exacerbations in daily life. Data were collected using the Experience Sampling Method (ESM), a time-sampling technique. Forty-eight chronic patients diagnosed with schizophrenia rated the intensity of pathological symptoms and mood states and described their thoughts and the environmental context during consecutive moments in daily life. Delusions were defined on the basis of self-rated suspicion, preoccupation, feeling controlled, and coded thought pathology. Daily context included current activity, persons present and location. Characteristics of DMs and non-delusional moments (nDMs) were compared, and a multilevel logistic regression model was used to identify contexts that might trigger or prevent DMs. On average, patients experienced delusions less than one-third of the time. DMs were characterized by higher negative affect and lower positive affect. The presence of family or acquaintances decreased the risk of subsequently experiencing a DM, whereas withdrawal from activities increased this risk. Data support the validity of ESM for investigating delusions in schizophrenia. Daily life contexts appear to alter the probability that delusions will occur. Knowledge about such contexts may therefore be useful in helping patients develop better coping strategies and in creating therapeutic interventions that can lessen emotional distress.


Genome-wide association study for sight-threatening diabetic retinopathy reveals association with genetic variation near the GRB2 gene.
Diabetic retinopathy is a serious complication of diabetes mellitus and can lead to blindness. A genetic component, in addition to traditional risk factors, has been well described although strong genetic factors have not yet been identified. Here, we aimed to identify novel genetic risk factors for sight-threatening diabetic retinopathy using a genome-wide association study. Retinopathy was assessed in white Australians with type 2 diabetes mellitus. Genome-wide association analysis was conducted for comparison of cases of sight-threatening diabetic retinopathy (n = 336) with diabetic controls with no retinopathy (n = 508). Top ranking single nucleotide polymorphisms were typed in a type 2 diabetes replication cohort, a type 1 diabetes cohort and an Indian type 2 cohort. A mouse model of proliferative retinopathy was used to assess differential expression of the nearby candidate gene GRB2 by immunohistochemistry and quantitative western blot. The top ranked variant was rs3805931 with p = 2.66 × 10(-7), but no association was found in the replication cohort. Only rs9896052 (p = 6.55 × 10(-5)) was associated with sight-threatening diabetic retinopathy in both the type 2 (p = 0.035) and the type 1 (p = 0.041) replication cohorts, as well as in the Indian cohort (p = 0.016). The study-wide meta-analysis reached genome-wide significance (p = 4.15 × 10(-8)). The GRB2 gene is located downstream of this variant and a mouse model of retinopathy showed increased GRB2 expression in the retina. Genetic variation near GRB2 on chromosome 17q25.1 is associated with sight-threatening diabetic retinopathy. Several genes in this region are promising candidates and in particular GRB2 is upregulated during retinal stress and neovascularisation.


Calcineurin controls hyphal growth, virulence, and drug tolerance of Candida tropicalis.
Candida tropicalis, a species closely related to Candida albicans, is an emerging fungal pathogen associated with high mortality rates of 40 to 70%. Like C. albicans and Candida dubliniensis, C. tropicalis is able to form germ tubes, pseudohyphae, and hyphae, but the genes involved in hyphal growth machinery and virulence remain unclear in C. tropicalis. Recently, echinocandin- and azole-resistant C. tropicalis isolates have frequently been isolated from various patients around the world, making treatment difficult. However, studies of the C. tropicalis genes involved in drug tolerance are limited. Here, we investigated the roles of calcineurin and its potential target, Crz1, for core stress responses and pathogenesis in C. tropicalis. We demonstrate that calcineurin and Crz1 are required for hyphal growth, micafungin tolerance, and virulence in a murine systemic infection model, while calcineurin but not Crz1 is essential for tolerance of azoles, caspofungin, anidulafungin, and cell wall-perturbing agents, suggesting that calcineurin has both Crz1-dependent and -independent functions in C. tropicalis. In addition, we found that calcineurin and Crz1 have opposite roles in controlling calcium tolerance. Calcineurin serves as a negative regulator, while Crz1 plays a positive role for calcium tolerance in C. tropicalis.


Selection of relevant features in a fuzzy genetic learning algorithm.
Genetic algorithms offer a powerful search method for a variety of learning tasks, and there are different approaches in which they have been applied to learning processes. Structural learning algorithm on vague environment (SLAVE) is a genetic learning algorithm that uses the iterative approach to learn fuzzy rules. SLAVE can select the relevant features of the domain, but when working with large databases the search space is too large and the running time can sometimes be excessive. We propose to improve SLAVE by including a feature selection model in which the genetic algorithm works with individuals (representing individual rules) composed of two structures: one structure representing the relevance status of the involved variables in the rule, the other one representing the assignments variable/value. For this general representation, we study two alternatives depending on the information coded in the first structure. When compared with the initial algorithm, this new approach of SLAVE reduces the number of rules, simplifies the structure of the rules and improves the total accuracy.


Pervasive hybridizations in the history of wheat relatives.
Cultivated wheats are derived from an intricate history of three genomes, A, B, and D, present in both diploid and polyploid species. It was recently proposed that the D genome originated from an ancient hybridization between the A and B lineages. However, this result has been questioned, and a robust phylogeny of wheat relatives is still lacking. Using transcriptome data from all diploid species and a new methodological approach, our comprehensive phylogenomic analysis revealed that more than half of the species descend from an ancient hybridization event but with a more complex scenario involving a different parent than previously thought-Aegilops mutica, an overlooked wild species-instead of the B genome. We also detected other extensive gene flow events that could explain long-standing controversies in the classification of wheat relatives.


Protective effects of [6]-paradol on histological lesions and immunohistochemical gene expression in DMBA induced hamster buccal pouch carcinogenesis.
The search for naturally occurring agents in routinely consumed foods that may inhibit cancer development is of high priority. [6]-Paradol is a pungent phenolic bioactive component from ginger with well- documented health promoting antioxidant, antimutagenic, antigenotoxic and anti-inflammatory properties. However, anticarcinogenic effects have yet to be fully explored. The objectives of the present study were therefore to assess protective effects against 7,12-dimethylbenz(a)anthracene (DMBA) induced buccal pouch carcinogenesis in male golden Syrian hamsters. Oral squamous cell carcinomas developed in the left buccal pouch of hamsters on painting with 0.5% of DMBA, three times in a week. To assess the apoptotic associated gene expressing potential of [6]-paradol, it was orally administered to DMBA treated hamsters on alternate days from DMBA painting for 14 weeks. We observed 100% tumor formation with marked levels of neoplastic changes and altered the expression of apoptotic associated gene (p53, bcl-2, caspase-3 and TNF-α) was observed in the DMBA alone painted hamsters as compared to control hamsters. Oral administration of [6]-paradol at a dose of 30 mg/kg b.wt to DMBA treated animals on alternative days for 14 weeks significantly reduced the neoplastic changes and improved the status of apoptosis associated gene expression. These observations confirmed that [6]-paradol acts as a tumor suppressing agent against DMBA induced oral carcinogenesis. We also conclude that [6]-paradol also effectively enhances apoptosis- associated gene expression in DMBA treated animals.


Conserved and variable features of Gag structure and arrangement in immature retrovirus particles.
The assembly of retroviruses is driven by oligomerization of the Gag polyprotein. We have used cryo-electron tomography together with subtomogram averaging to describe the three-dimensional structure of in vitro-assembled Gag particles from human immunodeficiency virus, Mason-Pfizer monkey virus, and Rous sarcoma virus. These represent three different retroviral genera: the lentiviruses, betaretroviruses and alpharetroviruses. Comparison of the three structures reveals the features of the supramolecular organization of Gag that are conserved between genera and therefore reflect general principles of Gag-Gag interactions and the features that are specific to certain genera. All three Gag proteins assemble to form approximately spherical hexameric lattices with irregular defects. In all three genera, the N-terminal domain of CA is arranged in hexameric rings around large holes. Where the rings meet, 2-fold densities, assigned to the C-terminal domain of CA, extend between adjacent rings, and link together at the 6-fold symmetry axis with a density, which extends toward the center of the particle into the nucleic acid layer. Although this general arrangement is conserved, differences can be seen throughout the CA and spacer peptide regions. These differences can be related to sequence differences among the genera. We conclude that the arrangement of the structural domains of CA is well conserved across genera, whereas the relationship between CA, the spacer peptide region, and the nucleic acid is more specific to each genus.


MFG-E8 (LACTADHERIN): a novel marker associated with cerebral amyloid angiopathy.
Brain accumulation of amyloid-beta (Aβ) is a crucial feature in Alzheimer´s disease (AD) and cerebral amyloid angiopathy (CAA), although the pathophysiological relationship between these diseases remains unclear. Numerous proteins are associated with Aβ deposited in parenchymal plaques and/or cerebral vessels. We hypothesized that the study of these proteins would increase our understanding of the overlap and biological differences between these two pathologies and may yield new diagnostic tools and specific therapeutic targets. We used a laser capture microdissection approach combined with mass spectrometry in the APP23 transgenic mouse model of cerebral-β-amyloidosis to specifically identify vascular Aβ-associated proteins. We focused on one of the main proteins detected in the Aβ-affected cerebrovasculature: MFG-E8 (milk fat globule-EGF factor 8), also known as lactadherin. We first validated the presence of MFG-E8 in mouse and human brains. Immunofluorescence and immunoblotting studies revealed that MFG-E8 brain levels were higher in APP23 mice than in WT mice. Furthermore, MFG-E8 was strongly detected in Aβ-positive vessels in human postmortem CAA brains, whereas MFG-E8 was not present in parenchymal Aβ deposits. Levels of MFG-E8 were additionally analysed in serum and cerebrospinal fluid (CSF) from patients diagnosed with CAA, patients with AD and control subjects. Whereas no differences were found in MFG-E8 serum levels between groups, MFG-E8 concentration was significantly lower in the CSF of CAA patients compared to controls and AD patients. Finally, in human vascular smooth muscle cells MFG-E8 was protective against the toxic effects of the treatment with the Aβ40 peptide containing the Dutch mutation. In summary, our study shows that MFG-E8 is highly associated with CAA pathology and highlights MFG-E8 as a new CSF biomarker that could potentially be used to differentiate cerebrovascular Aβ pathology from parenchymal Aβ deposition.


Modeling the target acquisition performance of active imaging systems.
Recent development of active imaging system technology in the defense and security community have driven the need for a theoretical understanding of its operation and performance in military applications such as target acquisition. In this paper, the modeling of active imaging systems, developed at the U.S. Army RDECOM CERDEC Night Vision & Electronic Sensors Directorate, is presented with particular emphasis on the impact of coherent effects such as speckle and atmospheric scintillation. Experimental results from human perception tests are in good agreement with the model results, validating the modeling of coherent effects as additional noise sources. Example trade studies on the design of a conceptual active imaging system to mitigate deleterious coherent effects are shown.


Alk3/Bmpr1a receptor is required for development of the atrioventricular canal into valves and annulus fibrosus.
Endocardial cushions are precursors of mature atrioventricular (AV) valves. Their formation is induced by signaling molecules originating from the AV myocardium, including bone morphogenetic proteins (BMPs). Here, we hypothesized that BMP signaling plays an important role in the AV myocardium during the maturation of AV valves from the cushions. To test our hypothesis, we used a unique Cre/lox system to target the deletion of a floxed Alk3 allele, the type IA receptor for BMPs, to cardiac myocytes of the AV canal (AVC). Lineage analysis indicated that cardiac myocytes of the AVC contributed to the tricuspid mural and posterior leaflets, the mitral septal leaflet, and the atrial border of the annulus fibrosus. When Alk3 was deleted in these cells, defects were seen in the same leaflets, ie, the tricuspid mural leaflet and mitral septal leaflet were longer, the tricuspid posterior leaflet was displaced and adherent to the ventricular wall, and the annulus fibrosus was disrupted resulting in ventricular preexcitation. The defects seen in mice with AVC-targeted deletion of Alk3 provide strong support for a role of Alk3 in human congenital heart diseases, such as Ebstein's anomaly. In conclusion, our mouse model demonstrated critical roles for Alk3 signaling in the AV myocardium during the development of AV valves and the annulus fibrosus.


MECHANISTIC MODELING PREDICTS NO SIGNIFICANT DOSE RATE EFFECT ON HEAVY-ION CARCINOGENESIS AT DOSE RATES RELEVANT FOR SPACE EXPLORATION.
Heavy ion-induced carcinogenesis is a challenge for human space exploration, and mechanistically-motivated mathematical models are needed to predict space-relevant low dose-rate risks, which are difficult to measure experimentally, based on data at higher dose rates. We present such a model, which quantifies targeted and non-targeted radiation effects. We fitted it to lung carcinogenesis data in radon-exposed miners and rats, which provide valuable information on carcinogenesis from protracted exposure to densely-ionizing radiation. We generated model-based estimates for the dose-rate-effect, relative to acute exposures, on heavy ion-induced carcinogenesis at doses/dose rates expected during a Mars mission. A small and not statistically-significant dose-rate effect was predicted: 1.00 (95% CI: 0.54, 1.40) for human data and for combined human and rat data 0.93 (0.06, 1.49). Consequently, heavy ion carcinogenesis estimates from moderate/high dose-rate experimental data may be applicable to doses/dose rates relevant for space exploration.