TOR1 and TOR2 have distinct locations in live cells.
TOR is a structurally and functionally conserved Ser/Thr kinase found in two multiprotein complexes that regulate many cellular processes to control cell growth. Although extensively studied, the localization of TOR is still ambiguous, possibly because endogenous TOR in live cells has not been examined. Here, we examined the localization of green fluorescent protein (GFP) tagged, endogenous TOR1 and TOR2 in live S. cerevisiae cells. A DNA cassette encoding three copies of green fluorescent protein (3XGFP) was inserted in the TOR1 gene (at codon D330) or the TOR2 gene (at codon N321). The TORs were tagged internally because TOR1 or TOR2 tagged at the N or C terminus was not functional. The TOR1(D330-3XGFP) strain was not hypersensitive to rapamycin, was not cold sensitive, and was not resistant to manganese toxicity caused by the loss of Pmr1, all indications that TOR1-3XGFP was expressed and functional. TOR2-3XGFP was functional, as TOR2 is an essential gene and TOR2(N321-3XGFP) haploid cells were viable. Thus, TOR1 and TOR2 retain function after the insertion of 748 amino acids in a variable region of their noncatalytic domain. The localization patterns of TOR1-3XGFP and TOR2-3XGFP were documented by imaging of live cells. TOR1-3XGFP was diffusely cytoplasmic and concentrated near the vacuolar membrane. The TOR2-3XGFP signal was cytoplasmic but predominately in dots at the plasma membrane. Thus, TOR1 and TOR2 have distinct localization patterns, consistent with the regulation of cellular processes as part of two different complexes.


Instantaneous Wave-free Ratio versus Fractional Flow Reserve to Guide PCI.
The instantaneous wave-free ratio (iFR) is an index used to assess the severity of coronary-artery stenosis. The index has been tested against fractional flow reserve (FFR) in small trials, and the two measures have been found to have similar diagnostic accuracy. However, studies of clinical outcomes associated with the use of iFR are lacking. We aimed to evaluate whether iFR is noninferior to FFR with respect to the rate of subsequent major adverse cardiac events. We conducted a multicenter, randomized, controlled, open-label clinical trial using the Swedish Coronary Angiography and Angioplasty Registry for enrollment. A total of 2037 participants with stable angina or an acute coronary syndrome who had an indication for physiologically guided assessment of coronary-artery stenosis were randomly assigned to undergo revascularization guided by either iFR or FFR. The primary end point was the rate of a composite of death from any cause, nonfatal myocardial infarction, or unplanned revascularization within 12 months after the procedure. A primary end-point event occurred in 68 of 1012 patients (6.7%) in the iFR group and in 61 of 1007 (6.1%) in the FFR group (difference in event rates, 0.7 percentage points; 95% confidence interval [CI], -1.5 to 2.8; P=0.007 for noninferiority; hazard ratio, 1.12; 95% CI, 0.79 to 1.58; P=0.53); the upper limit of the 95% confidence interval for the difference in event rates fell within the prespecified noninferiority margin of 3.2 percentage points. The results were similar among major subgroups. The rates of myocardial infarction, target-lesion revascularization, restenosis, and stent thrombosis did not differ significantly between the two groups. A significantly higher proportion of patients in the FFR group than in the iFR group reported chest discomfort during the procedure. Among patients with stable angina or an acute coronary syndrome, an iFR-guided revascularization strategy was noninferior to an FFR-guided revascularization strategy with respect to the rate of major adverse cardiac events at 12 months. (Funded by Philips Volcano; iFR SWEDEHEART ClinicalTrials.gov number, NCT02166736 .).


The Best Model of a Cat Is Several Cats.
Modern biotechnology is emerging at the intersection of engineering, biology, physics, and computer science. As such it carries with it history from several disparate fields of research including a strong tradition in deductive reasoning primarily derived from discovery focused molecular biology and physics. Engineering biological systems is a complex undertaking requiring a broader set of epistemic tools and methods than what is usually applied in today's discovery based research. Inductive reasoning as commonly used in computer science has proven to be a very efficient approach to build knowledge about complex megadimensional datasets, including synthetic biology applications. The authors conclude that the multi-heuristic nature of modern biotechnology makes it an engineering field primed for inductive reasoning to complement the dominating deductive tradition.


Repetitive and compulsive-like behaviors lead to cognitive dysfunction in Disc1Δ2-3/Δ2-3 mice.
Disrupted-in-schizophrenia 1 (Disc1) is a key molecular driver for the biology of mental diseases. In order to investigate its role in brain function, we previously generated mice lacking exons 2 and 3 of Disc1 on a C57BL/6J genetic background (Disc1Δ2-3/Δ2-3 mice), which have a deficiency of the full-length Disc1 protein. In the present study, we examined the role of Disc1 in cognitive function using a touchscreen-based visual discrimination (VD) task in which mice had to discriminate 1 of 2 stimuli simultaneously displayed on the screen and received a liquid reward. Disc1Δ2-3/Δ2-3 mice showed impaired performance in the VD task, and this was mainly attributed to the perseverative response being significantly stronger than that in wild-type (WT) mice. Furthermore, the numbers of marbles buried in the marble burying test and nestlets shredded in the nestlet shredding test by Disc1Δ2-3/Δ2-3 mice were significantly higher than those by WT mice, suggesting perseverative/compulsive behaviors by Disc1Δ2-3/Δ2-3 mice. A treatment with clozapine ameliorated behavioral deficits in the VD and marble burying tasks. c-Fos expression was significantly stronger in the dorsomedial striatum (DMS), but not the dorsolateral striatum (DLS) after the first VD session in Disc1Δ2-3/Δ2-3 mice than in WT mice. The treatment of mice that had previously expressed hM3Dq in the DMS with clozapine-N-oxide (CNO) impaired performance in the VD task. These results suggest that cognitive impairments accompanied by perseverative/compulsive behaviors in Disc1Δ2-3/Δ2-3 mice are associated with hyperactivity of the DMS.


Resource Effective Strategies to Prevent and Treat Cardiovascular Disease.
Cardiovascular disease (CVD) is the leading cause of global deaths, with the majority occurring in low- and middle-income countries. The primary and secondary prevention of CVD is suboptimal throughout the world, but the evidence-practice gaps are much more pronounced in low- and middle-income countries. Barriers at the patient, healthcare provider, and health system level prevent the implementation of optimal primary and secondary prevention. Identification of the particular barriers that exist in resource-constrained settings is necessary to inform effective strategies to reduce the identified evidence-practice gaps. Furthermore, targeting modifiable factors that contribute most significantly to the global burden of CVD, including tobacco use, hypertension, and secondary prevention for CVD, will lead to the biggest gains in mortality reduction. We review a select number of novel, resource-efficient strategies to reduce premature mortality from CVD, including (1) effective measures for tobacco control, (2) implementation of simplified screening and management algorithms for those with or at risk of CVD, (3) increasing the availability and affordability of simplified and cost-effective treatment regimens including combination CVD preventive drug therapy, and (4) simplified delivery of healthcare through task-sharing (nonphysician health workers) and optimizing self-management (treatment supporters). Developing and deploying systems of care that address barriers related to the above will lead to substantial reductions in CVD and related mortality.


cuTauLeaping: a GPU-powered tau-leaping stochastic simulator for massive parallel analyses of biological systems.
Tau-leaping is a stochastic simulation algorithm that efficiently reconstructs the temporal evolution of biological systems, modeled according to the stochastic formulation of chemical kinetics. The analysis of dynamical properties of these systems in physiological and perturbed conditions usually requires the execution of a large number of simulations, leading to high computational costs. Since each simulation can be executed independently from the others, a massive parallelization of tau-leaping can bring to relevant reductions of the overall running time. The emerging field of General Purpose Graphic Processing Units (GPGPU) provides power-efficient high-performance computing at a relatively low cost. In this work we introduce cuTauLeaping, a stochastic simulator of biological systems that makes use of GPGPU computing to execute multiple parallel tau-leaping simulations, by fully exploiting the Nvidia's Fermi GPU architecture. We show how a considerable computational speedup is achieved on GPU by partitioning the execution of tau-leaping into multiple separated phases, and we describe how to avoid some implementation pitfalls related to the scarcity of memory resources on the GPU streaming multiprocessors. Our results show that cuTauLeaping largely outperforms the CPU-based tau-leaping implementation when the number of parallel simulations increases, with a break-even directly depending on the size of the biological system and on the complexity of its emergent dynamics. In particular, cuTauLeaping is exploited to investigate the probability distribution of bistable states in the Schlögl model, and to carry out a bidimensional parameter sweep analysis to study the oscillatory regimes in the Ras/cAMP/PKA pathway in S. cerevisiae.


A binary method for simple and accurate two-dimensional cursor control from EEG with minimal subject training.
Brain-computer interfaces (BCI) use electroencephalography (EEG) to interpret user intention and control an output device accordingly. We describe a novel BCI method to use a signal from five EEG channels (comprising one primary channel with four additional channels used to calculate its Laplacian derivation) to provide two-dimensional (2-D) control of a cursor on a computer screen, with simple threshold-based binary classification of band power readings taken over pre-defined time windows during subject hand movement. We tested the paradigm with four healthy subjects, none of whom had prior BCI experience. Each subject played a game wherein he or she attempted to move a cursor to a target within a grid while avoiding a trap. We also present supplementary results including one healthy subject using motor imagery, one primary lateral sclerosis (PLS) patient, and one healthy subject using a single EEG channel without Laplacian derivation. For the four healthy subjects using real hand movement, the system provided accurate cursor control with little or no required user training. The average accuracy of the cursor movement was 86.1% (SD 9.8%), which is significantly better than chance (p = 0.0015). The best subject achieved a control accuracy of 96%, with only one incorrect bit classification out of 47. The supplementary results showed that control can be achieved under the respective experimental conditions, but with reduced accuracy. The binary method provides naïve subjects with real-time control of a cursor in 2-D using dichotomous classification of synchronous EEG band power readings from a small number of channels during hand movement. The primary strengths of our method are simplicity of hardware and software, and high accuracy when used by untrained subjects.


La vida normal: living with HIV in Santo Domingo, Dominican Republic.
In this study, we explore how individuals living with HIV in the Dominican Republic strive to live a 'normal' life and the consequences of this pursuit of normalcy. We conducted qualitative in-depth interviews with men (n = 20) and women (n = 20) living with HIV and receiving care at two urban clinics in Santo Domingo. We analysed the data using a combination of narrative analysis and thematic coding. We aimed to identify how fears and/or lived experiences with social rejection and HIV-related stigma and discrimination shaped participants' abilities to maintain social relationships, be economically productive and manage HIV within the context of sexual relationships. Participants used the discourse of una vida normal (a normal life) to frame their response to HIV. This pursuit of normality was driven by the social and economic pressures of living with a chronic condition in a context of HIV-related stigma; trying to keep things 'normal' further added to these pressures. We argue that the normal life discourse fails to recognise the dynamic and complex nature of negotiating this condition and may also create additional burdens for individuals living with HIV that could impact their wellbeing and preventive behaviours.


Impact of placental weight and fetal/placental weight ratio Z score on fetal growth and the perinatal outcome.
Objective: To classify the infants into 9 blocks based on the deviation of both placental weight (PW) and fetal/placental weight ratio (F/P) Z score and compared the incident rate of perinatal death in each of the small for date (SFD) vs. appropriate for date (AFD) vs. heavy for date (HFD) groups. Methods: The study population consisted of 93,034 placentas/infants from women who vaginally delivered a singleton infant. They were classified into 3 groups according to infants' weight: SFD (n=3,379), AFD (n=81,143) and HFD (n=8,512). The population was classified into 9 blocks according to the combination of i) low vs. middle vs. high placental weight (PW: a sex-, parity- and gestational-age-specific placental weight) and ii) low vs. middle vs. high F/P. In both i) and ii), ± 1.28 standard deviations in the in the Z scores was used for classifying low vs. middle vs. high, with 3x3 making 9 blocks. We then determined whether or not the perinatal death in each block differed among the three groups (SFD vs. AFD vs. HFD). Results: (1) The proportions of 'balanced growth of placenta and infant' (appropriate PW and F/P based on Z-score) were 37.6% in the SFD group, 78.8% in the AFD group, and 51.2% in HFD group. (2) The proportion of 'inappropriately heavy placenta' in the SFD group and that of 'inappropriately light placenta' in the HFD group were 0.3 and 0.4%, respectively, a very rare phenomenon. The proportions of 'inappropriately heavy placenta' and 'inappropriately light placenta' accounted for 4.1 and 5.5% in AFD group, respectively. (3) The rates of perinatal death in those with 'balanced growth of placenta and infant' were lowest in the SFD and AFD groups. Conclusion: By showing the fact that perinatal death was lowest in cases with balanced fetal/ placental growth, we conclude that 9-block categorization of PW and F/P based on deviation in the Z-score may be a candidate factor employable for understanding fetal and placental growth and perinatal deaths.


First Report of White Mold Caused by Sclerotinia sclerotiorum on Hutchinsia alpina in Italy.
Hutchinsia alpina (Chamois cress), a plant belonging to the Brassicaceae family, is cultivated as a potted ornamental plant in Italy. In the winter of 2002, leaves and stems of plants grown in pots (14-cm diameter) in commercial farms near Albenga (northern Italy) developed soft and watery tissues covered with whitish mycelium at the soil line. As necrosis progressed, infected plants wilted and died. Dark sclerotia developed on infected tissues. Because of high planting density, the infection spread very rapidly. Sclerotinia sclerotiorum was consistently recovered from infected stem pieces of H. alpina disinfested 1 min in 1% NaOCl and plated on potato dextrose agar (PDA) amended with 100 ppm of streptomycin sulfate. Sclerotia produced on PDA were ellipsoid and measured 1.3 to 9.3 × 1.3 to 4.5 mm (average 3.9 × 2.8 mm) (1). Pathogenicity of three isolates obtained from infected plants grown in a single greenhouse was confirmed by inoculating 90-day-old plants grown in pots (14 cm). Inoculum that consisted of wheat kernels infested with mycelium and sclerotia of each isolate were placed on the soil surface around the base of each of 10 plants. Plants treated with plain wheat kernels served as controls. The inoculation trial was repeated once. All plants were kept at temperatures ranging between 5 and 26°C and watered as needed. Inoculated plants developed symptoms of leaf yellowing, followed by the appearance of white mycelium within 15 days, and eventually wilted while control plants remained symptomless. White mycelium and sclerotia developed on infected tissues, and S. sclerotiorum was reisolated only from inoculated plants. To our knowledge, this is the first report of white mold on Hutchinsia alpina caused by S. sclerotiorum. Reference: (1) N. F. Buchwald. Den. Kgl. Veterin.er-og Landbohojskoles Aarsskrift, 1949.


Formation of the indigo precursor indican in genetically engineered tobacco plants and cell cultures.
The production of the blue dye indigo in plants has been assumed to be a possible route to the introduction of novel coloration into flowers or fibres. As the human cytochrome P450 mono-oxygenase 2A6 (CYP2A6) can form indigo in bacterial cultures, we investigated whether the expression of the corresponding cDNA in transgenic plants could lead to indigo formation. In a first attempt, we generated tobacco cell suspension cultures expressing the cDNA encoding human CYP2A6. Supplementation of the medium with indole led to the generation of indican (3-hydroxyindole-beta-d-glucoside), a metabolite usually exclusively present in indigoferous dye plants. Hence, the recombinant CYP2A6 converted indole to the reactive metabolite 3-hydroxyindole (indoxyl), whereas rapid glucosylation is obviously conducted by ubiquitous plant glucosyl transferases (GTs). Interestingly, of nine additionally tested plant cell suspension cultures from various plant families, five were also capable of the formation of indican after indole supplementation, although this metabolism was more pronounced in transgenic tobacco cell suspension cultures expressing CYP2A6 cDNA. To evaluate whether indican or even indigo could be produced in whole plants, we generated transgenic tobacco plants harbouring active CYP2A6 together with an indole synthase (BX1) from maize. The genetically engineered tobacco plants accumulated indican, but did not develop a blue coloration. Although the de novo formation of indican in transgenic tobacco plants hampered indigo formation, it supports the contention that biosynthetic pathways can be efficiently mimicked by metabolic engineering.


Commercial plant extracts may act as antioxidants or pro-oxidants in cosmetic emulsions based on argan oil.
Cosmetic emulsions containing plant extracts should be tested in a range of temperatures from 5°C to 40°C to be sure that they will be stable during general use by consumers and that plant extracts used as antioxidants do not accelerate oxidative degradation of their oil base. The oxidative stability of argan oil-in-water emulsions containing 1% and 5% commercial acerola, willow, and rose extracts [or 0.01% butylhydroxytoluene (BHT)], stored at 5°C and 20°C for 6 months and at 40°C for 4 weeks, was monitored by the determination of peroxide content. The antioxidant or pro-oxidant activities of extracts or BHT in emulsions were expressed as the protection factor (PF) and inhibition of peroxide formation (Ip). At the end of storage, 5% willow, 0.01% BHT, 1% willow, and 5% acerola were the most protective for emulsions stored at 5°C. At 20°C, the most effective was 0.01% BHT, 5% rose, and 5% acerola. At 40°C, inhibition of peroxide formation calculated for 1% rose, 5% acerola, and 0.01 % BHT was similar. Altogether, the results show that some plant extracts, depending on storage conditions, may act as pro-oxidants, whereas the others can be applied as natural antioxidants instead of synthetic BHT.


A Severe Presentation of Drug-Induced Lupus Erythematosus.
Drug-induced lupus erythematosus is a rare condition associated with the exposure to certain drugs capable of triggering an autoimmune disease similar to systemic lupus erythematosus. Although there are no available diagnostic criteria, clinical and serological findings and its temporal association with the initiation of the suspected drug are important to establish the diagnosis. The withdrawal of the drug usually resolves the symptoms. However, in some cases, therapy with corticosteroids and immunosuppressive agents may be required. We present a 74-year-old female with a bilateral venous thrombosis, ischemic stroke, polyserositis and diarrhea due to drug-induced lupus erythematosus that required immunosuppressive therapy.


A field trial to assess a blood-stage malaria vaccine.
Blood-stage malaria vaccines are intended to prevent clinical disease. The malaria vaccine FMP2.1/AS02(A), a recombinant protein based on apical membrane antigen 1 (AMA1) from the 3D7 strain of Plasmodium falciparum, has previously been shown to have immunogenicity and acceptable safety in Malian adults and children. In a double-blind, randomized trial, we immunized 400 Malian children with either the malaria vaccine or a control (rabies) vaccine and followed them for 6 months. The primary end point was clinical malaria, defined as fever and at least 2500 parasites per cubic millimeter of blood. A secondary end point was clinical malaria caused by parasites with the AMA1 DNA sequence found in the vaccine strain. The cumulative incidence of the primary end point was 48.4% in the malaria-vaccine group and 54.4% in the control group; efficacy against the primary end point was 17.4% (hazard ratio for the primary end point, 0.83; 95% confidence interval [CI], 0.63 to 1.09; P=0.18). Efficacy against the first and subsequent episodes of clinical malaria, as defined on the basis of various parasite-density thresholds, was approximately 20%. Efficacy against clinical malaria caused by parasites with AMA1 corresponding to that of the vaccine strain was 64.3% (hazard ratio, 0.36; 95% CI, 0.08 to 0.86; P=0.03). Local reactions and fever after vaccination were more frequent with the malaria vaccine. On the basis of the primary end point, the malaria vaccine did not provide significant protection against clinical malaria, but on the basis of secondary results, it may have strain-specific efficacy. If this finding is confirmed, AMA1 might be useful in a multicomponent malaria vaccine. (Funded by the National Institute of Allergy and Infectious Diseases and others; ClinicalTrials.gov number, NCT00460525.).


A sorting platform determines the order of protein secretion in bacterial type III systems.
Bacterial type III protein secretion systems deliver effector proteins into eukaryotic cells in order to modulate cellular processes. Central to the function of these protein-delivery machines is their ability to recognize and secrete substrates in a defined order. Here, we describe a mechanism by which a type III secretion system from the bacterial enteropathogen Salmonella enterica serovar Typhimurium can sort its substrates before secretion. This mechanism involves a cytoplasmic sorting platform that is sequentially loaded with the appropriate secreted proteins. The sequential loading of this platform, facilitated by customized chaperones, ensures the hierarchy in type III protein secretion. Given the presence of these machines in many important pathogens, these findings can serve as the bases for the development of novel antimicrobial strategies.


Opioid antagonists under heavy sedation or anaesthesia for opioid withdrawal.
Withdrawal (detoxification) is necessary prior to drug-free treatment or as the end point of long-term substitution treatment. To assess the effectiveness of opioid antagonists to induce opioid withdrawal with concomitant heavy sedation or anaesthesia, in terms of withdrawal signs and symptoms, completion of treatment and adverse effects. We searched the Cochrane Central Register of Controlled Trials (The Cochrane Library, Issue 3, 2009), Medline (January 1966 to 11 August 2009), Embase (January 1985 to 2009 Week 32), PsycINFO (1967 to July 2009), and reference lists of articles. Controlled studies of antagonist-induced withdrawal under heavy sedation or anaesthesia in opioid-dependent participants compared with other approaches, or a different regime of anaesthesia-based antagonist-induced withdrawal. One reviewer assessed studies for inclusion, undertook data extraction and assessed quality. Inclusion decisions and the overall process were confirmed by consultation between all authors. Nine studies (eight randomised controlled trials) involving 1109 participants met the inclusion criteria for the review.Antagonist-induced withdrawal is more intense but less prolonged than withdrawal managed with reducing doses of methadone, and doses of naltrexone sufficient for blockade of opioid effects can be established significantly more quickly with antagonist-induced withdrawal than withdrawal managed with clonidine and symptomatic medications. The level of sedation does not affect the intensity and duration of withdrawal, although the duration of anaesthesia may influence withdrawal severity. There is a significantly greater risk of adverse events with heavy, compared to light, sedation (RR 3.21, 95% CI 1.13 to 9.12, P = 0.03) and probably with this approach compared to other forms of detoxification. Heavy sedation compared to light sedation does not confer additional benefits in terms of less severe withdrawal or increased rates of commencement on naltrexone maintenance treatment. Given that the adverse events are potentially life-threatening, the value of antagonist-induced withdrawal under heavy sedation or anaesthesia is not supported. The high cost of anaesthesia-based approaches, both in monetary terms and use of scarce intensive care resources, suggest that this form of treatment should not be pursued.


Origins of submovements during pointing movements.
Submovements that are frequently observed in the final portion of pointing movements have traditionally been viewed as pointing accuracy adjustments. Here we re-examine this long-lasting interpretation by developing evidence that many of submovements may be non-corrective fluctuations arising from various sources of motor output variability. In particular, non-corrective submovements may emerge during motion termination and during motion of low speed. The contribution of these factors and the factor of accuracy regulation in submovement production is investigated here by manipulating movement mode (discrete, reciprocal, and passing) and target size (small and large). The three modes provided different temporal combinations of accuracy regulation and motion termination, thus allowing us to disentangle submovements associated with each factor. The target size manipulations further emphasized the role of accuracy regulation and provided variations in movement speed. Gross and fine submovements were distinguished based on the degree of perturbation of smooth motion. It was found that gross submovements were predominantly related to motion termination and not to pointing accuracy regulation. Although fine submovements were more frequent during movements to small than to large targets, other results show that they may also be not corrective submovements but rather motion fluctuations attributed to decreases in movement speed accompanying decreases in target size. Together, the findings challenge the traditional interpretation, suggesting that the majority of submovements are fluctuations emerging from mechanical and neural sources of motion variability. The implications of the findings for the mechanisms responsible for accurate target achievement are discussed.


Dynamics of Metal Partitioning at the Cell-Solution Interface: Implications for Toxicity Assessment under Growth-Inhibiting Conditions.
Metal toxicity toward microorganisms is usually evaluated by determining growth inhibition. To achieve a mechanistic interpretation of such toxic effects, the intricate coupling between cell growth kinetics and metal partitioning dynamics at the cell-solution interface over time must be considered on a quantitative level. A formalism is elaborated to evaluate cell-surface-bound, internalized, and extracellular metal fractions in the limit where metal uptake kinetics is controlled by internalization under noncomplexing medium conditions. Cell growth kinetics is tackled using the continuous logistic equation modified to include growth inhibition by metal accumulation to intracellular or cell surface sites. The theory further includes metal-proton competition for adsorption at cell-surface binding sites, as well as possible variation of cell size during exposure to metal ions. The formalism elucidates the dramatic impacts of initial cell concentration on metal bioavailability and toxicity over time, in agreement with reported algae bioassays. It further highlights that appropriate definition of toxicity endpoints requires careful inspection of the ratio between exposure time scale and time scale of metal depletion from bulk solution. The latter depends on metal internalization-excretion rate constants, microorganism growth, and the extent of metal adsorption on nonspecific, transporter, and growth inhibitory sites. As an application of the theory, Cd toxicity in the algae Pseudokirchneriella subcapitata is interpreted from constrained modeling of cell growth kinetics and of interfacial Cd-partitioning dynamics measured under various exposure conditions.


Interacting Epidemics in Amazonian Brazil: Prior Dengue Infection Associated With Increased Coronavirus Disease 2019 (COVID-19) Risk in a Population-Based Cohort Study.
Immunity after dengue virus (DENV) infection has been suggested to cross-protect from severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection and mortality. We tested whether serologically proven prior DENV infection diagnosed in September-October 2019, before the coronavirus disease 2019 (COVID-19) pandemic, reduced the risk of SARS-CoV-2 infection and clinically apparent COVID-19 over the next 13 months in a population-based cohort in Amazonian Brazil. Mixed-effects multiple logistic regression analysis was used to identify predictors of infection and disease, adjusting for potential individual and household-level confounders. Virus genomes from 14 local SARS-CoV-2 isolates were obtained using whole-genome sequencing. Anti-DENV immunoglobulin G (IgG) was found in 37.0% of 1285 cohort participants (95% confidence interval [CI]: 34.3% to 39.7%) in 2019, with 10.4 (95% CI: 6.7-15.5) seroconversion events per 100 person-years during the follow-up. In 2020, 35.2% of the participants (95% CI: 32.6% to 37.8%) had anti-SARS-CoV-2 IgG and 57.1% of the 448 SARS-CoV-2 seropositives (95% CI: 52.4% to 61.8%) reported clinical manifestations at the time of infection. Participants aged >60 years were twice more likely to have symptomatic COVID-19 than children under 5 years. Locally circulating SARS-CoV-2 isolates were assigned to the B.1.1.33 lineage. Contrary to the cross-protection hypothesis, prior DENV infection was associated with twice the risk of clinically apparent COVID-19 upon SARS-CoV-2 infection, with P values between .025 and .039 after adjustment for identified confounders. Higher risk of clinically apparent COVID-19 among individuals with prior dengue has important public health implications for communities sequentially exposed to DENV and SARS-CoV-2 epidemics.


Fat oxidation over a range of exercise intensities: fitness versus fatness.
Maximal fat oxidation (MFO), as well as the exercise intensity at which it occurs (Fatmax), have been reported as lower in sedentary overweight individuals but have not been studied in trained overweight individuals. The aim of this study was to compare Fatmax and MFO in lean and overweight recreationally trained males matched for cardiorespiratory fitness (CRF) and to study the relationships between these variables, anthropometric characteristics, and CRF. Twelve recreationally trained overweight (high fatness (HiFat) group, 30.0% ± 5.3% body fat) and 12 lean males (low fatness (LoFat), 17.2% ± 5.7% body fat) matched for CRF (maximal oxygen consumption (V̇O2max) 39.0 ± 5.5 vs. 41.4 ± 7.6 mL·kg(-1)·min(-1), p = 0.31) and age (p = 0.93) performed a graded exercise test on a cycle ergometer. V̇O2max and fat and carbohydrate oxidation rates were determined using indirect calorimetry; Fatmax and MFO were determined with a mathematical model (SIN); and % body fat was assessed by air displacement plethysmography. MFO (0.38 ± 0.19 vs. 0.42 ± 0.16 g·min(-1), p = 0.58), Fatmax (46.7% ± 8.6% vs. 45.4% ± 7.2% V̇O2max, p = 0.71), and fat oxidation rates over a wide range of exercise intensities were not significantly different (p > 0.05) between HiFat and LoFat groups. In the overall cohort (n = 24), MFO and Fatmax were correlated with V̇O2max (r = 0.46, p = 0.02; r = 0.61, p = 0.002) but not with % body fat or body mass index (p > 0.05). Fat oxidation during exercise was similar in recreationally trained overweight and lean males matched for CRF. Consistently, substrate oxidation rates during exercise were not related to adiposity (% body fat) but were related to CRF. The benefits of high CRF independent of body weight and % body fat should be further highlighted in the management of obesity.


Comparison of efficiency of direct observations by scuba diver and indirect observations via video camera for measuring reef-fish behaviour.
The present study investigates how the humbug damselfish Dascyllus aruanus, subject of a large number of ecological, evolutionary and behavioural studies, responds to the presence of human observers (effect of scuba diver presence-absence) and how the method of data collection (directly by a scuba diver v. indirectly via video camera) may affect the quality of behavioural data. Scuba diver presence had only subtle effects on fish behaviour. The efficiency of the method of scoring fish behaviour depended on the behaviour under consideration: those behaviours that occur in close proximity to the corals were scored more effectively directly by a scuba diver while those that are performed in a more rapid or repetitive fashion were scored more effectively indirectly via video camera. These results provide a foundation for future behavioural research on D. aruanus and other fishes where scuba divers or video cameras are the prevalent means of data collection.


Optimization in osmolality and range of density of a continuous ficoll-sodium-diatrizoate gradient for isopycnic purification of isolated human islets.
According to previous estimates from large animals and man, a minimum of approximately 5000 to 6000 engrafted islet equivalents (IEQ)/kg recipient weight is critical to establish insulin independence. Utilizing a single donor, this threshold yield of purified islets can be retrieved from approximately one third of all isolations. The aim of this study was to improve human islet purification by optimization of the osmolality and the density range of the continuous Ficoll-sodium-diatrizoate (FSD) gradient to facilitate consistent purities >80% of human islet preparations without considerable loss of islet yield. Aliquots of human pancreatic digests were placed on continuous density gradients. After centrifugation, sequential aliquots were extracted for amylase and insulin to determine the relative and cumulative density distribution of endocrine and exocrine tissue. We addressed the impact of two factors: (1) osmolalities (300 to 600 mosm/kg) in the gradient of FSD covering a density range of 1.070 to 1.100 g/cm(3); and (2) density (FSD 500/1.070 to 1.100) versus density-osmolarity gradient (DO-FSD 400-530/1.080 to 1.113). The density of exocrine and endocrine tissue increased with rising osmolality. Differences in density of both tissues were highest at 450 and lowest at 300 and 600 mOsmol/kg. Purity and recovery were highest at 450 versus 400 or 500 mOsm/kg (NS). Exocrine but not endocrine tissue was more dense in DO-FSD than in FSD gradient (P < .05). The differences in density were 0.004 versus 0.013 g/cm(3) (P < .01), resulting in an increased islet purity and recovery. The best osmolality for the FSD 1.070 to 1.100 g/cm(3) is at 450 mOsm/kg. Using the DO-FSD may improve human islet purification allowing successful clinical islet transplantation.


Rapid action in the Palaeogene, the relationship between phenotypic and taxonomic diversification in Coenozoic mammals.
A classic question in evolutionary biology concerns the tempo and mode of lineage evolution. Considered variously in relation to resource utilization, intrinsic constraints or hierarchic level, the question of how evolutionary change occurs in general has continued to draw the attention of the field for over a century and a half. Here we use the largest species-level phylogeny of Coenozoic fossil mammals (1031 species) ever assembled and their body size estimates, to show that body size and taxonomic diversification rates declined from the origin of placentals towards the present, and very probably correlate to each other. These findings suggest that morphological and taxic diversifications of mammals occurred hierarchically, with major shifts in body size coinciding with the birth of large clades, followed by taxonomic diversification within these newly formed clades. As the clades expanded, rates of taxonomic diversification proceeded independently of phenotypic evolution. Such a dynamic is consistent with the idea, central to the Modern Synthesis, that mammals radiated adaptively, with the filling of adaptive zones following the radiation.


Inflammation, Antiinflammatory Agents, and Alzheimer's Disease: The Last 22 Years.
Two basic discoveries spurred research into inflammation as a driving force in the pathogenesis of Alzheimer's disease (AD). The first was the identification of activated microglia in association with the lesions. The second was the discovery that rheumatoid arthritics, who regularly consume anti-inflammatory agents, were relatively spared from the disease. These findings led to an exploration of the inflammatory pathways that were involved in AD pathogenesis. A pivotal advance was the discovery that amyloid-β protein (Aβ) activated the complement system. This focused attention on anti-inflammatories as blockers of complement activation. More than 15 epidemiological studies have since showed a sparing effect of non-steroidal anti-inflammatory drugs (NSAIDs) in AD. A consistent finding has been that the longer the NSAIDs were used prior to clinical diagnosis, the greater the sparing effect. The reason has since emerged from studies of biomarkers such as amyloid-β (Aβ) levels in the cerebrospinal fluid and Aβ deposits in brain. They have established that the onset of AD commences at least a decade before cognitive decline permits clinical diagnosis. Such biomarker studies have revealed that a huge window of opportunity exists when application of NSAIDs, other anti-inflammatory agents, or complement activation blockers, could arrest further progress of AD, thus eliminating its manifestation. It can be anticipated that this principle will apply to many other chronic neurodegenerative diseases. Neuroinflammation, discovered in AD more than 30 years ago, has now become a major field of brain research today. Inhibiting it may be the key to successful treatment of many chronic neurological disorders.


A Parameter Estimation Method for Multiscale Models of Hepatitis C Virus Dynamics.
Mathematical models that are based on differential equations require detailed knowledge about the parameters that are included in the equations. Some of the parameters can be measured experimentally while others need to be estimated. When the models become more sophisticated, such as in the case of multiscale models of hepatitis C virus dynamics that deal with partial differential equations (PDEs), several strategies can be tried. It is possible to use parameter estimation on an analytical approximation of the solution to the multiscale model equations, namely the long-term approximation, but this limits the scope of the parameter estimation method used and a long-term approximation needs to be derived for each model. It is possible to transform the PDE multiscale model to a system of ODEs, but this has an effect on the model parameters themselves and the transformation can become problematic for some models. Finally, it is possible to use numerical solutions for the multiscale model and then use canned methods for the parameter estimation, but the latter is making the user dependent on a black box without having full control over the method. The strategy developed here is to start by working directly on the multiscale model equations for preparing them toward the parameter estimation method that is fully coded and controlled by the user. It can also be adapted to multiscale models of other viruses. The new method is described, and illustrations are provided using a user-friendly simulator that incorporates the method.


Unbalanced third-order correlations for full characterization of femtosecond pulses.
Phase and intensity from correlation and spectrum only (PICASO) is a simple and accurate method for fully characterizing femtosecond pulses. We extend this technique to make use of third-order intensity correlations. Unbalancing the interferometer makes the retrieval algorithm sensitive to the direction of time and improves the retrieval of certain pulse shapes. We investigate the sensitivity of the retrieval to direction of time as a function of the degree of imbalance in the correlator.


Time perception in narcolepsy in comparison to patients with Parkinson's disease and healthy controls - an exploratory study.
The striatum and the prefrontal cortex play an important role in cognitive time processing, and time perception depends on sustained attention. Narcolepsy patients are unable to maintain sustained attention, due probably to deficient hypocretin signalling. Impaired time perception has been found in Parkinson's disease (PD) and attributed to a dysfunctional dopaminergic striatal pacemaker. We aimed to assess time perception in patients with narcolepsy and PD and to compare the outcome to healthy control participants. Seventeen narcolepsy patients, 12 PD patients and 15 healthy controls performed a short time production task, where they had to produce an interval of 1, 2 or 5 s. The accuracy of time production differed significantly according to task target duration, and there was a trend towards a group difference with narcolepsy patients tending to overproduce all target durations. Absolute variability was significantly different between groups, with narcolepsy patients showing higher absolute variability in comparison to controls and PD patients. The analysis of the temporal course of time estimation showed more pronounced overproduction of each target duration at the end of each trial in narcolepsy patients, whereas performance was more or less stable in controls and PD patients. Overproduction and higher variability of all time durations in narcolepsy indicate impaired short interval timing in the seconds range, while the scalar property of timing was preserved. The time-course of accuracy and variability of time production within sessions indicate an attention-related mechanism of impaired interval timing.


Alternative lengthening of telomeres is a self-perpetuating process in ALT-associated PML bodies.
Alternative lengthening of telomeres (ALT) is mediated by break-induced replication (BIR), but how BIR is regulated at telomeres is poorly understood. Here, we show that telomeric BIR is a self-perpetuating process. By tethering PML-IV to telomeres, we induced telomere clustering in ALT-associated PML bodies (APBs) and a POLD3-dependent ATR response at telomeres, showing that BIR generates replication stress. Ablation of BLM helicase activity in APBs abolishes telomere synthesis but causes multiple chromosome bridges between telomeres, revealing a function of BLM in processing inter-telomere BIR intermediates. Interestingly, the accumulation of BLM in APBs requires its own helicase activity and POLD3, suggesting that BIR triggers a feedforward loop to further recruit BLM. Enhancing BIR induces PIAS4-mediated TRF2 SUMOylation, and PIAS4 loss deprives APBs of repair proteins and compromises ALT telomere synthesis. Thus, a BLM-driven and PIAS4-mediated feedforward loop operates in APBs to perpetuate BIR, providing a critical mechanism to extend ALT telomeres.


Infectious vaccine-derived rubella viruses emerge, persist, and evolve in cutaneous granulomas of children with primary immunodeficiencies.
Rubella viruses (RV) have been found in an association with granulomas in children with primary immune deficiencies (PID). Here, we report the recovery and characterization of infectious immunodeficiency-related vaccine-derived rubella viruses (iVDRV) from diagnostic skin biopsies of four patients. Sequence evolution within PID hosts was studied by comparison of the complete genomic sequences of the iVDRVs with the genome of the vaccine virus RA27/3. The degree of divergence of each iVDRV correlated with the duration of persistence indicating continuous intrahost evolution. The evolution rates for synonymous and nonsynonymous substitutions were estimated to be 5.7 x 10-3 subs/site/year and 8.9 x 10-4 subs/site/year, respectively. Mutational spectra and signatures indicated a major role for APOBEC cytidine deaminases and a secondary role for ADAR adenosine deaminases in generating diversity of iVDRVs. The distributions of mutations across the genes and 3D hotspots for amino acid substitutions in the E1 glycoprotein identified regions that may be under positive selective pressure. Quasispecies diversity was higher in granulomas than in recovered infectious iVDRVs. Growth properties of iVDRVs were assessed in WI-38 fibroblast cultures. None of the iVDRV isolates showed complete reversion to wild type phenotype but the replicative and persistence characteristics of iVDRVs were different from those of the RA27/3 vaccine strain, making predictions of iVDRV transmissibility and teratogenicity difficult. However, detection of iVDRV RNA in nasopharyngeal specimen and poor neutralization of some iVDRV strains by sera from vaccinated persons suggests possible public health risks associated with iVDRV carriers. Detection of IgM antibody to RV in sera of two out of three patients may be a marker of virus persistence, potentially useful for identifying patients with iVDRV before development of lesions. Studies of the evolutionary dynamics of iVDRV during persistence will contribute to development of infection control strategies and antiviral therapies.


The Effectiveness of Image Augmentation in Deep Learning Networks for Detecting COVID-19: A Geometric Transformation Perspective.
Chest X-ray imaging technology used for the early detection and screening of COVID-19 pneumonia is both accessible worldwide and affordable compared to other non-invasive technologies. Additionally, deep learning methods have recently shown remarkable results in detecting COVID-19 on chest X-rays, making it a promising screening technology for COVID-19. Deep learning relies on a large amount of data to avoid overfitting. While overfitting can result in perfect modeling on the original training dataset, on a new testing dataset it can fail to achieve high accuracy. In the image processing field, an image augmentation step (i.e., adding more training data) is often used to reduce overfitting on the training dataset, and improve prediction accuracy on the testing dataset. In this paper, we examined the impact of geometric augmentations as implemented in several recent publications for detecting COVID-19. We compared the performance of 17 deep learning algorithms with and without different geometric augmentations. We empirically examined the influence of augmentation with respect to detection accuracy, dataset diversity, augmentation methodology, and network size. Contrary to expectation, our results show that the removal of recently used geometrical augmentation steps actually improved the Matthews correlation coefficient (MCC) of 17 models. The MCC without augmentation (MCC = 0.51) outperformed four recent geometrical augmentations (MCC = 0.47 for Data Augmentation 1, MCC = 0.44 for Data Augmentation 2, MCC = 0.48 for Data Augmentation 3, and MCC = 0.49 for Data Augmentation 4). When we retrained a recently published deep learning without augmentation on the same dataset, the detection accuracy significantly increased, with a χ McNema r ' s statistic 2 = 163 . 2 and a p-value of 2.23 × 10-37. This is an interesting finding that may improve current deep learning algorithms using geometrical augmentations for detecting COVID-19. We also provide clinical perspectives on geometric augmentation to consider regarding the development of a robust COVID-19 X-ray-based detector.


Smoking reduction during pregnancy by a program of self-help and clinical support.
This study investigated the impact of a low-cost, pregnancy-specific self-help smoking-cessation program on patient smoking behavior both pre- and postpartum. The population consisted of 274 English-speaking women enrolled in a large health maintenance organization who reported smoking at the time of the baseline survey or had quit within the previous 3 months. A control group receiving standard obstetric care was compared with two experimental groups, one receiving the self-help materials and standard care and the other receiving the materials plus brief regular clinician interactions and counseling about smoking. Smoking data were obtained from two additional self-reported surveys conducted at 6 months' gestation and approximately 8 weeks postpartum. Self-reported smoking behavior was verified using a urine cotinine test, which revealed no significant differences between the groups. Among baseline smokers, although neither intervention yielded significantly higher 6-month nonsmoking rates compared with controls, both interventions significantly increased the proportion of women who were not smoking postpartum. Among those who had quit smoking at baseline, only the more intensive intervention significantly increased maintenance of non-smoking postpartum. Brief counseling, a simple charting system, and improved access to educational materials allowed the program to be integrated easily into routine prenatal care at a cost of $50-111 per patient.


Transfer and Vascular Effect of Endothelin Receptor Antagonists in the Human Placenta.
Increasing evidence suggests a role for the ET (endothelin) system in preeclampsia. Hence, blocking this system with endothelin receptor antagonists (ERAs) could be a therapeutic strategy. Yet, clinical studies are lacking due to possible teratogenic effects of ERAs. In this study, we investigated the placental transfer of ERAs and their effect on ET-1-mediated vasoconstriction. Term placentas were dually perfused with the selective ETAR (ET type A receptor) antagonists sitaxentan and ambrisentan or the nonselective ETAR/ETBR antagonist macitentan and subsequently exposed to ET-1 in the fetal circulation. ET-1 concentration-response curves after incubation with sitaxentan, ambrisentan, macitentan, or the selective ETBR antagonist BQ-788 were also constructed in isolated chorionic plate arteries using wire-myography, and gene expression of the ET-system was quantified in healthy and early onset preeclamptic placentas. At steady state, the mean fetal-to-maternal transfer ratios were 0.32±0.05 for sitaxentan, 0.21±0.02 for ambrisentan, and 0.05±0.01 for macitentan. Except for BQ-788, all ERAs lowered the response to ET-1, both in the perfused cotyledon and isolated chorionic plate arteries. Placental gene expression of ECE-1, ETAR, and ETBR were comparable in healthy and preeclamptic placentas, while ET-1 expression was higher in preeclampsia. Our study is the first to show direct transfer of ERAs across the term human placenta. Furthermore, ETAR exclusively mediates ET-1-induced constriction in the fetoplacental vasculature. Given its limited transfer, macitentan could be considered as potential preeclampsia therapy. Extending knowledge on placental transfer to placentas of preeclamptic pregnancies is required to determine whether ERAs might be applied safely in preeclampsia.


Automating Model Generation for Image-Based Cardiac Flow Simulation.
Computational fluid dynamics (CFD) modeling of left ventricle (LV) flow combined with patient medical imaging data has shown great potential in obtaining patient-specific hemodynamics information for functional assessment of the heart. A typical model construction pipeline usually starts with segmentation of the LV by manual delineation followed by mesh generation and registration techniques using separate software tools. However, such approaches usually require significant time and human efforts in the model generation process, limiting large-scale analysis. In this study, we propose an approach toward fully automating the model generation process for CFD simulation of LV flow to significantly reduce LV CFD model generation time. Our modeling framework leverages a novel combination of techniques including deep-learning based segmentation, geometry processing, and image registration to reliably reconstruct CFD-suitable LV models with little-to-no user intervention.1 We utilized an ensemble of two-dimensional (2D) convolutional neural networks (CNNs) for automatic segmentation of cardiac structures from three-dimensional (3D) patient images and our segmentation approach outperformed recent state-of-the-art segmentation techniques when evaluated on benchmark data containing both magnetic resonance (MR) and computed tomography(CT) cardiac scans. We demonstrate that through a combination of segmentation and geometry processing, we were able to robustly create CFD-suitable LV meshes from segmentations for 78 out of 80 test cases. Although the focus on this study is on image-to-mesh generation, we demonstrate the feasibility of this framework in supporting LV hemodynamics modeling by performing CFD simulations from two representative time-resolved patient-specific image datasets.


Laplacian sparse coding, Hypergraph Laplacian sparse coding, and applications.
Sparse coding exhibits good performance in many computer vision applications. However, due to the overcomplete codebook and the independent coding process, the locality and the similarity among the instances to be encoded are lost. To preserve such locality and similarity information, we propose a Laplacian sparse coding (LSc) framework. By incorporating the similarity preserving term into the objective of sparse coding, our proposed Laplacian sparse coding can alleviate the instability of sparse codes. Furthermore, we propose a Hypergraph Laplacian sparse coding (HLSc), which extends our Laplacian sparse coding to the case where the similarity among the instances defined by a hypergraph. Specifically, this HLSc captures the similarity among the instances within the same hyperedge simultaneously, and also makes the sparse codes of them be similar to each other. Both Laplacian sparse coding and Hypergraph Laplacian sparse coding enhance the robustness of sparse coding. We apply the Laplacian sparse coding to feature quantization in Bag-of-Words image representation, and it outperforms sparse coding and achieves good performance in solving the image classification problem. The Hypergraph Laplacian sparse coding is also successfully used to solve the semi-auto image tagging problem. The good performance of these applications demonstrates the effectiveness of our proposed formulations in locality and similarity preservation.


Introduction to "A Compendium of Strategies To Prevent Healthcare-Associated Infections in Acute Care Hospitals: 2014 updates".
Since the publication of "A Compendium of Strategies to Prevent Healthcare-Associated Infections in Acute Care Hospitals" in 2008, prevention of healthcare-associated infections (HAIs) has become a national priority. Despite improvements, preventable HAIs continue to occur. The 2014 updates to the Compendium were created to provide acute care hospitals with up-to-date, practical, expert guidance to assist in prioritizing and implementing their HAI prevention efforts. It is the product of a highly collaborative effort led by the Society for Healthcare Epidemiology of America (SHEA), the Infectious Diseases Society of America (IDSA), the American Hospital Association (AHA), the Association for Professionals in Infection Control and Epidemiology (APIC), and The Joint Commission, with major contributions from representatives of a number of organizations and societies with content expertise, including the Centers for Disease Control and Prevention (CDC), the Institute for Healthcare Improvement (IHI), the Pediatric Infectious Diseases Society (PIDS), the Society for Critical Care Medicine (SCCM), the Society for Hospital Medicine (SHM), and the Surgical Infection Society (SIS).


Connecting at Local Level: Exploring Opportunities for Future Design of Technology to Support Social Connections in Age-Friendly Communities.
Social connectedness in later life is an important dimension of an age-friendly community, with associated implications for individual health and wellbeing. In contrast with prior efforts focusing on connections at a distance or online communities where the digital technology is the interface, we explore the design opportunities and role of technology for connectedness within a geographically local community context. We present findings from interviews with 22 older adults and a linked ideation workshop. Our analysis identified shared concerns and negative perceptions around local relationships, connections and characteristics of the geographical area. However, local connectedness through technology was largely absent from day-to-day life and even perceived as contributing to disconnection. By uncovering how older adults use and perceive technology in their social lives and combining these findings with their ideas for improving local connections, we highlight the need for thoughtful consideration of the role of technology in optimising social connections within communities. Our research highlights a need for design work to understand the specifics of the local context and reduce emphasis on technology as the interface between people. We introduce an amended definition-'underpinned by a commitment to respect and social inclusion, an age-friendly community is engaged in a strategic and ongoing process to facilitate active ageing by optimising the community's physical, social and digital environments and its supporting infrastructure'-to conceptualise our approach. We conclude by suggesting areas for future work in developing digitally connected age-friendly communities.


Potential mediator of inflammation. Phagocyte-derived oxidants suppress the elastase-inhibitory capacity of alpha 1-proteinase inhibitor in vitro.
Human polymorphonuclear leukocytes, monocytes, or pulmonary alveolar macrophages, stimulated in vitro by phorbol myristate acetate (PMA), released reactive oxygen species able to suppress the elastase inhibitory capacity (EIC) of human serum. Immunoelectrophoresis using antibodies against alpha(1)-proteinase inhibitor (alpha(1)-Pi) and elastase showed that inactivation of alpha(1)-Pi was responsible for the decreased serum EIC. Treatment of phagocyte-inactivated serum with a reducing agent (dithiothreitol) resulted in significant recovery of EIC, suggesting that alpha(1)-Pi had been oxidatively inactivated. Serum EIC was partially protected by superoxide dismutase or catalase. Hydrogen peroxide alone had no effect on serum EIC. Thus, neither H(2)O(2) nor O(2) (-) alone, but a product of the two, may have oxidatively inactivated alpha(1)-Pi. In support of the foregoing, neutrophils or monocytes from a patient with chronic granulomatous disease failed to produce detectable levels of O(2) (-) after incubation with PMA. These cells also failed to suppress serum EIC. In the case of PMA-stimulated polymorphonuclear leukocytes or monocytes, extracellular myeloperoxidase may have also played a role in alpha(1)-Pi inactivation since serum EIC was partly protected by azide, cyanide, or the depletion of extracellular chloride. Indeed, in a cell-free system consisting of purified myeloperoxidase, a glucose oxidase-H(2)O(2)-generating system, and Cl(-), the EIC of human serum or purified alpha(1)-Pi could also be suppressed. Omission of any single reactant prevented this effect, as did NaN(3) or catalase, suggesting that enzymatically active myeloperoxidase and H(2)O(2) were necessary. Immunoelectrophoresis of myeloperoxidase-inactivated serum showed that, as before, inactivation of alpha(1)-Pi was responsible for the decreased EIC. Treating myeloperoxidase-inactivated serum with dithiothreitol led to significant recovery of EIC, again suggesting that oxidative inactivation of alpha(1)-Pi had occurred. Oxidative inactivation of alpha(1)-Pi in the microenvironment of inflammatory cells, at sites of acute or chronic inflammation, may allow proteases released from these cells to damage adjacent connective tissue components more readily.


The genome sequence of the metal-mobilizing, extremely thermoacidophilic archaeon Metallosphaera sedula provides insights into bioleaching-associated metabolism.
Despite their taxonomic description, not all members of the order Sulfolobales are capable of oxidizing reduced sulfur species, which, in addition to iron oxidation, is a desirable trait of biomining microorganisms. However, the complete genome sequence of the extremely thermoacidophilic archaeon Metallosphaera sedula DSM 5348 (2.2 Mb, approximately 2,300 open reading frames [ORFs]) provides insights into biologically catalyzed metal sulfide oxidation. Comparative genomics was used to identify pathways and proteins involved (directly or indirectly) with bioleaching. As expected, the M. sedula genome contains genes related to autotrophic carbon fixation, metal tolerance, and adhesion. Also, terminal oxidase cluster organization indicates the presence of hybrid quinol-cytochrome oxidase complexes. Comparisons with the mesophilic biomining bacterium Acidithiobacillus ferrooxidans ATCC 23270 indicate that the M. sedula genome encodes at least one putative rusticyanin, involved in iron oxidation, and a putative tetrathionate hydrolase, implicated in sulfur oxidation. The fox gene cluster, involved in iron oxidation in the thermoacidophilic archaeon Sulfolobus metallicus, was also identified. These iron- and sulfur-oxidizing components are missing from genomes of nonleaching members of the Sulfolobales, such as Sulfolobus solfataricus P2 and Sulfolobus acidocaldarius DSM 639. Whole-genome transcriptional response analysis showed that 88 ORFs were up-regulated twofold or more in M. sedula upon addition of ferrous sulfate to yeast extract-based medium; these included genes for components of terminal oxidase clusters predicted to be involved with iron oxidation, as well as genes predicted to be involved with sulfur metabolism. Many hypothetical proteins were also differentially transcribed, indicating that aspects of the iron and sulfur metabolism of M. sedula remain to be identified and characterized.


The relationship between social support and participation in stroke: A systematic review.
The incidence of cerebrovascular accidents with its devastating effects on individuals is increasing. Post-stroke, restrictions in participation are common and social support could have an influence on this. Social support provided to individuals post-stroke is vital, but the relationship between social support and participation is not well understood. This review aimed to systematically determine the relationship between social support and participation post-stroke, based on the literature available. Ebscohost, Science Direct, Biomed Central, Cochrane Library, Google Scholar, Pedro Central and Wiley Online were the electronic databases searched between 2001 and 2016. Articles were deemed to be eligible if they met the inclusion criteria and successfully underwent scrutiny to determine their relevance and methodological quality, using tools from the Critical Appraisal Skills Programme and Milton Keynes Primary Trust. A narrative synthesis method was used to analyse the included studies. A total of 54 articles were identified after screening, and six articles were deemed eligible for inclusion. The articles consisted of cross-sectional, qualitative and cohort studies. Articles showed distinct, significant relationships between social support and participation where the quality and quantity of social support were important. High levels of social support had a positive influence on participation, social and leisure activities, as well as returning to work post-stroke. A positive relationship exists between social support and participation post-stroke. Health professionals need to include social support interventions when attempting to manage the individual with stroke holistically, as this will have positive effects on participation.


Conformational behaviour of a synthetic peptide of the C-terminus of villin that interacts with actin: an NMR, CD and stimulated annealing study.
The solution structure of a synthetic 22-amino acid peptide (P1) corresponding to the extreme C-terminal end and one of the F-actin binding sites of villin has been determined by 1H NMR and CD spectroscopy. The structure of this peptide was compared to that of a peptide in which lysine to glutamic acid substitutions were introduced at positions 17 and 19 (P11), abolishing F-actin binding. Both peptides are largely unstructured in aqueous solution. Changes observed in the NMR and CD spectra of both peptides are consistent with alpha-helix formation in trifluoroethanol/water mixtures. A set of 189 interproton distances derived from nuclear Overhauser enhancement (NOE) measurements, 17 phi-angle constraints obtained from 3JNH alpha coupling constants, as well as about 10 N ... O distance restraints deduced from amide proton exchange kinetics with deuterium, were used for the structure determination. The three-dimensional structure of P1 and P11 is characterized by two helical regions, one extending from residues 2 to 5 and a second covering residues 7 to 17. The central fragment, ranging from Leu-7 to Leu-15, is more stable. The C-terminal residues are less structured, particularly within peptide P11. The significance of these structural results is discussed in relation to the biological activity of villin.


Risk of viral acute gastrointestinal illness from nondisinfected drinking water distribution systems.
Acute gastrointestinal illness (AGI) resulting from pathogens directly entering the piping of drinking water distribution systems is insufficiently understood. Here, we estimate AGI incidence from virus intrusions into the distribution systems of 14 nondisinfecting, groundwater-source, community water systems. Water samples for virus quantification were collected monthly at wells and households during four 12-week periods in 2006-2007. Ultraviolet (UV) disinfection was installed on the communities' wellheads during one study year; UV was absent the other year. UV was intended to eliminate virus contributions from the wells and without residual disinfectant present in these systems, any increase in virus concentration downstream at household taps represented virus contributions from the distribution system (Approach 1). During no-UV periods, distribution system viruses were estimated by the difference between well water and household tap virus concentrations (Approach 2). For both approaches, a Monte Carlo risk assessment framework was used to estimate AGI risk from distribution systems using study-specific exposure-response relationships. Depending on the exposure-response relationship selected, AGI risk from the distribution systems was 0.0180-0.0661 and 0.001-0.1047 episodes/person-year estimated by Approaches 1 and 2, respectively. These values represented 0.1-4.9% of AGI risk from all exposure routes, and 1.6-67.8% of risk related to drinking water exposure. Virus intrusions into nondisinfected drinking water distribution systems can contribute to sporadic AGI.


Speech defects in children aged 7 years: a national study.
A series of screening procedures applied on a national scale by doctors, teachers, and health visitors showed that between 10% and 13% of British 7-year-old children born in one week in 1958 were reported as having an appreciable degree of speech impairment. Between 1% and 2% had a marked speech defect though hearing normally. This latter group of speech-defective children were more often male and of poor family background, and more were born towards the end of a long family. They were often at a disadvantage educationally and had more clumsiness and defects of vision and visuomotor co-ordination than the rest of the sample. The methods used for screening provided a reliable guide in the selection of children who require further investigation.


Susoctocog-alfa (Obizur®) in the treatment of nine elderly patients with acquired haemophilia A: an Italian multicentre real world experience.
In 2016, a new recombinant B-domain deleted porcine FVIII (rpFVIII) was licensed in Italy for the treatment of acquired haemophilia A (AHA), but only a few cases of patients receiving this have been reported in the literature. Here we report the largest registry of the use of rpFVIII for the treatment of AHA. The objective of this retrospective study was to describe the efficacy and the safety of susoctocog-alfa for AHA. We studied a population of nine patients, recruited in five Italian haemophilia centres presenting AHA, and treated with Obizur® as first- or second-line therapy. rpFVIII was used as a first-line therapy in one-third of the patients. The median delay between clinical onset and diagnosis was 16 days. Initial bolus of infused susoctocog-alfa was 100 IU/kg, lower than the recommended dose. The treatment was maintained for a median of four days. Only one patient with serious co-morbidities and recurrent infections was treated for 32 days. All patients reached a complete resolution of AHA, and no recurrences were reported. Two patients developed a low-titre inhibitor against rpFVIII, neither experienced any complications. In our real world experience, susoctocog-alfa was proven to be an effective and safe therapeutic option for patients with AHA, also at a lower than recommended dosage. In our report, the appearance of low-titre inhibitors against rpFVIII, was not found to be clinically significant.


Synchronism of the siberian traps and the permian-triassic boundary.
Uranium-lead ages from an ion probe were taken for zircons from the ore-bearing Noril'sk I intrusion that is comagmatic with, and intrusive to, the Siberian Traps. These values match, within an experimental error of +/-4 million years, the dates for zircons extracted from a tuff at the Permian-Triassic (P-Tr) boundary. The results are consistent with the hypothesis that the P-Tr extinction was caused by the Siberian basaltic flood volcanism. It is likely that the eruption of these magmas was accompanied by the injection of large amounts of sulfur dioxide into the upper atmosphere, which may have led to global cooling and to expansion of the polar ice cap. The P-Tr extinction event may have been caused by a combination of acid rain and global cooling as well as rapid and extreme changes in sea level resulting from expansion of the polar ice cap.


Simvastatin reverses the hypertension of heterozygous mice lacking cystathionine beta-synthase and apolipoprotein A-I.
Double heterozygous mice lacking Apoa1 and Cbs genes show mild hyperhomocysteinemia in combination with hypoalphalipoproteinemia. This situation leads to a moderate hypertension associated with a dysregulation in nitric oxide metabolism. The aim of this study was to investigate the potential beneficial effects of statin treatment in these mice. After 4 weeks of simvastatin administration, plasma parameters; apolipoproteins A-I, A-II and A-IV; lipid profile; and blood pressure were assessed, Western blotting was performed in the aorta of these mice to measure endothelial nitric oxide synthase and caveolin-1 content. The high blood pressure level present in the double heterozygous group was corrected down to that of the wild-type group after simvastatin treatment (124+/-7.7 vs. 109+/-11.2 mmHg, p<0.01). Concomitant with this effect, an increase in nitric oxide levels was observed in these double heterozygous mice receiving simvastatin treatment probably mediated in part by a decrease in caveolin-1 levels. Blood pressure changes appeared to be independent of the arylesterase activity of paraoxonase or the lipid content. Another remarkable result was the significant increase in apoA-IV content in animals receiving simvastatin, an effect considered to be protective for the endothelium. In conclusion, the results of this study demonstrate that the use of simvastatin can improve blood pressure control in mice with elevated homocysteinemia and low levels of apoA-I, and this effect is mediated by mechanisms independent of plasma lipids and related to nitric oxide levels.


Racial discrimination as a mediator of racial disparities in insomnia disorder.
Racial and ethnic minorities are more likely to suffer from insomnia that is more severe; however, few studies have examined mechanisms by which racial disparities in severity of insomnia disorder may arise. One potential mechanism for disparities in insomnia severity is perceived discrimination. This study tested discrimination as a mediator in the relationship between race and insomnia. Participants were recruited from communities in the Detroit metropolitan area and were diagnosed with insomnia disorder using the DSM-5 (Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition). The final sample included 1,458 individuals. Insomnia symptom severity was assessed via the Insomnia Severity Index and self-reported racial discrimination was evaluated using a single item. Racial discrimination was tested as a mediator in the relationship between race and insomnia symptom severity. Individuals were categroized as either White or a racial minority (i.e., non White individuals), with sensitivity analyses examining Black individuals and non-Black racial minority groups. Consistent with our hypothesis, racial discrimination was a significant mediator accounting for 57.3% of the relationship between race and insomnia symptom severity. Sensitivity analyses indicated that the indirect effect of racial discrimination was stronger in the non-Black racial minority group compared to Black individuals. These results provide support that racial discrimination is likely an important mechanism by which racial and ethnic sleep disparities exist. Implications for prevention, intervention, and treatment of insomnia in racial minorities to reduce health disparities are discussed.


Final Report of the Mars Sample Return Science Planning Group 2 (MSPG2).
The Mars Sample Return (MSR) Campaign must meet a series of scientific and technical achievements to be successful. While the respective engineering responsibilities to retrieve the samples have been formalized through a Memorandum of Understanding between ESA and NASA, the roles and responsibilities of the scientific elements have yet to be fully defined. In April 2020, ESA and NASA jointly chartered the MSR Science Planning Group 2 (MSPG2) to build upon previous planning efforts in defining 1) an end-to-end MSR Science Program and 2) needed functionalities and design requirements for an MSR Sample Receiving Facility (SRF). The challenges for the first samples brought from another planet include not only maintaining and providing samples in pristine condition for study, but also maintaining biological containment until the samples meet sample safety criteria for distribution outside of biocontainment. The MSPG2 produced six reports outlining 66 findings. Abbreviated versions of the five additional high-level MSPG2 summary findings are: Summary-1. A long-term NASA/ESA MSR Science Program, along with the necessary funding and human resources, will be required to accomplish the end-to-end scientific objectives of MSR. Summary-2. MSR curation would need to be done concurrently with Biosafety Level-4 containment. This would lead to complex first-of-a-kind curation implementations and require further technology development. Summary-3. Most aspects of MSR sample science could, and should, be performed on samples deemed safe in laboratories outside of the SRF. However, other aspects of MSR sample science are both time-sensitive and sterilization-sensitive and would need to be carried out in the SRF. Summary-4. To meet the unique science, curation, and planetary protection needs of MSR, substantial analytical and sample management capabilities would be required in an SRF. Summary-5. Because of the long lead-time for SRF design, construction, and certification, it is important that preparations begin immediately, even if there is delay in the return of samples.


Functional consequences of the macrophage stimulating protein 689C inflammatory bowel disease risk allele.
Macrophage stimulating protein (MSP) is a serum growth factor that binds to and activates the receptor tyrosine kinase, Recepteur d'Origine Nantais (RON). A non-synonymous coding variant in MSP (689C) has been associated with genetic susceptibility to both Crohn's disease and ulcerative colitis, two major types of inflammatory bowel disease (IBD) characterized by chronic inflammation of the digestive tract. We investigated the consequences of this polymorphism for MSP-RON pathway activity and IBD pathogenesis. RON expression patterns were examined on mouse and human cells and tissues under normal and disease conditions to identify cell types regulated by MSP-RON. Recombinant MSP variants were tested for their ability to bind and stimulate RON and undergo proteolytic activation. MSP concentrations were quantified in the serum of individuals carrying the MSP 689R and 689C alleles. In intestinal tissue, RON was primarily expressed by epithelial cells under normal and disease conditions. The 689C polymorphism had no impact on the ability of MSP to bind to or signal through RON. In a cohort of normal individuals and IBD patients, carriers of the 689C polymorphism had lower concentrations of MSP in their serum. By reducing the quantities of circulating MSP, the 689C polymorphism, or a variant in linkage disequilibrium with this polymorphism, may impact RON ligand availability and thus receptor activity. Given the known functions of RON in regulating wound healing and our analysis of RON expression patterns in human intestinal tissue, these data suggest that decreased RON activity may impact the efficiency of epithelial repair and thus underlie the increased IBD susceptibility associated with the MSP 689C allele.


[Weill-Marchesani's syndrome: familial involvement].
We report the case of a child short in stature with brachydactyly and brachymorphy who was referred to our office complaining of poor vision. This was a case of Weill-Marchesani's syndrome described in a family, in which four of the eight children were affected by spherophakia, brachymorphy and brachydactyly. There are few familial cases of Weill-Marchesani's syndrome reported in the literature. Both autosomal dominant and recessive inheritances have been described. The opththalmologist plays a crucial role in its diagnosis and management, since the ocular involvement is the most severe one.


Does adding cognitive-behavioural physiotherapy to exercise improve outcome in patients with chronic neck pain? A randomised controlled trial.
To determine whether adding a physiotherapist-led cognitive-behavioural intervention to an exercise programme improved outcome in patients with chronic neck pain (CNP). Multicentre randomised controlled trial. Four outpatient physiotherapy departments. Fifty-seven patients with CNP. Follow-up data were provided by 39 participants [57% of the progressive neck exercise programme (PNEP) group and 79% of the interactive behavioural modification therapy (IBMT) group]. Twenty-eight subjects were randomised to the PNEP group and 29 subjects were randomised to the IBMT group. IBMT is underpinned by cognitive-behavioural principles, and aims to modify cognitive risk factors through interactive educational sessions, graded exercise and progressive goal setting. The main outcome measure was disability, measured by the Northwick Park Questionnaire (NPQ). Secondary outcomes were the Numeric Pain Rating Scale (NPRS), Pain Catastrophising Scale, Tampa Scale for Kinesiophobia (TSK), Chronic Pain Self-efficacy Scale (CPSS) and the Pain Vigilance and Awareness Questionnaire. No significant between-group differences in disability were observed (mean NPQ change: PNEP=-7.2, IBMT=-10.2). However, larger increases in functional self-efficacy (mean CPSS change: PNEP=1.0, IBMT=3.2) and greater reductions in pain intensity (mean NPRS change: PNEP=-1.0, IBMT=-2.2; P<0.05) and pain-related fear (mean TSK change: PNEP=0.2, IBMT=-4.7, P<0.05) were observed with IBMT. Additionally, a significantly greater proportion of participants made clinically meaningful reductions in pain (25% vs 55%, P<0.05) and disability (25% vs 59%, P<0.05) with IBMT. The primary outcome did not support the use of cognitive-behavioural physiotherapy in all patients with CNP. However, superior outcomes were observed for several secondary measures, and IBMT may offer additional benefit in some patients. ISRCTN27611394.


Scattering of light by multiple dielectric cylinders: comparison of radiative transfer and Maxwell theory.
We have compared radiative transfer theory with analytical solutions of the Maxwell equations for light scattering by multiple infinitely long parallel cylinders at perpendicular incidence. The calculated scattering cross sections for both methods show large differences, but the angle-dependent differential scattering cross-section results are very similar for small cylinder densities, except close to the forward direction. In contrast to recently published results, it is shown that the radiative transfer equation is a useful approximation for small cylinder concentrations.


Neural predictive error signal correlates with depressive illness severity in a game paradigm.
Considerable experimental evidence supports the existence of predictive error signals in various brain regions during associative learning in animals and humans. These regions include the prefrontal cortex, temporal lobe, cerebellum and monoamine systems. Various quantitative theories have been developed to describe behaviour during learning, including Rescorla-Wagner, Temporal Difference and Kalman filter models. These theories may also account for neural error signals. Reviews of imaging studies of depressive illness have consistently implicated the prefrontal and temporal lobes as having abnormal function, and sometimes structure, whilst the monoamine systems are directly influenced by antidepressant medication. It was hypothesised that such abnormalities may be associated with a dysfunction of associative learning that would be reflected by different predictive error signals in depressed patients when compared with healthy controls. This was tested with 30 subjects, 15 with a major depressive illness, using a gambling paradigm and fMRI. Consistent with the hypothesis, depressed patients differed from controls in having an increased error signal. Additionally, for some brain regions, the magnitude of the error signal correlated with Hamilton depression rating of illness severity. Structural equation modelling was used to investigate hypothesised change in effective connectivity between prespecified regions of interest in the limbic and paralimbic system. Again, differences were found that in some cases correlated with illness severity. These results are discussed in the context of quantitative theories of brain function, clinical features of depressive illness and treatments.


Computational insights on the isomerization of photochromic oxazines.
We investigated the isomerization of the simplest member of a family of photochromic oxazines with the aid of density functional theory, using three different functionals. Specifically, we simulated the thermal interconversion of the two enantiomers, associated with this compound, and established that the opening of the oxazine ring dictates the rate of the overall degenerate process. The M062X functional provides the best match to experimental data, whereas B3LYP calculations fail to model accurately the ground-state potential-energy surface of this system. In addition, we also modeled the absorption spectra of this compound and its photogenerated isomer with time-dependent calculations. The resulting data support the original assignment of the experimental spectra and confirm that the oxazine ring opens upon excitation. The MPW1PW91 functional provides the best match to experimental data, whereas M062X calculations fail to model accurately the spectroscopic parameters of this particular system. Furthermore, the MPW1PW91 calculations demonstrate that the photoinduced opening of the oxazine ring occurs along the potential-energy surface of the first triplet excited state. Indeed, the photoinduced isomerization appears to involve: (1) the initial excitation of one isomer to the second singlet excited state, (2) its thermal relaxation to the first triplet excited state, (3) its ring opening to produce the other isomer, and (4) the thermal relaxation of the product to the ground state. Thus, our calculations provide valuable information on the elementary steps governing the isomerization of this particular photochromic compound in the ground state and upon excitation. These useful mechanistic insights can guide the design of novel members of this family of photoresponsive compounds with specific properties.


Low-molecular-weight heparins in the treatment of acute coronary syndromes.
Platelet aggregation and activation of coagulation are key events in the development of acute coronary syndromes. Patients with an acute coronary syndrome are at high risk of death or myocardial infarction, and hence there is a strong rationale for the use of antithrombotic agents. Heparin has been shown to reduce the risk of death or myocardial infarction in aspirin-treated patients with acute coronary syndromes, but it has a number of limitations, including the need for regular monitoring and the risk of hemorrhage and thrombocytopenia. Low-molecular-weight heparins offer a number of practical and clinical advantages over unfractionated heparin, such as higher bioavailability and administration by subcutaneous injection. Several low-molecular-weight heparins are available that differ in their biochemical and pharmacologic properties, and it is not possible to predict their clinical efficacy from their pharmacologic profile. The decision regarding the use of a specific low-molecular-weight heparin should be based on the efficacy and safety data available for each product. In clinical trials comparing low-molecular-weight heparin with heparin, only enoxaparin sodium has been shown to reduce the risk of coronary events in patients with non-ST segment elevation acute coronary ischemia.


Objective and subjective sleep quality: Melatonin versus placebo add-on treatment in patients with schizophrenia or bipolar disorder withdrawing from long-term benzodiazepine use.
Benzodiazepines are frequently long-term prescribed for the treatment of patients with severe mental illness. This prescribing practice is problematic because of well-described side effects including risk of dependence. We examined the efficacy of prolonged-release melatonin on objective and subjective sleep quality during benzodiazepine discontinuation and whether sleep variables were associated with benzodiazepine withdrawal. Eligible patients included adults with a diagnosis of schizophrenia, schizoaffective disorder, or bipolar disorder and long-term use of benzodiazepines in combination with antipsychotics. All participants gradually tapered the use of benzodiazepines after randomization to add-on treatment with melatonin versus placebo. Here we report a subsample of 23 patients undergoing sleep recordings (one-night polysomnography) and 55 patients participating in subjective sleep quality ratings. Melatonin had no effect on objective sleep efficiency, but significantly improved self-reported sleep quality. Reduced benzodiazepine dosage at the 24-week follow-up was associated with a significantly decreased proportion of stage 2 sleep. These results indicate that prolonged-release melatonin has some efficacy for self-reported sleep quality after gradual benzodiazepine dose reduction, and that benzodiazepine discontinuation is not associated with rebound insomnia in medicated patients with severe mental illness. However, these findings were limited by a small sample size and a low retention rate.


White matter hyperintensities and CSF Alzheimer disease biomarkers in preclinical Alzheimer disease.
Recent studies suggest that white matter hyperintensities (WMH) on MRI, which primarily reflect small vessel cerebrovascular disease, may play a role in the evolution of Alzheimer disease (AD). In a longitudinal study, we investigated whether WMH promote the progression of AD pathology, or alter the association between AD pathology and risk of progression from normal cognition to mild cognitive impairment (MCI). Two sets of analyses were conducted. The relationship between whole brain WMH load, based on fluid-attenuated inversion recovery MRI, obtained in initially cognitively normal participants (n = 274) and time to onset of symptoms of MCI (n = 60) was examined using Cox regression models. In a subset of the participants with both MRI and CSF data (n = 204), the interaction of WMH load and CSF AD biomarkers was also evaluated. Baseline WMH load interacted with CSF total tau (t-tau) with respect to symptom onset, but not with CSF β-amyloid 1-42 or phosphorylated tau (p-tau) 181. WMH volume was associated with time to symptom onset of MCI among individuals with low t-tau (hazard ratio [HR] 1.35, confidence interval [CI] 1.06-1.73, p = 0.013), but not those with high t-tau (HR 0.86, CI 0.56-1.32, p = 0.47). The rate of change in the CSF biomarkers over time was not associated with the rate of change in WMH volumes. These results suggest that WMH primarily affect the risk of progression when CSF measures of neurodegeneration or neuronal injury (as reflected by t-tau) are low. However, CSF biomarkers of amyloid and p-tau and WMH appear to have largely independent and nonsynergistic effects on the risk of progression to MCI.


Cardiac arrhythmia and neuroexcitability gene variants in resected brain tissue from patients with sudden unexpected death in epilepsy (SUDEP).
Sudden unexpected death in epilepsy (SUDEP) is the leading cause of epilepsy-related mortality in young adults. The exact mechanisms are unknown but death often follows a generalized tonic-clonic seizure. Proposed mechanisms include seizure-related respiratory, cardiac, autonomic, and arousal dysfunction. Genetic drivers underlying SUDEP risk are largely unknown. To identify potential SUDEP risk genes, we compared whole-exome sequences (WES) derived from formalin-fixed paraffin embedded surgical brain specimens of eight epilepsy patients who died from SUDEP with seven living controls matched for age at surgery, sex, year of surgery and lobe of resection. We compared identified variants from both groups filtering known polymorphisms from publicly available data as well as scanned for epilepsy and candidate SUDEP genes. In the SUDEP cohort, we identified mutually exclusive variants in genes involved in µ-opiod signaling, gamma-aminobutyric acid (GABA) and glutamate-mediated synaptic signaling, including ARRB2, ITPR1, GABRR2, SSTR5, GRIK1, CTNAP2, GRM8, GNAI2 and GRIK5. In SUDEP patients we also identified variants in genes associated with cardiac arrhythmia, including KCNMB1, KCNIP1, DPP6, JUP, F2, and TUBA3D, which were not present in living epilepsy controls. Our data shows that genomic analysis of brain tissue resected for seizure control can identify potential genetic biomarkers of SUDEP risk.


From dinosaurs to birds: a tail of evolution.
A particularly critical event in avian evolution was the transition from long- to short-tailed birds. Primitive bird tails underwent significant alteration, most notably reduction of the number of caudal vertebrae and fusion of the distal caudal vertebrae into an ossified pygostyle. These changes, among others, occurred over a very short evolutionary interval, which brings into focus the underlying mechanisms behind those changes. Despite the wealth of studies delving into avian evolution, virtually nothing is understood about the genetic and developmental events responsible for the emergence of short, fused tails. In this review, we summarize the current understanding of the signaling pathways and morphological events that contribute to tail extension and termination and examine how mutations affecting the genes that control these pathways might influence the evolution of the avian tail. To generate a list of candidate genes that may have been modulated in the transition to short-tailed birds, we analyzed a comprehensive set of mouse mutants. Interestingly, a prevalent pleiotropic effect of mutations that cause fused caudal vertebral bodies (as in the pygostyles of birds) is tail truncation. We identified 23 mutations in this class, and these were primarily restricted to genes involved in axial extension. At least half of the mutations that cause short, fused tails lie in the Notch/Wnt pathway of somite boundary formation or differentiation, leading to changes in somite number or size. Several of the mutations also cause additional bone fusions in the trunk skeleton, reminiscent of those observed in primitive and modern birds. All of our findings were correlated to the fossil record. An open question is whether the relatively sudden appearance of short-tailed birds in the fossil record could be accounted for, at least in part, by the pleiotropic effects generated by a relatively small number of mutational events.


The stigma of low opioid prescription in the hospitalized multimorbid elderly in Italy.
The primary aim of this study was to evaluate the prevalence of opioid prescriptions in hospitalized geriatric patients. Other aims were to evaluate factors associated with opioid prescription, and whether or not there was consistency between the presence of pain and prescription. Opioid prescriptions were gathered from the REgistro POliterapie Societa` Italiana di Medicina Interna (REPOSI) data for the years 2008, 2010 and 2012. 1,380 in-patients, 65+ years old, were enrolled in the first registry run, 1,332 in the second and 1,340 in the third. The prevalence of opioid prescription was calculated at hospital admission and discharge. In the third run of the registry, the degree of pain was assessed by means of a numerical scale. The prevalence of patients prescribed with opioids at admission was 3.8% in the first run, 3.6% in the second and 4.1% in the third, whereas at discharge rates were slightly higher (5.8, 5.3, and 6.6%). The most frequently prescribed agents were mild opioids such as codeine and tramadol. The number of total prescribed drugs was positively associated with opioid prescription in the three runs; in the third, dementia and a better functional status were inversely associated with opioid prescription. Finally, as many as 58% of patients with significant pain at discharge were prescribed no analgesic at all. The conservative attitude of Italian physicians to prescribe opioids in elderly patients changed very little between hospital admission and discharge through a period of 5 years. Reasons for such a low opioid prescription should be sought in physicians' and patients' concerns and prejudices.


Knowing the boundaries: extending the differential adhesion hypothesis in embryonic cell sorting.
Successful embryogenesis requires proper sorting and compartmentalization of different cell types. Mechanical interactions between cells help govern these processes. In the past, physics-based theories have guided in vitro studies of cell sorting and tissue surface tension. Recent experiments have challenged this approach, indicating that adhesive molecules also act as signaling molecules that initiate local reorganization of actomyosin and demonstrating that cells at the boundary of a colony of initially identical cells become "mechanically polarized." Extending physical models to account for mechanical polarization helps solve a long-standing paradox about magnitudes of tissue surface tensions and potentially explains discrepancies between recent in vivo and in vitro cell-sorting experiments. New experiments are needed to further explore the connection between mechanical polarization and tissue boundary formation in vivo.


Variation in the transmission near-infrared signal with depth in turbid media.
Transmission near-infrared (NIR) measurements of a 1 mm thick aspirin disk were made at different positions as it was moved through a stack of eight 0.5 mm thick disks of microcrystalline cellulose (Avicel). The magnitude of the first derivative of absorbance for the aspirin interlayer at 8934 cm(-1) was lower when the disk was placed at the top or bottom of the stack of Avicel disks, with the largest signal observed when the aspirin was positioned at the central positions. The variation in signal with depth is consistent with that observed previously for transmission Raman spectrometry. In both cases, the trend observed can be attributed to lower photon density at the air-sample interface, relative to the center of the sample, owing to loss of photons to the air. This results in a reduction in the number of photons absorbed or Raman photons generated and subsequently detected when the interlayer occupies a near-surface position.