Hematopoietic stem cell transplantation in patients with active fungal infection: not a contraindication for transplantation.
Increasing use of more aggressive treatment approaches in patients with hematologic malignancies leads to an increased frequency of invasive fungal infections, which is a major cause of transplant-related mortality in hematopoietic stem cell recipients. In this respect, the presence of an active fungal infection prior to transplantation may hinder subsequent hematopoietic stem cell transplantation (HSCT); which sometimes is the only curative treatment. We report here the results of 13 consecutive patients transplanted with active fungal infection. Thirteen patients (7 males and 6 females) with a median age of 34 years (range, 16-53 years) underwent 15 HSCT between September 2003 and April 2007. In this group of 15 patients, consisting of hematologic malignancies with high risk of relapse or severe aplastic anemia, 11 (73%) transplants performed in subjects with active invasive fungal infection (IFI) patients survived 30 days after transplantation. Three patients (1 patient with primary disease relapse, 1 patient with graft versus host disease [GVHD] complicated with fungal pneumonia, and 1 patient with severe sinusoidal obstruction syndrome and GVHD complicated with aspiration pneumonia) died on days +66, +74, and +62 posttransplantation, respectively, within the first 100 days of HSCT. After a median follow-up time of 306 days (range, 145-680 days), four of 13 (31%) patients with active IFI were alive and disease free. Among a population of HSCT recipients with a dismal prognosis without transplantation, performing the procedure despite active IFI saved a considerable proportion of the patients. The presence of active IFI did not seem to be an absolute contraindication for HSCT, particularly among high-risk patients in whom a treatment delay could be fatal.


Identification and molecular characterization of Medicago truncatula NRT2 and NAR2 families.
Nitrate transporters received little attention to legumes probably because these species are able to adapt to N starvation by developing biological N2 fixation. Still it is important to study nitrate transport systems in legumes because nitrate intervenes as a signal in regulation of nodulation probably through nitrate transporters. The aim of this work is to achieve a molecular characterization of nitrate transporter 2 (NRT2) and NAR2 (NRT3) families to allow further work that would unravel their involvement in nitrate transport and signaling. Browsing the latest version of the Medicago truncatula genome annotation (v4 version) revealed three putative NRT2 members that we have named MtNRT2.1 (Medtr4g057890.1), MtNRT2.2 (Medtr4g057865.1) and MtNRT2.3 (Medtr8g069775.1) and two putative NAR2 members we named MtNAR2.1 (Medtr4g104730.1) and MtNAR2.2 (Medtr4g104700.1). The regulation and the spatial expression profiles of MtNRT2.1, the coincidence of its expression with that of MtNAR2.1 and MtNAR2.2 and the size of the encoded protein with 12 transmembrane (TM) spanning regions strongly support the idea that MtNRT2.1 is a nitrate transporter with a major contribution to the high-affinity transport system (HATS), while a very low level of expression characterized MtNRT2.2. Unlike MtNRT2.1, MtNRT2.3 showed a lower level of expression in the root system but was expressed in the shoots and in the nodules thus suggesting an involvement of the encoded protein in nitrate transport inside the plant and/or in nitrate signaling pathways controlling post-inoculation processes that govern nodule functioning.


The nature and development of sex attractant specificity in cockroaches of the genus Periplaneta. I. Sexual dimorphism in the distribution of antennal sense organs in five species.
Sexual dimorphism in the distribution of antennal sense organs is common among adults of the genus Periplaneta. In three out of the four strains of Periplaneta americana examined, adult males had more contact chemoreceptros than females. In the fourth strain of P. americana and in P. australasiae, P. brunnea, P. fuliginosa, and P. japonica, no statistically supportable sexual dimorphism of contact chemoreceptors was found. However, in all strains and species of Periplaneta examined, sexual dimorphism was found in the total number and/or density of olfactory sensilla. Male adults had nearly twice as many olfactory sensilla as female adults. These observations are consistent with the behavioral observation that males within the genus Periplaneta rely on the reception of an airborne pheromone for the initiation of courtship behavior. In P. americana, where sexual dimorphism was found in the contact chemoreceptors, contact stimuli release the full wing raising display and presentation in males during courtship.


Developmental toxic potential of 1,3-dichloro-2-propanol in Sprague-Dawley rats.
This study investigated the potential adverse effects of 1,3-dichloro-2-propanol (1,3-DCP) on pregnant dams and the embryo-fetal development after maternal exposure on gestational days (GD) 6 through 19 in Sprague-Dawley rats. The test chemical was administered to pregnant rats by gavage at dose levels of 0, 10, 30, and 90mg/kg per day (n=10 for each group). All dams underwent Caesarean sections on GD 20, and their fetuses were examined for morphological abnormalities. Maternal toxicity was noted at 90mg/kg/day. Manifestations of toxicity included clinical signs of illness, lower body weight gain, decreased food intake, and increases in the weight of the adrenal glands and the liver. Developmental toxic effects including decreases in fetal body weight and increases in visceral and skeletal variations also occurred at the highest dose. At 30mg/kg, only a minimal maternal toxicity, including a decrease in maternal food intake and an increase in the liver weight, was observed. No adverse maternal or developmental effects were observed at 10mg/kg/day. These results revealed that a 14-day repeated oral dose of 1,3-DCP was minimally embryotoxic but not teratogenic at a maternal toxic dose (90mg/kg/day), and was not embryotoxic at a minimally maternal toxic dose (30mg/kg/day) in rats. Because the developmental toxicity of 1,3-DCP was observed only in the presence of maternal toxicity, it is concluded that the developmental findings observed in the present study are secondary effects to maternal toxicity. Under these experimental conditions, the no-observed-adverse-effect level of 1,3-DCP is considered to be 10mg/kg/day for dams and 30mg/kg/day for embryo-fetal development.


Nonlinear Imaging with All-Dielectric Metasurfaces.
Nonlinear metasurfaces incorporate many of the functionalities of their linear counterparts such as wavefront shaping, but simultaneously they perform nonlinear optical transformations. This dual functionality leads to a rather unintuitive physical behavior which is still widely unexplored for many photonic applications. The nonlinear processes render some basic principles governing the functionality of linear metasurfaces. Exemplarily, the superposition principle and the geometric optics approximation become not directly applicable to nonlinear metasurfaces. On the other hand, nonlinear metasurfaces facilitate new phenomena that are not possible in the linear regime. Here, we study the imaging of objects through a dielectric nonlinear metalens. We illuminate objects by infrared light and record their generated images at the visible third-harmonic wavelengths. We revisit the classical lens theory and suggest a generalized Gaussian lens equation for nonlinear imaging, verified both experimentally and analytically. We also demonstrate experimentally higher-order spatial correlations facilitated by the nonlinear metalens, resulting in additional image features.


Using Coherence-based spectro-spatial filters for stimulus features prediction from electro-corticographic recordings.
The traditional approach in neuroscience relies on encoding models where brain responses are related to different stimuli in order to establish dependencies. In decoding tasks, on the contrary, brain responses are used to predict the stimuli, and traditionally, the signals are assumed stationary within trials, which is rarely the case for natural stimuli. We hypothesize that a decoding model assuming each experimental trial as a realization of a random process more likely reflects the statistical properties of the undergoing process compared to the assumption of stationarity. Here, we propose a Coherence-based spectro-spatial filter that allows for reconstructing stimulus features from brain signal's features. The proposed method extracts common patterns between features of the brain signals and the stimuli that produced them. These patterns, originating from different recording electrodes are combined, forming a spatial filter that produces a unified prediction of the presented stimulus. This approach takes into account frequency, phase, and spatial distribution of brain features, hence avoiding the need to predefine specific frequency bands of interest or phase relationships between stimulus and brain responses manually. Furthermore, the model does not require the tuning of hyper-parameters, reducing significantly the computational load attached to it. Using three different cognitive tasks (motor movements, speech perception, and speech production), we show that the proposed method consistently improves stimulus feature predictions in terms of correlation (group averages of 0.74 for motor movements, 0.84 for speech perception, and 0.74 for speech production) in comparison with other methods based on regularized multivariate regression, probabilistic graphical models and artificial neural networks. Furthermore, the model parameters revealed those anatomical regions and spectral components that were discriminant in the different cognitive tasks. This novel method does not only provide a useful tool to address fundamental neuroscience questions, but could also be applied to neuroprosthetics.


Immunohistochemical detection of progesterone receptors in paraffin sections. A novel method using microwave oven pretreatment.
The benefits of microwave oven pretreatment of formalin-fixed routinely processed paraffin sections were assessed using citric acid solution to demonstrate progesterone receptors (PR). Parallel frozen and paraffin sections from 25 cases of breast cancer were stained with the PR-ICA kit (Abbott). Compared with untreated paraffin sections a great enhancement of PR immunostaining occurred after microwave irradiation. In 21 cases the percentage of positively stained tumor cell nuclei in microwave oven-pretreated paraffin sections was practically identical to that in the frozen ones. After microwave irradiation the PR score in paraffin sections was in three cases higher than in the frozen material. In comparison with the frozen sections, only one tumor of 25 showed a lower percentage of stained malignant cells after the irradiation. It is concluded that microwave oven pretreatment is a simple, reliable and reproducible method to detect PR in routinely fixed paraffin-embedded tissues.


Lysosomal dysfunction on hydrogen peroxide-induced apoptosis of osteoarthritic chondrocytes.
The purpose of this study was to examine the mechanism of hydrogen peroxide-induced apoptosis in osteoarthritic chondrocytes. We evaluated the reactive oxygen species (ROS) formation, lysosomal staining and dysfunction of the mitochondrial membrane potential in these cells after exposure to hydrogen peroxide. Osteoarthritic chondrocytes were isolated, and divided into 4 dishes in which different concentrations (0.1 mM, 1 mM and 10 mM) of hydrogen peroxide, or no additive (control) was added. The cells were incubated for 1 or 4 h, then assayed for ROS formation, mitochondrial membrane potential and lysosomal staining. ROS formation was detected in chondrocytes after 1 h of exposure to hydrogen peroxide concentrations over 0.1 mM. Lysosomal swelling was detected after 1 h of exposure to hydrogen peroxide concentrations of 0.1 mM and over, possibly revealing lysosomal membrane instability. Moreover, indications of lysosomal rupture, including release of lysosomal enzymes, were apparent 1 h after addition of 10 mM of hydrogen peroxide. The addition of hydrogen peroxide to chondrocytes induces ROS formation and lysosomal dysfunction, revealed by swelling and rupture, prior to dysfunction of the mitochondrial membrane potential. Anti-oxidants may have a therapeutic application in the prevention of lysosomal dysfunction to inhibit chondrocyte apoptosis and degradation of the cartilage matrix.


Arrhythmogenic right ventricular dysplasia/cardiomyopathy according to revised 2010 task force criteria with inclusion of non-desmosomal phospholamban mutation carriers.
Arrhythmogenic right ventricular dysplasia/cardiomyopathy (ARVD/C) is frequently associated with desmosomal mutations. However, nondesmosomal mutations may be involved. The aim of this study was to assess the contribution of a phospholamban (PLN) gene mutation to ARVD/C diagnosis according to the revised 2010 task force criteria (TFC). In 142 Dutch patients (106 men, mean age 51 ± 13 years) with proven ARVD/C (fulfillment of 2010 TFC for diagnosis), 5 known desmosomal genes (PKP2, DSP, DSC2, DSG2, and JUP) and the nondesmosomal PLN gene were screened. After genetic analysis, phenotypic characteristics of desmosomal versus PLN mutation carriers were compared. In 59 of 142 patients with ARVD/C (42%), no desmosomal mutation was found. In 19 of 142 patients (13%), the PLN founder mutation c.40_42delAGA (p.Arg14del) was identified. PLN mutation carriers more often had low-voltage electrocardiograms (p = 0.004), inverted T waves in leads V4 to V6 (p <0.001), and additional structural (p = 0.007) or functional (p = 0.017) left ventricular impairment, whereas desmosomal mutation carriers had more solitary right ventricular abnormalities. The revised TFC included 21 of 142 patients with proven ARVD/C who did not meet the 1994 TFC, including 7 PLN mutation carriers. In conclusion, there is a substantial contribution of PLN mutation to ARVD/C diagnosis by the 2010 TFC. In 32% of patients (19 of 59) with genetically unexplained proven ARVD/C, this nondesmosomal mutation was found. PLN mutation carriers have ARVD/C characteristics, including important right ventricular involvement, and additionally more often low-voltage electrocardiograms, inverted T waves in the left precordial leads, and left ventricular involvement.


Gut Microbiota and Its Role in Anti-aging Phenomenon: Evidence-Based Review.
The gut microbiota widely varies from individual to individual, but the variation shows stability over a period of time. The presence of abundant bacterial taxa is a common structure that determines the microbiota of human being. The presence of this microbiota greatly varies from geographic location, sex, food habits and age. Microbiota existing within the gut plays a significant role in nutrient absorption, development of immunity, curing of diseases and various developmental phases. With change in age, chronology diversification and variation of gut microbiota are observed within human being. But it has been observed that with the enhancement of age the richness of the microbial diversity has shown a sharp decline. The enhancement of age also results in the drift of the characteristic of the microbes associated with the microbiota from commensals to pathogenic. Various studies have shown that age associated gut-dysbiosis may result in decrease in tlongevity along with unhealthy aging. The host signalling pathways regulate the presence of the gut microbiota and their longevity. The presence of various nutrients regulates the presence of various microbial species. Innate immunity can be triggered due to the mechanism of gut dysbiosis resulting in the development of various age-related pathological syndromes and early aging. The gut microbiota possesses the ability to communicate with the host system with the help of various types of biomolecules, epigenetic mechanisms and various types of signalling-independent pathways. Drift in this mechanism of communication may affect the life span along with the health of the host. Thus, this review would focus on the use of gut-microbiota in anti-aging and healthy conditions of the host system.


Leukocyte esterase strip test: matched for musculoskeletal infection society criteria.
The presence of leukocyte esterase in the synovial fluid has recently been proposed as a marker for periprosthetic joint infection. However, the sensitivity and specificity of leukocyte esterase has not been determined when matched for the current, most inclusive Musculoskeletal Infection Society (MSIS) criteria for periprosthetic joint infection. The presence of leukocyte esterase was prospectively evaluated in synovial joint aspirates from hips and knees from May 2009 to May 2013. The cohort consisted of 189 hip and knee aspirations (fifty-two positive and 137 negative for infection). If the aspirate was bloody, a centrifuge was used to precipitate red blood cells and obtain clear synovial fluid. A standard chemical test strip (graded as negative, trace, +, or ++) was used to detect the presence of leukocyte esterase. The sensitivity, specificity, positive predictive value, and negative predictive value of the leukocyte esterase strip test were calculated using ++ and ++/+ as two positive strip result scenarios. Synovial fluid was obtained from 221 joints that underwent revision total hip or total knee arthroplasty for either mechanical failure or periprosthetic infection. Due to the lack of adequate criteria for MSIS criteria classification, thirty-two joints were excluded. The leukocyte esterase test with a threshold of +/++ had a sensitivity, specificity, positive predictive value, and negative predictive value of 79.2% (95% confidence interval [CI], 65.9% to 89.2%), 80.8% (95% CI, 73.3% to 87.1%), 61.8% (95% CI, 49.2% to 73.3%), and 90.1% (95% CI, 84.3% to 95.4%), respectively. Using the ++ as a positive leukocyte esterase result, the sensitivity, specificity, positive predictive value, and negative predictive value were 66.0% (95% CI, 51.7% to 78.5%), 97.1% (95% CI, 92.6% to 99.2%), 89.7% (95% CI, 75.8% to 97.1%), and 88.0% (95% CI, 81.7% to 92.7%), respectively. When matched to the current MSIS criteria, the leukocyte esterase strip test yielded a high specificity, positive predictive value, negative predictive value, and moderate sensitivity. These results demonstrate that leukocyte esterase is an accurate, effective marker of periprosthetic joint infection as defined by the MSIS criteria. The leukocyte esterase strip test is a valuable tool that can be used in conjunction with the current battery of diagnostic tests available.


Cutting stress off at the pass: reducing vigilance and responsiveness to social threat by manipulating attention.
Personality processes relating to social perception have been shown to play a significant role in the experience of stress. In 5 studies, the authors demonstrate that early stage attentional processes influence the perception of social threat and modify the human stress response. The authors first show that cortisol release in response to a stressful situation correlates with selective attention toward social threat. Second, the authors show in 2 laboratory studies that this attentional pattern, most evident among individuals with low self-esteem, can be modified with a repetitive training task. Next, in a field study, students trained to modify their attentional pattern to reduce vigilance for social threat showed lower self-reported stress related to their final exam. In a final field study with telemarketers, the attentional training task led to increased self-esteem, decreased cortisol and perceived stress responses, higher confidence, and greater work performance. Taken together, these results demonstrate the impact of antecedent-focused strategies on the late-stage consequences of social stress.


Male gender is a predictor of higher mortality in hospitalized adults with COVID-19.
The coronavirus disease 2019 (COVID-19) pandemic continues to be a global threat, with tremendous resources invested into identifying risk factors for severe COVID-19 illness. The objective of this study was to analyze the characteristics and outcomes of male compared to female adults with COVID-19 who required hospitalization within US academic centers. Using the Vizient clinical database, discharge records of adults with a diagnosis of COVID-19 between March 1, 2020 and November 30, 2020 were reviewed. Outcome measures included demographics, characteristics, length of hospital stay, rate of respiratory intubation and mechanical ventilation, and rate of in-hospital mortality of male vs female according to age, race/ethnicity, and presence of preexisting comorbidities. Among adults with COVID-19, 161,206 were male while 146,804 were female. Adult males with COVID-19 were more likely to have hypertension (62.1% vs 59.6%, p <0.001%), diabetes (39.2% vs 36.0%, p <0.001%), renal failure (22.3% vs 18.1%, p <0.001%), congestive heart failure (15.3% vs 14.6%, p <0.001%), and liver disease (5.9% vs 4.5%, p <0.001%). Adult females with COVID-19 were more likely to be obese (32.3% vs 25.7%, p<0.001) and have chronic pulmonary disease (23.7% vs 18.1%, p <0.001). Gender was significantly different among races (p<0.001), and there was a lower proportion of males versus females in African American patients with COVID-19. Comparison in outcomes of male vs. female adults with COVID-19 is depicted in Table 2. Compared to females, males with COVID-19 had a higher rate of in-hospital mortality (13.8% vs 10.2%, respectively, p <0.001); a higher rate of respiratory intubation (21.4% vs 14.6%, p <0.001); and a longer length of hospital stay (9.5 ± 12.5 days vs. 7.8 ± 9.8 days, p<0.001). In-hospital mortality analyzed according to age groups, race/ethnicity, payers, and presence of preexisting comorbidities consistently showed higher death rate among males compared to females (Table 2). Adult males with COVID-19 were associated with higher odds of mortality compared to their female counterparts across all age groups, with the effect being most pronounced in the 18-30 age group (OR, 3.02 [95% CI, 2.41-3.78]). This large analysis of 308,010 COVID-19 adults hospitalized at US academic centers showed that males have a higher rate of respiratory intubation and longer length of hospital stay compared to females and have a higher death rate even when compared across age groups, race/ethnicity, payers, and comorbidity.


Selective harvesting and habitat loss produce long-term life history changes in a mouflon population.
We examined the long-term effects (28 years) of habitat loss and phenotype-based selective harvest on body mass, horn size, and horn shape of mouflon (Ovis gmelini musimon) in southern France. This population has experienced habitat deterioration (loss of 50.8% of open area) since its introduction in 1956 and unrestricted selective hunting of the largest horned males since 1973. Both processes are predicted to lead to a decrease in phenotype quality by decreasing habitat quality and by reducing the reproductive contribution of individuals carrying traits that are targeted by hunters. Body mass and body size of both sexes and horn measurements of males markedly decreased (by 3.4-38.3%) in all age classes from the 1970s. Lamb body mass varied in relation to the spatiotemporal variation of habitat closure within the hunting-free reserve, suggesting that habitat closure explains part of these changes. However, the fact that there was no significant spatial variation in body mass in the early part of the study, when a decline in phenotypic quality already had occurred, provided support for the influence of selective harvesting. We also found that the allometric relationship between horn breadth and horn length changed over the study period. For a given horn length, horn breadth was lower during the second part of the study. This result, as well as changes in horn curve diameter, supports the interpretation that selective harvesting of males based on their horn configuration had evolutionary consequences for horn shape, since this phenotypic trait is less likely to be affected by changes in habitat characteristics. Moreover, males required more time (approximately four years) to develop a desirable trophy, suggesting that trophy hunting favors the reproductive contribution of animals with slow-growing horns. Managers should exploit hunters' desire for trophy males to finance management strategies which ensure a balance between the population and its environment. However, for long-term sustainable exploitation, harvest strategy should also ensure that selectively targeted males are allowed to contribute genetically to the next generations.


Taxonomical re-evaluation of Phoma-like soybean pathogenic fungi.
Coelomycetous fungi classified in Ascochyta, Phoma, and Phyllosticta have been recorded from spots on leaves and pods of soybeans. Based on the Genealogical Concordance Phylogenetic Species Concept, the authors suggest the re-evaluation of the taxonomic status of Phoma sojicola (syn.=Ascochyta sojicola) and Phyllosticta sojicola. In spite of the former delimitation of Phoma sojicola based on small differences in morphological features, it has proved to be identical to Phoma pinodella. Similarly, it was also confirmed that Phyllosticta sojicola was identical to Phoma exigua var. exigua. The authors supply tools for identification of Phoma-like fungi by combined conventional and molecular methods. Protein-encoding genes (tef1 and beta-tubulin) were successfully applied within the Phoma genus to infer phylogenetic relationships.


Surgical Treatment of Superior Sulcus Tumors: A 15-Year Single-center Experience.
This paper reports on the characteristics, treatment modalities, and outcomes of patients with superior sulcus tumors who underwent surgery over a period of 15 years in 1 institution. Clinical records of 94 consecutive patients operated on by the same surgical team for non-small cell lung cancer between July 1998 and December 2013 were retrospectively reviewed. All patients received lung and chest wall en bloc resection. Forty-eight (51%) received induction treatments. Surgery was an anterior approach in 46 patients (48.9%), Paulson incision in 35 (37.2%), and a combined approach in 13 (13.8%). Lung resections were 78 lobectomies (83%), 3 were pneumonectomies (3.2%), 6 were bronchoplastic reconstructions (6.4%), and 7 were wedge resections (7.4%). Nodal dissection was systematic in 96% of patients. The median number of resected ribs was 2 (1-5), chest wall residual defect was reconstructed in 42 patients (44.7%), and 21 patients had an associated vascular resection (22.3%). Resection was radical in 85 patients (90.4%). Overall 90-day mortality was 9.6%. After a median follow-up of 1.9 years, 5-year and 10-year overall survival rates were 35% and 23%, respectively. A lower 5-year survival was observed in patients with nodal disease (48% in N0 vs 18% in N+; P < 0.0001), incomplete resection (21% for incomplete vs 37% for complete resection; P = 0.15), and anteriorly located tumor (anterior vs posterior: 26% vs 50%; P = 0.05). Pancoast tumor is a severe condition, but long-term survival may be achieved in selected cases. Nodal involvement, completeness of resection, and vascular invasion are the most important prognostic factors, and induction treatment may play a role.


Estrous cycle variation of TRPV1-mediated cross-organ sensitization between uterus and NMDA-dependent pelvic-urethra reflex activity.
Cross-organ sensitization between the uterus and the lower urinary tract (LUT) underlies the high concurrence of pelvic pain syndrome and LUT dysfunctions, and yet the role of gonadal steroids is still unknown. We tested the hypothesis that cross-organ sensitization on pelvic-urethra reflex activity caused by uterine capsaicin instillation is estrous cycle dependent. When compared with the baseline reflex activity (1.00 +/- 0.00 spikes/stimulation), uterine capsaicin instillation significantly increased reflex activity (45.42 +/- 9.13 spikes/stimulation, P < 0.01, n = 7) that was corroborated by an increase in phosphorylated NMDA NR2B (P < 0.05, n = 4) but not NR2A subunit (P > 0.05, n = 4) expression. Both intrauterine pretreatment with capsazepine (5.02 +/- 2.11 spikes/stimulation, P < 0.01, n = 7) and an intrathecal injection of AP5 (3.21 +/- 0.83 spikes/stimulation, P < 0.01, n = 7) abolished the capsaicin-induced cross-organ sensitization and the increment in the phosphorylated NR2B level (P < 0.05, n = 4). The degrees of the cross-organ sensitization increased in a dose-dependent manner with the concentration of instilled capsaicin from 100 to 300 microM in both the proestrus and metestrus stages, whereas they weakened when the concentrations were higher than 1,000 microM. Moreover, the cross-organ sensitization caused by the uterine capsaicin instillation increased significantly in the rats during the proestrus stage when compared with the metestrus stage (P < 0.01, n = 7). These results suggest that estrogen levels might modulate the cross-organ sensitization between the uterus and the urethra and underlie the high concurrence of pelvic pain syndrome and LUT dysfunctions.


Fermi surface dichotomy of the superconducting gap and pseudogap in underdoped pnictides.
High-temperature superconductivity in iron-arsenic materials (pnictides) near an antiferromagnetic phase raises the possibility of spin-fluctuation-mediated pairing. However, the interplay between antiferromagnetic fluctuations and superconductivity remains unclear in the underdoped regime, which is closer to the antiferromagnetic phase. Here we report that the superconducting gap of underdoped pnictides scales linearly with the transition temperature, and that a distinct pseudogap coexisting with the superconducting gap develops on underdoping. This pseudogap occurs on Fermi surface sheets connected by the antiferromagnetic wavevector, where the superconducting pairing is stronger as well, suggesting that antiferromagnetic fluctuations drive both the pseudogap and superconductivity. Interestingly, we found that the pseudogap and the spectral lineshape vary with the Fermi surface quasi-nesting conditions in a fashion that shares similarities with the nodal-antinodal dichotomous behaviour observed in underdoped copper oxide superconductors.


Inelastic collisions of relativistic electrons with atomic targets in a laser field.
We consider collisions of relativistic electrons with atomic targets in a laser field assuming that the parameters of the latter are such that the field does not influence the target directly. Concentrating on target transitions we show that they can be substantially affected by the presence of the laser field. This may occur either via strong modifications in the motion of the relativistic electrons caused by the laser field or via the Compton effect when the incident electrons convert laser photon(s) into photons with frequencies equal to target transition frequencies.


Toxic Emissions: The Role of Semen in GWS Narratives.
Narratives about Gulf War Syndrome (GWS) contain discussions of sex and reproduction and there is a high level of anxiety about these subjects. Although similar to other medically unexplained conditions, GWS has distinctive features. The most salient of these is its contagious nature, with the main vehicle for contamination being semen. GWS sufferers believe their semen to be affected by their participation in the Gulf War. This paper focuses on a number of specific symptoms described by Gulf veterans including: Burning Semen Syndrome, low libido, impotence and birth defects and aims to interpret why certain symptoms became powerful markers of the condition. Furthermore, the paper looks at the meaning conveyed by such symptom reporting. Data were generated from 14 months ethnographic fieldwork in the UK including participant observation, semi-structured interviews and document analysis. Concerns about lack of potency, toxicity and quality suggest that semen itself is a substance in which social concerns are enacted. The paper argues that such a focus on and anxiety about semen suggests that GWS narratives express concerns about masculinity, or, more precisely a loss of masculinity.


Weakened IL-15 Production and Impaired mTOR Activation Alter Dendritic Epidermal T Cell Homeostasis in Diabetic Mice.
Diabetes is associated with impaired wound healing, which may be caused primarily by a deficiency in dendritic epidermal T cells (DETCs). In the epidermis, IL-15, IGF-1, and mTOR are known to regulate the maintenance of DETCs; however, it is unclear how these molecules may intersect to regulate DETC homeostasis in diabetes. Here, we show that the reduction of DETCs in the epidermis of diabetic mice is caused by altered homeostasis mediated by a reduction in IL-15 levels. Both impaired mTOR activation and reduction of IL-15 in the epidermis play important roles in DETC homeostasis. Moreover, IGF-1 drives keratinocytes to produce IL-15. The activation of IL-15 is dependent on mTOR, and conversely, mTOR regulates IGF-1 production in DETC, in a classic feedback regulatory loop. Our data suggest that in the setting of diabetes, reduced IGF-1, impaired mTOR pathway activation and reduced IL-15 in the epidermis function coordinately to promote altered DETC homeostasis and delayed skin wound closure.


LigaSure versus monopolar cautery for recipient hepatectomy in liver transplantation: a propensity score-matched analysis.
Recipient hepatectomy during liver transplantation (LT) is one of the most challenging aspects of surgery due to the possibility of massive bleeding. This study aimed to compare and analyze the effectiveness between LigaSure and monopolar cautery in recipients. We reviewed 187 recipients who underwent LT from March 2019 to June 2020. We compared the surgical outcomes of the 69 recipients who underwent recipient hepatectomy with LigaSure (LigaSure group) and 118 recipients who underwent with monopolar cautery. Propensity score matching (PSM) was performed using the nearest-neighbor method at a ratio of 1:1 based on 14 baseline characteristics and possible factors that influence postoperative bleeding. A total of 187 adult recipients were reviewed retrospectively. In the propensity score-matched analysis, The rates of bleeding and infectious complication were significantly lower in the LigaSure group than in the monopolar cautery group (3/69, 4.35% versus 13/69, 18.8%; P=0.015 and 1/69, 1.45% versus 9/69, 13.0%; P=0.017). The length of postoperative hospital stay was shorter in the LigaSure group (mean: 23.1±16.1 versus 39.6±58.2 days; P=0.024). Recipient hepatectomy with LigaSure is associated with a short hospital stay due to low re-operation rates, postoperative bleeding, and secondary infection related to bleeding.


Structural diversity repertoire of gene silencing small interfering RNAs.
Since the discovery of double-stranded (ds) RNA-mediated RNA interference (RNAi) phenomenon in Caenorhabditis elegans, specific gene silencing based upon RNAi mechanism has become a novel biomedical tool that has extended our understanding of cell biology and opened the door to an innovative class of therapeutic agents. To silence genes in mammalian cells, short dsRNA referred to as small interfering RNA (siRNA) is used as an RNAi trigger to avoid nonspecific interferon responses induced by long dsRNAs. An early structure-activity relationship study performed in Drosophila melanogaster embryonic extract suggested the existence of strict siRNA structural design rules to achieve optimal gene silencing. These rules include the presence of a 3' overhang, a fixed duplex length, and structural symmetry, which defined the structure of a classical siRNA. However, several recent studies performed in mammalian cells have hinted that the gene silencing siRNA structure could be much more flexible than that originally proposed. Moreover, many of the nonclassical siRNA structural variants reported improved features over the classical siRNAs, including increased potency, reduced nonspecific responses, and enhanced cellular delivery. In this review, we summarize the recent progress in the development of gene silencing siRNA structural variants and discuss these in light of the flexibility of the RNAi machinery in mammalian cells.


Classical intermittency and the quantum Anderson transition.
We investigate the properties of quantum systems whose classical counterpart presents intermittency. It is shown, by using recent semiclassical techniques, that the quantum spectral correlations of such systems are expressed in terms of the eigenvalues of an anomalous diffusion operator. For certain values of the parameters leading to ballistic diffusion and 1/f noise the spectral properties of our model show similarities with those of a disordered system at the Anderson transition. In Hamiltonian systems, intermittency is closely related to the presence of cantori in the classical phase space. We suggest, based on this relation, that our findings may be relevant for the description of the spectral correlations of Hamiltonians with a classical phase space homogeneously filled by cantori. Finally we discuss the extension of our results to higher dimensions and their relation to Anderson models with long-range hopping.


Overcoming Barriers: Adolescents' Experiences Using a Mobile Phone Dietary Assessment App.
The use of new technology has the potential to increase participation rates in dietary studies and improve the validity of collected dietary data. However, to evaluate the usability of developed dietary methods, qualitative studies of participants' experiences and perceptions are needed. To explore adolescents' experiences using a newly developed mobile phone dietary assessment app, with a focus on factors that could affect their recording of dietary intake. Focus group interviews were conducted with 75 participants who had used a newly developed mobile phone dietary assessment app in a quantitative evaluation study. The interviews were analyzed using qualitative content analysis and the theoretical framework of Self Determination Theory was applied. The adolescents' use of the mobile phone dietary assessment app was characterized by their struggle to overcome several perceived barriers. Facilitators that helped adolescents complete the method were also identified. Motivation was found to be an important facilitator, and intrinsically motivated participants completed the method because they found it fun to use. The autonomous extrinsically motivated participants completed the method for the greater good, in order to contribute to the study. The controlled extrinsically motivated participants completed the method to get a reward or avoid punishment. Amotivated participants did not complete the method. More motivated participants were assumed to be more able to overcome barriers and needed less facilitators. Future studies that examine the recording of food intake should include systematic efforts that aim to minimize identified barriers and promote identified facilitators. Further research should specifically aim at studying methods for (and effects of) increasing intrinsic motivation by supporting autonomy, competence, and relatedness among adolescents asked to participate in dietary studies.


Progression to dementia in a population with amnestic mild cognitive impairment: clinical variables associated with conversion.
The aim of this study was to investigate clinical predictors of, and rates of conversion to, dementia syndrome in a case series of patients with amnestic mild cognitive impairment (aMCI). Two hundred and eight aMCI subjects were followed over a six-year period. A lower Mini Mental State Examination score was a significant predictor of dementia, and mild cognitive impairment patients with behavioral and psychiatric symptoms showed a faster conversion rate.


Posterior reconstruction and outcomes of laparoscopic radical prostatectomy in a high-risk setting.
To detail the technique and evaluate the impact of a personal modified posterior reconstruction technique (PDR) on the outcomes of extrafascial laparoscopic radical prostatectomy (eLRP) in a consecutive series of 52 patients affected by high-risk prostate cancer (HRPCa). From October 2007 to March 2012, 52 patients underwent PDR during eLRP for HRPCa. Fifty-four patients who underwent eLRP for HRPCa with no PDR were considered as historical controls. Mean operative time (MOT), mean catheterization time (MCT), % continence and quality of life (QoL) at a scheduled follow-up, % anastomotic leakage, % adjuvant therapy were compared between the groups. Percentage of continence and QoL were prospectively assessed by self-administered validated questionnaires (ICI-Q-SF; SF-36) at 1, 3, 6, and 12 months. PDR was associated wither higher continence rates at 1 and 3 mo (P = .028, P = .006), a lower incidence of cystographic leakage (P = .002), and an increased adjuvant radiotherapy rate (P = .008). At 1- and 3-mo interval, in the PDR group, we found a higher number of patients reporting better general health, (P = .01, P = .03) reduced role limitations due to physical health, (P = .02, P = .001), and emotional problems (P = .001, P = .02). PDR is associated with a lower degree of anastomotic leakage, and it significantly enhances urinary continence at 1 and 3 mo. The increased adjuvant radiotherapy rate and quality of life after surgery observed with our technique suggest that in the high-risk setting an early functional recovery may substantially influence the oncologic outcome of eLRP.


Pharmacokinetics of 5-fluorouracil following hepatic intra-arterial infusion in a VX2 hepatic metastasis model.
Hepatic intra-arterial infusion chemotherapy of 5-fluorouracil (5-FU) or fluorodeoxyuridine (FUDR) has been a treatment option for liver metastasis from colorectal cancer. However, an optimal administration schedule of 5-FU is still controversial. This study was conducted to evaluate a suitable schedule from the viewpoint of 5-FU metabolites and related enzymes. 5-FU was infused into the hepatic artery of rabbits having hepatic deposits of VX2 tumor cells in a daily dose of 1, 4, or 8 mg/kg using various schedules. 5-FU, Thymidylate synthase (TS), TS inhibition rate (TSIR), and the amount of fluoro-RNA (F-RNA) were measured. A high concentration of 5-FU was detected in the tumors of the group that was administered a dose of 8 mg/kg. TSIR in the tumor was about two-fold higher in the rabbits that were administered a total dose of 8 mg/kg than in those that were administered doses of 4 mg/kg or less. F-RNA, ranging from 27 to 36 ng/mg RNA, was detected in the tumor of the rabbits that were administered a total dose of 8 mg/kg. No difference was observed between the short period and the continuous administration schedules of rabbits that were administered a dose of 8 mg/kg of 5-FU. However, DNA synthesis inhibition in normal hepatic tissue was more dependent on the administration schedule than on the total dose of 5-FU because TSIR was significantly higher with shorter periods of drug administration. Intermittent bolus administration of large doses of 5-FU might cause more severe hepatic impairment than continuous administration. These results suggest that hepatic intra-arterial infusion of 5-FU should be administered continuously for liver metastasis, although further experiments including a longer administration period of 5-FU are required.


Assessment of Aedes albopictus reference genes for quantitative PCR at different stages of development.
Members of the Aedes genus of mosquitoes are widely recognized as vectors of viral diseases. Ae.albopictus is its most invasive species, and are known to carry viruses such as Dengue, Chikugunya and Zika. Its emerging importance puts Ae.albopictus on the forefront of genetic interaction and evolution studies. However, a panel of suitable reference genes specific for this insect is as of now undescribed. Nine reference genes, namely ACT, eEF1-γ, eIF2α, PP2A, RPL32, RPS17, PGK1, ILK and STK were evaluated. Expression patterns of the candidate reference genes were observed in a total of seventeen sample types, separated by stage of development and age. Gene stability was inferred from obtained quantification data through three widely cited evaluation algorithms i.e. BestKeeper, geNorm, and NormFinder. No single gene showed a satisfactory degree of stability throughout all developmental stages. Therefore, we propose combinations of PGK and ILK for early embryos; RPL32 and RPS17 for late embryos, all four larval instars, and pupae samples; eEF1-γ with STK for adult males; eEF1-γ with RPS17 for non-blood fed females; and eEF1-γ with eIF2α for both blood-fed females and cell culture. The results from this study should be able to provide a more informed selection of normalizing genes during qPCR in Ae.albopictus.


Cytogenetic analysis and developmental assessment of mouse embryos derived from in vitro fertilization of oocytes reconstructed by meiosis-II chromosome transplantation.
An electrofusion methodology for transferring meiosis-II chromosomes (M-II-t) has not been completely established. The present study compared the use of two temperatures (fusion at 37 C for Group A and 25 C for Group B) during an electrofusion procedure for mouse oocyte M-II-t and investigated the cytogenetic normality and developmental competence of embryos derived from in vitro fertilization using oocytes reconstructed by M-II-t. The M-II-t oocytes were fertilized in vitro and cultured to the blastocyst stage; the resultant embryos were analyzed cytogenetically. Subsequently, chromosomal normality of the resultant embryos at the prometaphase stage of first cleavage division and the integrity of the meiosis-II spindles of the reconstructed oocytes were analyzed. The success rate of electrofusion in Group B was 92.1%, which was significantly different from that in Group A (49.2%) (P<0.05). The fertilization rates (A, 80.7%; B, 77.2%) and development rates (A, 70.9%; B, 65.5%) in the M-II-t groups were significantly lower than those in the control group (95.0 and 92.2%, respectively) (P<0.05). The incidence of chromosomal abnormalities in the Group A embryos (20.5%) at the blastocyst stage was significantly higher than that in the control group embryos (8.5%) (P<0.05), but the incidence of chromosomal abnormalities in Group B (12.5%) was not significantly different compared with the other groups. A temperature of 25 C during the electrofusion procedure for M-II-t resulted in a good fusion rate, good development rate, and efficient production of chromosomally normal blastocysts. Furthermore, the incidence of chromosomal abnormalities in the first cleavage embryos at the prometaphase stage in Group B (9.6%) did not differ significantly from that in the control group (6.6%). The spindle morphology of the M-II-t oocytes in Group B was normal.


Chitosan-Based Antibacterial Films for Biomedical and Food Applications.
Antibacterial chitosan films, versatile and eco-friendly materials, have garnered significant attention in both the food industry and medicine due to their unique properties, including biodegradability, biocompatibility, and antimicrobial activity. This review delves into the various types of chitosan films and their distinct applications. The categories of films discussed span from pure chitosan films to those enhanced with additives such as metal nanoparticles, metal oxide nanoparticles, graphene, fullerene and its derivatives, and plant extracts. Each type of film is examined in terms of its synthesis methods and unique properties, establishing a clear understanding of its potential utility. In the food industry, these films have shown promise in extending shelf life and maintaining food quality. In the medical field, they have been utilized for wound dressings, drug delivery systems, and as antibacterial coatings for medical devices. The review further suggests that the incorporation of different additives can significantly enhance the antibacterial properties of chitosan films. While the potential of antibacterial chitosan films is vast, the review underscores the need for future research focused on optimizing synthesis methods, understanding structure-property relationships, and rigorous evaluation of safety, biocompatibility, and long-term stability in real-world applications.


Gene selection using a two-level hierarchical Bayesian model.
The fundamental problem of gene selection via cDNA data is to identify which genes are differentially expressed across different kinds of tissue samples (e.g. normal and cancer). cDNA data contain large number of variables (genes) and usually the sample size is relatively small so the selection process can be unstable. Therefore, models which incorporate sparsity in terms of variables (genes) are desirable for this kind of problem. This paper proposes a two-level hierarchical Bayesian model for variable selection which assumes a prior that favors sparseness. We adopt a Markov chain Monte Carlo (MCMC) based computation technique to simulate the parameters from the posteriors. The method is applied to leukemia data from a previous study and a published dataset on breast cancer. http://stat.tamu.edu/people/faculty/bmallick.html.


Comorbid anxiety disorders in late-life depression.
We examined the prevalence and correlates of comorbid anxiety disorders in two groups of older depressed patients assessed at the University of Pittsburgh. A total of 336 older outpatients and inpatients with major depression were comprehensively evaluated with several instruments including the Hamilton Depression Rating Scale, and either the SADS-L or the SCID for DSM-III-R. These patients presented with major depression, associated with a wide range of functional, cognitive, and medical impairment. One-third to one-half of them also presented with severe symptomatic anxiety. However, only a small proportion (less than 5%) met diagnostic criteria for lifetime or current panic, obsessive-compulsive, or phobic disorders. At baseline, lifetime comorbid anxiety disorders were associated with a higher rate of alcoholism and higher symptomatic anxiety. Lifetime comorbid anxiety disorders did not affect the rate of response of depression, but they were associated with a higher use of benzodiazepines and a 50% increase in the time outpatients needed to respond. These findings suggest that, even in psychiatric patients with major depression, the lifetime prevalence of anxiety disorders is lower in late life, but that it has important clinical and therapeutic implications.


The carbon monoxide stretching modes in camphor-bound cytochrome P-450cam. The effect of solvent conditions, temperature, and pressure.
The effect of pH, monovalent cations, glycerol, temperature, and pressure on the carbonmonoxy (CO) stretching mode of camphor-bound cytochrome P-450cam (CYP 101) was studied. Two effects, band overlap and frequency shift, have been observed. The CO stretch infrared band located at about 1940 cm-1 is asymmetric because of the overlap of three bands at about 1931 cm-1, 1939 cm-1, and 1942 cm-1 with strongly different populations. Reducing the temperature or increasing the pressure leads to splitting the band or switching the asymmetry from the lower energy side to the higher energy side of the infrared band. The overlap of several CO stretch bands indicates conformational substates within the heme pocket. A frequency shift of the predominantly populated band is observed by changing all the parameters mentioned. The pH-induced frequency shift follows an S-shape with the pK at 6.2, which matches the pK observed for the pH-induced high-spin/low-spin transition. Conformational changes on the proximal heme side are suggested to be the origin. Monovalent cations at saturating concentration induce a small frequency shift depending on the ion radius. The potassium ion is the one that induces a CO stretch frequency with the highest wave-number while sodium and lithium (smaller radii) and rubidium and caesium ion (larger radii) have diminished values, which is supporting evidence for the special function of the potassium ion within the structure. Glycerol and hydrostatic pressure induce a red shift of the CO stretching frequency. Forced contact of the polar hydroxyl group of Thr252 of the I helix induced by pressure and indirectly by glycerol is suggested to change the CO dipole moment, reflecting in the decreased CO stretching frequency.


Isolation of Yersinia enterocolitica and related species from the faeces of cows.
A total of 203 samples of faeces from 124 cows was examined for the presence of Yersinia enterocolitica and related species by a variety of isolation procedures. Cold enrichment at 5 degrees C for three weeks, followed by plating on cefsulodin-irgasannovobiocin agar yielded Yersinia species most frequently. Yersinia enterocolitica or related species were isolated from 50% of the cows.


Transcriptional Profiling Reveals the Importance of RcrR in the Regulation of Multiple Sugar Transportation and Biofilm Formation in Streptococcus mutans.
The ability of Streptococcus mutans to survive and cause dental caries is dependent on its ability to metabolize various carbohydrates, accompanied by extracellular polysaccharide synthesis and biofilm formation. Here, the role of an rel competence-related regulator (RcrR) in the regulation of multiple sugar transportation and biofilm formation is reported. The deletion of the rcrR gene in S. mutans caused delayed growth, decreased biofilm formation ability, and affected the expression level of its multiple sugar transportation-related genes. Transcriptional profiling revealed 17 differentially expressed genes in the rcrR mutant. Five were downregulated and clustered with the sugar phosphotransferase (PTS) systems (mannitol- and trehalose-specific PTS systems). The conserved sites bound by the rcrR promoter were then determined by electrophoretic mobility shift assays (EMSAs) and DNase I footprinting assays. Furthermore, a potential binding motif in the promoters of the two PTS operons was predicted using MEME Suite 5.1.1. RcrR could bind to the promoter regions of the two operons in vitro, and the sugar transporter-related genes of the two operons were upregulated in an rcrR-overexpressing strain. In addition, when RcrR-binding sites were deleted, the growth rates and final yield of S. mutans were significantly decreased in tryptone-vitamin (TV) medium supplemented with different sugars, but not in absolute TV medium. These results revealed that RcrR acted as a transcription activator to regulate the two PTS systems, accompanied by multiple sugar transportation and biofilm formation. Collectively, these results indicate that RcrR is a critical transcription factor in S. mutans that regulates bacterial growth, biofilm formation, and multiple sugar transportation. IMPORTANCE The human oral cavity is a constantly changing environment. Tooth decay is a commonly prevalent chronic disease mainly caused by the cariogenic bacterium Streptococcus mutans. S. mutans is an oral pathogen that metabolizes various carbohydrates into extracellular polysaccharides (EPSs), biofilm, and tooth-destroying lactic acid. The host diet strongly influences the availability of multiple carbohydrates. Here, we showed that the RcrR transcription regulator plays a significant role in the regulation of biofilm formation and multiple sugar transportation. Further systematic evaluation of how RcrR regulates the transportation of various sugars and biofilm formation was also conducted. Notably, this study decrypts the physiological functions of RcrR as a potential target for the better prevention of dental caries.


A Comprehensive Comparison of Tissue Processing Methods for High-Quality MALDI Imaging of Lipids in Reconstructed Human Epidermis.
Matrix-assisted laser desorption/ionization (MALDI) mass spectrometry imaging (MSI) has become an important tool for skin analysis, as it allows the simultaneous detection and localization of diverse molecular species within a sample. The use of in vivo and ex vivo human skin models is costly and presents ethical issues; therefore, reconstructed human epidermis (RHE) models, which mimic the upper part of native human skin, represent a suitable alternative to investigate adverse effects of chemicals applied to the skin. However, there are few publications investigating the feasibility of using MALDI MSI on RHE models. Therefore, the aim of this study was to investigate the effect of sample preparation techniques, i.e., substrate, sample thickness, washing, and matrix recrystallization, on the quality of MALDI MSI for lipids analysis of the SkinEthic RHE model. Images were generated using an atmospheric pressure MALDI source coupled to a high-resolution mass spectrometer with a pixel size of 5 μm. Masses detected in a defined region of interest were analyzed and annotated using the LipostarMSI platform. The results indicated that the combination of (1) coated metallic substrates, such as APTES-coated stainless-steel plates, (2) tissue sections of 6 μm thickness, and (3) aqueous washing before HCCA matrix spraying (without recrystallization), resulted in images with a significant signal intensity as well as numerous m/z values. This refined methodology using AP-MALDI coupled to a high-resolution mass spectrometer should improve the current sample preparation workflow to evaluate changes in skin composition after application of dermatocosmetics.


A novel negative-stranded RNA virus mediates sex ratio in its parasitoid host.
Parasitoid wasps are important natural enemies of arthropod hosts in natural and agricultural ecosystems and are often associated with viruses or virion-like particles. Here, we report a novel negative-stranded RNA virus from a parasitoid wasp (Pteromalus puparum). The complete viral genome is 12,230 nucleotides in length, containing five non-overlapping, linearly arranged open reading frames. Phylogenetically, the virus clusters with and is a novel member of the mononegaviral family Nyamiviridae, here designated as Pteromalus puparum negative-strand RNA virus 1 (PpNSRV-1). PpNSRV-1 is present in various tissues and life stages of the parasitoid wasp, and is transmitted vertically through infected females and males. Virus infections in field populations of P. puparum wasps ranged from 16.7 to 37.5%, without linearly correlating with temperature. PpNSRV-1 increased adult longevity and impaired several fitness parameters of the wasp, but had no influence on successful parasitism. Strikingly, PpNSRV-1 mediated the offspring sex ratio by decreasing female offspring numbers. RNA interference knockdown of virus open reading frame I eliminated these PpNSRV-1-induced effects. Thus, we infer that PpNSRV-1 has complex effects on its insect host including sex ratio distortion towards males, as well as possible mutualistic benefits through increasing wasp longevity.


A spatially resolved ion temperature diagnostic for the National Ignition Facility.
The concepts and initial development efforts for a spatially resolved ion temperature diagnostic are described. The diagnostic is intended for Inertial Confinement Fusion experiments at the National Ignition Facility and is an integration of neutron aperture imaging and ion temperature techniques. The neutron imaging technique is extended by recording tomographic projections of the radiation-to-light converter on a streak camera. The streak record is used to calculate images at multiple times during the arrival of the thermally broadened 14.1 MeV neutron flux. The resulting set of images is used to determine the spatially resolved ion temperature.


Examining Use and Dual Use of Tobacco Products and Marijuana among Minnesota Adults.
An increasing number of states are legalizing the medicinal and/or recreational use of marijuana. Adult perceptions of harm have decreased and marijuana use has increased. This is in contrast to declining cigarette smoking. In this article we examine independent use and dual use of marijuana and tobacco products. Data are from the 2018 Minnesota Adult Tobacco Survey (N = 6055). Estimates were calibrated on sex, race, location, and education from the American Community Survey. In 2018, 15.4% of adults smoked cigarettes in the past 30 days, 7.6% used marijuana and 6.0%, 3.0%, and 1.1% used e-cigarettes, cigars, and waterpipe, respectively. Use of marijuana and cigarettes was 3.3% and use of marijuana and e-cigarettes was 2.2%. Among past 30-day marijuana users, 89.7% smoked it as a joint, blunt, or in waterpipes, 22.1% vaped it in an e-cigarette or a vaping device. Across multinomial regression models, marijuana use and dual use with tobacco products was more likely among males, younger age groups, and African Americans. As policies to expand the sale and use of marijuana are considered, states should anticipate the need to monitor trends and to plan surveys of sufficient sample size with specific questions on marijuana use. Understanding the proportion of the population that uses both marijuana and tobacco has implications for prevention and treatment of both substances.


Heavy Tau Burden with Subtle Amyloid β Accumulation in the Cerebral Cortex and Cerebellum in a Case of Familial Alzheimer's Disease with APP Osaka Mutation.
We previously identified a novel mutation in amyloid precursor protein from a Japanese pedigree of familial Alzheimer's disease, FAD (Osaka). Our previous positron emission tomography (PET) study revealed that amyloid β (Aβ) accumulation was negligible in two sister cases of this pedigree, indicating a possibility that this mutation induces dementia without forming senile plaques. To further explore the relationship between Aβ, tau and neurodegeneration, we performed tau and Aβ PET imaging in the proband of FAD (Osaka) and in patients with sporadic Alzheimer's disease (SAD) and healthy controls (HCs). The FAD (Osaka) patient showed higher uptake of tau PET tracer in the frontal, lateral temporal, and parietal cortices, posterior cingulate gyrus and precuneus than the HCs (>2.5 SD) and in the lateral temporal and parietal cortices than the SAD patients (>2 SD). Most noticeably, heavy tau tracer accumulation in the cerebellum was found only in the FAD (Osaka) patient. Scatter plot analysis of the two tracers revealed that FAD (Osaka) exhibits a distinguishing pattern with a heavy tau burden and subtle Aβ accumulation in the cerebral cortex and cerebellum. These observations support our hypothesis that Aβ can induce tau accumulation and neuronal degeneration without forming senile plaques.


A hybrid approach for fatigue life prediction of in-service asphalt pavement.
Fatigue cracking is one of the main pavement failures, which makes accurate fatigue life prediction for the design and maintenance of asphalt pavements crucial. The majority of traditional prediction methods are based entirely on the laboratory fatigue test, without considering the field condition and maintenance data. This paper aims to propose a hybrid approach to fill this gap. The key idea is that the damage condition is back-calculated by an artificial intelligence-based finite-element (FE) model updating using field-monitoring information (data-driven component), which is used to update the parameters in the mechanistic composition-specific fatigue life prediction equation (model-driven component). The laboratory test of field cores gives the material non-destructive properties. The simulated pavement response subjected to truck loading shows good agreement with measured values, which indicates that the verified constitutive relationship could be used in the data-driven component. Furthermore, in view that the fatigue test is time- and money-consuming, this paper proposes a non-test estimation of the fatigue characteristic curve based on FE simulation of a repeated direct tension test. Three test pavement sections were employed as case studies. Results showed that the predicted fatigue life changes with the service time. At the early age, semi-rigid pavement has a larger fatigue life than flexible and inverted pavements. This article is part of the theme issue 'Artificial intelligence in failure analysis of transportation infrastructure and materials'.


Nonorgan-specific autoantibodies in HIV-infected patients in the HAART era.
Nonorgan-specific autoantibodies (AAbs) are used for diagnosing autoimmune diseases but can also be detected in other conditions. We carried out a cross-sectional study with the aim to screen HIV1-infected patients in the era of highly active antiretroviral therapy (HAART) for AAbs and to analyze the association of their presence with hypergammaglobulinemia and immunovirological status.Blood samples from HIV1-infected patients without major concomitant illnesses followed in 2 hospitals in Paris, France were tested for immunovirological status, serum immunoglobulin G (IgG) level, antinuclear antibodies (ANAs), anti-double-stranded DNA (anti-dsDNA), anti-extractable nuclear antigens (anti-ENAs), anticardiolipin (aCL), anti-β2glycoprotein1 (anti-β2GP1), and antineutrophil cytoplasmic antibodies (ANCAs). Clinically relevant AAbs were defined as ANAs with titers ≥1:160, anti-dsDNA or anti-ENA antibodies; aCL or anti-β2GP1 antibodies with a level ≥40 U/ml; and ANCAs reacting with proteinase 3 or myeloperoxidase.We included 92 patients (mean age 47 years, men 55%, sub-Saharan African background 55%, HAART 85%, mean CD4 lymphocyte count 611/mm, viral load < 40 copies/mL 74%). At least 1 AAb was detected in 45% of patients, mostly ANAs (33%) and ANCAs (13%); 12% had ≥1 clinically relevant AAb. Above-normal IgG levels were found in 71% of patients. We found an inverse association between the presence of ≥1 AAb and CD4 lymphocyte count (P = 0.03) and between above-normal IgG levels and duration of virological control (P = 0.02) and non-sub-Saharan African background (P = 0.001).In sum, in HIV1-infected patients without any major concomitant illness in the HAART era, the prevalence of AAbs remains high but AAb patterns leading to high suspicion of autoimmune diseases are rather uncommon. AAb presence is associated with reduced CD4 lymphocyte count but not hypergammaglobulinemia.


Orthodontic-surgical management of a case of severe mandibular deficiency due to condylar ankylosis.
Dentofacial deformities involve deviations from the normal facial proportions and dental relationships and can range from mild to being severe enough to be severely handicapping.The term handicapping malocclusions though not a term commonly used, involves a fortunately small section (2-4%) of patients who can suffer from esthetic,psychological and functional problems. Craniofacial Orthodontics is the area of orthodontics that treats patients with congenital and acquired deformities of the integument and it's underlying musculoskeletal system within the craniofacial area and associated structures.This case report of a young woman with severe mandibular deficiency and facial asymmetry due to condylar ankylosis highlights the importance of team work in rehabilitation of such severe craniofacial deformities.


Parent perceptions of mealtime behaviors in children fed enterally.
Parent reports of mealtime behavioral problems were examined within a sample of medically complicated young children with documented feeding difficulties. Mealtime behavior problems of children who were fed orally were compared with children who received their total nutrition enterally. A chart review of 140 pediatric patients presenting to an outpatient Interdisciplinary Feeding Team (IFT) clinic was conducted. The sample consisted of 81 males and 59 females ranging from 1.5 months to 12.6 years of age (mean age, 36.5 months). Information included for analyses was obtained from the IFT intake form, final IFT report, and the Behavioral Pediatrics Feeding Assessment Scale (BPFAS). Parents of children in both groups found child mealtime behaviors equally problematic according to mean intensity ratings and frequency of problems regarding both parent behavior and child behaviors. Regardless of feeding status (enteral versus oral feeding) of the child, parents of children with feeding and nutrition concerns benefit from intervention and support surrounding mealtimes. The specific mealtime strategies and needs of the parents, however, may differ depending on the feeding status of the child.


Evaluation of Nestin Expression in the Developing and Adult Mouse Inner Ear.
Adult stem cells are undifferentiated cells with the capacity to proliferate and form mature tissue-specific cell types. Nestin is an intermediate filament protein used to identify cells with stem cell characteristics. Its expression has been observed in a population of cells in developing and adult cochleae. In vitro studies using rodent cochlear tissue have documented the potential of nestin-expressing cells to proliferate and form hair and supporting cells. In this study, nestin coupled to green fluorescent protein (GFP) transgenic mice were used to provide a more complete characterization of the spatial and temporal expression of nestin in the inner ear, from organogenesis to adulthood. During development, nestin is expressed in the spiral ganglion cell region and in multiple cell types in the organ of Corti, including nascent hair and supporting cells. In adulthood, its expression is reduced but persists in the spiral ganglion, in a cell population medial to and below the inner hair cells, and in Deiters' cells in the cochlear apex. Moreover, nestin-expressing cells can proliferate in restricted regions of the inner ear during development shown by coexpression with Ki67 and MCM2 and by 5-ethynyl-2'-deoxyuridine incorporation. Results suggest that nestin may label progenitor cells during inner ear development and may not be a stem cell marker in the mature organ of Corti; however, nestin-positive cells in the spiral ganglion exhibit some stem cell characteristics. Future studies are necessary to determine if these cells possess any latent stem cell-like qualities that may be targeted as a regenerative approach to treat neuronal forms of hearing loss.


The antifibrinolytic activity of sulfamylon solution.
Sulfamylon (mafenide) solution, a potent experimental topical antimicrobial, is used in our burn unit to treat burn wounds both before and after skin grafting. The importance of fibrin to early graft adherence prompted this in vitro study of the effect of Sulfamylon upon fibrin clot. Assessing fibrinolysis by in vitro proteolysis of [125I] fibrin monomers, Sulfamylon, at relevant clinical concentrations, produced dose-related inhibition of streptokinase-mediated fibrinolysis. In addition, Sulfamylon had no intrinsic fibrinolytic activity. This antifibrinolytic property of Sulfamylon solution may, in vivo, protect against early graft loss when used on burn wounds and other potentially contaminated graft sites.


Personality profile in adult female fragile X carriers: assessed with the Minnesota Multiphasic Personality Profile (MMPI).
To assess if the higher incidence of psychiatric morbidity in fragile X carriers is related to a particular pathological personality profile, we obtained a Minnesota Multiphasic Personality Profile from 11 normally intelligent (female) fragile X carriers. The sample mean for the clinical and validity scales all fell within the normal range. Although no pathological profile was found, some unexpected results emerged: low scores for the scales "schizophrenia" and "social introversion" and a so-called faking-good profile on the validity scales. This combination suggests that the subjects might not be aware of some personality characteristics in these areas. Implications for further research are discussed.


'They Shall See His Face': Blindness in British India, 1850-1950.
This paper explores the social, medical, institutional and enumerative histories of blindness in British India from 1850 to 1950. It begins by tracing the contours and causes of blindness using census records, and then outlines how colonial physicians and observers ascribed both infectious aetiologies and social pathologies to blindness. Blindness was often interpreted as the inevitable consequence of South Asian ignorance, superstition and backwardness. This paper also explores the social worlds of the Blind, with a particular focus on the figure of the blind beggar. This paper further interrogates missionary discourse on 'Indian' blindness and outlines how blindness was a metaphor for the perceived civilisational inferiority and religious failings of South Asian peoples. This paper also describes the introduction of institutions for the Blind in addition to the introduction of Braille and Moon technologies.


Synthesis and evaluation of an anti-MLC1 × anti-CD90 bispecific antibody for targeting and retaining bone-marrow-derived multipotent stromal cells in infarcted myocardium.
A key issue regarding the use of stem cells in cardiovascular regenerative medicine is their retention in target tissues. Here, we have generated and assessed a bispecific antibody heterodimer designed to improve the retention of bone-marrow-derived multipotent stromal cells (BMMSC) in cardiac tissue damaged by myocardial infarction. The heterodimer comprises an anti-human CD90 monoclonal antibody (mAb) (clone 5E10) and an anti-myosin light chain 1 (MLC1) mAb (clone MLM508) covalently cross-linked by a bis-arylhydrazone. We modified the anti-CD90 antibody with a pegylated-4-formylbenzamide moiety to a molar substitution ratio (MSR) of 2.6 and the anti-MLC1 antibody with a 6-hydrazinonicotinamide moiety to a MSR of 0.9. The covalent modifications had no significant deleterious effect on mAb epitope binding. Furthermore, the binding of anti-CD90 antibody to BMMSCs did not prevent their differentiation into adipo-, chondro-, or osteogenic lineages. Modified antibodies were combined under mild conditions (room temperature, pH 6, 1 h) in the presence of a catalyst (aniline) to allow for rapid generation of the covalent bis-arylhydrazone, which was monitored at A(354). We evaluated epitope immunoreactivity for each mAb in the construct. Flow cytometry demonstrated binding of the bispecific construct to BMMSCs that was competed by free anti-CD90 mAb, verifying that modification and cross-linking were not detrimental to the anti-CD90 complementarity-determining region. Similarly, ELISA-based assays demonstrated bispecific antibody binding to plastic-immobilized recombinant MLC1. Excess anti-MLC1 mAb competed for bispecific antibody binding. Finally, the anti-CD90 × anti-MLC1 bispecific antibody construct induced BMMSC adhesion to plastic-immobilized MLC1 that was resistant to shear stress, as measured in parallel-plate flow chamber assays. We used mAbs that bind both human antigens and the respective pig homologues. Thus, the anti-CD90 × anti-MLC1 bispecific antibody may be used in large animal studies of acute myocardial infarction and may provide a starting point for clinical studies.


U.S. national response assets for radiological incidents.
The federal government has had the ability to respond to incidents of national significance for decades. Since 11 September 2001, there have been enhancements to existing federal assets and the creation of new federal assets. This presentation will provide an overview of the more significant federal assets. Pivotal to a response of national significance is the U.S. Department of Energy (DOE) Federal Radiological Monitoring and Assessment Center, which organizes and coordinates federal agency monitoring activities during an emergency. DOE manages the Federal Radiological Monitoring and Assessment Center during the emergency phase, and the Environmental Protection Agency (EPA) manages the response during the recovery phase once the emergency is terminated. EPA monitoring teams provide support during both the emergency and recovery phases of an emergency. Other DOE teams are available to respond to major nuclear power plant events, transportation accidents, or terrorism events involving the use of radiological materials, including the Radiological Assistance Program, the Aerial Measuring System, the National Atmospheric Release Advisory Center, and the Radiation Emergency Assistance Center/Training Site. For incidents involving a nuclear weapon, an improvised nuclear device, or a radiological dispersal device, DOE assets such as the Nuclear Emergency Support Team and the Accident Response Group could provide capabilities for weapon or device search, recovery, and removal. The Radiological Triage System harnesses the weapons scientists and engineers at the DOE national laboratories to provide gamma spectroscopy interpretation for agencies responding to an incident. In recent years, National Guard Weapons of Mass Destruction-Civil Support Teams have been created to support state and local response to terrorism events. The Civil Support Teams normally come under direct control of the state and can respond without requiring authorization from the U.S. Department of Defense (DoD). Changes brought about by the events of September 11 also extend to changing federal response policy and planning. Therefore, the Catastrophic Incident Response Annex to the National Response Plan is discussed. DoD also provides specifically designated radiological response capabilities that can be utilized within the guidelines of the National Response Plan. While optimally designed to support military missions, these resources also help provide for a well-equipped set of national assets to temporarily support and augment the local, state, and federal civil agencies that have primary authority and responsibility for domestic disaster assistance. The military's role in domestic emergencies is well defined in military regulations, as well as the national plan.


Absence of translational control of histone synthesis during the HeLa cell life cycle.
The cell-free synthesis of histone-like polypeptides has been achieved using a selected class of small polyribosomes as the only particulate fraction. This synthesis is prevented if the deoxyribonucleic acid (DNA) inhibitor, cytosine arabinoside, is added to the cells prior to disruption, and it is not detected when the cytoplasm used is derived from postmitotic (G(1)) cells. When the 100,000 g supernate from pure metaphase populations was compared with that from S phase cells, the cell-free synthesis of histone-like polypeptides in the presence of S phase polyribosomes remained unchanged. These data suggest that, except for the histone messenger RNA-ribosome complex, the cytoplasmic factors requisite for histone synthesis are present throughout the cycle, and that the shut-off of this synthesis is not under translational control.


A Pair of Pharyngeal Gustatory Receptor Neurons Regulates Caffeine-Dependent Ingestion in Drosophila Larvae.
The sense of taste is an essential chemosensory modality that enables animals to identify appropriate food sources and control feeding behavior. In particular, the recognition of bitter taste prevents animals from feeding on harmful substances. Feeding is a complex behavior comprised of multiple steps, and food quality is continuously assessed. We here examined the role of pharyngeal gustatory organs in ingestion behavior. As a first step, we constructed a gustatory receptor-to-neuron map of the larval pharyngeal sense organs, and examined corresponding gustatory receptor neuron (GRN) projections in the larval brain. Out of 22 candidate bitter compounds, we found 14 bitter compounds that elicit inhibition of ingestion in a dose-dependent manner. We provide evidence that certain pharyngeal GRNs are necessary and sufficient for the ingestion response of larvae to caffeine. Additionally, we show that a specific pair of pharyngeal GRNs, DP1, responds to caffeine by calcium imaging. In this study we show that a specific pair of GRNs in the pharyngeal sense organs coordinates caffeine sensing with regulation of behavioral responses such as ingestion. Our results indicate that in Drosophila larvae, the pharyngeal GRNs have a major role in sensing food palatability to regulate ingestion behavior. The pharyngeal sense organs are prime candidates to influence ingestion due to their position in the pharynx, and they may act as first level sensors of ingested food.


[Relation between the quality of cattle embryos after thawing and the pregnancy rate after their transfer].
One hundred and forty-two deep-frozen seven days old bovine embryos were, after thawing and stepwise dilution of cryoprotectant, morphologically evaluated under the stereomicroscope. According to the morphology the embryos were divided into four categories as follows: I--fully expanded blastocysts, II--slightly contracted embryos with a minute part of degenerated cells, III--contracted embryos with some degenerated cells, IV--degenerated embryos and those with heavy-damaged zona pellucida, or its complete loss. After surgical transfer of 37 embryos of class I, 16 (43.2%) recipients were pregnant. Transfer of 53 embryos of class II established 20 (37.7%) pregnancies. After transfer of 28 embryos of class III, 10 (35.7%) recipients were pregnant. Twenty four (17%) embryos included in class IV were excluded from transfer. These results indicate that simple morphological evaluation of embryo after freezing and thawing secures relatively objective selection in field conditions. At least this method enables to reveal morphological changes which are not compatible with further development.


miR-19 promotes development of renal fibrosis by targeting PTEN-mediated epithelial-mesenchymal transition.
In recent years, it has been found that miRNA may play an important role in the field of gene regulation; miRNAs can participate in the regulation of various physiologic processes such as cell differentiation, proliferation, apoptosis, metabolism, and insulin secretion by regulation of target genes. The purpose of this study is to observe the relationship between the expression of miR-19 and renal fibrosis, to analyze the regulatory effect of miR-19 on renal tubular EMT, and to reveal its role and working mechanism in renal fibrosis. We found that the expression of miR-19 was significantly increased in peripheral blood of patients with renal fibrosis, in renal tissue of unilateral ureteral occlusion (UUO) mice, and in NRK-52E cells treated with TGF-β1. Overexpression of miR-19 could decrease the expression of E-cadherin and increase the expression of α-SMA and fibronectin, while inhibition of miR-19 reverses TGF-β1-induced EMT. Further studies revealed that miR-19 could inhibit its expression by binding to the 3'-UTR of PTEN. MiR-19 inhibitor or Akt inhibitor blocks phospho-Akt by TGF-β1, and Akt inhibitors block miR-19 mimic-induced EMT. In UUO mice, overexpression of miR-19 promoted the development of renal fibrosis, while inhibition of miR-19 expression produced the opposite result. These results indicate that abnormal expression of miR-19 is associated with renal fibrosis. Moreover, miR-19 activates the Akt signaling pathway by targeting PTEN, and induces EMT in renal tubular epithelial cells, thereby promoting renal fibrosis.


Quantitative interaction proteomics reveals differences in the interactomes of amyloid precursor protein isoforms.
The generation of the amyloid-β (Aβ) peptides from the amyloid precursor protein (APP) through sequential proteolysis by β- and γ-secretases is a key pathological event in the initiation and propagation of Alzheimer's disease. Aβ and the transcriptionally active APP intracellular domain are generated preferentially from the APP695 isoform compared to the longer APP751 isoform. As the Aβ and amyloid precursor protein intracellular domain produced from cleavage of APP695 and APP751 are identical we hypothesised that the two isoforms have differences within their interactomes which mediate the differential processing of the two isoforms. To investigate this, we applied a proteomics-based approach to identify differences in the interactomes of the APP695 and APP751 isoforms. Using stable isotope labelling of amino acids in cell culture and quantitative proteomics, we compared the interactomes of APP695 and APP751 expressed in human SH-SY5Y cells. Through this approach, we identified enrichment of proteins involved in mitochondrial function, the nuclear pore and nuclear transport specifically in the APP695 interactome. Further interrogation of the APP interactome and subsequent experimental validation (co-immunoprecipitation and siRNA knockdown) revealed GAP43 as a specific modulator of APP751 proteolysis, altering Aβ generation. Our data indicate that interrogation of the APP interactome can be exploited to identify proteins which influence APP proteolysis and Aβ production in an isoform dependent-manner. Cover Image for this issue: doi: 10.1111/jnc.14504.


Integrated microfluidic chip for rapid DNA digestion and time-resolved capillary electrophoresis analysis.
An integrated microfluidic chip is proposed for rapid DNA digestion and time-resolved capillary electrophoresis (CE) analysis. The chip comprises two gel-filled chambers for DNA enrichment and purification, respectively, a T-form micromixer for DNA/restriction enzyme mixing, a serpentine channel for DNA digestion reaction, and a CE channel for on-line capillary electrophoresis analysis. The DNA and restriction enzyme are mixed electroomostically using a pinched-switching DC field. The experimental and numerical results show that a mixing performance of 97% is achieved within a distance of 1 mm from the T-junction when a driving voltage of 90 V/cm and a switching frequency of 4 Hz are applied. Successive mixing digestion and capillary electrophoresis operation clearly present the changes on digesting φx-174 DNA in different CE runs. The time-resolved electropherograms show that the proposed device enables a φx-174 DNA sample comprising 11 fragments to be concentrated and analyzed within 24 min. Overall, the results presented in this study show that the proposed microfluidic chip provides a rapid and effective tool for DNA digestion and CE analysis applications.


Alcohol use disorder (AUD) is associated with enhanced sensitivity to cellular lipopolysaccharide challenge.
Inflammation has been associated with alcohol use disorder (AUD). A novel method to characterize AUD-related immune signaling involves probing Toll-like receptor (TLR)-4 stimulated monocyte production of intracellular cytokines (ICCs) via lipopolysaccharide (LPS). We evaluated relationships between AUD and ICC production at rest and after LPS stimulation. We analyzed blood samples from 36 participants (AUD N = 14; Controls N = 22), collected across time, with ICC expression assessed at rest (i.e., unstimulated) and following stimulation with LPS (i.e., a total of 5 repeated unstimulated or stimulated measures/participant). Markers assessed included tumor necrosis factor-α (TNF-α), interleukin-6 (IL-6), TNF-α and IL-6 co-expression, and interferon (IFN). For each marker, we constructed linear mixed models with AUD, LPS, and timepoint as fixed effects (BMI as covariate), allowing for random slope and intercept. AUD × LPS was included as an interaction. For TLR4-stimulated monocyte production of TNF-α, there were effects of AUD (p < 0.01), LPS (p < 0.001), and AUD × LPS interaction (p < 0.05), indicating that individuals with AUD showed greater unstimulated- and stimulated monocyte expression of TNF-α. Similarly, for TLR4-stimulated monocyte co-expression of TNF-α and IL-6, there were effects of AUD (p < 0.01), LPS (p < 0.001), and AUD × LPS interaction (p < 0.05). No AUD or LPS effects were found for IL-6. Timepoint effects were observed on IL-6 and TNF-α/IL-6 co-expression (p < 0.001). Finally, for IFN there were also effects of AUD (p < 0.05), LPS (p < 0.001), and AUD × LPS (p < 0.001). Individuals with AUD showed greater resting or unstimulated levels of intracellular monocyte expression of TNF-α and IL-6/TNF-α co-expression than controls. AUD was associated with increases in TLR4-stimulated monocyte production of TNF-α and co-production of IL-6 and TNF-α. This is, to our knowledge, the first study to investigate relationships between AUD and monocyte production of proinflammatory cytokines, at rest and in response to TLR4 stimulation with LPS. The study extends previous findings on the roles of proinflammatory cytokines in AUD and serves as a critical proof of concept for the use of this method to probe neuroimmune mechanisms underlying AUD.


Machine Learning Models Improve the Diagnostic Yield of Peripheral Blood Flow Cytometry.
Peripheral blood flow cytometry (PBFC) is useful for evaluating circulating hematologic malignancies (HM) but has limited diagnostic value for screening. We used machine learning to evaluate whether clinical history and CBC/differential parameters could improve PBFC utilization. PBFC cases with concurrent/recent CBC/differential were split into training (n = 626) and test (n = 159) cohorts. We classified PBFC results with abnormal blast/lymphoid populations as positive and used two models to predict results. Positive PBFC results were seen in 58% and 21% of training cases with and without prior HM (P < .001). % neutrophils, absolute lymphocyte count, and % blasts/other cells differed significantly between positive and negative PBFC groups (areas under the curve [AUC] > 0.7). Among test cases, a decision tree model achieved 98% sensitivity and 65% specificity (AUC = 0.906). A logistic regression model achieved 100% sensitivity and 54% specificity (AUC = 0.919). We outline machine learning-based triaging strategies to decrease unnecessary utilization of PBFC by 35% to 40%.


To be or not to be solitary: Phytophthora infestans' dilemma for optimizing its reproductive fitness in multiple infections.
The success of parasitic life lies in an optimal exploitation of the host to satisfy key functions directly involved in reproductive fitness. Resource availability generally decreases over time with host mortality, but also during multiple infections, where different strains of parasite share host resources. During multiple infections, the number of parasite strains and their genetic relatedness are known to influence their reproductive rates. Using infections of the potato plant Solanum tuberosum with the parasite Phytophthora infestans, we set up an experimental design to separate dose effects (double- vs. single-site infections) from genetic relatedness (different vs. identical genotypes) on the reproductive fitness of competing parasite genotypes. We showed the existence of two basic response patterns--increase or decrease in reproductive fitness in multiple infections- depending on the parasite genotype. In all cases, the intensity of the response of any genotype depended on the genotype of the competing strain. This diversity of responses to multiple infections is probably maintained by the fluctuating frequencies of multiple infections in nature, arising from variations in disease pressure over the course of an epidemic and between successive epidemics. It allows a rapid response of parasitic populations to changing environments, which are particularly intense in agricultural systems.


Antimicrobial activity of foodborne Paenibacillus and Bacillus spp. against Clostridium botulinum.
The saprophytic Paenibacillus and Bacillus spp. found in cooked chilled foods may have an effect on the growth of Clostridium botulinum, a major microbiological hazard, especially for pasteurized vacuum-packaged products. Culture supernatants of 200 strains of Paenibacillus and Bacillus strains isolated from commercial cooked chilled foods containing vegetables were screened for activity against C. botulinum type A, proteolytic type B, and type E strains in a well diffusion assay. Nineteen strains were positive against C. botulinum. Among those, seven Paenibacillus polymyxa strains showed the highest antibotulinal activity and the largest antimicrobial spectrum against C. botulinum strains. The antibotulinal activity was evaluated throughout the growth of a representative strain of the positive P. polymyxa strains. The antimicrobial activity was detected in the culture supernatant from late-log/early stationary phase of the bacteria, which occurred after 7 to 10 days of incubation at 10 degrees C and after 2 to 3 days at 20 degrees C in nutrient broth and in vegetable purées under aerobic or anaerobic conditions. In co-cultures with the positive strain of P. polymyxa in nutrient broth and vegetable purées, a C. botulinum type E strain was inhibited whenever P. polymyxa reached stationary phase and produced its antimicrobial activity before C. botulinum began its exponential growth phase. The antimicrobial activity of P. polymyxa against C. botulinum was attributed to the production of antimicrobial peptides resistant to high temperature and acidity. Other gram-positive and -negative bacteria (Escherichia coli, Streptococcus mutans, Leuconostoc mesenteroides, and Bacillus subtilis) were also sensitive to these antimicrobial peptides.


Developing an active implementation model for a chronic disease management program.
Introduction and diffusion of new disease management programs in healthcare is usually slow, but active theory-driven implementation seems to outperform other implementation strategies. However, we have only scarce evidence on the feasibility and real effect of such strategies in complex primary care settings where municipalities, general practitioners and hospitals should work together. The Central Denmark Region recently implemented a disease management program for chronic obstructive pulmonary disease (COPD) which presented an opportunity to test an active implementation model against the usual implementation model. The aim of the present paper is to describe the development of an active implementation model using the Medical Research Council's model for complex interventions and the Chronic Care Model. We used the Medical Research Council's five-stage model for developing complex interventions to design an implementation model for a disease management program for COPD. First, literature on implementing change in general practice was scrutinised and empirical knowledge was assessed for suitability. In phase I, the intervention was developed; and in phases II and III, it was tested in a block- and cluster-randomised study. In phase IV, we evaluated the feasibility for others to use our active implementation model. The Chronic Care Model was identified as a model for designing efficient implementation elements. These elements were combined into a multifaceted intervention, and a timeline for the trial in a randomised study was decided upon in accordance with the five stages in the Medical Research Council's model; this was captured in a PaTPlot, which allowed us to focus on the structure and the timing of the intervention. The implementation strategies identified as efficient were use of the Breakthrough Series, academic detailing, provision of patient material and meetings between providers. The active implementation model was tested in a randomised trial (results reported elsewhere). The combination of the theoretical model for complex interventions and the Chronic Care Model and the chosen specific implementation strategies proved feasible for a practice-based active implementation model for a chronic-disease-management-program for COPD. Using the Medical Research Council's model added transparency to the design phase which further facilitated the process of implementing the program. http://www.clinicaltrials.gov/(NCT01228708).


Recombinant antibodies with MHC-restricted, peptide-specific, T-cell receptor-like specificity: new tools to study antigen presentation and TCR-peptide-MHC interactions.
The advent in recent years of the application of tetrameric arrays of class I peptide-MHC complexes now enables us to detect and study rare populations of antigen-specific CD8+ T cells. However, available methods cannot visualize or determine the number and distribution of these TCR ligands on individual cells or detect antigen-presenting cells (APCs) in tissues. Here we describe a new approach that enables study of human class I peptide-MHC ligand-presentation as well as TCR-peptide-MHC interactions. Such studies are facilitated by applying novel tools in the form of peptide-specific, HLA-A2-restricted human recombinant antibodies directed toward a large variety of tumor-associated as well as viral T-cell epitope peptides. Using a large human antibody phage display library, a large panel of recombinant antibodies that are specific for a particular peptide-MHC class I complex in a peptide-dependent, MHC-restricted manner was isolated. These antibodies were used to directly visualize the specific MHC-peptide complex on tumor cells, antigen-presenting cells or virus-infected cells by flow cytometry. They enabled direct quantitation of the number of MHC-peptide complexes as well as in situ detection of the complex on the surface of APCs after naturally occurring active intracellular processing of the cognate antigen. These studies will enable also the development of a new class of targeting molecules to deliver drugs or toxins to tumor or virus-infected cells. Thus, we demonstrate our ability to transform the unique fine specificity but low intrinsic affinity of TCRs into high-affinity soluble antibody molecules endowed with a TCR-like specificity toward human tumor or viral epitopes. These molecules may prove to be crucial useful tools for studying MHC class I antigen presentation in health and disease as well as for therapeutic purposes in cancer, infectious diseases and autoimmune disorders.