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Abstract Pervasive SARS-CoV-2 infections in humans have led to multiple transmission events to animals. While SARS-CoV-2 has a potential broad wildlife host range, most documented infections have been in captive animals and a single wildlife species, the white-tailed deer. The full extent of SARS-CoV-2 exposure among wildlife communities and the factors that influence wildlife transmission risk remain unknown. We sampled 23 species of wildlife for SARS-CoV-2 and examined the effects of urbanization and human use on seropositivity. Here, we document positive detections of SARS-CoV-2 RNA in six species, including the deer mouse, Virginia opossum, raccoon, groundhog, Eastern cottontail, and Eastern red bat between May 2022–September 2023 across Virginia and Washington, D.C., USA. In addition, we found that sites with high human activity had three times higher seroprevalence than low human-use areas. We obtained SARS-CoV-2 genomic sequences from nine individuals of six species which were assigned to seven Pango lineages of the Omicron variant. The close match to variants circulating in humans at the time suggests at least seven recent human-to-animal transmission events. Our data support that exposure to SARS-CoV-2 has been widespread in wildlife communities and suggests that areas with high human activity may serve as points of contact for cross-species transmission.

Psychiatric conditions, such as depression, anxiety, bipolar disorder, and schizophrenia, are increasingly recognized as significant risk factors for cardiovascular disease (CVD). This review systematically analyzes evidence from various databases to provide a comprehensive understanding of the impact of psychiatric illnesses on the incidence, management, and prognosis of CVD. Key findings suggest a bidirectional relationship between psychiatric disorders and CVD, indicating that mental health conditions can predispose individuals to CVD, while CVD can exacerbate or trigger psychiatric symptoms. The review explores the underlying mechanisms of these associations, including behavioral factors, stress responses, and medication side effects. It also examines the challenges in managing CVD patients with comorbid psychiatric conditions, emphasizing the importance for integrated care approaches. This review underscores the necessity of considering mental health as an integral component of cardiovascular care and calls for further research to develop tailored management strategies for these complex conditions, ultimately aiming to improve patient outcomes and quality of life. This comprehensive analysis provides valuable insights for future investigations and guides clinicians in optimizing care for patients with both psychiatric and cardiovascular conditions.

Abstract To prevent the outbreak of the Coronavirus disease (COVID-19), many countries around the world went into lockdown and imposed unprecedented containment measures. These restrictions progressively produced changes to social behavior and global mobility patterns, evidently disrupting social and economic activities. Here, using maritime traffic data collected via a global network of Automatic Identification System (AIS) receivers, we analyze the effects that the COVID-19 pandemic and containment measures had on the shipping industry, which accounts alone for more than 80% of the world trade. We rely on multiple data-driven maritime mobility indexes to quantitatively assess ship mobility in a given unit of time. The mobility analysis here presented has a worldwide extent and is based on the computation of: Cumulative Navigated Miles (CNM) of all ships reporting their position and navigational status via AIS, number of active and idle ships, and fleet average speed. To highlight significant changes in shipping routes and operational patterns, we also compute and compare global and local vessel density maps. We compare 2020 mobility levels to those of previous years assuming that an unchanged growth rate would have been achieved, if not for COVID-19. Following the outbreak, we find an unprecedented drop in maritime mobility, across all categories of commercial shipping. With few exceptions, a generally reduced activity is observable from March to June 2020, when the most severe restrictions were in force. We quantify a variation of mobility between −5.62 and −13.77% for container ships, between +2.28 and −3.32% for dry bulk, between −0.22 and −9.27% for wet bulk, and between −19.57 and −42.77% for passenger traffic. The presented study is unprecedented for the uniqueness and completeness of the employed AIS dataset, which comprises a trillion AIS messages broadcast worldwide by 50,000 ships, a figure that closely parallels the documented size of the world merchant fleet.

Abstract The present paper discusses about optimal shape solution for a non-prismatic planar beam. The proposed model is based on the standard Timoshenko kinematics hypothesis (i.e., planar cross-section remains planar in consequence of a deformation, but it is able to rotate with respect to the beam center-line). The analytical solution for this type of beam is thus used to obtain deformations and stresses of the beam, under different constraints, when load is assumed as the sum of a generic external variable vertical one and the self-weight. The solution is obtained by numerical integration of the beam equation and constraints are posed both on deflection and maximum stress under the hypothesis of an ideal material. The section variability is, thus, described assuming a rectangular cross section with constant base and variable height which can be described in general with a trigonometric series. Other types of empty functions could also be analyzed in order to find the best strategy to get the optimal solution. Optimization is thus performed by minimizing the beam volume considering the effects of non-prismatic geometry on the beam behavior. Finally, several analytical and numerical solutions are compared with results existing in literature, evaluating the solutions’ sensibility to some key parameters like beam span, material density, maximum allowable stress and load distribution. In conclusion, the study finds a critical threshold in terms of emptying function beyond which it is not possible to neglect the arch effect and the curvature of the actual axis for every different case study described in this work. In order to achieve this goal, the relevance of beam span, emptying function level and maximum allowable stress are investigated.

Abstract The COVID-19 pandemic is a public health crisis that has the potential to exacerbate worldwide malnutrition. This study examines whether patients with a history of malnutrition are predisposed to severe COVID-19. To do so, data on 103,099 COVID-19 inpatient encounters from 56 hospitals in the United States between March 2020 and June 2020 were retrieved from the Cerner COVID-19 Dataset. Patients with a history of malnutrition between 2015 and 2019 were identified, and a random intercept logistic regression models for pediatric and adult patients were built controlling for patient demographics, socioeconomic status, admission vital signs, and related comorbidities. Statistical interactions between malnutrition and patient age were significant in both the pediatric [log-odds and 95% confidence interval: 0.094 (0.012, 0.175)] and adult [− 0.014 (− 0.021, − 0.006] models. These interactions, together with the main effect terms of malnutrition and age, imply higher odds for severe COVID-19 for children between 6 and 17 years with history of malnutrition. Even higher odds of severe COVID-19 exist for adults (with history of malnutrition) between 18 and 79 years. These results indicate that the long-term effect of malnutrition predisposes patients to severe COVID-19 in an age-dependent way.

Abstract Diseases and injuries that compromise the ocular surface cause considerable patient distress and have long term consequences for their quality of life. Treatment modalities that can address the delicate balance of tissue regeneration, inflammation and maintenance of corneal transparency are therefore needed. We have recently formulated two novel eye drops from placental tissues: cord blood platelet lysate (CBED) and amniotic membrane extract eye drops (AMED), which can be used to treat severe ocular disorders. Here we characterise these two preparations by measuring: (a) growth factors (GF) and cytokines composition, (b) promotion of human corneal epithelial cell (HCEC) growth and (c) effects on immune cells in a lymphocyte culture assay. Finally, their bioavailability was assayed in an ex vivo porcine corneal model. We show that both preparations contain GF and cytokines that were able to promote the in vitro growth of HCEC and support repair in an in vitro scratch test. When assessed in a lymphocyte culture, both favoured immune suppression reducing the cellular expression of NKG2D and CD107a as well as the production of interferon gamma (IFN-γ) in natural killer, NKT and T cells. Regarding bioavailability, CBED active molecules were found mainly in the pre-corneal fraction with some penetration into the corneal fraction, in an ex vivo model. In summary, both placental-derived allogeneic preparations, CBED and AMED, display regenerative and immunomodulatory capabilities. These results will help define mechanisms of action and the best indications and doses of each product for use in a particular patient and support the development of off-the-shelf therapies for ocular surface pathologies in which wound healing defects and inflammatory events are contributing factors.

Abstract In this paper, we used time-domain functional near infrared spectroscopy (TD-fNIRS) to evaluate the haemodynamic response function (HRF) in the occipital cortex following visual stimulation in glaucomatous eyes as compared to healthy eyes. A total of 98 subjects were enrolled in the study and clinically classified as healthy subjects, glaucoma patients (primary open-angle glaucoma) and mixed subjects (i.e. with a different classification for the two eyes). After quality check data were used from HRF of 73 healthy and 62 glaucomatous eyes. The amplitudes of the oxygenated and deoxygenated haemoglobin concentrations, together with their latencies with respect to the stimulus onset, were estimated by fitting their time course with a canonical HRF. Statistical analysis showed that the amplitudes of both haemodynamic parameters show a significant association with the pathology and a significant discriminating ability, while no significant result was found for latencies. Overall, our findings together with the ease of use and noninvasiveness of TD-NIRS, make this technique a promising candidate as a supporting tool for a better evaluation of the glaucoma pathology.

Abstract During the course of an epidemic, one of the most challenging tasks for authorities is to decide what kind of restrictive measures to introduce and when these should be enforced. In order to take informed decisions in a fully rational manner, the onset of a critical regime, characterized by an exponential growth of the contagion, must be identified as quickly as possible. Providing rigorous quantitative tools to detect such an onset represents an important contribution from the scientific community to proactively support the political decision makers. In this paper, leveraging the quickest detection theory, we propose a mathematical model of the COVID-19 pandemic evolution and develop decision tools to rapidly detect the passage from a controlled regime to a critical one. A new sequential test—referred to as MAST (mean-agnostic sequential test)—is presented, and demonstrated on publicly available COVID-19 infection data from different countries. Then, the performance of MAST is investigated for the second pandemic wave, showing an effective trade-off between average decision delay $$\Delta$$ Δ and risk $$R$$ R , where $$R$$ R is inversely proportional to the time required to declare the need to take unnecessary restrictive measures. To quantify risk, in this paper we adopt as its proxy the average occurrence rate of false alarms, in that a false alarm risks unnecessary social and economic disruption. Ideally, the decision mechanism should react as quick as possible for a given level of risk. We find that all the countries share the same behaviour in terms of quickest detection, specifically the risk scales exponentially with the delay, $$R \sim \exp {(-\omega \Delta )}$$ R ∼ exp ( - ω Δ ) , where $$\omega$$ ω depends on the specific nation. For a reasonably small risk level, say, one possibility in ten thousand (i.e., unmotivated implementation of countermeasures every 27 years, on the average), the proposed algorithm detects the onset of the critical regime with delay between a few days to 3 weeks, much earlier than when the exponential growth becomes evident. Strictly from the quickest-detection perspective adopted in this paper, it turns out that countermeasures against the second epidemic wave have not always been taken in a timely manner. The developed tool can be used to support decisions at different geographic scales (regions, cities, local areas, etc.), levels of risk, instantiations of controlled/critical regime, and is general enough to be applied to different pandemic time-series. Additional analysis and applications of MAST are made available on a dedicated website.

Abstract This study was designed to develop and validate an early warning system for sepsis based on a predictive model of critical decompensation. Data from the electronic medical records for 537,837 visits to a pediatric Emergency Department (ED) from March 2013 to December 2019 were collected. A multiclass stochastic gradient boosting model was built to identify early warning signs associated with death, severe sepsis, non-severe sepsis, and bacteremia. Model features included triage vital signs, previous diagnoses, medications, and healthcare utilizations within 6 months of the index ED visit. There were 483 patients who had severe sepsis and/or died, 1102 had non-severe sepsis, 1103 had positive bacteremia tests, and the remaining had none of the events. The most important predictors were age, heart rate, length of stay of previous hospitalizations, temperature, systolic blood pressure, and prior sepsis. The one-versus-all area under the receiver operator characteristic curve (AUROC) were 0.979 (0.967, 0.991), 0.990 (0.985, 0.995), 0.976 (0.972, 0.981), and 0.968 (0.962, 0.974) for death, severe sepsis, non-severe sepsis, and bacteremia without sepsis respectively. The multi-class macro average AUROC and area under the precision recall curve were 0.977 and 0.316 respectively. The study findings were used to develop an automated early warning decision tool for sepsis. Implementation of this model in pediatric EDs will allow sepsis-related critical decompensation to be predicted accurately after a few seconds of triage.

Abstract Predicting the therapeutic response to ocular hypotensive drugs is crucial for the clinical treatment and management of glaucoma. Our aim was to identify a possible genetic contribution to the response to current pharmacological treatments of choice in a white Mediterranean population with primary open-angle glaucoma (POAG) or ocular hypertension (OH). We conducted a prospective, controlled, randomized, partial crossover study that included 151 patients of both genders, aged 18 years and older, diagnosed with and requiring pharmacological treatment for POAG or OH in one or both eyes. We sought to identify copy number variants (CNVs) associated with differences in pharmacological response, using a DNA pooling strategy of carefully phenotyped treatment responders and non-responders, treated for a minimum of 6 weeks with a beta-blocker (timolol maleate) and/or prostaglandin analog (latanoprost). Diurnal intraocular pressure reduction and comparative genome wide CNVs were analyzed. Our finding that copy number alleles of an intronic portion of the MLIP gene is a predictor of pharmacological response to beta blockers and prostaglandin analogs could be used as a biomarker to guide first-tier POAG and OH treatment. Our finding improves understanding of the genetic factors modulating pharmacological response in POAG and OH, and represents an important contribution to the establishment of a personalized approach to the treatment of glaucoma.

Castiglione D'Adda is one of the municipalities more precociously and severely affected by the Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) epidemic in Lombardy. With our study we aimed to understand the diffusion of the infection by mass serological screening. We searched for SARS-CoV-2 IgGs in the entire population on a voluntary basis using lateral flow immunochromatographic tests (RICT) on capillary blood (rapid tests). We then performed chemioluminescent serological assays (CLIA) and naso-pharyngeal swabs (NPS) in a randomized representative sample and in each subject with a positive rapid test. Factors associated with RICT IgG positivity were assessed by uni- and multivariate logistic regression models. Out of the 4143 participants, 918 (22·2%) showed RICT IgG positivity. In multivariable analysis, IgG positivity increases with age, with a significant non-linear effect (p = 0·0404). We found 22 positive NPSs out of the 1330 performed. Albeit relevant, the IgG prevalence is lower than expected and suggests that a large part of the population remains susceptible to the infection. The observed differences in prevalence might reflect a different infection susceptibility by age group. A limited persistence of active infections could be found after several weeks after the epidemic peak in the area.

PurposeTo report corneal transplant activity carried out in Catalonia (Spain) and the evolving indications for keratoplasty over an 8-year period.MethodsAnnual reports from the Catalan Transplant Organization, Spain, on corneal graft indications and techniques from 2011 to 2018 were reviewed.ResultsA total of 9457 keratoplasties were performed in Catalonia, from January 2011 to December 2018. The most frequent indications were bullous keratopathy (BK; 20.5%), Fuchs endothelial dystrophy (FED; 17.9%), re-graft (13.7%), and keratoconus (11.3%). Penetrating keratoplasty (PKP) accounted for 63.4% of all performed keratoplasties. Since the introduction of eye bank precut tissue for Descemet stripping automated endothelial keratoplasty (DSAEK) in 2013 and for Descemet membrane endothelial keratoplasty (DMEK) in 2017 the number of endothelial keratoplasties has drastically increased. An increasing trend of posterior lamellar techniques over the total of keratoplasties was found (pConclusionEndothelial diseases represented the top indication for keratoplasty over the 8-year period. PKP is still the most used technique in Catalonia, but endothelial keratoplasties and especially DMEK showed a significant increasing trend over the last years. This is congruent with the main rationale nowadays for keratoplasties: to customize and transplant as less tissue as possible. Therefore, the availability of precut tissue could have definitely enforced such approach.

Andros Island, The Bahamas, composed of porous carbonate rock, has about 175 inland blue holes and over 50 known submerged ocean caves along its eastern barrier reef. These ocean blue holes can have both vertical and horizontal zones that penetrate under the island. Tidal forces drive water flow in and out of these caves. King Kong Cavern has a vertical collapse zone and a deep penetration under Andros Island that emits sulfidic, anoxic water and masses of thin, mucoid filaments ranging to meters in length and off-white turbid water during ebb flow. Our objective was to determine the microbial composition of this mucoid material and the unconsolidated water column turbidity based on the concept that they represent unique lithoautotrophic microbial material swept from the cave into the surrounding ocean. Bacterial DNA extracted from these filaments and surrounding turbid water was characterized using PCR that targeted a portion of the 16S rRNA gene. The genus Arcobacter dominated both the filaments and the water column above the cave entrance. Arcobacter nitrofigilis and Arcobacter sp. UDC415 in the mucoid filaments accounted for as much as 80% of mapped DNA reads. In the water column Arcobacter comprised from 65% to over 85% of the reads in the depth region from about 18 m to 34 m. Bacterial species diversity was much higher in surface water and in water deeper than 36 m than in the intermediate zone. Community composition indicates that ebb flow from the cavern influences the entire water column at least to within 6 m of the surface and perhaps the near surface as well.

An amendment to this paper has been published and can be accessed via a link at the top of the paper.

Abstract Conformational changes in disease-associated or mutant proteins represent a key pathological aspect of Huntington’s disease (HD) and other protein misfolding diseases. Using immunoassays and biophysical approaches, we and others have recently reported that polyglutamine expansion in purified or recombinantly expressed huntingtin (HTT) proteins affects their conformational properties in a manner dependent on both polyglutamine repeat length and temperature but independent of HTT protein fragment length. These findings are consistent with the HD mutation affecting structural aspects of the amino-terminal region of the protein, and support the concept that modulating mutant HTT conformation might provide novel therapeutic and diagnostic opportunities. We now report that the same conformational TR-FRET based immunoassay detects polyglutamine- and temperature-dependent changes on the endogenously expressed HTT protein in peripheral tissues and post-mortem HD brain tissue, as well as in tissues from HD animal models. We also find that these temperature- and polyglutamine-dependent conformational changes are sensitive to bona-fide phosphorylation on S13 and S16 within the N17 domain of HTT. These findings provide key clinical and preclinical relevance to the conformational immunoassay, and provide supportive evidence for its application in the development of therapeutics aimed at correcting the conformation of polyglutamine-expanded proteins as well as the pharmacodynamics readouts to monitor their efficacy in preclinical models and in HD patients.

Langerhans cell histiocytosis (LCH) is characterized by the accumulation of Langerin (CD207)-expressing histiocytes. Mutational activation of mitogen-activated protein kinase pathway genes, in particular BRAF, drives most cases. To test whether activated BRAF is sufficient for the development of LCH, we engineered mice to express BRAF V600E under the control of the human Langerin promoter. These mice have shortened survivals, smaller lymphoid organs, absent Leydig cells, and fewer epidermal LCs than controls, but do not accumulate histiocytes. To test whether the absence of histiocyte proliferation could be due to oncogene-induced senescence, we engineered homozygous Pten loss in the same cells that expressed BRAF V600E. Like mice with intact Pten, these mice have shortened survivals, smaller thymi, and absent Leydig cells. However, loss of Pten also leads to the accumulation of CD207+ histiocytes in spleen, thymus, and some lymph nodes. While many CD207+ histiocytes in the thymus are CD8-, reminiscent of LCH cells, the CD207+ histiocytes in the spleen and lymph nodes are CD8+. These mice also accumulate large numbers of CD207- cells in the lamina propria (LP) of the small intestine. Both the lymphoid and LP phenotypes are likely due to human Langerin promoter-driven BRAF V600E expression in resident CD8+ dendritic cells in the former and LP dendritic cells in the latter and confirm that Pten loss is required to overcome inhibitory pathways induced by BRAF V600E expression. The complex phenotype of these mice is a consequence of the multiple murine cell types in which the human Langerin promoter is active.

An amendment to this paper has been published and can be accessed via a link at the top of the paper.

In budding yeast the G1/S transition requires the attainment of a critical cell size. Here the authors unravel its basic control mechanism by integrating simulations of a mathematical model of multisite phosphorylation of Whi5 by Cln3–Cdk1, with molecular analyses of a Whi5 phospho-mimetic mutant.

Oral squamous cell carcinoma (OSCC) is the most common secondary solid malignancy after hematopoietic stem-cell transplantation (HSCT). OSCC following HSCT is frequently preceded by chronic graft-versus-host disease (cGVHD). The aim of this study was to describe a cohort of post-HSCT patients and to evaluate the onset of oral epithelial dysplasia and/or OSCC over time. In this retrospective cohort study, we present a cohort of hematological patients that underwent HSCT. Demographic variables, clinical hematological data, data regarding acute graft-versus-host disease (aGVHD) and cGVHD, and oral clinical features were analyzed. We focused on clinicopathological features of a subgroup of 22 patients with oral cGVHD and OSCC after HSCT. Among 80 included patients, 46 patients (57.5%) developed aGVHD and 39 patients (48.7%) developed cGVHD. Oral mucosa was involved in 17 patients with aGVHD (36.9%) and in 22 patients (56.4%) with cGVHD. Out of a total of 22 oral biopsies, roughly 40% revealed mild to moderate dysplasia, and 32% were OSCC. In the absence of international agreement on the best timing of oral follow-up after HSCT, it is mandatory to establish a close multidisciplinary evaluation in order to prevent the onset of HSCT-related OSCC and to reduce post-transplant mortality due to secondary tumors.

[This corrects the article DOI: 10.1371/journal.pone.0180864.].

Globally, an estimated 2.5 billion people lack access to improved sanitation. Unimproved sanitation increases the risk of morbidity and mortality, especially in protracted refugee situations where sanitation is based on pit latrine use. Once the pit is full, waste remains in the pit, necessitating the construction of a new latrine, straining available land and funding resources. A viable, sustainable solution is needed. This study used qualitative and quantitative methods to design, implement, and pilot a novel sanitation system in Kakuma refugee camp, Kenya. An initial round of 12 pre-implementation focus group discussions (FGDs) were conducted with Dinka and Somali residents to understand sanitation practices, perceptions, and needs. FGDs and a supplementary pre-implementation survey informed the development of an innovative sanitation management system that incorporated the provision of urine and liquid-diverting toilets, which separate urine and fecal waste, and a service-based sanitation system that included weekly waste collection. The new system was implemented on a pilot scale for 6 weeks. During the implementation, bi-weekly surveys were administered in each study household to monitor user perceptions and challenges. At the end of the pilot, the sanitation system was assessed using a second round of four post-implementation FGDs. Those who piloted the new sanitation system reported high levels of user satisfaction. Reported benefits included odor reduction, insect/pest reduction, the sitting design, the appropriateness for special populations, and waste collection. However, urine and liquid diversion presented a challenge for users who perform anal washing and for women who had experienced female genital mutilation. Refugee populations are often culturally and ethnically diverse. Using residents' input to inform the development of sanitation solutions can increase user acceptability and provide opportunities to improve sanitation system designs based on specific needs.

Since 2013 in Emilia-Romagna, Italy, surveillance information generated in the public health and in the animal health sectors has been shared and used to guide public health interventions to mitigate the risk of West Nile virus (WNV) transmission via blood transfusion. The objective of the current study was to identify and estimate the costs and benefits associated with this One Health surveillance approach, and to compare it to an approach that does not integrate animal health information in blood donations safety policy (uni-sectoral scenario). Costs of human, animal, and entomological surveillance, sharing of information, and triggered interventions were estimated. Benefits were quantified as the averted costs of potential human cases of WNV neuroinvasive disease associated to infected blood transfusion. In the 2009-2015 period, the One Health approach was estimated to represent a cost saving of €160,921 compared to the uni-sectoral scenario. Blood donation screening was the main cost for both scenarios. The One Health approach further allowed savings of €1.21 million in terms of avoided tests on blood units. Benefits of the One Health approach due to short-term costs of hospitalization and compensation for transfusion-associated disease potentially avoided, were estimated to range from €0 to €2.98 million according to the probability of developing WNV neuroinvasive disease after receiving an infected blood transfusion.

To target taxanes to castration-resistant prostate cancer cells, glycol-chitosan nanobubbles loaded with paclitaxel and docetaxel were constructed. The loaded nanobubbles were then combined with Extracorporeal Shock Waves, acoustic waves widely used in urology and orthopedics, with no side effects. Nanobubbles, with an average diameter of 353.3 ± 15.5 nm, entered two different castration-resistant prostate cancer cells (PC3 and DU145) as demonstrated by flow cytometry and immunofluorescence. The shock waves applied increased the amount of intracellular nanobubbles. Loading nanobubbles with paclitaxel and docetaxel and combining them with shock waves generated the highest cytotoxic effects, resulting in a paclitaxel GI50 reduction of about 55% and in a docetaxel GI50 reduction of about 45% respectively. Combined treatment also affected cell migration. Paclitaxel-loaded nanobubbles and shock waves reduced cell migration by more than 85% with respect to paclitaxel alone; whereas docetaxel-loaded nanobubbles and shock waves reduced cell migration by more than 82% with respect to docetaxel alone. The present data suggest that nanobubbles can act as a stable taxane reservoir in castration-resistant prostate cancer cells and shock waves can further increase drug release from nanobubbles leading to higher cytotoxic and anti-migration effect.

Oligosaccharides aberrantly expressed on tumor cells influence processes such as cell adhesion and modulation of the cell’s microenvironment resulting in an increased malignancy. Schmidt’s imidate strategy offers an effective method to synthesize libraries of various oligosaccharide mimetics. With the aim to perturb interactions of tumor cells with extracellular matrix proteins and host cells, molecules with 3,4-bis(hydroxymethyl)furan as core structure were synthesized and screened in biological assays for their abilities to interfere in cell adhesion and other steps of the metastatic cascade, such as tumor-induced angiogenesis.The most active compound, (4-{[(β-D-galactopyranosyl)oxy]methyl}furan-3-yl)methyl hydrogen sulfate (GSF), inhibited the activation of matrix-metalloproteinase-2 (MMP-2) as well as migration of the human melanoma cells of the lines WM-115 and WM-266-4 in a two-dimensional migration assay. GSF inhibited completely the adhesion of WM-115 cells to the extracellular matrix (ECM) proteins, fibrinogen and fibronectin.In an in vitro angiogenesis assay with human endothelial cells, GSF very effectively inhibited endothelial tubule formation and sprouting of blood vessels, as well as the adhesion of endothelial cells to ECM proteins. GSF was not cytotoxic at biologically active concentrations; neither were 3,4-bis{[(β-D-galactopyranosyl)oxy]methyl}furan (BGF) nor methyl β-D-galactopyranoside nor 3,4-bis(hydroxymethyl)furan, which were used as controls, eliciting comparable biological activity. In silico modeling experiments, in which binding of GSF to the extracellular domain of the integrin αvβ3 was determined, revealed specific docking of GSF to the same binding site as the natural peptidic ligands of this integrin. The sulfate in the molecule coordinated with one manganese ion in the binding site.These studies show that this chemically easily accessible molecule GSF, synthesized in three steps from 3,4-bis(hydroxymethyl)furan and benzoylated galactose imidate, is nontoxic and antagonizes cell physiological processes in vitro that are important for the dissemination and growth of tumor cells in vivo.

Los hongos zoospóricos verdaderos, los straminipilas heterotróficos y los plasmodioforidios, son grupos de organismos filogenéticamente no relacionados pertenecientes a los reinos Fungi, Straminipila y Protozoa. Existe escasa información disponible acerca de estos organismos en ecosistemas de gran biodiversidad, particularmente en áreas tropicales y neotropicales. En Sudamérica, las investigaciones sobre su diversidad han sido principalmente realizadas en Argentina y en Brasil utilizando técnicas de cebado múltiple, resultando en el descubrimiento de nuevos taxones y nuevas citas. Hasta el momento, en ambos países se han registrado 434 especies pertenecientes a estos grupos, lo que demuestra que se necesitan más investigaciones para ampliar su conocimiento en Sudamérica. Existen pocos especialistas disponibles para estudiar áreas tan extensas, las cuales están siendo degradadas por la deforestación, la contaminación, y otras actividades antrópicas que afectan el hábitat de estos organismos, antes de que su diversidad pueda ser estudiada por micólogos y protistólogos. De esta forma, los estudios tendientes a reunir información sobre la diversidad de los hongos zoospóricos verdaderos, los Straminipilas heterotróficos y los Plasmodioforidios deben ser considerados altamente prioritarios en Sudamérica.

Cuatro especies de Saprolegniales fueron encontradas en ambientes acuáticos de los partidos de La Plata y Ensenada (charcas semipermanentes, arroyo Las Cañas y zanjón Los Helechos), provincia de Buenos Aires, Argentina. Scoliolegnia asterophora, Aphanomyces laevis, A. stellatus y A. parasiticus, son citadas por primera vez para la Argentina. Tres de ellas fueron encontradas como saprótrofas en muestras de materia orgánica flotante (restos vegetales) y agua, y la cuarta, como parásita en hifas de una especie no identificada del género Achlya.

El género Nowakowskiella comprende organismos acuáticos y terrestres, que se encuentran como saprótrofos principalmente sobre restos vegetales en descomposición. El género es citado por primera vez para Argentina y en esta contribución, se describen cuatro especies, analizándose su frecuencia y abundancia en los ambientes estudiados, brindándose una clave basada en caracteres morfológicos para diferenciarlas.The genus Nowakowskiella comprises aquatic and terrestrial organisms, which occur as saprotrophs on decomposed vegetable debris mainly. This genus is recorded for the first time in Argentina and in this contribution four species are described, analyzing their frequency and abundance in the studied environments and providing an identification key based on morphological characters to differentiate them.

The Ficoncella site in northern Latium (Italy) represents a unique opportunity to investigate the modalities of a short occupation in an alluvial setting during the Lower Palaeolithic. The small excavation area yielded a lithic assemblage, a carcass of Palaeoloxodon antiquus, and some other faunal remains. The main objectives of the study are to better characterize the depositional context where the Palaeoloxodon and the lithic assemblage occur, and to evaluate with greater precision the occupation dynamics. A 25 m-long well was drilled just above the top of the terrace of the Ficoncella site and faunal and lithic remains were analyzed with current and innovative techniques. The archaeological site contains floodplain deposits as it is located next to a small incised valley that feeds into a larger valley of the Mignone River. A tephra layer capping the site is 40Ar/39Ar dated to 441± 8 ka. Collectively, the geochronologic, tephrochronologic and geologic data, suggest the site was occupied during MIS 13. The new results should prompt further research at Ficoncella in order to improve our understanding of the dynamics of human settlement in Europe during the Early to Middle Pleistocene.

Se colectaron muestras de suelo de dos lotes de frutilla en el Partido de Luján (Provincia de Buenos Aires), las que fueron incubadas y cebadas en laboratorio con sustratos celulósicos, queratínicos y quitínicos, con el objetivo de aislar a R. rosea (de Bary & Woronin) Fisch. Todos los tipos de materiales empleados fueron positivos para esta especie. Estandarizando los sustratos adicionados, se analizó su frecuencia y abundancia y se contabilizó el número de talos que crecieron en ellos, pudiéndose obtener la densidad de talos y el número de talos por gramo de suelo (NTG). Se colectaron asimismo muestras de agua y sedimento de ambientes acuáticos, con el objetivo de registrar caracteres morfológicos provenientes de distintas cepas y realizar una descripción completa de R. rosea. Esta especie es citada por primera vez para la Argentina y en esta contribución se muestran por primera vez resultados cuantitativos de hongos zoospóricos del suelo pertenecientes al Phylum Chytridiomycota. El género Rhizophlyctis A. Fischer es también una nueva cita para el país.Soil samples from two strawberry fields in Partido de Luján (Provincia de Buenos Aires) were collected, flooded and baited with cellulose, queratinic and chitinic substrates in order to obtain R. rosea (de Bary & Woronin) A. Fisch. All kinds of materials employed, proved positive for this species. By standardizing the substrata addition, we analyzed frequency and abundance and by counting the thalli that grew on it, derivations of thallus density and thallus recovery per gram of soil (TRG) were possible. Water and sediment samples from aquatic environments were also taken, with the aim of reporting morphological characters from different strains, and make a complete description of R. rosea. This species is recorded for the first time in Argentina and this contribution shows first quantitative results of soil fungi belonging to the Phylum Chytridiomycota , for our country. The genus Rhizophlyctis A. Fischer is also a new record for the country.

Rhizidiomyces apophysatus and R. hirsutus fueron encontrados en un ambiente acuático de la Provincia de Buenos Aires, Argentina. Ambas especies y el género son citados por primera vez para la Argentina, y constituyen los hallazgos más australes de estas especies para el hemisferio occidental. Fueron encontradas como parásitas sobre los oogonios de una especie no identificada del género Achlya.

Previous studies identified comorbidities as predictors of older driver performance and driving pattern, while the direct impact of comorbidities on road crash risk in elderly drivers is still unknown. The present study is a cross-sectional aimed at investigating the association between levels of comorbidity and crash involvement in adult and elderly drivers. 327 drivers were stratified according to age range in two groups: elderly drivers (age ≥70 years old, referred as older) and adult drivers (age

A Food and Drug Administration (FDA) safety communication in August 2011 warned that citalopram was associated with a dose dependent risk of QT prolongation and recommended dose restriction in patients over the age of 60 but did not provide data for this age group.CitAD was a randomized, double-masked, placebo-controlled, multicenter clinical trial for agitation in Alzheimer's disease (AD). Participants were assigned to citalopram (target dose of 30 mg/day) or placebo in a 1 ∶ 1 ratio. 186 people, 181 of whom were over the age of 60, having probable AD with clinically significant agitation were recruited from September 2009 to January 2013. After the FDA safety communication about citalopram, ECG was added to the required study procedures before enrollment and repeated at week 3 to monitor change in QTc interval. Forty-eight participants were enrolled after enhanced monitoring began.Citalopram treatment was associated with a larger increase in QTc interval than placebo (difference in week 3 QTc adjusting for baseline QTc: 18.1 ms [95% CI: 6.1, 30.1]; p = 0.004). More participants in the citalopram group had an increase ≥ 30 ms from baseline to week 3 (7 in citalopram versus 1 in placebo; Fisher's exact p = 0.046), but only slightly more in the citalopram group met a gender-specific threshold for prolonged QTc (450 ms for males; 470 ms for females) at any point during follow-up (3 in citalopram versus 1 in placebo, Fisher's exact p = 0.611). One of the citalopram participants who developed prolonged QTc also displayed ventricular bigeminy. No participants in either group had a cardiovascular-related death.Citalopram at 30 mg/day was associated with improvement in agitation in patients with AD but was also associated with QT prolongation.ClinicalTrials.gov NCT00898807.

OBJECTIVE: The study examined the personal resources, Self-efficacy and Coping Strategies, in a sample of pre-adolescents who experienced an emotionally and socially critical event, such as the earthquake of the 6(th) of April 2009, related to age and gender. METHODS: 198 pre-adolescents, 84 girls and 114 boys (Age Mean 12 years), attending Secondary School in L'Aquila meso-seismic area. The emotional, behavioural and social capacities have been assessed with specific questionnaires administered collectively ten months after the earthquake. RESULTS: Multidimensional analyses produced differentiated profiles according to gender and age: self-efficacy-perception and coping strategy profiles, based on quartiles calculations, revealed the difficulties of the subjects in estimating their ability to cope with the world of relations and emotions after the critical event. CONCLUSIONS: The intervention could be specific to the cognitive, emotional and relational state of children and adolescents and differentiated before (prevention), during (intervention) and after the event (intervention and prevention).

Prolactin is a versatile hormone with over 300 known functions and predominantly expressed in the pituitary. However, its expression has additionally been found in a number of extrapituitary organs. Recently, we described the expression of prolactin in the inner ear of mice, where it was correlated to age. Previous research has shown prolactin to be linked to abnormal bone metabolism and hearing loss due to changes in morphology of the bony otic capsule. Here we further investigated the relationship between prolactin, hearing loss and cochlea bone metabolism. BALB/c mice were tested for hearing using ABR at 6 and 12 months of age. Bone mineral density of the cochlea was evaluated using microCT scanning. Prolactin expression was calculated using quantitative real time PCR. Expression of the key regulators of bone metabolism, osteoprotegerin and receptor activator of nuclear factor-kappaB ligand were also determined. We found that prolactin expression was exclusive to the female mice. This also correlated to a greater threshold shift in hearing for the females between 6 and 12 months of age. Analyses of the cochlea also show that the bone mineral density was lower in females compared to males. However, no gender differences in expression of osteoprotegerin or receptor activator of nuclear factor-kappaB ligand could be found. Further analysis of cochlea histological sections revealed larger ostocyte lacunae in the females. These results provide a possible mechanism for an age related hearing loss sub-type that is associated with gender and provides clues as to how this gender bias in hearing loss develops. In addition, it has the potential to lead to treatment for this specific type of hearing loss.

The global trade in wildlife has historically contributed to the emergence and spread of infectious diseases. The United States is the world's largest importer of wildlife and wildlife products, yet minimal pathogen surveillance has precluded assessment of the health risks posed by this practice. This report details the findings of a pilot project to establish surveillance methodology for zoonotic agents in confiscated wildlife products. Initial findings from samples collected at several international airports identified parts originating from nonhuman primate (NHP) and rodent species, including baboon, chimpanzee, mangabey, guenon, green monkey, cane rat and rat. Pathogen screening identified retroviruses (simian foamy virus) and/or herpesviruses (cytomegalovirus and lymphocryptovirus) in the NHP samples. These results are the first demonstration that illegal bushmeat importation into the United States could act as a conduit for pathogen spread, and suggest that implementation of disease surveillance of the wildlife trade will help facilitate prevention of disease emergence.

The global spread of infectious diseases is facilitated by the ability of infected humans to travel thousands of miles in short time spans, rapidly transporting pathogens to distant locations. Mathematical models of the actual and potential spread of specific pathogens can assist public health planning in the case of such an event. Models should generally be parsimonious, but must consider all potentially important components of the system to the greatest extent possible. We demonstrate and discuss important assumptions relative to the parameterization and structural treatment of airline travel in mathematical models. Among other findings, we show that the most common structural treatment of travelers leads to underestimation of the speed of spread and that connecting travel is critical to a realistic spread pattern. Models involving travelers can be improved significantly by relatively simple structural changes but also may require further attention to details of parameterization.

BACKGROUND: T. J. Crow suggested that the genetic variance associated with the evolution in Homo sapiens of hemispheric dominance for language carries with it the hazard of the symptoms of schizophrenia. Individuals lacking the typical left hemisphere advantage for language, in particular for phonological components, would be at increased risk of the typical symptoms such as auditory hallucinations and delusions. METHODOLOGY/PRINCIPAL FINDINGS: Twelve schizophrenic patients treated with low levels of neuroleptics and twelve matched healthy controls participated in an event-related potential experiment. Subjects matched word-pairs in three tasks: rhyming/phonological, semantic judgment and word recognition. Slow evoked potentials were recorded from 26 scalp electrodes, and a laterality index was computed for anterior and posterior regions during the inter stimulus interval. During phonological processing individuals with schizophrenia failed to achieve the left hemispheric dominance consistently observed in healthy controls. The effect involved anterior (fronto-temporal) brain regions and was specific for the Phonological task; group differences were small or absent when subjects processed the same stimulus material in a Semantic task or during Word Recognition, i.e. during tasks that typically activate more widespread areas in both hemispheres. CONCLUSIONS/SIGNIFICANCE: We show for the first time how the deficit of lateralization in the schizophrenic brain is specific for the phonological component of language. This loss of hemispheric dominance would explain typical symptoms, e.g. when an individual's own thoughts are perceived as an external intruding voice. The change can be interpreted as a consequence of "hemispheric indecision", a failure to segregate phonological engrams in one hemisphere.