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ABSTRACT During voluntary or involuntary spills, the total dissolved gas (TDG) may increase with potential of causing gas bubble disease (GBD) in affected fish. Bubbles entrained during spill events in Colider are transported by plunging jets to deep, high pressure, regions in the tailrace where dissolution is enhanced increasing TDG concentrations. The most common alternative to minimize TDG supersaturation downstream of hydropower dams is to install deflectors on the spillway face. In order to reduce TDG levels downstream of the Colider's spillway, Copel retrofitted the four spillway bays with deflectors, finalizing the construction in November 2021. The design of the deflectors were assisted with two studies. The first study comprised the development of a physical model in 1:60 scale, and other study was a numerical model based on the open-source toolbox OpenFoam.

River regularization plays an important role in socio economic development. However, it also modifies the natural flow system of the river and its biotic and abiotic characteristics, causing significant impacts on rivers. To evaluate the impacts on the macroinvertebrate community caused by dam construction on the Poxim-Açú River, metrics of composition and community structure of the macroinvertebrates were analyzed, as well as ecological and biological traits of the region. Macroinvertebrates were collected at three sites located downstream the dam, before (2013) and after (2015) dam construction. The water quality was classified as “good” to “excellent” according to the biotics indices. The alterations of the flow regime of the river after the dam construction influenced the macroinvertebrate communities, modifying their diversity, equitability, richness, and the number of individuals.

Heavy machinery is critical to agriculture, construction, mining, and other sectors of a country’s economy. However, such vehicles consume a high amount of fuel, increasing production costs and the emission of polluting gases into the atmosphere. One of the alternatives to reduce fuel consumption is the electrification of these vehicles, but the definition of an optimal topology for the electrification of heavy vehicles is still under study, and works with electric drive systems projects for these machines are scarce. This paper presents the main characteristics of the design of an electric drive system for the electrification of a backhoe, including the control and simulation of the motor drive system, and presents a prototype bench and experimental tests carried out in the context of the hybridization topology presented. Based in these results, improvements are proposed and discussed with aid of computational simulation.

Malware applications typically use a command and control (C&C) server to manage bots to perform malicious activities. Domain Generation Algorithms (DGAs) are popular methods for generating pseudo-random domain names that can be used to establish a communication between an infected bot and the C&C server. In recent years, machine learning based systems have been widely used to detect DGAs. There are several well known state-of-the-art classifiers in the literature that can detect DGA domain names in real-time applications with high predictive performance. However, these DGA classifiers are highly vulnerable to adversarial attacks in which adversaries purposely craft domain names to evade DGA detection classifiers. In our work, we focus on hardening DGA classifiers against adversarial attacks. To this end, we train and evaluate state-of-the-art deep learning and random forest (RF) classifiers for DGA detection using side information that is harder for adversaries to manipulate than the domain name itself. Additionally, the side information features are selected such that they are easily obtainable in practice to perform inline DGA detection. The performance and robustness of these models is assessed by exposing them to one day of real-traffic data as well as domains generated by adversarial attack algorithms. We found that the DGA classifiers that rely on both the domain name and side information have high performance and are more robust against adversaries.

Domain generation algorithms (DGAs) are commonly leveraged by malware to create lists of domain names, which can be used for command and control (C&C) purposes. Approaches based on machine learning have recently been developed to automatically detect generated domain names in real-time. In this paper, we present a novel DGA called CharBot, which is capable of producing large numbers of unregistered domain names that are not detected by state-of-the-art classifiers for real-time detection of the DGAs, including the recently published methods FANCI (a random forest based on human-engineered features) and LSTM.MI (a deep learning approach). The CharBot is very simple, effective, and requires no knowledge of the targeted DGA classifiers. We show that retraining the classifiers on CharBot samples is not a viable defense strategy. We believe these findings show that DGA classifiers are inherently vulnerable to adversarial attacks if they rely only on the domain name string to make a decision. Designing a robust DGA classifier may, therefore, necessitate the use of additional information besides the domain name alone. To the best of our knowledge, the CharBot is the simplest and most efficient black-box adversarial attack against DGA classifiers proposed to date.

ABSTRACT In this paper we synthesize the special sessions of the XXIII Brazilian Water Resources Symposium 2019 in order to understand the major advances and challenges in the water sciences in Brazil. We analyzed more than 250 papers and presentations of 16 special sessions covering topics of Climate Variability and Change, Disasters, Modeling, Large Scale Hydrology, Remote Sensing, Education, and Water Resources Management. This exercise highlighted the unique diversity of natural and human water features in Brazil, that offers a great opportunity for understanding coupled hydrological and societal systems. Most contributions were related to methods and the quantification of water phenomena, therefore, there is a clear necessity for fostering more research on phenomena comprehension. There is a vast network of co-authorship among institutions but mostly from academia and with some degree of regional fragmentation. The ABRhidro community now has the challenge to enhance its collaboration network, the culture of synthesis analysis, and to build a common agenda for water resources research. It is also time for us to be aligned with the international water science community and to use our experiences to actively contribute to the tackling of global water issues.

O presente estudo teve por objetvo gerar um produto automatizado para a emissão diária de avisos de extremos de temperatura mínima e de temperatura máxima do ar em Santa Catarina para os dois dias próximos.

This paper presents a mathematical model to simulate the trajectory of a meteor as seen by a single observer located anywhere on Earth. Our strategy is to define a new coordinate system, called Radiant Coordinate System, which is centered on the observer and has its z-axis aligned with the radiant. This new coordinate system allows us to describe the meteors’ path by applying a reduced number of equations in a simple solution. We also present a computational implementation of this model, which is developed as a new plug-in of Stellarium, a free and open-source planetarium software. Moreover, we show that our model can be used to simulate both meteor showers and sporadic meteors. In particular, meteor showers are simulated using data provided by real catalogs.

ABSTRACT Contamination of water body by diffuse and point sources in springs has caused concerns mainly due to restrictions on its quality. The problem becomes more serious when contamination affects water for human consumption, as occurs in the river São Francisco, which supplies several municipalities of Sergipe. In this sense, the objective of the study was to evaluate water quality in eleven tributaries of the São Francisco river in its low course in the period from 2013 to 2014, in order to subsidize decision making by public management bodies operating in the region. For this purpose, it was used the Water Quality Index (WQI) and the Trophic State Index (TSI), as well the hierarchical grouping techniques associated to the samples to compare the different causes of contamination of each source. The lowest WQI values were observed in the rivers Betume and Jacaré and they were associated with high concentrations of coliforms related to the disposal of domestic effluents from the riverside cities. It was observed a tendency to eutrophication in the Jacaré stream, Santo Antônio, Pilões, Papagaio and Capivara rivers demonstrated by the high TSI in the rainy season. The results of the cluster analysis were close to their Euclidean distance, and showed that there were similarity relationships between the different water sources related to their parameters of water quality. In this piece of work, we also used the Factor Analysis resulted in the selection of five factors of water quality indicators which are mainly related to mineral content, organic matter, surface runoff and the level of pollution. Thus, it is concluded that the water quality of the São Francisco river tributaries is at a strong tendency towards contamination and that its tributaries need a constant monitoring for the environmental management decisions to be the most adequate for the sustainable survival of the riverside communities.

PURPOSE: To report initial findings with the GORE Flow Reversal System®, with a focus on major/minor adverse events in the 30 first postoperative days. METHODS: The first 24 patients submitted to carotid angioplasty using the GORE system, from June 2010 to May 2012, were retrospectively assessed with regard to indications, anatomic details, technical difficulties, and early clinical outcomes, including major (stroke, death, acute myocardial infarction) and minor (hematoma) adverse events. RESULTS: Systemic hypertension was present in 100% of the patients, diabetes mellitus in 58.3%, and coronary disease in 37.5%. Type II aortic arch was encountered in 62.5% of the patients and atherosclerotic lesion predominantly at the carotid bifurcation affecting the internal and common carotid arteries in 79.2%. Angiographic data revealed contralateral carotid arteries with OBJETIVO: Relatar os achados iniciais da utilização do GORE Flow Reversal System® (Sistema de Fluxo de Reversão), com foco em eventos adversos maiores/menores nos primeiros 30 dias do pós-operatório. MÉTODOS: Os primeiros 24 pacientes submetidos a angioplastia carotídea com a utilização do sistema GORE, de junho de 2010 a maio de 2012, foram avaliados retrospectivamente com relação a indicações, detalhes anatômicos, dificuldades técnicas e desfechos clínicos imediatos, incluindo eventos adversos maiores (acidente vascular cerebral, morte, infarto agudo do miocárdio) e menores (hematoma). RESULTADOS: Hipertensão sistêmica estava presente em 100% dos pacientes, diabete melito em 58,3% e doença coronariana em 37,5%. Arco aórtico tipo II foi encontrado em 62,5% dos pacientes e lesão de aterosclerose predominantemente na bifurcação carotídea que afeta as artérias carótidas internas e comuns em 79,2%. Dados angiográficos revelaram artérias carótidas contralaterais com estenose

A crescente atividade agrícola em áreas de mananciais tem causado preocupações quanto à contaminação por herbicidas em áreas agrícolas. O problema se torna mais importante quando a contaminação pode afetar a água para uso humano, como ocorre com a água do Rio Poxim, que abastece a cidade de Aracaju, capital do Estado de Sergipe. O objetivo do estudo foi avaliar o risco de contaminação de águas superficiais e subterrâneas por herbicidas no alto da Sub-bacia do Rio Poxim e detectar a presença dos princípios ativos Diuron e Ametrina, à montante das plantações de cana-de-açúcar. A análise de risco foi realizada mediante critérios da Environmental Protection Agency (EPA), índice de GUS e método de GOSS. Observou-se que vários princípios ativos sofrem risco de lixiviação, demonstrando a importância do monitoramento do rio para controle tanto da qualidade da água como da frequência e volume de herbicidas aplicado na região. A partir do resultado, foi realizado um monitoramento bimensal de julho de 2009 a julho de 2010, em dois pontos de amostragem. As amostras de água foram analisadas em laboratório, onde se, constatou a presença de Diuron e Ametrina. A qualidade da água na Sub-bacia do Rio Poxim está sendo influenciada pelo uso de herbicidas na região. Ocorreu um aumento nas concentrações dos herbicidas na água superficial, durante o período chuvoso, provocado possivelmente pelo escoamento superficial.Increased agricultural activity in watershed areas has been causing concern over contamination by herbicides in agricultural areas. The problem becomes more important when contamination can affect water for human consumption, as happens with water from the Poxim river, which supplies the city of Aracaju, capital of the State of Sergipe. The aim of this study was to evaluate the risk of contamination by herbicides to both surface and groundwater in the upper sub-basin of the Poxim River, and to detect the presence of the active ingredients Diuron and Ametrine up-river from the sugar-cane plantations. Risk analysis was carried out using criteria from the Environmental Protection Agency (EPA), the GUS index, and the GOSS method. It was observed that several active ingredients are at risk of leaching, demonstrating the importance of monitoring the river to control both the quality of water and the frequency and volume of herbicides used in the region. Based on the results, monitoring was carried out bi-monthly from July 2009 to July 2010 at two sampling points. Water samples were analyzed in the laboratory, where the presence of Diuron and Ametrine was noted. Water quality in the Sub-basin of the Rio Poxim is being influenced by the use of herbicides in the region. There was an increase in herbicide concentration in the surface water during the rainy season, possibly caused by soil runoff.

The study of regeneration and maintenance of spring areas is fundamentally important for the conservation of water resources. Considering the need for restoration of the surrounding areas of the springs of the sub-basin of the Piauitinga River, in Lagarto-Sergipe, this study aimed to characterize the soils in their local environment which will serve as a benchmark for future comparisons between areas of springs already degraded and in the recovering process. The springs were classified according to their origin and their stage of preservation. For the study of the local soil, reforested areas of each spring were selected and grouped according to their position in the landscape. The soil classification of the study sites was performed based on local landscape observation, description of opened micro-trenches and analyses of soil samples. The soils were described and classified morphologically. It was observed that from 22 analyzed spring areas, only two (9%) were considered according to their origin as diffuse and the remaining twenty (91%) as punctual. Considering the preservation stage five spring areas (22%) were identified as disturbed and the other ones as degraded (88%). The sites around the springs’ headwaters of the upper course of the Piauitinga river basin are located in erosion spots, depressions and a single case in the foothills coastal tablelands. The most striking characteristics of local soils are the strong hydromorphic (Gleissolos and gleic Cambisols) and, or, the low level of development (Cambisols and Plinthosols, both with much skeletal material, many of them in eroded phase).

The zooplankton of aquatic environments is composed mostly of protozoans, rotifers, cladocerans and copepods, which play an important role in the food chain, transferring mass and energy from primary producers to higher trophic levels. This work was prepared with the objective of contributing to the knowledge of zooplankton biodiversity that occurs in the Sub-basin of Rio Poxim. Water samples were taken at monthly intervals at four sampling stations located along the sub-basin in the period August 2009 to July 2010. To obtain the zooplankton community, 100 L of water were filtered on nylon net with an aperture of 50 mm. Were identified 72 taxa distributed in the following taxonomic categories Rotifera, Protozoa, Porifera, Nematoda, Anellida, Cladocera, Copepoda, Ostracoda, Isopoda and Insecta. In terms of species richness, the phylum Rotifera followed by the Protoctista were the most relevant with forty and fifteen taxa, respectively. The most representative taxa in numerical terms were Arcella vulgaris, Notholca sp. Rotary sp. and nematodes. Regarding the community diversity index, the community was characterized as low diversity, but the taxa were distributed evenly in all monitoring points.

The dynamics of the land use and cover in the Poxim river basin, in Sergipe, Brazil, is a determinant factor for reducing the superficial water quality. This study aimed to identify aspects of water quality related to the land use and cover in four different monitoring stations, in the rainy and dry season. The monitored parameters were pH, DO, BOD, COD, turbidity, total dissolved solids (TDS), total phosphorus, ammonia, nitrite and nitrate, between July 2009 and June 2010. Water samples were collected at four monitoring stations (E1, in the Poxim-Mirim River; E2, in the Poxim-Açu River; E3, in the main river, near the confluence of the two tributaries; and E4, at the Sanitation Company of Sergipe State water supply intake) and analyzed at the Laboratory of Analytical Chemistry of the Federal University of Sergipe State. The results were compared with Brazilian standards for fresh water quality (Class 2), according to CONAMA Resolution nº 357/2005. BOD and COD showed a higher input of organic matter in the monitoring station E3. OD values were critical in all four stations. The nutrients nitrogen and phosphorus had higher concentrations at stations E1 and E2 (upper basin, with agricultural practices). In the lower basin, there is a considerable deterioration of water quality, possibly due to the urbanization process. The studied parameters indicate the low quality of water in the Poxim River basin and the need to adopt appropriate mitigation measures.

OBJECTIVE: The aim of this study was to (1) observe the extent to which hemodynamic and glucose measurements change in patients submitted to a dental procedure with and without a local anesthetic and a vasoconstrictor (LAVA; 2% mepivacaine with adrenaline 1100,000) and (2) correlate those parameters with the patients' anxiety levels. METHOD: This was an unblinded, random, prospective, and observational study with paired groups. Patients were evaluated during two different consultations during which they either did or did not receive a local anesthetic/vasoconstrictor. RESULTS: Thirty-seven patients ranging in age from 18 to 45 years (mean 30.4 ± 5.5 years) were evaluated. Hemodynamic parameters, including systolic blood pressure, diastolic blood pressure, heart rate, and glucose levels, did not change significantly in healthy patients, regardless of whether a LAVA was administered during the dental treatment. CONCLUSION: The patients' anxiety statuses neither varied significantly nor showed any correlation with the studied hemodynamic parameters and glucose levels, regardless of whether local anesthetics were used.

Aim: To verify the relationship between orofacial pain and absenteeism in workers of slaughter and meat processing industries in the Southern region of Brazil. Methods: A cross-sectional study, with the random sample of 401 workers of slaughter and meat processing industries in the Southern region of Brazil, was carried out. A questionnaire referred to the situation of absenteeism caused by nine different types of orofacial pain and also the amount of time the employee was kept from work. Results: Only 60 workers (15%) reported having missed work due to orofacial pain in the six months prior to the study. The prevalence of absenteeism resulting from orofacial pain was of 15%. The types of orofacial pain that resulted in absenteeism were: spontaneous toothache (9.7 %); toothache caused by cold or hot liquids or by sweet foodstuff (6.5%) and pain around and behind the eyes (3.2%). There was a predominance of absenteeism in half and full work shifts for the types of orofacial pain experienced. Associations between absenteeism from induced toothache and gender (p < 0.05), absenteeism and spontaneous toothache and family income (p = 0.011), and between absenteeism and the self awareness of their oral health condition, as well as the nine types of orofacial pain (p < 0.001) were observed. Conclusions: The prevalence of absenteeism as a result of orofacial pain was low.

OBJETIVO: O propósito deste estudo é demonstrar que o reposicionamento do músculo papilar é uma técnica confiável para o reparo do prolapso da cúspide anterior, portanto, nós descrevemos esta técnica e seus resultados propondo-a como padrão. MÉTODO: Entre 1989 e 2005, 120 plastias da valva mitral foram consecutivamente realizadas por meio do reposicionamento do músculo papilar no prolapso da cúspide anterior. Oitenta e sete pacientes eram do sexo masculino e 33 do feminino, sendo, a média de idade de 59 ± 11,5 anos. Cinqüenta e nove por cento dos pacientes estavam em classe funcional (NYHA) III ou IV, a média da fração de ejeção foi 65,7 ± 8,9%. A etiologia predominante na regurgitação da valva mitral (RM) foi doença degenerativa: Barlow (n=43) e distrofia (n=62). As outras etiologias eram: endocardite cicatrizada (n=5), reumática (n=5), isquêmica (n=4), congênita (n=1). O reposicionamento do músculo papilar posterior foi realizado em 111 (92,5%) casos e do anterior em 38 (31,7%). Procedimentos associados foram realizados em 76 (63,3%) pacientes. RESULTADOS: Não houve óbito hospitalar. Durante o acompanhamento, 14 (11,7%) pacientes foram a óbito, incluindo sete (5,8%) por causas cardíacas. As taxas da curva de sobrevida acumulada em 1, 5, 10 e 15 anos foram 98,3%, 97,2%, 94,1% e 81,4%, respectivamente. Dois (1,7%) pacientes foram reoperados por regurgitação recorrente, eles foram submetidos à troca da valva 1 e 5 anos depois do reparo e morreram 3 e 6 anos após esta troca valvar. Não houve movimento anterior sistólico. As taxas de sobrevida acumulada livre de reoperação envolvendo a valva mitral em 1, 5, 10, e 15 anos foram 97,4%, 97,4%, 92,8% e 86,7%, respectivamente. Nós não achamos nenhum fator de risco de mortalidade e de reoperação. O acompanhamento completo foi realizado em todos os pacientes. Após um tempo de acompanhamento mediano de 5,9 anos (de 0,1 a 15,6 anos), 87 (72,5%) pacientes estavam na classe I - NYHA, o controle ecocardiográfico mostrou nenhuma ou mínima regurgitação em 89 (74,2 %) pacientes, leve regurgitação em oito (6,7%) e moderada regurgitação em nove (7,5%). CONCLUSÃO: O reposicionamento do músculo papilar é uma técnica confiável e segura, com excelentes resultados clínicos e ecocardiográficos a longo prazo. Desta maneira, estamos propondo-a como padrão para o reparo da cúspide anterior prolapsada.OBJECTIVE: The aim of this study was to demonstrate that papillary muscle repositioning is a reliable technique to repair anterior leaflet prolapse. Therefore we describe this technique and its long term results to propose it as a gold standard. METHOD: Between 1989 and 2005, 120 mitral valve repairs were consecutively performed using papillary muscle repositioning in cases of anterior leaflet prolapse. There were 87 males and 33 females, the mean age was 59 ± 11.5 years. 59% of patients were in NYHA III or IV. Mean ejection fraction was 65.7 ± 8.9%. Predominant aetiology of mitral regurgitation (MR) was degenerative: Barlow (n=43) and dystrophic (n=62). The other aetiologies were: healed endocarditis (n=5), rheumatic (n=5), ischemic (n=4), congenital (n=1). A posterior papillary muscle repositioning was performed in 111 (92.5%) cases and an anterior in 38 (31.7%). Associated procedures were carried out in 76 (63.3%) patients. RESULTS: There were no in-hospital deaths. During the follow-up, 14 patients (11.7%) died, including seven (5.8%) due to cardiac causes. The cumulated survival rates at 1, 5, 10 and 15 years were 98.3%, 97.2%, 94.1% and 81.4% respectively. Two patients (1.7%) were reoperated for recurrency of the regurgitation, they underwent a replacement of the valve 1 and 5 years after the repair and died 3 and 6 years, respectively after this replacement. There was no systolic anterior motion. The cumulated survival rates free from reoperation involving the mitral valve at 1, 5, 10 and 15 years were 97.4%, 97.4%, 92.8 % and 86.7% respectively. We did not find any risk factor of mortality or of reoperation. The follow-up was completed for all the patients. After a median follow-up time of 5.9 years (range from 0.1 to 15.6 years) 87 patients were in NYHA class I (72.5%), the echographic control showed no or minimal insufficiency in 89 patients (74.2%), mild insufficiency in eight patients (6.7%) and moderate insufficiency in nine patients (7.5%). CONCLUSIONS: Papillary muscle repositioning is a reliable and safe technique, with excellent clinical and echocardiographic long term results. Therefore we propose it as a gold standard to repair anterior leaflet prolapse.

A Empresa Carbonífera Rio Deserto Ltda está implantando a Mina Santa Cruz, localizada no município de Içara, SC. Desde as primeiras atividades de implantação da mina, tem havido forte oposição por parte da comunidade local sob a alegação de que a atividade de lavra em subsolo está causando muitos impactos ambientais, principalmente no que se refere ao uso e à alteração da qualidade da água. Recentemente, durante a forte estiagem que atinge o sul de Santa Catarina, houve o rebaixamento do nível de água e/ou secamento de alguns poços. Como consequência, houve mobilização de parte da comunidade, a qual denunciou ao Ministério Público Federal - MPF que o bombeamento realizado no subsolo da mina era responsável pelo rebaixamento do nível da água e/ou secamento de alguns poços. Em vista disso, ficou estabelecido junto ao MPF que se realizaria um estudo hidrogeológico para a caracterização dos sistemas aquíferos presentes na área de concessão da mina, para a definição das causas responsáveis pelo rebaixamento do nível de água nos poços, e implantar-se-ia uma rede de monitoramento para avaliar a influência do bombeamento praticado para retirar a água de subsolo da mina no comportamento dos referidos sistemas.

Abstract Background Genomic imprinting is an epigenetic phenomenon resulting in parent-of-origin specific monoallelic gene expression. It is postulated to have evolved in placental mammals to modulate intrauterine resource allocation to the offspring. In this study, we determined the imprint status of metatherian orthologues of eutherian imprinted genes. Results L3MBTL and HTR2A were shown to be imprinted in Monodelphis domestica (the gray short-tailed opossum). MEST expressed a monoallelic and a biallelic transcript, as in eutherians. In contrast, IMPACT, COPG2, and PLAGL1 were not imprinted in the opossum. Differentially methylated regions (DMRs) involved in regulating imprinting in eutherians were not found at any of the new imprinted loci in the opossum. Interestingly, a novel DMR was identified in intron 11 of the imprinted IGF2R gene, but this was not conserved in eutherians. The promoter regions of the imprinted genes in the opossum were enriched for the activating histone modification H3 Lysine 4 dimethylation. Conclusions The phenomenon of genomic imprinting is conserved in Therians, but the marked difference in the number and location of imprinted genes and DMRs between metatherians and eutherians indicates that imprinting is not fully conserved between the two Therian infra-classes. The identification of a novel DMR at a non-conserved location as well as the first demonstration of histone modifications at imprinted loci in the opossum suggest that genomic imprinting may have evolved in a common ancestor of these two Therian infra-classes with subsequent divergence of regulatory mechanisms in the two lineages.

Abstract Background Global forests capture and store significant amounts of CO2 through photosynthesis. When carbon is removed from forests through harvest, a portion of the harvested carbon is stored in wood products, often for many decades. The United States Forest Service (USFS) and other agencies are interested in accurately accounting for carbon flux associated with harvested wood products (HWP) to meet greenhouse gas monitoring commitments and climate change adaptation and mitigation objectives. This paper uses the Intergovernmental Panel on Climate Change (IPCC) production accounting approach and the California Forest Project Protocol (CFPP) to estimate HWP carbon storage from 1906 to 2010 for the USFS Northern Region, which includes forests in northern Idaho, Montana, South Dakota, and eastern Washington. Results Based on the IPCC approach, carbon stocks in the HWP pool were increasing at one million megagrams of carbon (MgC) per year in the mid 1960s, with peak cumulative storage of 28 million MgC occurring in 1995. Net positive flux into the HWP pool over this period is primarily attributable to high harvest levels in the mid twentieth century. Harvest levels declined after 1970, resulting in less carbon entering the HWP pool. Since 1995, emissions from HWP at solid waste disposal sites have exceeded additions from harvesting, resulting in a decline in the total amount of carbon stored in the HWP pool. The CFPP approach shows a similar trend, with 100-year average carbon storage for each annual Northern Region harvest peaking in 1969 at 937,900 MgC, and fluctuating between 84,000 and 150,000 MgC over the last decade. Conclusions The Northern Region HWP pool is now in a period of negative net annual stock change because the decay of products harvested between 1906 and 2010 exceeds additions of carbon to the HWP pool through harvest. However, total forest carbon includes both HWP and ecosystem carbon, which may have increased over the study period. Though our emphasis is on the Northern Region, we provide a framework by which the IPCC and CFPP methods can be applied broadly at sub-national scales to other regions, land management units, or firms.

ABSTRACT Objective: To compare radiation exposure to the surgeon, patient and radiation technician during percutaneous access of the vertebral pedicle, using three different fluoroscopic imaging set up. Methods: Percutaneous access in pedicle T9-L5 of nine adult male cadavers using three different fluoroscopic set ups: standard C-arm, C-arm with L-arm, and the biplanar technique. The radiation dose exposure of the surgeon, radiation technician, and cadaver were measured using dosimeter in each procedure and in real time. Results: The radiation dose absorbed by the surgeon was higher when using the standard C-arm fluoroscopic technique than when using the C-arm with L-arm or the biplanar technique. Conclusions: The use of the C-arm with L-arm, or the biplanar fluoroscopic technique, for percutaneous access to the vertebral pedicle, reduces the radiation exposure of the surgeon compared to the standard C-arm fluoroscopic technique.

ABSTRACT Objective: The objective of this study was to describe the results of anatomic pulmonary resections performed by video-assisted thoracoscopy in Brazil. Methods: Thoracic surgeons (members of the Brazilian Society of Thoracic Surgery) were invited, via e-mail, to participate in the study. Eighteen surgeons participated in the project by providing us with retrospective databases containing information related to anatomic pulmonary resections performed by video-assisted thoracoscopy. Demographic, surgical, and postoperative data were collected with a standardized instrument, after which they were compiled and analyzed. Results: The surgeons provided data related to a collective total of 786 patients (mean number of resections per surgeon, 43.6). However, 137 patients were excluded because some data were missing. Therefore, the study sample comprised 649 patients. The mean age of the patients was 61.7 years. Of the 649 patients, 295 (45.5%) were male. The majority-521 (89.8%)-had undergone surgery for neoplasia, which was most often classified as stage IA. The median duration of pleural drainage was 3 days, and the median hospital stay was 4 days. Of the 649 procedures evaluated, 598 (91.2%) were lobectomies. Conversion to thoracotomy was necessary in 30 cases (4.6%). Postoperative complications occurred in 124 patients (19.1%), the most common complications being pneumonia, prolonged air leaks, and atelectasis. The 30-day mortality rate was 2.0%, advanced age and diabetes being found to be predictors of mortality. Conclusions: Our analysis of this representative sample of patients undergoing pulmonary resection by video-assisted thoracoscopy in Brazil showed that the procedure is practicable and safe, as well as being comparable to those performed in other countries.

The previously unreported combination of nucleophilic phosphine catalysis and energy transfer catalysis allows for the rapid construction of structurally distinct 2-oxabicyclo[2.1.1]hexanes (2-oxa-BCH) from readily available building blocks with high atom economy. Previous multistep routes to these important phenyl ring bioisosteres have largely depended on the use of bespoke strain-release agents or on multiple post-functionalisation reactions to access structural diversity of the scaffold. In contrast, this cascade reaction allows the medicinal chemist to exploit the breadth of commercial allyl alcohols to synthesise systematically diverse 2-oxa-BCH architectures. Using a combination of polar and radical disconnections in the same reaction flask, every position of the scaffold can be substituted with useful functional handles such as protected amines, esters and alcohols, as well as arenes and alkyl groups. Cyclic allyl alcohols can even be employed to yield single diastereomers of sp 3 -rich bridged spirocyclic structures. Aromatic groups at the 1-position can be varied to incorporate a plethora of arenes including medicinally relevant heterocycles such as indole, pyrazole and pyridine., Competing Interests: There are no conflicts to declare., (This journal is © The Royal Society of Chemistry.)

Background: Hypoxia-ischemia predisposes to atrial arrhythmia. Atrial ATP-sensitive potassium channel (K ATP ) modulation during hypoxia has not been explored. We investigated the effects of hypoxia on atrial electrophysiology in mice with global deletion of K ATP pore-forming subunits., Methods: Whole heart K ATP RNA expression was probed. Whole-cell K ATP current and action potentials were recorded in isolated wild-type (WT), Kir6.1 global knockout (6.1-gKO), and Kir6.2 global knockout (6.2-gKO) murine atrial myocytes. Langendorff-perfused hearts were assessed for atrial effective refractory period (ERP), conduction velocity, wavefront path length (WFPL), and arrhymogenicity under normoxia/hypoxia using a microelectrode array and programmed electrical stimulation. Heart histology was assessed., Results: Expression patterns were essentially identical for all K ATP subunit RNA across human heart, whereas in mouse, Kir6.1 and SUR2 (sulphonylurea receptor subunit) were higher in ventricle than atrium, and Kir6.2 and SUR1 were higher in atrium. Compared with WT, 6.2-gKO atrial myocytes had reduced tolbutamide-sensitive current and action potentials were more depolarized with slower upstroke and reduced peak amplitude. Action potential duration was prolonged in 6.1-gKO atrial myocytes, absent of changes in other ion channel gene expression or atrial myocyte hypertrophy. In Langendorff-perfused hearts, baseline atrial ERP was prolonged and conduction velocity reduced in both K ATP knockout mice compared with WT, without histological fibrosis. Compared with baseline, hypoxia led to conduction velocity slowing, stable ERP, and WFPL shortening in WT and 6.1-gKO hearts, whereas WFPL was stable in 6.2-gKO hearts due to ERP prolongation with conduction velocity slowing. Tolbutamide reversed hypoxia-induced WFPL shortening in WT and 6.1-gKO hearts through ERP prolongation. Atrial tachyarrhythmias inducible with programmed electrical stimulation during hypoxia in WT and 6.1-gKO mice correlated with WFPL shortening. Spontaneous arrhythmia was not seen., Conclusions: K ATP block/absence leads to cellular and tissue level atrial electrophysiological modification. Kir6.2 global knockout prevents hypoxia-induced atrial WFPL shortening and atrial arrhythmogenicity to programmed electrical stimulation. This mechanism could be explored translationally to treat ischemically driven atrial arrhythmia., Competing Interests: Disclosures None.

Background: Ingrown toenails are a common condition requiring outpatient procedures in podiatric medical clinics. To prevent recurrence, chemical matrixectomy is often recommended. Postprocedural pain management is largely based on preferences rather than on a formal guideline. This study aims to explore the postprocedural prescribing behavior among practicing podiatric physicians to foster future guideline and policy development., Methods: We administered an open, voluntary, anonymous questionnaire via an online survey platform that included a common nail procedure scenario (chemical matrixectomy) and a prescribed demographics section. Podiatric physicians were asked what they would prescribe to manage postprocedural pain. Opioid and nonopioid options were provided. We developed two multiple logistic regression models to identify associations between prescriber characteristics and prescribing opioids after "standard" chemical matrixectomy., Results: Of the 860 podiatrists who completed the survey, 8.7% opted to prescribe an opioid. Hydrocodone was most commonly chosen. A median of 18 opioid pills were prescribed. No prescriber characteristics were associated with prescribing opioids after chemical matrixectomy scenario. There is a large discrepancy and knowledge gap in the literature on the optimal postprocedural pain management for outpatient procedures, including procedures in specialties such as dentistry and dermatology. The median number of opioids prescribed by podiatrists is higher than that by dentists for management of third molar extraction. In contrast, opioid-prescribing behavior among the 8.7% of respondents is similar to dermatologic management of postprocedural pain in Mohs surgery., Conclusions: Podiatric physicians cannot assume that their prescribing of opioids does not affect the opioid abuse problem in the United States. The presented study serves to be an initiation for procedure-specific opioid prescription benchmarking to foster future guideline and policy development. After nail procedures, opioids should not be routinely prescribed.

Trypanosoma evansi is a parasite that is phylogenetically close to Trypanosoma brucei and is the causative agent of a disease known as surra. Surra is responsible for a high mortality rate in livestock and large economic losses in the Americas, Africa, and Asia. This work aimed to analyze in vitro secreted proteins from T. evansi and identify potential treatment and diagnostic biomarkers for surra diagnosis. Two groups were used. In one group the parasites were purified using a DEAE-Cellulose column and maintained in a secretion medium while in the other group the parasites were not purified. Each group was further divided to be maintained at either 37 °C or 27 °C. We identified 246 proteins through mass spectrometry and found that the temperature appears to modulate protein secretion. We found minimal variations in the protein pools from pure and non-purified sets. We observed an emphasis on proteins associated to vesicles, glycolysis, and cellular homeostasis through the enrichment of GO. Also, we found that most secretome proteins share homologous proteins with T. b. brucei, T. b. gambiense, T. vivax, T. equiperdum, and T. b. rhodesiense secretome but unique T. evansi epitopes with potential biomarkers for surra diagnosis were detected. SIGNIFICANCE: Trypanosoma evansi is a parasite of African origin that is phylogenetically close to Trypanosoma brucei. As with other trypanosomatids and blood parasites, its infection causes non-pathognomonic symptoms, which makes its diagnosis difficult. One great problem is the fact that no diagnostic test differentiates between Trypanosoma equiperdum and T. evansi, which is a problem in South America and Asia, and Africa. Thus, it is urgent to study the biochemistry of the parasite to discover proteins that can be used for differential diagnosis or be possible therapeutic targets. In addition, the study of the secretome can point out proteins that are used by the parasite in its interactions with the host, helping to understand the progression of the disease., Competing Interests: Declaration of Competing Interest The authors report no declarations of interest., (Copyright © 2022 Elsevier B.V. All rights reserved.)

Poly(ethylene glycol), PEG, known to inhibit protein adsorption, is widely used on the surfaces of biomedical devices when biofilm formation is undesirable. Poly(desaminotyrosyl-tyrosine ethyl ester carbonate), PDTEC, PC for short, has been a promising coating polymer for insertion devices, and it has been anticipated that PEG plays a similar role if it is copolymerized with PC. Earlier studies show that no fibrinogen (Fg) is adsorbed onto PC polymers with PEG beyond the threshold weight percentage. This is attributed to the phase separation of PEG. Further, iodination of the PC units in the PC polymer, (I 2 PC), has been found to counteract this Fg-repulsive effect by PEG. In this study, we employ surface-sensitive X-ray techniques to demonstrate the surface affinity of Fg toward the air-water interface, particularly in the presence of self-assembled PC-based film, in which its constituent polymer units are assumed to be much more mobile as a free-standing film. Fg is found to form a Gibbs monolayer with its long axis parallel to the aqueous surface, thus maximizing its interactions with hydrophobic interfaces. It influences the amount of insoluble, surface-bound I 2 PC likely due to the desorption of the formed Fg-I 2 PC complex and/or the penetration of Fg onto the I 2 PC film. The results show that the phase behavior at the liquid-polymer interface shall be taken into account for the surface behavior of bulk polymers surrounded by tissue. The ability of PEG units rearranging into a protein-blocking layer, rather than its mere presence in the polymer, is the key to antifouling characteristics desired for polymeric coating on insertion devices.

The bromodomain and extra terminal (BET) family of proteins are an integral part of human epigenome regulation, the dysregulation of which is implicated in multiple oncology and inflammatory diseases. Disrupting the BET family bromodomain acetyl-lysine (KAc) histone protein-protein interaction with small-molecule KAc mimetics has proven to be a disease-relevant mechanism of action, and multiple molecules are currently undergoing oncology clinical trials. This work describes an efficiency analysis of published GSK pan-BET bromodomain inhibitors, which drove a strategic choice to focus on the identification of a ligand-efficient KAc mimetic with the hypothesis that lipophilic efficiency could be drastically improved during optimization. This focus drove the discovery of the highly ligand-efficient and structurally distinct benzoazepinone KAc mimetic. Following crystallography to identify suitable growth vectors, the benzoazepinone core was optimized through an explore-exploit structure-activity relationship (SAR) approach while carefully monitoring lipophilic efficiency to deliver I-BET432 ( 41 ) as an oral candidate quality molecule.

A concise strategy for the total synthesis of several Aspidosperma alkaloids is reported. A Suzuki-Miyaura cross-coupling provides access to a 2-vinyl indole that undergoes a Diels-Alder cascade reaction with butyn-2-one to deliver a pyrroloindoline intermediate. This undergoes cascade amidation, reduction, skeletal rearrangement, and intramolecular Michael addition to provide a common intermediate containing the full framework of the Aspidosperma alkaloids. The utility of this intermediate is shown in the synthesis of four different natural products.

Epitopes are portions of a protein that are recognized by antibodies. These small amino acid sequences represent a significant breakthrough in a branch of bioinformatics called immunoinformatics. Various software are available for linear B-cell epitope (BCE) prediction such as ABCPred , SVMTrip , EpiDope , and EpitopeVec ; a well-known BCE predictor is BepiPred-2.0. However, despite the prediction, there are several essential steps, such as epitope assembly, evaluation, and searching for epitopes in other proteomes. Here, we present EpiBuilder (https://epibuilder.sourceforge.io), a user friendly software that assists in epitope assembly, classifying and searching using input results of BepiPred-2.0. EpiBuilder generates several output results from these data and supports a proteome-wide processing approach. In addition, this software provides the following features: Chou & Fasman beta-turn prediction, Emini surface accessibility prediction, Karplus and Schulz flexibility prediction, Kolaskar and Tongaonkar antigenicity, Parker hydrophilicity prediction, N -glycosylation domains, and hydropathy. These information generate a unique topology for each epitope, visually demonstrating its characteristics. The software can search the entire epitope sequence in various FASTA files, and it allows to use BLASTP to identify epitopes that eventually have sequence variations. As an EpiBuilder application, we developed a epitope dataset from the protozoan Trypanosoma brucei gambiense , the gram-positive bacterium Clostridioides difficile , and severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2)., Competing Interests: Declaration of conflicting interests: The author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article., (© The Author(s) 2022.)

Optimization of a previously reported lead series of PI3Kδ inhibitors with a novel binding mode led to the identification of a clinical candidate compound 31 (GSK251). Removal of an embedded Ames-positive heteroaromatic amine by reversing a sulfonamide followed by locating an interaction with Trp760 led to a highly selective compound 9 . Further optimization to avoid glutathione trapping, to enhance potency and selectivity, and to optimize an oral pharmacokinetic profile led to the discovery of compound 31 (GSK215) that had a low predicted daily dose (45 mg, b.i.d) and a rat toxicity profile suitable for further development.

Trypanosoma evansi is the agent of "surra," a trypanosomosis endemic in many areas worldwide. Trypanosoma proteins released/secreted during infection are attractive biomarkers for disease detection and monitoring. Using liquid chromatography-tandem mass spectrometry (LC-MS/MS), we performed a comprehensive analysis of the serum proteome of mice infected with T.evansi and detected changes in the abundance of parasite and host serum proteins during infection. Following bioinformatics analysis, 30 T. evansi proteins were identified in the mice serum including known targets such as pyruvate kinase 1, β-tubulin, actin A, heat shock protein 70, and cyclophilin A. We also identified two exclusive VSG epitopes which are novel putative biomarker targets. In addition, upregulation of 31 mouse proteins, including chitinase-like protein 3 and monocyte differentiation antigen CD14, were observed. Identification of parasite-specific biomarkers in the host serum is critical for the development of reliable serological/ assays for differential diagnosis., (Copyright © 2021 Elsevier B.V. All rights reserved.)

K ATP channels in the vasculature composed of Kir6.1 regulate vascular tone and may contribute to the pathogenesis of endotoxemia. We used mice with cell-specific deletion of Kir6.1 in smooth muscle (smKO) and endothelium (eKO) to investigate this question. We found that smKO mice had a significant survival disadvantage compared with their littermate controls when treated with a sub-lethal dose of lipopolysaccharide (LPS). All cohorts of mice became hypotensive following bacterial LPS administration; however, mean arterial pressure in WT mice recovered to normal levels, whereas smKO struggled to overcome LPS-induced hypotension. In vivo and ex vivo investigations revealed pronounced cardiac dysfunction in LPS-treated smKO, but not in eKO mice. Similar results were observed in a cecal slurry injection model. Metabolomic profiling of hearts revealed significantly reduced levels of metabolites involved in redox/energetics, TCA cycle, lipid/fatty acid and amino acid metabolism. Vascular smooth muscle-localised K ATP channels have a critical role in the response to systemic infection by normalising cardiac function and haemodynamics through metabolic homeostasis. KEY MESSAGES: • Mice lacking vascular K ATP channels are more susceptible to death from infection. • Absence of smooth muscle K ATP channels depresses cardiac function during infection. • Cardiac dysfunction is accompanied by profound changes in cellular metabolites. • Findings from this study suggest a protective role for vascular K ATP channels in response to systemic infection.

Inhibitors of CDK4 and CDK6 have emerged as important FDA-approved treatment options for breast cancer patients. The properties and pharmacology of CDK4/6 inhibitor medicines have been extensively profiled, and investigations into the degradation of these targets via a PROTAC strategy have also been reported. PROTACs are a novel class of small-molecules that offer the potential for differentiated pharmacology compared to traditional inhibitors by redirecting the cellular ubiquitin-proteasome system to degrade target proteins of interest. We report here the preparation of palbociclib-based PROTACs that incorporate binders for three different E3 ligases, including a novel IAP-binder, which effectively degrade CDK4 and CDK6 in cells. In addition, we show that the palbociclib-based PROTACs in this study that recruit different E3 ligases all exhibit preferential CDK6 vs. CDK4 degradation selectivity despite employing a selection of linkers between the target binder and the E3 ligase binder., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2020 Elsevier Ltd. All rights reserved.)

The heterodimeric transmembrane αv integrin receptors have recently emerged as potential targets for the treatment of idiopathic pulmonary fibrosis. Herein, we describe how subtle modifications of the central aromatic ring of a series of phenylbutyrate-based antagonists of the vitronectin receptors αvβ3 and αvβ5 significantly change the biological activities against αvβ6 and αvβ8. This resulted in the discovery of a pan αv antagonist (compound 39 , 4-40 nM for the integrin receptors named above) possessing excellent oral pharmacokinetic properties in rats (with a clearance of 7.6 mL/(min kg) and a bioavailability of 97%).

Interleukin-1 Receptor-Associated Kinase 4 (IRAK4) is a key mediator of innate immunity. IRAK4 overactivation is linked with several autoimmune diseases. To date, many IRAK4 inhibitors have been developed to block the protein's kinase activity with the most advanced reaching Phase II clinical trials. Nevertheless, several reports suggest kinase activity is not disease-relevant in certain cell types, so removing scaffolding signaling in addition to IRAK4 kinase activity may offer a better therapeutic outcome. Herein, we describe the design and synthesis of an IRAK4 Proteolysis Targeted Chimera (PROTAC). We show that IRAK4 degradation induced by compound 9 leads to the inhibition of multiple cytokines in PBMCs. However, in IL-1β stimulated human dermal fibroblasts, inhibition of IL-6 and TNF-α release was not observed despite IRAK4 degradation. Nonetheless, the possibility of targeting both IRAK4 kinase and scaffolding function could potentially lead to new therapeutic opportunities to treat autoimmune, inflammatory, and oncological diseases., Competing Interests: The authors declare the following competing financial interest(s): The authors are employees and shareholders of GlaxoSmithKline.

RIP1 kinase regulates necroptosis and inflammation and may play an important role in contributing to a variety of human pathologies, including inflammatory and neurological diseases. Currently, RIP1 kinase inhibitors have advanced into early clinical trials for evaluation in inflammatory diseases such as psoriasis, rheumatoid arthritis, and ulcerative colitis and neurological diseases such as amyotrophic lateral sclerosis and Alzheimer's disease. In this paper, we report on the design of potent and highly selective dihydropyrazole (DHP) RIP1 kinase inhibitors starting from a high-throughput screen and the lead-optimization of this series from a lead with minimal rat oral exposure to the identification of dihydropyrazole 77 with good pharmacokinetic profiles in multiple species. Additionally, we identified a potent murine RIP1 kinase inhibitor 76 as a valuable in vivo tool molecule suitable for evaluating the role of RIP1 kinase in chronic models of disease. DHP 76 showed efficacy in mouse models of both multiple sclerosis and human retinitis pigmentosa.

Objective: To assess brachial artery distensibility and associated factors in healthy primigravidas., Methods: We assessed brachial artery distensibility using the DynaPulse 5,000A in 37 women each trimester, and 6-8 weeks and 1-5 years postpartum. Associations with physical and cardiometabolic measures were considered., Results: Mean (SE) brachial artery distensibility (%Δ/mmHg) decreased (stiffened) from 7.50 (0.20) 12-14 weeks to 6.93 (0.22) 36-38 weeks (p < .01) and returned to baseline 7.52 (0.44) at 2.7 years postpartum. Weight gain and greater cardiac output were significantly related to greater stiffness., Conclusion: Increased weight and cardiac output of pregnancy were associated with brachial artery stiffening.

A series of 3-aryl(pyrrolidin-1-yl)butanoic acids were synthesized using a diastereoselective route, via a rhodium catalyzed asymmetric 1,4-addition of arylboronic acids in the presence of ( R)-BINAP to a crotonate ester to provide the ( S) absolute configuration for the major product. A variety of aryl substituents including morpholine, pyrazole, triazole, imidazole, and cyclic ether were screened in cell adhesion assays for affinity against α v β 1 , α v β 3 , α v β 5 , α v β 6 , and α v β 8 integrins. Numerous analogs with high affinity and selectivity for the α v β 6 integrin were identified. The analog ( S)-3-(3-(3,5-dimethyl-1 H-pyrazol-1-yl)phenyl)-4-(( R)-3-(2-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)ethyl)pyrrolidin-1-yl)butanoic acid hydrochloride salt was found to have very high affinity for α v β 6 integrin in a radioligand binding assay (p K i = 11), a long dissociation half-life (7 h), very high solubility in saline at pH 7 (>71 mg/mL), and pharmacokinetic properties commensurate with inhaled dosing by nebulization. It was selected for further clinical investigation as a potential therapeutic agent for the treatment of idiopathic pulmonary fibrosis.

Research examining factors that predict youth's involvement in organized activities is very limited, despite associations with positive outcomes. Using data from 1043 youth (49% female; 46.4% Hispanic, 35.4% African American, 14.0% Caucasian, and 4.2% other) from the Project on Human Development in Chicago Neighborhoods, this study examined how characteristics of parents (supervision, warmth) and neighborhoods (perceived neighborhood safety and collective efficacy) predict patterns of adolescents' involvement in organized activities concurrently (i.e., intensity) and longitudinally (i.e., type and breadth). Parental supervision predicted adolescents' participation in organized activities across multiple waves. Neighborhood violence was positively associated with concurrent participation in organized activities after controlling for socioeconomic status (SES), whereas higher neighborhood collective efficacy predicted greater breadth in organized activity participation across time. These findings have important implications regarding how to attract and sustain organized activity participation for low-income, urban youth.

Background: High parity is associated with greater cardiovascular disease (CVD) among mid-life and older women. Prospective studies of arterial change throughout pregnancy are needed to provide insight into potential mechanisms. This study assessed vascular adaptation across pregnancy in healthy first-time pregnant women., Methods: The Maternal Vascular Adaptation to Healthy Pregnancy Study (Pittsburgh, PA, 2010-2015) assessed 37 primigravid women each trimester, 6-8 weeks after delivery and 1-5 years postpartum, with B-mode ultrasound imaging of common carotid artery (CCA) intima-media thickness (IMT) and inter-adventitial diameter (IAD) to assess associations with physical and cardiometabolic measures., Results: Thirty-seven women (age 28.2 ± 4.5 years, pre-pregnant BMI 24.4 ± 3.2 kg/m 2 ) experienced uncomplicated pregnancies. After adjustment for age and pre-pregnancy BMI, mean (SE) IAD (mm) increased each trimester, from 6.38 (0.08) in the 1st trimester to 6.92 (0.09) in the 3rd trimester, and then returned to 1st trimester levels postpartum (6.35 [0.07], P <  0.001). In contrast, mean (SE) CCA IMT (mm) increased from the 2nd trimester (i.e., 0.546 [0.01]) onward, and remained higher at an average of 2.7 years postpartum (0.581 [0.02], P = 0.03). Weight partially explained changes in IAD., Conclusions: In uncomplicated first pregnancies, IAD increased and returned to 1st trimester levels postpartum. In contrast, CCA IMT remained increased 2 years postpartum. Maternal weight explained vascular changes better than did metabolic changes. Increased postpartum CCA IMT may persist and contribute to long-term CVD risk.

Functionalized bicyclic amino-azaheterocycles are rapidly accessed in a one-pot cross-coupling/reduction sequence enabled by the use of COware. Incompatible reagents are physically separated in a single reaction vessel to effect two chemoselective transformations-Suzuki-Miyaura cross-coupling and heteroarene reduction. The developed method allows access to novel heterocyclic templates, including semisaturated Hedgehog and dual PI3K/mTOR inhibitors, which show enhanced physicochemical properties compared to their unsaturated counterparts.

We report the direct chemoselective Brown-type oxidation of aryl organoboron systems containing two oxidizable boron groups. Basic biphasic reaction conditions enable selective formation and phase transfer of a boronic acid trihydroxyboronate in the presence of boronic acid pinacol (BPin) esters, while avoiding speciation equilibria. Spectroscopic investigations validate a base-promoted phase-selective discrimination of organoboron species. This phenomenon is general across a broad range of organoboron compounds and can also be used to invert conventional protecting group strategies, enabling chemoselective oxidation of BMIDA species over normally more reactive BPin substrates. We also demonstrate the selective oxidation of diboronic acid systems with chemoselectivity predictable a priori . The utility of this method is exemplified through the development of a chemoselective oxidative nucleophile coupling.

A diastereoselective synthesis of (S)-3-(3-(3,5-dimethyl-1H-pyrazol-1-yl)phenyl)-4-((R)-3-(2-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)ethyl)pyrrolidin-1-yl)butanoic acid (1), a potential therapeutic agent for the treatment of Idiopathic Pulmonary Fibrosis, which is currently undergoing Phase I clinical trials is reported. The key steps in the synthesis involved alkylation of 2-methylnaphthyridine with (R)-N-Boc-3-(iodomethyl)-pyrrolidine, and an asymmetric Rh-catalysed addition of an arylboronic acid to a 4-(N-pyrrolidinyl)crotonate ester. The overall yield of the seven linear step synthesis was 8% and the product was obtained in >99.5% ee proceeding with 80% de. The absolute configuration of 1 was established by an alternative asymmetric synthesis involving alkylation of an arylacetic acid using Evans oxazolidinone chemistry, acylation using the resulting 2-arylsuccinic acid, and reduction. The absolute configuration of the benzylic asymmetric centre was established as (S).

Floral attraction traits can significantly affect pollinator visitation patterns, but adaptive evolution of these traits may be constrained by correlations with other traits. In some cases, molecular pathways contributing to floral attraction are well characterized, offering the opportunity to explore loci potentially underlying variation among individuals. Here, we quantify the range of variation in floral UV patterning (i.e. UV 'bulls-eye nectar guides) among crop and wild accessions of Brassica rapa. We then use experimental crosses to examine the genetic architecture, candidate loci and biochemical underpinnings of this patterning as well as phenotypic manipulations to test the ecological impact. We find qualitative variation in UV patterning between wild (commonly lacking UV patterns) and crop (commonly exhibiting UV patterns) accessions. Similar to the majority of crops, recombinant inbred lines (RILs) derived from an oilseed crop × WI fast-plant® cross exhibit UV patterns, the size of which varies extensively among genotypes. In RILs, we further observe strong statistical-genetic and QTL correlations within petal morphological traits and within measurements of petal UV patterning; however, correlations between morphology and UV patterning are weak or nonsignificant, suggesting that UV patterning is regulated and may evolve independently of overall petal size. HPLC analyses reveal a high concentration of sinapoyl glucose in UV-absorbing petal regions, which, in concert with physical locations of UV-trait QTLs, suggest a regulatory and structural gene as candidates underlying observed quantitative variation. Finally, insects prefer flowers with UV bulls-eye patterns over those that lack patterns, validating the importance of UV patterning in pollen-limited populations of B. rapa., (© 2016 John Wiley & Sons Ltd.)

Phenylpropanoids are phenylalanine-derived specialized metabolites and include important structural components of plant cell walls, such as lignin and hydroxycinnamic acids, as well as ultraviolet and visible light-absorbing pigments, such as hydroxycinnamate esters (HCEs) and anthocyanins. Previous work has revealed a remarkable degree of plasticity in HCE biosynthesis, such that most Arabidopsis (Arabidopsis thaliana) mutants with blockages in the pathway simply redirect carbon flux to atypical HCEs. In contrast, the ferulic acid hydroxylase1 (fah1) mutant accumulates greatly reduced levels of HCEs, suggesting that phenylpropanoid biosynthesis may be repressed in response to the loss of FERULATE 5-HYDROXYLASE (F5H) activity. Here, we show that in fah1 mutant plants, the activity of HCE biosynthetic enzymes is not limiting for HCE accumulation, nor is phenylpropanoid flux diverted to the synthesis of cell wall components or flavonol glycosides. We further show that anthocyanin accumulation is also repressed in fah1 mutants and that this repression is specific to tissues in which F5H is normally expressed. Finally, we show that repression of both HCE and anthocyanin biosynthesis in fah1 mutants is dependent on the MED5a/5b subunits of the transcriptional coregulatory complex Mediator, which are similarly required for the repression of lignin biosynthesis and the stunted growth of the phenylpropanoid pathway mutant reduced epidermal fluorescence8. Taken together, these observations show that the synthesis of HCEs and anthocyanins is actively repressed in a MEDIATOR-dependent manner in Arabidopsis fah1 mutants and support an emerging model in which MED5a/5b act as central players in the homeostatic repression of phenylpropanoid metabolism., (© 2015 American Society of Plant Biologists. All Rights Reserved.)

Objective: Development of a new framework for the National Institute on Aging (NIA) to assess progress and opportunities toward stimulating and supporting rigorous research to address health disparities., Design: Portfolio review of NIA's health disparities research portfolio to evaluate NIA's progress in addressing priority health disparities areas., Results: The NIA Health Disparities Research Framework highlights important factors for health disparities research related to aging, provides an organizing structure for tracking progress, stimulates opportunities to better delineate causal pathways and broadens the scope for malleable targets for intervention, aiding in our efforts to address health disparities in the aging population., Conclusions: The promise of health disparities research depends largely on scientific rigor that builds on past findings and aggressively pursues new approaches. The NIA Health Disparities Framework provides a landscape for stimulating interdisciplinary approaches, evaluating research productivity and identifying opportunities for innovative health disparities research related to aging.