Smaller is better (when sampling from the crowd within): Low memory-span individuals benefit more from multiple opportunities for estimation.
Recently, Vul and Pashler (2008) demonstrated that the average of 2 responses from a single subject to general knowledge questions was more accurate than either single estimate. Importantly, this reveals that each guess contributes unique evidence relevant to the decision, contrary to views that eschew probabilistic representations of the evidence-gathering and decision-making processes. We tested an implication of that view by evaluating this effect separately in individuals with a range of memory spans. If memory span is the buffer in which retrieved information is assembled into an evaluation, then multiple estimates in individuals with lower memory spans should exhibit greater independence from one another than in individuals with higher spans. Our results supported this theory by showing that averaging 2 guesses from lower span individuals is more beneficial than averaging 2 guesses from higher span individuals. These results demonstrate a rare circumstance in which lower memory span confers a relative advantage on a cognitive task.


Nicotine interferes with purinergic signaling in smooth muscle cells isolated from urinary bladders of patients with lower urinary tract symptoms.
In patients with outlet obstruction, the contraction of the base is reduced compared to that of healthy individuals, while the contraction of the dome is not affected. Here, we investigated the cellular mechanisms that might be responsible for cholinergic effects blocking non-adrenergic non-cholinergic contractions in the base of the urinary bladder. Smooth muscle cells either from the base or from the dome of human urinary bladders were cultured to determine the contribution of cholinergic and purinergic mechanisms to their Ca2+ homeostasis. While ATP evoked Ca2+ transients in all the cells, nicotine and carbachol induced Ca2+ transients only in 56% and 44% of the cells, respectively. When ATP was administered together with nicotine or carbachol, the amplitudes of the Ca2+ transients recorded from cells prepared from the base of bladders were significantly smaller (42 ± 6% with nicotine and 56 ± 9% with carbachol) than those evoked by ATP alone. This inhibition was much less apparent in the dome of bladders. The inhibition between the cholinergic and purinergic signaling pathways reported in this work may decrease the strength of the contraction of the base of the urinary bladder in patients with outlet obstruction during voiding.


[Of what relevance is the diagnosis of "pneumatosis intestinalis" and portal gas for the surgeon?].
Pneumatosis intestinalis (PI) describes the existence of gas in the wall of the gastrointestinal tract; portal gas (PG) describes gas in the portovenous system. Both are predominantly diagnosed radiologically (computed tomography as the most sensitive method) and do not represent per se self-contained syndromes, but PI and PG are possible symptoms of a variety of diseases. Possible sources of gas are bacterial gas (e. g., bowel wall invasion by aerogenic bacteria), intraluminal and extraluminal enteric gas (e. g., increased intraluminal pressure e.g. endoscopy), and pulmonary gas (e. g., COPD). The treatment of PI /PG depends on the underlying disease. The decision for laparotomy/ laparoscopy should be a conclusion of clinical and possibly radiological signs. Since in many cases, the simultaneous detection of PI and PG, is caused by mesenterial ischemia and has a poor prognosis, in these cases, the decision for operation (laparotomy/ laparoscopy) should be made liberally. A symptomatic therapy with metronidazole and oxygen should be considered, if despite the adequate treatment of the underlying disease, PI continues with abdominal symptoms (such as intestinal pseudo-obstruction or nonspecific abdominal pain).


Internet of Medical Things and Healthcare 4.0: Trends, Requirements, Challenges, and Research Directions.
Healthcare 4.0 is a recent e-health paradigm associated with the concept of Industry 4.0. It provides approaches to achieving precision medicine that delivers healthcare services based on the patient's characteristics. Moreover, Healthcare 4.0 enables telemedicine, including telesurgery, early predictions, and diagnosis of diseases. This represents an important paradigm for modern societies, especially with the current situation of pandemics. The release of the fifth-generation cellular system (5G), the current advances in wearable device manufacturing, and the recent technologies, e.g., artificial intelligence (AI), edge computing, and the Internet of Things (IoT), are the main drivers of evolutions of Healthcare 4.0 systems. To this end, this work considers introducing recent advances, trends, and requirements of the Internet of Medical Things (IoMT) and Healthcare 4.0 systems. The ultimate requirements of such networks in the era of 5G and next-generation networks are discussed. Moreover, the design challenges and current research directions of these networks. The key enabling technologies of such systems, including AI and distributed edge computing, are discussed.


Cognitive impairment and "invisible symptoms" are not associated with CCSVI in MS.
We investigated the association between chronic cerebrospinal venous insufficiency (CCSVI) and cognitive impairment (CI) in multiple sclerosis (MS). Moreover, we evaluated the association between CCSVI and other frequent self-reported MS symptoms. We looked at the presence of CI in incident MS patients with CCVSI in a population-based cohort of Catania, Italy. All subjects were group-matched by age, sex, disease duration and EDSS score with MS patients without CCSVI, serving as controls. CI was assessed with the Brief Repeatable Battery (BRB) and the Stroop Test (ST) and it was defined by the presence of at least three impaired tests. Fatigue and depressive symptoms were assessed with Fatigue Severity Scale (FSS) and Hamilton Depressive Rating Scale (HDRS), respectively. Bladder and sexual symptoms were assessed with the respective items of the Italian version of Guy's Neurological Disability Scale (GNDS). Quality of life was evaluated with Multiple Sclerosis Quality of Life-54 Instrument (MSQOL-54). Out of 61 MS patients enrolled in the study, 27 were CCSVI positive and 34 were CCSVI negative. Of them, 43 were women (70.5%); the mean age was 43.9 ± 11.8 years; the mean disease duration was 159.7 ± 113.7 months; mean EDSS was 3.0 ± 2.6. Of them, 36 (59.0%) were classified relapsing-remitting (RR), 12 (19.7%) secondary progressive (SP), seven (11.5%) primary progressive (PP) and six (9.3%) Clinically Isolated Syndrome (CIS). Overall, CI was detected in 29/61 (47.5%) MS patients; particularly 13/27 (48.1%) in the CCSVI positive group and 16/34 (47.0%) in the CCSVI negative group. Presence of CCSVI was not significantly associated with the presence of CI (OR 1.04; 95% CI 0.37-2.87; p-value = 0.9). Not significant differences were found between the two groups regarding the other MS symptoms investigated. Our findings suggest a lack of association between CCSVI and CI in MS patients. Fatigue, depressive, bladder/sexual symptoms and self-reported quality of life are not associated with CCSVI.


The critical role of complement alternative pathway regulator factor H in allergen-induced airway hyperresponsiveness and inflammation.
Activation of the alternative pathway of complement plays a critical role in the development of allergen-induced airway hyperresponsiveness (AHR) and inflammation in mice. Endogenous factor H, a potent inhibitor of the alternative pathway, is increased in the airways of sensitized and challenged mice, but its role in regulating inflammation or AHR has been unknown. We found that blocking the tissue-binding function of factor H with a competitive antagonist increased complement activation and tissue inflammation after allergen challenge of sensitized mice. Conversely, administration of a fusion protein that contains the iC3b/C3d binding region of complement receptor 2 linked to the inhibitory region of factor H, a molecule directly targeting complement-activating surfaces, protected mice in both primary and secondary challenge models of AHR and lung inflammation. Thus, although endogenous factor H does play a role in limiting the development of AHR, strategies to deliver the complement-regulatory region of factor H specifically to the site of inflammation provide greater protection than that afforded by endogenous regulators. Such an agent may be an effective therapy for the treatment of asthma.


Immune function in PTSD.
Disturbed regulation of both the hypothalamic-pituitary-adrenal (HPA) axis and sympathoadrenomedullary system in posttraumatic stress disorder (PTSD) suggests that immune function, which is modulated by these systems, may also be dysregulated. Two dermatologic, in vivo measures of immune function, delayed-type hypersensitivity (DTH) and skin barrier function recovery, were examined in female subjects with PTSD and compared to measures in healthy female comparison subjects. In addition, at the time of DTH test placement, circulating numbers of lymphocyte subtypes were assessed. In separate studies, the effects of acute psychological stress on DTH and skin barrier function recovery were examined in healthy volunteer subjects. Both DTH and barrier function recovery were enhanced in women with PTSD. These findings contrast with the effects of acute stress in healthy control subjects, which was associated with suppression of DTH responses and skin barrier function recovery. There was no difference between subjects with PTSD and healthy control subjects in proportions of circulating lymphocyte subsets or in expression of the lymphocyte markers CD62, CD25, and CD45RO/CD45RA. These results suggest that cell-mediated immune function is enhanced in individuals with PTSD, a condition that imposes chronic physiologic and mental stress on sufferers. These findings contrast with suppression of DTH and skin barrier function recovery in healthy volunteers in response to acute psychological stress.


Perspectives in melanoma treatment with signal transduction.
Data from all parts of the world show a rising incidence of cutaneous malignant melanoma. The latter is one of the most difficult malignancies to treat. Early stage melanoma is curable but once metastatic it is almost uniformly fatal. Systemic therapy for advanced melanoma includes chemotherapy, either with dacarbazine alone or a multiagent combination chemotherapy, and biological therapy with recombinant interferon-alpha and/or interleukine-2. However none of these treatments options has produced long-term control of the disease except on rare occasion. In the present review, new strategies in the treatment of malignant melanoma that are now under investigations are discussed. Such new strategies might could be open new perspectives avoiding the toxicity of the conventional treatments too. In particular, possible agents acting on signal transduction pathways, such as Protein Kinase C modulators, and on the cell cycle are reviewed. Melanoma is the most immunogenic tumor among all tumor neoplasia. The feature has led to test several immunological strategies for manipulating immune responses in order to induce tumor growth control in vivo. Thus, the most interesting and recent strategies in this field and in particular the possibility to use specific vaccines are also considered.


[The role of liver antioxidant system in predisposition of rats to hepatotoxic effect of ethanol].
A new methodological approach capable of revealing factors responsible for the susceptibility of rat liver to ethanol hepatotoxicity has been developed. Using the correlation, dispersion, iteration, multifactor regression, and canonical analyses, a relation was established between the initial state of the liver antioxidant system and the character and degree of the subsequent ethanol-induced damage. In particular, it was found that intact animals with initially low level of reduced glutathione and retinols in the liver, as well as those with enzymopathy of cytosol HDNB-glutathione-8-transferase, are more susceptible to the ethanol liver damage.


Distribution and conservation of the Indo-Pacific humpback dolphin in China.
The Indo-Pacific humpback dolphin (Sousa chinensis Osbeck, 1765) is a threatened species inhabiting the waters of China. Despite being of conservation concern, the distribution and abundance of this species has not been comprehensively evaluated. From 1994 to 2008 we performed over 14 000 km of line-transect surveys and administered over 700 questionnaires to collect basic information on the geographic range and likely abundance of Indo-Pacific humpback dolphins along the southern and eastern coasts of China. Through our study we were able to establish a reporting network of stranding and incidental catches for this species. Our quantitative data suggests that only 76 animals remain around Xiamen, 39 in the Hepu Nature Reserve and 114 in the estuary of the Dafengjiang River. Qualitative data from local fishing people and government officials suggests that dolphins may exist year-round in waters off Ningde and Shantou. We found that wild populations of Sousa chinensis in this important region are clearly being affected by human disturbance and habitat deterioration, including underwater blasting, vessel collision, fishing, aquaculture and water pollution. Although some protected areas have been established and this species is protected under Chinese law, there remains virtually no protection for this animal.


[Conditions and strategies for the development of guidelines for the rehabilitation of patients with psychiatric and psychosomatic disorders].
In comparison to other countries, the German health care system can be characterized by an exceptionally extended system of inpatient psychotherapeutic treatment. About 20,000 beds are available in three different, partly mutually competitive medical settings: psychosomatic/psychotherapeutic hospital treatment, psychiatric hospital treatment and psychosomatic rehabilitation. The article first describes the latest developments and issues concerning the demarcation of tasks in these three therapeutic inpatient settings. The implementation of guidelines may contribute to a common understanding and function as a rational corrective with regard to the treatment appropriate for each individual case. Previous efforts to develop guidelines for the treatment of patients with psychiatric disorders are described. A special focus is put on the question of whether existing guidelines already fulfil the specific requirements for the rehabilitative treatment of these patients. The analysis reveals substantial deficits concerning the development of guidelines for the inpatient psychotherapeutic treatment in general as well as for the specific setting of psychosomatic/psychotherapeutic rehabilitation. Given this situation, the authors propose a strategy with 5 stages to the development of guidelines for this target group.


N6-methyladenosine mRNA methylation of PIK3CB regulates AKT signalling to promote PTEN-deficient pancreatic cancer progression.
Pancreatic ductal adenocarcinoma (PDAC) is one of the most lethal cancers worldwide. Thus far, most drugs have failed to significantly improve patient survival. N6-methyladenosine (m6A) plays an important role in the progression of PDAC, but its aberrant regulation driven by germline variants in human diseases remains unclear. We first performed an exome-wide association analysis in 518 PDAC patients with overall survival and replicated in an independent population containing 552 PDAC patients. Then, a series of biochemical experiments in vitro and in vivo were conducted to investigate potential mechanisms of the candidate variant and its target gene PIK3CB underlying the PDAC progression. Moreover, the PIK3CB-selective inhibitor KIN-193 was used to block PDAC tumour growth. We identified a missense variant rs142933486 in PIK3CB that is significantly associated with the overall survival of PDAC by reducing the PIK3CB m6A level, which facilitated its mRNA and protein expression levels mediated by the m6A 'writer' complex (METTL13/METTL14/WTAP) and the m6A 'reader' YTHDF2. The upregulation of PIK3CB is widely found in PDAC tumour tissues and significantly correlated with the poor prognosis of PDAC, especially in PTEN-deficient patients. We further demonstrated that PIK3CB overexpression substantially enhanced the proliferation and migration abilities of PTEN-deficient PDAC cells and activated AKT signalling pathway. Remarkably, KIN-193, a PIK3CB-selective inhibitor, is shown to serve as an effective anticancer agent for blocking PTEN-deficient PDAC. These findings demonstrate aberrant m6A homoeostasis as an oncogenic mechanism in PDAC and highlight the potential of PIK3CB as a therapeutic target for this disease.


Activation of Siamois by the Wnt pathway.
The Wnt pathway and the recently described Xenopus homeobox gene Siamois share the ability to mimic Nieuwkoop organizer signaling activity when ectopically expressed, prompting us to ask whether the Wnt pathway can activate Siamois expression. We show that activators of the Wnt pathway, and the dorsalizing substance LiCl, activate Siamois expression in Xenopus animal caps. Furthermore, Siamois expression is shown to be activated by beta-catenin cell-autonomously. Although certain TGF-beta family members, such as Vg1, are potent dorsal mesoderm inducers, the TGF-beta pathway only weakly activated Siamois. Finally, we demonstrate that Siamois expression is eliminated from the marginal zone of UV-irradiated Xenopus embryos, supporting the hypothesis that cortical rotation moves a Wnt-like activity into the dorsal region. These results suggest that formation of the Nieuwkoop organizer is dependent on activation of Siamois by a localized Wnt-like signaling activity, which may act synergistically with a vegetally localized TGF-beta signal.


Genetic parameters and across-line SNP associations differ for natural antibody isotypes IgM and IgG in laying hens.
In an earlier study, serum levels of natural antibody isotypes IgM- and IgG-binding keyhole limpet hemocyanin were found to be indicative for survival through the laying period of hens and therefore considered as promising traits for future implementation in breeding programs for higher survival of layers. In the present study, we first estimated the genetic parameters for the two isotypes at 20, 40 and 65 weeks of age (IgM20, IgM40 and IgM65; IgG20, IgG40 and IgG65). Pooled genetic parameters were estimated from the total population of 2504 hens from nine purebred layer lines, with line included in the model to account for admixture. Moderate heritabilities (0.14-0.44) indicated that selection for isotype titers is feasible, especially for IgM. Secondly, associations between 1022 SNP markers and the above-mentioned six immunological traits were estimated in 650 genotyped hens from the nine lines. The association study was performed across lines to detect markers that are closer to the QTL and have the same phase of association in the entire population. Forty-three significant associations between SNPs and isotype titers were detected. The SNPs of interleukins IL10 and IL19 were associated with both isotypes; SNPs of tripartite motif containing 33 (TRIM33) and IL6 showed significant association with IgG20 and IgM20 respectively; SNPs of heat shock protein 90kDa alpha (cytosolic), class B member 1 (HSP90AB1) were associated with IgG titers at older ages. Some detected SNPs were also reported associated with other immune and behavioral traits.


Addressing Social Needs in Health Care Settings: Evidence, Challenges, and Opportunities for Public Health.
There has been an explosion of interest in addressing social needs in health care settings. Some efforts, such as screening patients for social needs and connecting them to needed social services, are already in widespread practice. These and other major investments from the health care sector hint at the potential for new multisector collaborations to address social determinants of health and individual social needs. This article discusses the rapidly growing body of research describing the links between social needs and health and the impact of social needs interventions on health improvement, utilization, and costs. We also identify gaps in the knowledge base and implementation challenges to be overcome. We conclude that complementary partnerships among the health care, public health, and social services sectors can build on current momentum to strengthen social safety net policies, modernize social services, and reshape resource allocation to address social determinants of health.


Oxalic acid and diacylglycerol 36:3 are cross-species markers of sleep debt.
Sleep is an essential biological process that is thought to have a critical role in metabolic regulation. In humans, reduced sleep duration has been associated with risk for metabolic disorders, including weight gain, diabetes, obesity, and cardiovascular disease. However, our understanding of the molecular mechanisms underlying effects of sleep loss is only in its nascent stages. In this study we used rat and human models to simulate modern-day conditions of restricted sleep and addressed cross-species consequences via comprehensive metabolite profiling. Serum from sleep-restricted rats was analyzed using polar and nonpolar methods in two independent datasets (n = 10 per study, 3,380 measured features, 407 identified). A total of 38 features were changed across independent experiments, with the majority classified as lipids (18 from 28 identified). In a parallel human study, 92 metabolites were identified as potentially significant, with the majority also classified as lipids (32 of 37 identified). Intriguingly, two metabolites, oxalic acid and diacylglycerol 36:3, were robustly and quantitatively reduced in both species following sleep restriction, and recovered to near baseline levels after sleep restriction (P < 0.05, false-discovery rate < 0.2). Elevated phospholipids were also noted after sleep restriction in both species, as well as metabolites associated with an oxidizing environment. In addition, polar metabolites reflective of neurotransmitters, vitamin B3, and gut metabolism were elevated in sleep-restricted humans. These results are consistent with induction of peroxisome proliferator-activated receptors and disruptions of the circadian clock. The findings provide a potential link between known pathologies of reduced sleep duration and metabolic dysfunction, and potential biomarkers for sleep loss.


Near infrared fluorescent biliproteins generated from bacteriophytochrome AphB of Nostoc sp. PCC 7120.
The genome of the cyanobacterium Nostoc sp. PCC 7120 encodes a large number of putative bacteriophytochrome and cyanobacteriochrome photoreceptors that, due to their long-wavelength absorption and fluorescence emission, might serve as fluorescent tags in intracellular investigations. We show that the PAS-GAF domain of the bacteriophytochrome, AphB, binds biliverdin covalently and exhibits, besides its reversible photochemistry, a moderate fluorescence in the near infrared (NIR) spectral region. It was selected for further increasing the brightness while retaining the NIR fluorescence. In the first step, amino acids assumed to improve fluorescence were selectively mutated. The resulting variants were then subjected to several rounds of random mutagenesis and screened for enhanced fluorescence in the NIR. The brightness of optimized PAS-GAF variants increased more than threefold compared to that of wt AphB(1-321), with only insignificant spectral shifts (Amax around 695 nm, and Fmax around 720 nm). In general, the brightness increases with decreasing wavelengths, which allows for a selection of the fluorophore depending on the optical properties of the tissue. A spectral heterogeneity was observed when residue His260, located in close proximity to the chromophore, was mutated to Tyr, emphasizing the strong effects of the environment on the electronic properties of the bound biliverdin chromophore.


Staphylococcus aureus activates NRLP3-dependent IL-1β secretion from human conjunctival goblet cells using α toxin and toll-like receptors 2 and 1.
We used cultured human conjunctival goblet cells to determine (i) whether the toxigenic S. aureus- induced activation of the epithelial goblet cells requires two signals to activate the NLRP3 inflammasome, (ii) if one signal is mediated by TLR1, TLR2, or TLR6, and (iii) if the S. aureus toxin α toxin is another signal for the activation of the inflammasome and secretion of mature IL-1β. Cultured cells were incubated with siRNA to knock down the different TLRs. After stimulation with toxigenic S. aureus RN6390, pro-IL-1β synthesis, caspase-1 activity, and mature IL-1β secretion were measured. In a separate set of experiments, the cells were incubated with toxigenic S. aureus RN6390 or mutant S. aureus ALC837 that does not express α toxin with or without exogenous α toxin. A gentamicin protection assay was used to determine if intracellular bacteria were active. We conclude that α toxin from toxigenic S. aureus triggers two separate mechanisms required for the activation of the NLRP3 inflammasome and secretion of mature IL-1β. In the first mechanism, α toxin secreted from internalized S. aureus produces a pore, allowing the internalized bacteria and associated pathogen-associated molecular patterns to interact with intracellular TLR2 and, to a lesser extent, TLR1. In the second mechanism, α toxin forms a pore in the plasma membrane, leading to an efflux of cytosolic K+ and influx of Ca2+. We conclude that α toxin by these two different mechanisms triggers the synthesis of pro-IL-1β and NLRP3 components, activation of capase-1, and secretion of mature IL-1β to defend against bacterial infection.


Identification and Mitigation of Transient Phenomena That Complicate the Characterization of Halide Perovskite Photodetectors.
Halide perovskites have shown promise to advance the field of light detection in next-generation photodetectors, offering performance and functionality beyond what is currently possible with traditional inorganic semiconductors. Despite a relatively high density of defects in perovskite thin films, long carrier diffusion lengths and lifetimes suggest that many defects are benign. However, perovskite photodetectors show detection behavior that varies with time, creating inconsistent device performance and difficulties in accurate characterization. Here, we link the changing behavior to mobile defects that migrate through perovskites, leading to detector currents that drift on the time scale of seconds. These effects not only complicate reproducible device performance but also introduce characterization challenges. We demonstrate that such transient phenomena generate measurement artifacts that mean the value of specific detectivity measured can vary by up to 2 orders of magnitude even in the same device. The presence of defects can lead to photoconductive gain in photodetectors, and we show batch-to-batch processing variations in perovskite devices gives varying degrees of charge carrier injection and photocurrent amplification under low light intensities. We utilize the passivating effect of aging to reduce the impact of defects, minimizing current drifts and eliminating the gain. This work highlights the potential issues arising from mobile defects, which lead to inconsistent photodetector operation, and identifies the potential for defects to tune photodetection behavior in perovskite photodetectors.


Characterising the epigenome as a key component of the fetal exposome in evaluating in utero exposures and childhood cancer risk.
Recent advances in laboratory sciences hold a promise for a 'leap forward' in understanding the aetiology of complex human diseases, notably cancer, potentially providing an evidence base for prevention. For example, remarkable advances in epigenomics have an important impact on our understanding of biological phenomena and importance of environmental stressors in complex diseases. Environmental and lifestyle factors are thought to be implicated in the development of a wide range of human cancers by eliciting changes in the epigenome. These changes, thus, represent attractive targets for biomarker discovery intended for the improvement of exposure and risk assessment, diagnosis and prognosis and provision of short-term outcomes in intervention studies. The epigenome can be viewed as an interface between the genome and the environment; therefore, aberrant epigenetic events associated with environmental exposures are likely to play an important role in the onset and progression of different human diseases. The advent of powerful technologies for analysing epigenetic patterns in both cancer tissues and normal cells holds promise that the next few years will be fundamental for the identification of critical cancer- and exposure-associated epigenetic changes and for their evaluation as new generation of biomarkers. Here, we discuss new opportunities in the current age of 'omics' technologies for studies with prospective design and associated biospecimens that represent exciting potential for characterising the epigenome as a key component of the fetal exposome and for understanding causal pathways and robust predictors of cancer risk and associated environmental determinants during in utero life. Such studies should improve our knowledge concerning the aetiology of childhood cancer and identify both novel biomarkers and clues to causation, thus, providing an evidence base for cancer prevention.


Mechanisms and Models of Kidney Tubular Necrosis and Nephron Loss.
Understanding nephron loss is a primary strategy for preventing CKD progression. Death of renal tubular cells may occur by apoptosis during developmental and regenerative processes. However, during AKI, the transition of AKI to CKD, sepsis-associated AKI, and kidney transplantation ferroptosis and necroptosis, two pathways associated with the loss of plasma membrane integrity, kill renal cells. This necrotic type of cell death is associated with an inflammatory response, which is referred to as necroinflammation. Importantly, the necroinflammatory response to cells that die by necroptosis may be fundamentally different from the tissue response to ferroptosis. Although mechanisms of ferroptosis and necroptosis have recently been investigated in detail, the cell death propagation during tubular necrosis, although described morphologically, remains incompletely understood. Here, we argue that a molecular switch downstream of tubular necrosis determines nephron regeneration versus nephron loss. Unraveling the details of this "switch" must include the inflammatory response to tubular necrosis and regenerative signals potentially controlled by inflammatory cells, including the stimulation of myofibroblasts as the origin of fibrosis. Understanding in detail the molecular switch and the inflammatory responses to tubular necrosis can inform the discussion of therapeutic options.


[Megestrol in the treatment of AIDS associated cachexia. Evaluation by bioelectric impedance analysis of body composition].
To value the effects of megestrol acetate wer the weight and the body composition (fat, lean and body water) in patients with AIDS associated cachexia, by bioelectric impedance analysis. 25 patients between 23 and 57 years of age, with confirmed HIV infection and prior weight lost of 7.96 +/- 4.6 kg in relation to their habitual weight in the previous months. All the patients were under antiretroviral therapy. Basal determination, before the beginning of the antianorexic treatment and at the end of it, using bioelectric impedance analysis by Maltron BF 905 analyzer, calculating fat, lean and total body water in relation to weight, height, age and sex. Oral administration of 320 mg/day megestrol acetate for three consecutive months. Statistical comparation (RSIGMA and SPSS) by paired t-test of the mean weight, body mass index, fat, lean and total body water. During the three months treatment the mean basal body weight of the patients increased 3.54 Kg (p < 0.001) at the expense of an increase of 2.24 kg in the total body lean (p < 0.01), while the increment of the body fat (1.2 kg) was not statistically significant. The total body water increased 1.48 L (p < 0.001) and the body mass index in 1.22 kg/m2 (p < 0.001). Treatment with megestrol acetate results in a substained and very significant increase of the weight and body mass index in patients with AIDS related cachexia. This increment in weight is at the expense of body lean.


Influence of sugar availability and indoor microclimate on survival of Anopheles gambiae (Diptera: Culicidae) under semifield conditions in western Kenya.
The influence of indoor microclimate on survival of female Anopheles gambiae sensu stricto Giles (Diptera: culicidae) mosquitoes fed on different nutrition sources was evaluated in a semifield experimental hut exposed to ambient climate in western Kenya. Cages of mosquitoes (n approximately 50 per cage) were placed in nine positions within the hut combining three different sides and three different heights. At each height and side, mosquitoes were offered either human blood (once every 2 d), glucose (6% wt:vol) or a combination of the two diets over three experiments so that each cage position received one diet source. The effect of diet on survival was significant with mean survival times of 14 d for mosquitoes fed blood alone, 29 d for sugar alone and 33 d for blood plus sugar. Sugar availability decreased the odds of mortality approximately 85% compared with the blood group. Micro heterogeneities of temperature but not relative humidity also influenced survival although to a much lesser extent. The side but not height within the hut at which mosquitoes were placed, influenced survival but could not be explained by either temperature or relative humidity differences. The potential influence of seemingly minor heterogeneities of indoor microclimate upon vector longevity and vectorial capacity may merit further investigation. Also, the availability of sugar was shown to be a potentially crucial determinant of vectorial capacity. Compared with blood alone, the availability of sugar served to increase survival potential of vectors beyond ages at which they are old enough to transmit malaria.


Moral tales of parental living kidney donation: a parenthood moral imperative and its relevance for decision making.
Free and informed choice is an oft-acknowledged ethical basis for living kidney donation, including parental living kidney donation. The extent to which choice is present in parental living kidney donation has, however, been questioned. Since parents can be expected to have strong emotional bonds to their children, it has been asked whether these bonds make parents unable to say no to this donation. This article combines a narrative analysis of parents' stories of living kidney donation with a philosophical discussion of conditions for parental decision-making. Previous research has shown that parents often conclude that it is "natural" to donate. Our study shows that this naturalness needs to be understood as part of a story where parental living kidney donation is regarded as natural and as a matter of non-choice. Our study also highlights the presence of a parenthood moral imperative of always putting one's child's needs before one's own. On the basis of these results, we discuss conditions for decision-making in the context of parental LKD. We argue that the presence of a parenthood moral imperative can matter with regard to the decision-making process when parents consider whether to volunteer as living kidney donors, but that it need not hamper choice. We emphasise the need for exploring relational and situational factors in order to understand parental decision-making in the context of parental LKD.


Evaluation of tooth size in non-syndromic cleft lip and palate patients: A retrospective Italian study.
This study aims to evaluate the dental dimension in cleft lip and palate patients presenting agenesis of at least an upper lateral incisor and to compare the results with those of two control groups. A control group consisted of general orthodontic patients without agenesis, while the other group consisted of orthodontic patients with agenesis of at least one upper lateral incisor. Records of 40 (30 male, 10 female) cleft lip and palate patients (Group A), 40 (17 male, 23 female) patients representing the control group of general orthodontic patients (Group B) and 40 patients (14 male, 26 female) with at least one missing lateral incisor (Group C) were collected and analysed. Mesiodistal tooth size of all teeth (except second and third molars) was measured on digital or plaster dental casts. Tooth size in cleft lip and palate patients (Group A) was similar to that of the control group (Group B) of general orthodontic patients without tooth agenesis, except for the upper central incisors and the second upper left bicuspids that presented a significant reduction in the mesiodistal dental width. Non-syndromic patients with at least one missing upper lateral incisor showed a significant reduction of mesiodistal tooth size compared to Group A and to Group B. Dental width of cleft lip and palate patients is similar to that of a normal orthodontic population, with the exception of the upper central incisor and upper premolars on one side.


Making and Breaking of an Essential Poison: the Cyclases and Phosphodiesterases That Produce and Degrade the Essential Second Messenger Cyclic di-AMP in Bacteria.
Cyclic di-AMP is a second-messenger nucleotide that is produced by many bacteria and some archaea. Recent work has shown that c-di-AMP is unique among the signaling nucleotides, as this molecule is in many bacteria both essential on one hand and toxic upon accumulation on the other. Moreover, in bacteria, like Bacillus subtilis, c-di-AMP controls a biological process, potassium homeostasis, by binding both potassium transporters and riboswitch molecules in the mRNAs that encode the potassium transporters. In addition to the control of potassium homeostasis, c-di-AMP has been implicated in many cellular activities, including DNA repair, cell wall homeostasis, osmotic adaptation, biofilm formation, central metabolism, and virulence. c-di-AMP is synthesized and degraded by diadenylate cyclases and phosphodiesterases, respectively. In the diadenylate cyclases, one type of catalytic domain, the diadenylate cyclase (DAC) domain, is coupled to various other domains that control the localization, the protein-protein interactions, and the regulation of the enzymes. The phosphodiesterases have a catalytic core that consists either of a DHH/DHHA1 or of an HD domain. Recent findings on the occurrence, domain organization, activity control, and structural features of diadenylate cyclases and phosphodiesterases are discussed in this review.


A case-control study of risk factors for bovine brucellosis seropositivity in Peninsular Malaysia.
Bovine brucellosis was first reported in Peninsular Malaysia in 1950. A subsequent survey conducted in the country revealed that the disease was widespread. Current knowledge on the potential risk factors for brucellosis occurrence on cattle farms in Malaysia is lacking. Therefore, we conducted a case-control study to identify the potential herd-level risk factors for bovine brucellosis occurrence in four states in the country, namely Kelantan, Pahang, Selangor and Negeri Sembilan. Thirty-five cases and 36 controls of herds were selected where data on farm management, biosecurity, medical history and public health were collected. Multivariable logistic regression identified that Brucella seropositive herds were more likely to; have some interaction with wildlife (OR 8.9, 95% CI = 1.59-50.05); originated from farms where multiple species such as buffalo/others (OR 41.8, 95% CI = 3.94-443.19) and goat/sheep (OR 8.9, 95%Cl = 1.10-71.83) were reared, practice extensive production system (OR 13.6, 95% CI 1.31-140.24) and have had episodes of abortion in the past (OR 51.8, 95% CI = 4.54-590.90) when compared to seronegative herds. Considering the lack of information on the epidemiology of bovine brucellosis in peninsular Malaysia and absence of information on preventing the inception or spread of the disease, this report could contribute to the on-going area-wise national brucellosis eradication program.


Airway management in patients with isolated Pierre Robin sequence during the first year of life.
Managing the airway of patients with Pierre Robin sequence is diagnostically and therapeutically challenging. Like many other pathologies, Pierre Robin sequence is best managed with a multidisciplinary team. Providing a comprehensive evaluation is important to detect patients who may have silent events during activities of early life. Children with airway obstruction should have a complete assessment to anatomically define the site of airway obstruction. Therefore, management options can be targeted to the specific deficiency. The present article outlines a treatment protocol for patients who present with isolated Pierre Robin sequence. The authors propose that initial diagnostic and therapeutic interventions remain relatively noninvasive. Using this protocol, more than 80% of patients with isolated Pierre Robin sequence who the authors have examined for airway obstruction in the neonatal period have been effectively treated with positioning or tongue-lip adhesion. While more aggressive and successful techniques have been reported, the authors have not found them necessary for the majority of patients with isolated Pierre Robin sequence. The following review details their approach to patients with Pierre Robin sequence.


Increased Levels of VEGF-A and HIF-1α in Turkish Children with Crimean-Congo Hemorrhagic Fever.
Crimean-Congo Hemorrhagic Fever (CCHF) is a disease characterized by serious course, including acute viral fever, ecchymosis, thrombocytopenia, liver dysfunction and high rate of mortality. Hypoxia Inducible Factor-1α (HIF-1α) and Vascular Endothelial Growth Factor-A (VEGF-A) play an important role both in the inflammatory process and plasma leakage. The aim of this study was to define HIF-1α and VEGF-A serum levels obtained from CCHF patients and control group and to investigate whether these factors were correlated with the pathogenesis of this disease. Thirty cases younger than 17yr confirmed by RT-PCR and/or ELISA for CCHF were included in this study. Thirty age and sex matched healthy peoples were enrolled as controls. Blood samples collected from the patient and control groups. Serum levels of HIF-1α and VEGF-A were measured with ELISA. Levels of HIF-1α and VEGF-A were statistically significantly increased in CCHF patients compared to the control group (P< 0.05). A significant positive correlation was found between the levels of HIF-1α and VEGF-A in the patient group (P< 0.01). The levels of ALT, AST, CK, aPTT, WBC and Thrombocyte count were significantly higher in the patients than in the control group (P< 0.001). A positive correlation was found among the levels of AST and CK from biochemical parameters and VEGF and HIF-1α in the patient group (P< 0.05). HIF-1α and VEGF-A might play an important role in CCHF pathogenesis.


Harvesting Blue Energy Based on Salinity and Temperature Gradient: Challenges, Solutions, and Opportunities.
Greenhouse gas emissions associated with power generation from fossil fuel combustion account for 25% of global emissions and, thus, contribute greatly to climate change. Renewable energy sources, like wind and solar, have reached a mature stage, with costs aligning with those of fossil fuel-derived power but suffer from the challenge of intermittency due to the variability of wind and sunlight. This study aims to explore the viability of salinity gradient power, or "blue energy", as a clean, renewable source of uninterrupted, base-load power generation. Harnessing the salinity gradient energy from river estuaries worldwide could meet a substantial portion of the global electricity demand (approximately 7%). Pressure retarded osmosis (PRO) and reverse electrodialysis (RED) are more prominent technologies for blue energy harvesting, whereas thermo-osmotic energy conversion (TOEC) is emerging with new promise. This review scrutinizes the obstacles encountered in developing osmotic power generation using membrane-based methods and presents potential solutions to overcome challenges in practical applications. While certain strategies have shown promise in addressing some of these obstacles, further research is still required to enhance the energy efficiency and feasibility of membrane-based processes, enabling their large-scale implementation in osmotic energy harvesting.


Mucinous ovarian cancer.
Mucinous epithelial ovarian cancer (mEOC) accounts for approximately 10% of EOCs. Patients presenting with early-stage disease have an excellent prognosis, however, those with advanced disease have a poor outcome with relative resistance to standard ovarian cancer chemotherapy. Molecular and genetic studies demonstrate differences between mucinous and serous EOC supporting the concept that these tumors develop along separate pathways. Together with the observed differences in clinical behavior and outcome for mEOC, there is a need to develop specific therapeutic strategies for this histologic subtype. The relative rarity of advanced mEOC has resulted in few patients enrolled in major ovarian cancer trials. The results of such trials may not necessarily reflect those specific to mEOC. Separate trials testing alternative chemotherapeutics are required. Metastatic mucinous tumors from other sites such as the gastrointestinal tract may present with ovarian involvement. For all mucinous tumors of the ovary, establishing primary as opposed to metastatic cancers is important. Clinical presentation, tumor markers, histologic, and immunohistochemical features are helpful in distinguishing most cases.


Pharmacokinetics of hydromorphone hydrochloride after intravenous and intramuscular administration of a single dose to American kestrels (Falco sparverius).
To determine the pharmacokinetics of hydromorphone hydrochloride after IV and IM administration in American kestrels (Falco sparverius). 12 healthy adult American kestrels. A single dose of hydromorphone (0.6 mg/kg) was administered IM (pectoral muscles) and IV (right jugular vein); the time between IM and IV administration experiments was 1 month. Blood samples were collected at 5 minutes, 1 hour, and 3 hours (n = 4 birds); 0.25, 1.5, and 9 hours (4); and 0.5, 2, and 6 hours (4) after drug administration. Plasma hydromorphone concentrations were determined by means of liquid chromatography with mass spectrometry, and pharmacokinetic parameters were calculated with a noncompartmental model. Mean plasma hydromorphone concentration for each time was determined with naïve averaged pharmacokinetic analysis. Plasma hydromorphone concentrations were detectable in 2 and 3 birds at 6 hours after IM and IV administration, respectively, but not at 9 hours after administration. The fraction of the hydromorphone dose absorbed after IM administration was 0.75. The maximum observed plasma concentration was 112.1 ng/mL (5 minutes after administration). The terminal half-life was 1.25 and 1.26 hours after IV and IM administration, respectively. Results indicated hydromorphone hydrochloride had high bioavailability and rapid elimination after IM administration, with a short terminal half-life, rapid plasma clearance, and large volume of distribution in American kestrels. Further studies regarding the effects of other doses, other administration routes, constantrate infusions, and slow release formulations on the pharmacokinetics of hydromorphone hydrochloride and its metabolites in American kestrels may be indicated.


KSR: a MAPK scaffold of the Ras pathway?
Kinase Suppressor of Ras (KSR) is an intriguing component of the Ras pathway that was first identified by genetic studies performed in Drosophila melanogaster and Caenorhabditis elegans. In both organisms, inactivating mutations in KSR suppress the phenotypic effects induced by activated Ras. These findings together with the fact that KSR contains many structural features characteristic of a protein kinase led to early speculation that KSR is a kinase functioning upstream of the Ras pathway component Raf-1 or in a parallel Ras-dependent pathway. However, in the six years since its discovery, KSR has been found to lack several key properties of known protein kinases, which has cast doubt on whether KSR is indeed a functional enzyme. A major breakthrough in our understanding of the role of KSR in signal transduction has come from recent findings that KSR interacts with several components of the MAP kinase cascade, including Raf-1, MEK1/2 and ERK1/2. The model now emerging is that KSR acts as a scaffolding protein that coordinates the assembly of a membrane-localized, multiprotein MAP kinase complex, a vital step in Ras-mediated signal transduction. Thus, while Kinase Suppressor of Ras may be its name, phosphorylation may not be its game.


Dietary red palm oil supplementation reduces myocardial infarct size in an isolated perfused rat heart model.
Recent studies have shown that dietary red palm oil (RPO) supplementation improves functional recovery following ischaemia/reperfusion in isolated hearts. The main aim of this study was to investigate the effects of dietary RPO supplementation on myocardial infarct size after ischaemia/reperfusion injury. The effects of dietary RPO supplementation on matrix metalloproteinase-2 (MMP2) activation and PKB/Akt phosphorylation were also investigated. Male Wistar rats were divided into three groups and fed a standard rat chow diet (SRC), a SRC supplemented with RPO, or a SRC supplemented with sunflower oil (SFO), for a five week period, respectively. After the feeding period, hearts were excised and perfused on a Langendorff perfusion apparatus. Hearts were subjected to thirty minutes of normothermic global ischaemia and two hours of reperfusion. Infarct size was determined by triphenyltetrazolium chloride staining. Coronary effluent was collected for the first ten minutes of reperfusion in order to measure MMP2 activity by gelatin zymography. Dietary RPO-supplementation decreased myocardial infarct size significantly when compared to the SRC-group and the SFO-supplemented group (9.1 +/- 1.0% versus 30.2 +/- 3.9% and 27.1 +/- 2.4% respectively). Both dietary RPO- and SFO-supplementation were able to decrease MMP2 activity when compared to the SRC fed group. PKB/Akt phosphorylation (Thr 308) was found to be significantly higher in the dietary RPO supplemented group when compared to the SFO supplemented group at 10 minutes into reperfusion. There was, however, no significant changes observed in ERK phosphorylation. Dietary RPO-supplementation was found to be more effective than SFO-supplementation in reducing myocardial infarct size after ischaemia/reperfusion injury. Both dietary RPO and SFO were able to reduce MMP2 activity, which suggests that MMP2 activity does not play a major role in protection offered by RPO. PKB/Akt phosphorylation may, however, be involved in RPO mediated protection.


Neuromuscular Electrical Stimulation Therapy for Dysphagia Caused by Wilson's Disease.
Wilson's disease is an autosomal recessive disorder of abnormal copper metabolism. Although dysphagia is a common complaint of patients with Wilson's disease and pneumonia is an important cause of death in these patients, management of swallowing function has rarely been reported in the context of Wilson's disease. Hence, we report a case of Wilson's disease presenting with dysphagia. A 33-year-old man visited our hospital with a complaint of difficulty in swallowing, since about last 7 years and which had worsened since the last 2-3 months. He was diagnosed with Wilson's disease about 13 years ago. On the initial VFSS, reduced hyoid bone movement, impaired epiglottic movement and moderate amount of residue in the valleculae during the pharyngeal phase were noted. After 10 sessions of neuromuscular electrical stimulation for 1 hour per day, decreased amount of residue was observed in the valleculae during the pharyngeal phase on the follow-up VFSS.


Surveillance of infant pertussis in Sweden 1998-2012; severity of disease in relation to the national vaccination programme.
In Sweden, pertussis was excluded from the national vaccination programme in 1979 until acellular vaccination was introduced in a highly endemic setting in 1996. The general incidence dropped 10-fold within a decade, less in infants. Infant pertussis reached 40-45 cases per 100,000 in 2008 to 2012; few of these cases were older than five months. We present an observational 15-year study on the severity of infant pertussis based on 1,443 laboratory-confirmed cases prospectively identified from 1998 to 2012 in the national mandatory reporting system and followed up by telephone contact. Analyses were made in relation to age at onset of symptoms and vaccination history. Pertussis decreased in non-vaccinated infants (2003 to 2012, p<0.001), indicating herd immunity, both in those too young to be vaccinated and those older than three months. The hospitalisation rates also decreased (last five-year period vs the previous five-year periods, p <0.001), but 70% of all cases in under three month-old infants and 99% of cases with apnoea due to pertussis were admitted to hospital in 1998 to 2012. Median duration of hospitalisation was seven days for unvaccinated vs four days for vaccinated infants aged 3-5 months. Nine unvaccinated infants died during the study period.


Cancer of the pancreas. Pylorus-preserving resection of the pancreas.
Pylorus-preserving pancreaticoduodenectomy represents an important advance in the history of pancreatic surgery. The operation can be performed with a low operative mortality and morbidity, is technically easier than the standard Whipple resection, and it minimizes the long-term physiological disturbance to the patient. Clinical and experimental evidence has substantiated the view that preservation of the pylorus reduces the incidence of marginal anastomotic ulceration following pancreatectomy. Although gastric emptying may be prolonged transiently in the immediate postoperative period, this complication is easily managed, and is hardly a frequent long-term problem. PPPD is associated with a lower incidence of enterogastric reflux, dumping and diarrhoea than the classical Whipple operation, and patients who have had PPPD are more likely to regain their preoperative and preillness weight. Initial concerns about the use of PPPD in malignant disease have not been borne out, and should now be considered for curative or palliative resections of lesions in the periampullary region including the head of the pancreas. Present data suggest that PPPD does not compromise the long-term survival in patients with periampullary cancers. There is little doubt that the excellent results reported with this procedure as with other forms of major pancreatic surgery, are not simply related to improvements in surgical technique but to establishment of specialist pancreatic surgery.


A plastid-localized glycogen synthase kinase 3 modulates stress tolerance and carbohydrate metabolism.
Glycogen synthase kinase 3 (GSK-3) was originally identified as a regulator of glycogen synthesis in mammals. Like starch in plants, glycogen is a polymer of glucose, and serves as an energy and carbon store. Starch is the main carbohydrate store in plants. Regulation of starch metabolism, in particular in response to environmental cues, is of primary importance for carbon and energy flow in plants but is still obscure. Here, we provide evidence that MsK4, a novel Medicago sativa GSK-3-like kinase, connects stress signalling with carbon metabolism. MsK4 was found to be a plastid-localized protein kinase that is associated with starch granules. High-salt stress rapidly induced the in vivo kinase activity of MsK4. Metabolic profiling of MsK4 over-expressor lines revealed changes in sugar metabolism, including increased amounts of maltose, the main degradation product of starch in leaves. Plants over-expressing MsK4 showed improved tolerance to salt stress. Moreover, under high-salinity conditions, MsK4-over-expressing plants accumulated significantly more starch and showed modified carbohydrate content compared with wild-type plants. Overall, these data indicate that MsK4 is an important regulator that adjusts carbohydrate metabolism to environmental stress.


A combined process of non-thermal plasma with sludge stabilization for the simultaneous reduction of odor and organic waste.
Odor emissions and sludge disposals have become most challenging issues in many sludge treatment plants, and separate chemical oxidation processes have been commonly employed for these problems. It is, therefore, necessary to develop a combined process that simultaneously reduces the odor emissions and the amount of waste sludge. In this study, a non-thermal plasma reactor using a dielectric barrier discharge type was employed to treat a gas stream contaminated with 10 ppm(v) of H(2)S, and then the ozone-laden gas stream was supplied to a sludge stabilizer to reduce the organic constituents. The specific energy input to the plasma was varied to investigate the performance of the combined process. When the specific energy inputs were 200, 260, and 360 J/L, the rates of ozone generation from the plasma reactor were 0.036, 0.070, 0.144 g-O(3)/h, respectively. At these experimental conditions, the removal efficiencies of H(2)S were 60, 75, and >99%, and total chemical oxygen demand (TCOD) reduction efficiencies of 33, 61 and 67% were observed. In addition, a soluble organic fraction of the sludge increased at ratios of 1.9, 8.9, and 10.7%, respectively. Consequently, the combined process effectively and simultaneously reduced the odor compounds as well as the organic constituents and particles in the waste sludge.


An archaeal virus-encoded anti-CRISPR protein inhibits type III-B immunity by inhibiting Cas RNP complex turnover.
CRISPR-Cas systems are widespread in prokaryotes and provide adaptive immune against viral infection. Viruses encode a type of proteins called anti-CRISPR to evade the immunity. Here, we identify an archaeal virus-encoded anti-CRISPR protein, AcrIIIB2, that inhibits Type III-B immunity. We find that AcrIIIB2 inhibits Type III-B CRISPR-Cas immunity in vivo regardless of viral early or middle-/late-expressed genes to be targeted. We also demonstrate that AcrIIIB2 interacts with Cmr4α subunit, forming a complex with target RNA and Cmr-α ribonucleoprotein complex (RNP). Furtherly, we discover that AcrIIIB2 inhibits the RNase activity, ssDNase activity and cOA synthesis activity of Cmr-α RNP in vitro under a higher target RNA-to-Cmr-α RNP ratio and has no effect on Cmr-α activities at the target RNA-to-Cmr-α RNP ratio of 1. Our results suggest that once the target RNA is cleaved by Cmr-α RNP, AcrIIIB2 probably inhibits the disassociation of cleaved target RNA, therefore blocking the access of other target RNA substrates. Together, our findings highlight the multiple functions of a novel anti-CRISPR protein on inhibition of the most complicated CRISPR-Cas system targeting the genes involved in the whole life cycle of viruses.


Air movement visualization in the workplace: current methods and new approaches.
Airflow visualization in the workplace to assess containment, ventilation, or general air movements is often carried out using smoke tracers. The most prevalent method uses a disposable smoke tube that generates a plume of concentrated sulfuric acid fume. However, use of the smoke tube exposes occupational hygienists to the risk of sulfuric acid exposure through inhalation or dermal contact, as well as injury from sharps. Following concern over the potential health hazard associated with smoke tube usage, alternative flow visualization methods and technologies have been reviewed. Methods of generating smoke or bubbles other than using smoke tubes suitable for visualizing air movements include heated element smoke generators, combustion generators, generation of metallic chlorides and ammonium chloride, generation of neutral density bubbles, and water fog generation. Some of these methods are applicable in specific workplace situations. However, there is no commercially available smoke or bubble generator currently available that matches the smoke tube for cost effectiveness, ease of use, and wide applicability, while also reducing the potential health risks associated with smoke tube usage. Despite this, certain technologies, in particular water/glycerol smoke generation using heated element generators, have the potential to be developed into viable alternatives to the smoke tube. Thus, with further development, an air movement visualization method that poses a significantly lower health hazard than the smoke tube is feasible.


FISIK: Framework for the Inference of In Situ Interaction Kinetics from Single-Molecule Imaging Data.
Recent experimental and computational developments have been pushing the limits of live-cell single-molecule imaging, enabling the monitoring of intermolecular interactions in their native environment with high spatiotemporal resolution. However, interactions are captured only for the labeled subset of molecules, which tends to be a small fraction. As a result, it has remained a challenge to calculate molecular interaction kinetics, in particular association rates, from live-cell single-molecule tracking data. To overcome this challenge, we developed a mathematical modeling-based Framework for the Inference of in Situ Interaction Kinetics (FISIK) from single-molecule imaging data with substoichiometric labeling. FISIK consists of (I) devising a mathematical model of molecular movement and interactions, mimicking the biological system and data-acquisition setup, and (II) estimating the unknown model parameters, including molecular association and dissociation rates, by fitting the model to experimental single-molecule data. Due to the stochastic nature of the model and data, we adapted the method of indirect inference for model calibration. We validated FISIK using a series of tests in which we simulated trajectories of diffusing molecules that interact with each other, considering a wide range of model parameters, and including resolution limitations, tracking errors, and mismatches between the model and the biological system it mimics. We found that FISIK has the sensitivity to determine association and dissociation rates, with accuracy and precision depending on the labeled fraction of molecules and the extent of molecule tracking errors. For cases where the labeled fraction is too low (e.g., to afford accurate tracking), combining dynamic but sparse single-molecule imaging data with almost-whole population oligomer distribution data improves FISIK's performance. All in all, FISIK is a promising approach for the derivation of molecular interaction kinetics in their native environment from single-molecule imaging data with substoichiometric labeling.


Compact vibration isolation and suspension for Australian International Gravitational Observatory: local control system.
High performance vibration isolators are required for ground based gravitational wave detectors. To attain very high performance at low frequencies we have developed multistage isolators for the proposed Australian International Gravitational Observatory detector in Australia. New concepts in vibration isolation including self-damping, Euler springs, LaCoste springs, Roberts linkages, and double preisolation require novel sensors and actuators. Double preisolation enables internal feedback to be used to suppress low frequency seismic noise. Multidegree of freedom control systems are required to attain high performance. Here we describe the control components and control systems used to control all degrees of freedom. Feedback forces are injected at the preisolation stages and at the penultimate suspension stage. There is no direct actuation on test masses. A digital local control system hosted on a digital signal processor maintains alignment and position, corrects drifts, and damps the low frequency linear and torsional modes without exciting the very high Q-factor test mass suspension. The control system maintains an optical cavity locked to a laser with a high duty cycle even in the absence of an autoalignment system. An accompanying paper presents the mechanics of the system, and the optical cavity used to determine isolation performance. A feedback method is presented, which is expected to improve the residual motion at 1 Hz by more than one order of magnitude.


Later outcomes and alpha/beta estimate from hypofractionated conformal three-dimensional radiotherapy versus standard fractionation for localized prostate cancer.
Now that the follow-up time has exceeded 5 years, an estimate of the α/β ratio can be presented. The additional late outcomes in patients treated with three-dimensional conformal external beam radiotherapy for localized prostate cancer using a hypofractionated vs. a standard fractionation regimen are reported from this prospective nonrandomized contemporary comparison. A total of 114 nonrandomized patients chose hypofractionation delivered in 20 fractions of 3 Gy or 3.15 Gy (mean 3.06 Gy) for localized prostate cancer within a median overall time of 32 days (range, 29-49) using four fractions weekly. A total of 160 comparable patients were contemporarily treated within a median of 55 days (range 49-66). The median follow-up was 66 months (range, 24-95) for the hypofractionated arm and 63 months (range, 36-92) for the standard arm. The percentage of patients in the low-, medium-, and high-risk groups was 36%, 46%, and 18% in the hypofractionated arm and 44%, 50%, and 6% in standard arm (2 Gy), respectively. The 5-year actuarial biochemical absence of disease (prostate-specific antigen nadir + 2 ng/mL) and disease-free survival rate was the same at 89% in both arms, making the α/β calculation unambiguous. The point ratio of α/β was 1.86 (95% confidence interval, 0.7-5.1 Gy). The 95% confidence interval was determined entirely by the binomial confidence limits in the numbers of patients. Rectal reactions of grade 3 and 4 occurred in 1 of 114 (hypofractionated) and 2 of 160 (standard) patients. The presented three-dimensional conformal regimen was acceptable, and the α/β value was 1.8, in agreement with other very recent low meta-analyses (reviewed in the "Discussion" section).


Rheumatoid Arthritis Saudi Database (RASD): Disease Characteristics and Remission Rates in a Tertiary Care Center.
National Registries are essential to direct current practice. Rheumatoid arthritis (RA) registries in the middle east and North Africa remain scarcely represented. To describe a population of Saudi RA patients and to compare the findings to internationally reported data. This is an observational study that was conducted at Doctor Soliman Fakeeh Hospital (DSFH) in Saudi Arabia. The study ran from 2014 to 2018 using a pool of 433 patients. Inclusion criteria included adults older than 18 years of age who fulfilled the 2010 American College of Rheumatology criteria for the diagnosis of RA and who were also regular visitors in our rheumatology clinics. Data were collected directly from patients and entered in a specially designed program. At initial presentation, 45.5% had demonstrated active disease (moderate or high disease activity) based on DAS-28-CRP scores, while 54.5% were in low disease activity or remission. The remission rates after 1 year had increased to 79.6% (345 patients), while 9.7% (42 patients) and 10.6% (46 patients) had low disease activity and moderate disease activity, respectively. It was also found that the female gender, higher Health Assessment Questionnaire-Disability Index (HAQ-DI) and longer lag1/lag2 periods were associated with higher disease activity in our population. We detected higher remission rates at 1 year of follow-up. This could be attributed to many factors, including good referral systems with easier access to biologics. We aim to expand this registry to the national level.


Increased temperature reduces herbivore host-plant quality.
Globally increasing temperatures may strongly affect insect herbivore performance, as their growth and development is directly linked to ambient temperature as well as host-plant quality. In contrast to direct effects of temperature on herbivores, indirect effects mediated via thermal effects on host-plant quality are only poorly understood, despite having the potential to substantially impact performance and thereby to alter responses to the changing climatic conditions. We here use a full-factorial design to explore the direct (larvae were reared at 17 °C or 25 °C) and indirect effects (host plants were reared at 17 °C or 25 °C) of temperature on larval growth and life-history traits in the temperate-zone butterfly Pieris napi. Direct temperature effects reflected the common pattern of prolonged development and increased body mass at lower temperatures. At the higher temperature, efficiency of converting food into body matter was much reduced being accompanied by an increased food intake, suggesting compensatory feeding. Indirect temperature effects were apparent as reduced body mass, longer development time, an increased food intake, and a reduced efficiency of converting food into body matter in larvae feeding on plants grown at the higher temperature, thus indicating poor host-plant quality. The effects of host-plant quality were more pronounced at the higher temperature, at which compensatory feeding was much less efficient. Our results highlight that temperature-mediated changes in host-plant quality are a significant, but largely overlooked source of variation in herbivore performance. Such effects may exaggerate negative effects of global warming, which should be considered when trying to forecast species' responses to climate change.


Relationship between insulin resistance and muscle triglyceride content in nonobese and obese experimental models of insulin resistance syndrome.
In nonobese hereditary hypertriglyceridemic (HTg) rats and obese HTg Koletsky SHROB/Kol rats, muscle triglyceride accumulation and its relationship to glucose homeostasis and tissue sensitivity to insulin action were examined. Soleus muscle and diaphragm triglyceride contents were markedly increased in HTg rats as compared with controls and were further increased in obese animals. On the other hand, glucose intolerance and impairment of insulin-stimulated in vitro glycogen synthesis were of a similar degree in nonobese as well as obese animals. Results indicate that insulin resistance did not increase proportionally to muscle triglyceride content.


Double Allee effects and extinction in the island fox.
An Allee effect (AE) occurs in populations when individuals suffer a decrease in fitness at low densities. If a fitness component is reduced (component AE), per capita population growth rates may decline as a consequence (demographic AE) and extinction risk is increased. The island fox (Urocyon littoralis) is endemic to six of the eight California Channel Islands. Population crashes have coincided with an increase in predation by Golden Eagles (Aquila chrysaetos). We propose that AEs could render fox populations more sensitive and may be a likely explanation for their sharp decline. We analyzed demographic data collected between 1988 and 2000 to test whether fox density (1) influences survival and reproductive rates; (2) interacts with eagle presence and affects fox fitness parameters; and (3) influences per capita fox population trends. A double component AE simultaneously influenced survival (of adults and pups) and proportion of breeding adult females. The adult survival AE was driven by predation by eagles. These component AEs led to a demographic AE. Multiple-component AEs, a predation-driven AE, and the simultaneous occurrence of both component and demographic AEs in a mammal are all previously unreported processes. Populations below 7 foxes/km(2) could have suboptimal population growth rates due to the demographic AE, and AEs may have contributed to the dramatic declines in three fox populations. Because fox densities in critically endangered populations are well below this level, removing Golden Eagles appears necessary to prevent a predation-driven AE. Conservationists should also be aware of AEs when planning the release of captive foxes. More generally, our findings highlight the danger of overlooking AEs in the conservation of populations of rare or threatened species.


Anti-inflammatory activity of PYNOD and its mechanism in humans and mice.
Many members of the nucleotide-binding and oligomerization domain (NOD)- and leucine-rich-repeat-containing protein (NLR) family play important roles in pathogen recognition and inflammation. However, we previously reported that human PYNOD/NLRP10, an NLR-like protein consisting of a pyrin domain and a NOD, inhibits inflammatory signal mediated by caspase-1 and apoptosis-associated speck-like protein containing a caspase recruitment domain (ASC) in reconstitution experiments using HEK293 cells. In this study, we investigated the molecular mechanism of PYNOD's anti-inflammatory activity in vitro and its expression and function in mice. Human PYNOD inhibited the autoprocessing of caspase-1 and caspase-1-mediated IL-1beta processing and suppressed the aggregation of ASC, a hallmark of ASC activation. Interestingly, the NOD of human PYNOD was sufficient to inhibit caspase-1-mediated IL-1beta secretion, whereas its pyrin domain was sufficient to inhibit ASC-mediated NF-kappaB activation and apoptosis and to reduce ASC's ability to promote caspase-1-mediated IL-1beta production. Mouse PYNOD protein was detected in the skin, tongue, heart, colon, peritoneal macrophages, and several cell lines of hematopoietic and myocytic lineages. Mouse PYNOD colocalized with ASC aggregates in LPS + R837-stimulated macrophages; however, unlike human PYNOD, mouse PYNOD failed to inhibit ASC aggregation. Macrophages and neutrophils from PYNOD-transgenic mice exhibited reduced IL-1beta processing and secretion upon microbial infection, although mouse PYNOD failed to inhibit caspase-1 processing, which was inhibited by caspase-4 inhibitor z-LEED-fluoromethylketone. These results suggest that mouse PYNOD colocalizes with ASC and inhibits caspase-1-mediated IL-1beta processing without inhibiting caspase-4 (mouse caspase-11)-mediated caspase-1 processing. Furthermore, PYNOD-transgenic mice were resistant to lethal endotoxic shock. Thus, PYNOD is the first example of an NLR that possesses an anti-inflammatory function in vivo.


Perfluoroalkyl substances exposure and hearing impairment in US adults.
Per- and polyfluoroalkyl substances (PFAS) are widely applied in consumer and industrial products such as nonstick cookware, waterproof clothing, food packaging materials, and fire-fighting foams. These "forever chemicals" are hypothesized to impact neurobehavioral functions. Yet no previous study has explored the role of PFAS on audiometrically determined hearing impairment (HI). To investigate the associations of serum concentrations of perfluoroalkyl substances with low-frequency HI (LFHI) and high-frequency HI (HFHI) in US adults. We evaluated the cross-sectional associations in 2371 adults aged 20-69 years who participated in the National Health and Nutrition Examination Survey (NHANES) 2003-2004, 2011-2012 and 2015-2016; and 449 adults aged ≥70 years from NHANES 2005-2006 and 2009-2010. Serum concentrations of perfluorohexane sulfonic acid (PFHxS), perfluorooctane sulfonic acid (PFOS), perfluorooctanoic acid (PFOA), perfluorononanoic acid (PFNA) and perfluorodecanoic acid (PFDA), were measured using solid-phase extraction coupled to High Performance Liquid Chromatography-Turbo Ion Spray ionization-tandem Mass Spectrometry. LFHI was defined as a pure-tone average (PTA) of thresholds across 0.5-1-2 kHz >25 dB; HFHI defined as a PTA across 3-4-6 kHz >25 dB in the worse ear. Survey-weighted logistic regression models were used to compute odds ratios (ORs) and 95% confidence intervals (CIs) with adjustment for age, age-squared, sex, race/ethnicity, education, poverty-to-income ratio, body mass index, smoking status, exposures to occupational, recreational and firearm noises, and NHANES cycles. There were no significant associations when perfluoroalkyl variables were fitted as a linear (log-transformed) term. However, statistically significant associations of HFHI with PFNA (OR = 1.70, 95% CI: 1.13-2.56) and PFDA (OR = 1.75, 95% CI: 1.00-3.05) were observed when comparing participants with serum concentrations ≥90th vs. <90th percentiles of PFNA (90th percentile = 1.8 ng/mL) and PFDA (90th percentile = 0.5 ng/mL), respectively, in adults aged 20-69 years. No significant associations were observed for other compounds in adults aged 20-69 years and for all compounds in adults ≥70 years. Our study does not provide strong evidence to support the ototoxicity of PFAS exposure. Non-linear threshold dose-response associations between serum concentrations of PFNA and PFDA and HFHI need further investigation.


Enhanced secretion of amylase from exocrine pancreas of connexin32-deficient mice.
To determine whether junctional communication between pancreatic acinar cells contributes to their secretory function in vivo, we have compared wild-type mice, which express the gap junctional proteins connexin32 (Cx32) and connexin26, to mice deficient for the Cx32 gene. Pancreatic acinar cells from Cx32 (-/-) mice failed to express Cx32 as evidenced by reverse transcription-PCR and immunolabeling and showed a marked reduction (4.8- and 25-fold, respectively) in the number and size of gap junctions. Dye transfer studies showed that the extent of intercellular communication was inhibited in Cx32 (-/-) acini. However, electrical coupling was detected by dual patch clamp recording in Cx32 (-/-) acinar cell pairs. Although wild-type and Cx32 (-/-) acini were similarly stimulated to release amylase by carbamylcholine, Cx32 (-/-) acini showed a twofold increase of their basal secretion. This effect was caused by an increase in the proportion of secreting acini, as detected with a reverse hemolytic plaque assay. Blood measurements further revealed that Cx32 (-/-) mice had elevated basal levels of circulating amylase. The results, which demonstrate an inverse relationship between the extent of acinar cell coupling and basal amylase secretion in vivo, support the view that the physiological recruitment of secretory acinar cells is regulated by gap junction mediated intercellular communication.


The Bcl-2 family member Bfl-1/A1 is strongly repressed in normal and malignant plasma cells but is a potent anti-apoptotic factor for myeloma cells.
Terminal B-cell differentiation is a multi-step process, from short-lived plasmablasts to mature long-lived plasma cells (PC). The anti-apoptotic Bcl-2 family member Bfl-1/A1 plays a critical role in the survival of mature B cells. However, its potential involvement at the later stages of B-cell development remains highly controversial. Our aim was thus to clarify the place of Bfl-1/A1 in the biology of normal PC and in the pathogenesis of multiple myeloma (MM), the major PC dyscrasia. Using gene expression profiling and quantifiable reverse transcription polymerase chain reaction experiments, we found a similar down-regulation of Bfl-1/A1 in both normal immature plasmablasts and mature PC when compared with B cells. In myeloma cells, the level of Bfl-1/A1 was low and Bfl-1/A1 was not a nuclear factor kappaB-inducible gene. Collectively, these data demonstrate that Bfl-1/A1 is not involved in the prolonged survival of normal mature PC, and that Bfl-1/A1 deregulation is not a common oncogenic event in MM. However, overexpression of Bfl-1/A1 by retroviral transduction promoted autonomous survival of an interleukin-6-dependent myeloma cell line and rendered it less sensitive to dexamethasone. Thus, Bfl-1/A1 transduction could be an interesting tool to obtain myeloma cell lines from primary samples and to favour the in vitro generation of antibody-secreting, long-lived normal PC.


Association of menopause age and N-terminal pro brain natriuretic peptide: the Multi-Ethnic Study of Atherosclerosis.
Menopause age can affect the risk of developing cardiovascular disease (CVD). The purpose of this study was to investigate the associations of early menopause (menopause occurring before age 45 y) and menopause age with N-terminal pro brain natriuretic peptide (NT-proBNP), a potential risk marker of CVD and heart failure. Our cross-sectional study included 2,275 postmenopausal women, aged 45 to 85 years and without clinical CVD (2000-2002), from the Multi-Ethnic Study of Atherosclerosis. Participants were classified as having or not having early menopause. NT-proBNP was log-transformed. Multivariable linear regression was used for analysis. Five hundred sixty-one women had early menopause. The median (25th-75th percentiles) NT-proBNP value was 79.0 (41.1-151.6) pg/mL for all participants, 83.4 (41.4-164.9) pg/mL for women with early menopause, and 78.0 (40.8-148.3) pg/mL for women without early menopause. The mean (SD) age was 65 (10.1) and 65 (8.9) years for women with and without early menopause, respectively. No significant interactions between menopause age and ethnicity were observed. In multivariable analysis, early menopause was associated with a 10.7% increase in NT-proBNP levels, whereas each 1-year increase in menopause age was associated with a 0.7% decrease in NT-proBNP levels. Early menopause is associated with greater NT-proBNP levels, whereas each 1-year increase in menopause age is associated with lower NT-proBNP levels, in postmenopausal women.


The pancreatic duct epithelium in vitro: bile acid injury and the effect of epidermal growth factor.
Pancreatic duct epithelial cells form a barrier against parenchymal injury. The capacity of these cells to respond to injury has not been investigated. We hypothesized that epidermal growth factor (EGF), normally found in pancreatic juice, could protect the duct epithelium from damage. An explant system of duct cell culture developed in our lab with the bovine main pancreatic duct was used. Explants were exposed to bile acid (taurodeoxycholic acid [TDCA] 0, 0.05, 0.5, and 1 mmol/L) in the presence or absence of EGF (0, 1, 10, and 100 nmol/L) for 48 hours. Epithelial proliferation, damage, and growth out from the explant edge were assessed histologically. Expression of ductal markers and the extent of cell proliferation were determined by immunohistochemistry using specific antibodies. Explant duct cells proliferated and demonstrated continued expression of key duct antigens in culture. TDCA produced dose-dependent mucosal damage and reduced epithelial density and growth from the edge. EGF increased cellular density in the native epithelium, but did not significantly alter growth from the edge. Mucosal damage created by TDCA exposure was significantly decreased with EGF and both growth from the edge and cell density were preserved. Explants created from the bovine main pancreatic duct serve as an excellent model for the study of duct epithelial cells in vitro. These cells proliferate in response to EGF and are damaged by TDCA at concentrations below those normally associated with detergent-like activity and below levels observed in bile and duodenal secretions. The ability of EGF to protect from this injury suggests a potential physiologic role in the maintenance of the pancreatic duct mucosal barrier.


Risk factors for severe neonatal hyperbilirubinemia in low and middle-income countries: a systematic review and meta-analysis.
Available evidence suggests that low- and middle-income countries (LMICs) bear the greatest burden of severe neonatal hyperbilirubinemia characterized by disproportionately high rates of morbidity, mortality and neurodevelopmental disorders compared to high-income countries. We set out to identify the risk factors that contribute to the burden of severe hyperbilirubinemia in the most developmentally disadvantaged LMICs to highlight areas for action and further research. We systematically searched PubMed, Scopus, Ovid EMBASE, Cumulative Index to Nursing and Allied Health Literature (CINAHL), WHO Library Database (WHOLIS), African Index Medicus (AIM), African Journals Online (AJOL), LILACS, and IndMed for reports published between January 1990 and June 2014. We included only studies that controlled for the effects of confounding variables in determining maternal and infant risk factors for severe hyperbilirubinemia. We conducted meta-analysis of the eligible studies and computed the summary risk estimates with random effects models. A total of 13 studies with 1,951 subjects and 32,208 controls from India, Nigeria, Pakistan, Nepal and Egypt were identified and analyzed. The pooled data showed that primiparity (OR, 1.59; 95% CI:1.26-2.00), delivery outside public hospitals (OR, 6.42; 95% CI:1.76-23.36), ABO incompatibility (OR, 4.01; 95% CI:2.44-6.61), Rhesus hemolytic disease (OR, 20.63; 95% CI:3.95-107.65), G6PD deficiency (OR, 8.01; 95% CI:2.09-30.69), UGT1A1 polymorphisms (OR, 4.92; 95% CI:1.30-18.62), low gestational age (OR, 1.71; 95% CI:1.40-2.11), underweight/weight loss (OR, 6.26; 95% CI:1.23-31.86), sepsis (OR, 9.15; 95% CI:2.78-30.10) and high transcutaneous/total serum bilirubin levels (OR, 1.46; 95% CI:1.10-1.92) placed infants at increased risk of severe hyperbilirubinemia or bilirubin induced neurologic dysfunctions. Low social class was not associated with an increased risk of severe hyperbilirubinemia. Infants at risk of severe hyperbilirubinemia in LMICs are associated with maternal and neonatal factors that can be effectively addressed by available interventions to curtail the disease burden prevailing in the affected countries.


Deleterious Effects of Neonicotinoid Pesticides on Drosophila melanogaster Immune Pathways.
Neonicotinoid insecticides are common agrochemicals that are used to kill pest insects and improve crop yield. However, sublethal exposure can exert unintentional toxicity to honey bees and other beneficial pollinators by dysregulating innate immunity. Generation of hydrogen peroxide (H2O2) by the dual oxidase (Duox) pathway is a critical component of the innate immune response, which functions to impede infection and maintain homeostatic regulation of the gut microbiota. Despite the importance of this pathway in gut immunity, the consequences of neonicotinoid exposure on Duox signaling have yet to be studied. Here, we use a Drosophila melanogaster model to investigate the hypothesis that imidacloprid (a common neonicotinoid) can affect the Duox pathway. The results demonstrated that exposure to sublethal imidacloprid reduced H2O2 production by inhibiting transcription of the Duox gene. Furthermore, the reduction in Duox expression was found to be a result of imidacloprid interacting with the midgut portion of the immune deficiency pathway. This impairment led to a loss of microbial regulation, as exemplified by a compositional shift and increased total abundance of Lactobacillus and Acetobacter spp. (dominant microbiota members) found in the gut. In addition, we demonstrated that certain probiotic lactobacilli could ameliorate Duox pathway impairment caused by imidacloprid, but this effect was not directly dependent on the Duox pathway itself. This study is the first to demonstrate the deleterious effects that neonicotinoids can have on Duox-mediated generation of H2O2 and highlights a novel coordination between two important innate immune pathways present in insects.IMPORTANCE Sublethal exposure to certain pesticides (e.g., neonicotinoid insecticides) is suspected to contribute to honey bee (Apis mellifera) population decline in North America. Neonicotinoids are known to interfere with immune pathways in the gut of insects, but the underlying mechanisms remain elusive. We used a Drosophila melanogaster model to understand how imidacloprid (a common neonicotinoid) interferes with two innate immune pathways-Duox and Imd. We found that imidacloprid dysregulates these pathways to reduce hydrogen peroxide production, ultimately leading to a dysbiotic shift in the gut microbiota. Intriguingly, we found that presupplementation with probiotic bacteria could mitigate the harmful effects of imidacloprid. Thus, these observations uncover a novel mechanism of pesticide-induced immunosuppression that exploits the interconnectedness of two important insect immune pathways.


Permeability pulmonary edema. Diagnosis and management.
The adult respiratory distress syndrome (ARDS) is a common syndrome of diffuse lung injury with high mortality. An underlying mechanism is pulmonary microvascular injury leading to increased permeability, pulmonary edema and impaired gas exchange. Currently ARDS can only be diagnosed as a constellation of symptoms and signs. The development of an accurate clinical marker of pulmonary microvascular injury or a technique to measure pulmonary microvascular permeability may allow earlier and more specific diagnosis. We review ARDS with emphasis on recent work concerning the mechanisms of lung injury, diagnosis, and therapy.


Anti-inflammatory effects of Flos Lonicerae Japonicae Water Extract are regulated by the STAT/NF-κB pathway and HO-1 expression in Virus-infected RAW264.7 cells.
This study examined the effect of the Flos Lonicerae Japonicae water extract (FLJWE), chlorogenic acid, and luteolin on pseudorabies virus (PRV)-induced inflammation in RAW264.7 cells and elucidated related molecular mechanisms. The results revealed that FLJWE and luteolin, but not chlorogenic acid, inhibited the production of inducible nitric oxide synthase (iNOS), cyclooxygenase-2 (COX-2), and inflammatory cytokines in PRV-infected RAW 264.7 cells. We found that the FLJWE and luteolin suppressed nuclear factor (NF)-κB activation by inhibiting the phosphorylation of signal transducer and activator of transcription 1 and 3 (STAT1 and STAT3, respectively). Moreover, the FLJWE significantly upregulated the expression of pNrf2 and its downstream target gene heme oxygenase-1 (HO-1). Our data indicated that FLJWE and luteolin reduced the expression of proinflammatory mediators and inflammatory cytokines, such as COX-2 and iNOS, through the suppression of the JAK/STAT1/3-dependent NF-κB pathway and the induction of HO-1 expression in PRV-infected RAW264.7 cells. The findings indicate that the FLJWE can be used as a potential antiviral agent.


Effect of cellular changes and onset of humoral immunity on the replication of porcine reproductive and respiratory syndrome virus in the lungs of pigs.
Twenty-two 4- to 5-week-old gnotobiotic pigs were intranasally inoculated with 10(6.0) TCID(50) of porcine reproductive and respiratory syndrome virus (PRRSV) (Lelystad) and euthanized at different time intervals post-inoculation (p.i.). Bronchoalveolar lavage (BAL) cell populations were characterized, together with the pattern of virus replication and appearance of antibodies in the lungs. Total BAL cell numbers increased from 140x10(6) at 5 days p.i. to 948x10(6) at 25 days p.i. and remained at high levels until the end of the experiment. The number of monocytes/macrophages, as identified by monoclonal antibodies 74-22-15 and 41D3, increased two- to fivefold between 9 and 52 days p.i. with a maximum at 25 days p.i. Flow cytometry showed that the population of differentiated macrophages was reduced between 9 and 20 days p.i. and that between the same time interval, both 74-22-15-positive and 41D3-negative cells, presumably monocytes, and 74-22-15- and 41D3-double negative cells, presumably non-phagocytes, entered the alveolar spaces. Virus replication was highest at 7 to 9 days p.i., decreased slowly thereafter and was detected until 40 days p.i. Anti-PRRSV antibodies were detected starting at 9 days p.i. but neutralizing antibodies were only demonstrated in one pig euthanized at 35 days and another at 52 days p.i. The decrease of virus replication in the lungs from 9 days p.i. can be attributed to (i) shortage of susceptible differentiated macrophages, (ii) lack of susceptibility of the newly infiltrated monocytes and (iii) appearance of anti-PRRSV antibodies in the lungs. Neutralizing antibodies may contribute to the clearance of PRRSV from the lungs.


Spatio-Temporal Dynamics of Free and Bound Carriers in Photovoltaic Materials.
Charge transfer and subsequent separation into free carriers are key processes that govern the efficiencies of third generation solar cell technologies based on donor-acceptor heterojunctions. As these processes typically occur on picosecond to femtosecond timescales, it is necessary to employ ultrafast spectroscopic techniques to further our understanding of these processes in order to provide vital information that can aide in furthering material design. Within the framework of the National Centre of Competence in Research "Molecular Ultrafast Science and Technology" (NCCR MUST), we have developed and utilized a suite of different ultrafast spectroscopic techniques to study charge generation, separation and recombination in a variety of small molecule based organic solar cells and lead halide perovskites. Here, we provide an overview of the main techniques used in our laboratory and the recent results obtained using these spectroscopic techniques.


A methodology for the comparative evaluation of alternative bioseparation technologies.
Advances in upstream technologies and growing commercial demand have led to cell culture processes of ever larger volumes and expressing at higher product titers. This has increased the burden on downstream processing. Concerns regarding the capacity limitations of packed-bed chromatography have led process engineers to begin investigating new bioseparation techniques that may be considered as "alternatives" to chromatography, and which could potentially offer higher processing capacities but at a lower cost. With the wide range of alternatives, which are currently available, each with their own strengths and inherent limitations, coupled with the time pressures associated with process development, the challenge for process engineers is to determine which technologies are most worth investigating. This article presents a methodology based on a multiattribute decision making (MADM) analysis approach, utilizing both quantitative and qualitative data, which can be used to determine the "industrial attractiveness" of bioseparation technologies, accounting for trade-offs between their strengths and weaknesses. By including packed-bed chromatography in the analysis as a reference point, it was possible to determine the alternatives, which show the most promise for use in large-scale manufacturing processes. The results of this analysis show that although the majority of alternative techniques offer certain advantages over conventional packed-bed chromatography, their attractiveness overall means that currently none of these technologies may be considered as viable alternatives to chromatography. The methodology introduced in this study may be used to gain significant quantitative insight as to the key areas in which improvements are required for each technique, and thus may be used as a tool to aid in further technological development.


Platelet-activating factor binding to human platelet membranes.
Previously reported methods for quantifying platelet-activating factor (PAF) binding to rabbit platelet membranes were modified for studies of PAF binding to human platelet membranes. The membranes were prepared by the "glycerol lysis" method and PAF binding was quantified by using polyethylene glycol precipitation to recover membrane-bound PAF. Optimal PAF binding required buffers containing 3 to 10 mm KCl and either 5 to 10 mM MgCl2 or 5 to 10 mM CaCl2. NaCl was not as effective as KCl and concentrations of NaCl greater than 3 mM strongly inhibited PAF binding. Maximal binding occurred after incubation for 60 min at 0 degree C and was reversed by the addition of excess unlabeled PAF. PAF binding was saturable. Scatchard analysis of PAF binding to 50 micrograms of membrane protein revealed 10.3 +/- 1.7 x 10(11) receptors per milligram of membrane protein and the receptors had a Kd of 7.6 +/- 1.9 nM. The calculated receptor number, binding affinity, and specificity of binding are similar to those previously calculated for PAF binding to intact human platelets, suggesting that the membrane binding site for PAF is the PAF receptor.


Inhibition of epidermal growth factor binding to Swiss 3T3 cells by human platelet release-products.
Human platelet ionophore release-products (IRP) inhibit the binding of 125I-labelled epidermal growth factor (125I-EGF) to its receptors on Swiss 3T3 cells. The inhibition appears to be caused by platelet-derived growth factor (PDGF) in the IRP and results from a decrease in the apparent affinity of cellular receptors for 125I-EGF. However, our results indicate that PDGF does not bind directly to EGF receptors, since (1) PDGF does not down-regulate EGF receptors; (2) the PDGF-mediated inhibition of 125I-EGF binding is temperature-dependent; (3) cells which possess EGF receptors but lack PDGF receptors do not exhibit a PDGF-mediated inhibition of 125I-EGF binding.