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https://www.readbyqxmd.com/read/29775538/discovery-of-potent-and-centrally-active-6-substituted-5-fluoro-1-3-dihydro-oxazine-%C3%AE-secretase-bace1-inhibitors-via-active-conformation-stabilization
#1
Kenji Nakahara, Kouki Fuchino, Kazuo Komano, Naoya Asada, Genta Tadano, Tsuyoshi Hasegawa, Takahiko Yamamoto, Yusuke Sako, Masayoshi Ogawa, Chie Unemura, Motoko Hosono, Hisanori Ito, Gaku Sakaguchi, Shigeru Ando, Shuichi Ohnishi, Yasuto Kido, Tamio Fukushima, Deborah Dhuyvetter, Herman Borghys, Harrie J M Gijsen, Yoshinori Yamano, Yasuyoshi Iso, Ken-Ichi Kusakabe
β-Secretase (BACE1) has an essential role in the production of amyloid β peptides that accumulate in patients with Alzheimer's disease (AD). Thus, inhibition of BACE1 is considered to be a disease-modifying approach for the treatment of AD. Our hit-to-lead efforts led to a cellular potent 1,3-dihydro-oxazine 6, which however inhibited hERG and showed high P-gp efflux. The close analog of 5-fluoro-oxazine 8 reduced P-gp efflux; further introduction of electron withdrawing groups at the 6-position improved potency and also mitigated P-gp efflux and hERG inhibition...
May 18, 2018: Journal of Medicinal Chemistry
https://www.readbyqxmd.com/read/29775471/host-directed-combinatorial-rnai-improves-inhibition-of-diverse-strains-of-influenza-a-virus-in-human-respiratory-epithelial-cells
#2
Michael A Estrin, Islam T M Hussein, Wendy B Puryear, Anne C Kuan, Stephen C Artim, Jonathan A Runstadler
Influenza A virus infections are important causes of morbidity and mortality worldwide, and currently available prevention and treatment methods are suboptimal. In recent years, genome-wide investigations have revealed numerous host factors that are required for influenza to successfully complete its life cycle. However, only a select, small number of influenza strains were evaluated using this platform, and there was considerable variation in the genes identified across different investigations. In an effort to develop a universally efficacious therapeutic strategy with limited potential for the emergence of resistance, this study was performed to investigate the effect of combinatorial RNA interference (RNAi) on inhibiting the replication of diverse influenza A virus subtypes and strains...
2018: PloS One
https://www.readbyqxmd.com/read/29774041/report-on-the-current-inventory-of-the-toolbox-for-plant-cell-wall-analysis-proteinaceous-and-small-molecular-probes
#3
REVIEW
Maja G Rydahl, Aleksander R Hansen, Stjepan K Kračun, Jozef Mravec
Plant cell walls are highly complex structures composed of diverse classes of polysaccharides, proteoglycans, and polyphenolics, which have numerous roles throughout the life of a plant. Significant research efforts aim to understand the biology of this cellular organelle and to facilitate cell-wall-based industrial applications. To accomplish this, researchers need to be provided with a variety of sensitive and specific detection methods for separate cell wall components, and their various molecular characteristics in vitro as well as in situ ...
2018: Frontiers in Plant Science
https://www.readbyqxmd.com/read/29773889/searching-for-a-compromise-between-biological-and-economic-demands-to-protect-vulnerable-habitats
#4
M Grazia Pennino, Marie-Christine Rufener, Mario J F Thomé-Souza, Adriana R Carvalho, Priscila F M Lopes, U Rashid Sumaila
Identifying vulnerable habitats is necessary to designing and prioritizing efficient marine protected areas (MPAs) to sustain the renewal of living marine resources. However, vulnerable habitats rarely become MPAs due to conflicting interests such as fishing. We propose a spatial framework to help researchers and managers determine optimal conservation areas in a multi-species fishery, while also considering the economic relevance these species may have in a given society, even in data poor situations. We first set different ecological criteria (i...
May 17, 2018: Scientific Reports
https://www.readbyqxmd.com/read/29773702/exploring-variation-in-human-papillomavirus-vaccination-uptake-in-switzerland-a-multilevel-spatial-analysis-of-a-national-vaccination-coverage-survey
#5
Maurane Riesen, Garyfallos Konstantinoudis, Phung Lang, Nicola Low, Christoph Hatz, Mirjam Maeusezahl, Anne Spaar, Marc Bühlmann, Ben D Spycher, Christian L Althaus
OBJECTIVE: Understanding the factors that influence human papillomavirus (HPV) vaccination uptake is critically important to the design of effective vaccination programmes. In Switzerland, HPV vaccination uptake (≥1 dose) by age 16 years among women ranges from 31% to 80% across 26 cantons (states). Our objective was to identify factors that are associated with the spatial variation in HPV vaccination uptake. METHODS: We used cross-sectional data from the Swiss National Vaccination Coverage Survey 2009-2016 on HPV vaccination status (≥1 dose) of 14-17-year-old girls, their municipality of residence and their nationality for 21 of 26 cantons (n=8965)...
May 17, 2018: BMJ Open
https://www.readbyqxmd.com/read/29773527/acceptability-and-feasibility-of-real-time-antiretroviral-therapy-adherence-interventions-in-rural-uganda-mixed-method-pilot-randomized-controlled-trial
#6
Angella Musiimenta, Esther C Atukunda, Wilson Tumuhimbise, Emily E Pisarski, Melanie Tam, Monique A Wyatt, Norma C Ware, Jessica E Haberer
BACKGROUND: Wireless electronic adherence monitors can detect antiretroviral therapy (ART) adherence lapses and trigger interventions in real time, thus potentially avoiding unnecessary HIV viremia. Evidence about the acceptability and feasibility of these monitors and associated interventions, however, is limited. OBJECTIVE: The aim of this study was to assess the acceptability and feasibility of real-time adherence monitoring linked to text messaging (short message service, SMS) reminders and notifications to support adherence among individuals living with HIV who are taking ART in rural southwestern Uganda...
May 17, 2018: JMIR MHealth and UHealth
https://www.readbyqxmd.com/read/29773489/county-level-trends-in-suicide-rates-in-the-u-s-2005-2015
#7
Lauren M Rossen, Holly Hedegaard, Diba Khan, Margaret Warner
INTRODUCTION: Understanding the geographic patterns of suicide can help inform targeted prevention efforts. Although state-level variation in age-adjusted suicide rates has been well documented, trends at the county-level have been largely unexplored. This study uses small area estimation to produce stable county-level estimates of suicide rates to examine geographic, temporal, and urban-rural patterns in suicide from 2005 to 2015. METHODS: Using National Vital Statistics Underlying Cause of Death Files (2005-2015), hierarchical Bayesian models were used to estimate suicide rates for 3,140 counties...
May 8, 2018: American Journal of Preventive Medicine
https://www.readbyqxmd.com/read/29772280/an-analysis-of-palliative-care-development-in-africa-a-ranking-based-on-region-specific-macro-indicators
#8
John Y Rhee, Eduardo Garralda, Eve Namisango, Emmanuel Luyirika, Liliana de Lima, Richard A Powell, Jesús López-Fidalgo, Carlos Centeno
CONTEXT: To date, there is no study comparing palliative care (PC) development among African countries. OBJECTIVE: To analyze comparatively PC development in African countries based on region-specific indicators. METHODS: Data were obtained from the APCA Atlas of PC in Africa and a comparative analysis conducted. Nineteen indicators were developed and defined through qualitative interviews with African PC experts and a two-round modified Delphi consensus process with international experts on global PC indicators...
May 14, 2018: Journal of Pain and Symptom Management
https://www.readbyqxmd.com/read/29772228/3d-bioprinting-of-a-corneal-stroma-equivalent
#9
Abigail Isaacson, Stephen Swioklo, Che J Connon
Corneal transplantation constitutes one of the leading treatments for severe cases of loss of corneal function. Due to its limitations, a concerted effort has been made by tissue engineers to produce functional, synthetic corneal prostheses as an alternative recourse. However, successful translation of these therapies into the clinic has not yet been accomplished. 3D bioprinting is an emerging technology that can be harnessed for the fabrication of biological tissue for clinical applications. We applied this to the area of corneal tissue engineering in order to fabricate corneal structures that resembled the structure of the native human corneal stroma using an existing 3D digital human corneal model and a suitable support structure...
May 14, 2018: Experimental Eye Research
https://www.readbyqxmd.com/read/29772220/cue-awareness-in-avoiding-effortful-control
#10
Timothy L Dunn, Connor Gaspar, Evan F Risko
Based on a recent metacognitive account, cognitive effort is the result of an inferential evaluation made over explicitly available cues. Following from this account, we present here a pre-registered experiment that tested the specific hypothesis that explicit awareness of cues that are aligned with cognitive demand is a prerequisite in avoiding effortful lines of action. We attempted to modulate levels of effort avoidance behavior by introducing an incentive (between-subjects) to monitor two lines of action that, unbeknownst to individuals, varied in the probability of a task switch...
May 14, 2018: Neuropsychologia
https://www.readbyqxmd.com/read/29771990/parental-involvement-could-mitigate-the-effects-of-physical-activity-and-dietary-habits-on-mental-distress-in-ghanaian-youth
#11
Franklin N Glozah, Kwaku Oppong Asante, Nuworza Kugbey
INTRODUCTION: Parental involvement in physical activity and dietary habits have been found to play a substantial role in the mental health of young people. However, there is little evidence about the associations between parental involvement, health behaviours and mental health among Ghanaian youth. This study sought to examine the role of parental involvement in the association between physical activity, dietary habits and mental health among Ghanaian youth. METHODS: Data were obtained from the 2012 Ghana Global School-based Student Health Survey (GSHS)...
2018: PloS One
https://www.readbyqxmd.com/read/29771960/the-great-indian-joint-families-of-free-ranging-dogs
#12
Manabi Paul, Anindita Bhadra
Cooperative breeding is an excellent example of cooperation in social groups. Domestic dogs have evolved from cooperatively hunting and breeding ancestors but have adapted to a facultatively social scavenging lifestyle on streets, and solitary living in human homes. Pets typically breed and reproduce under human supervision, but free-ranging dogs can provide insights into the natural breeding ecology of dogs. We conducted a five year-long field based behavioural study on parental care of free-ranging dogs in India...
2018: PloS One
https://www.readbyqxmd.com/read/29771627/efficiency-and-perceived-exertion-of-novel-wheelchair-wheels-a-comparative-study
#13
Laura Sanches Rocha, Bonita Sawatzky, W Ben Mortenson
New geared wheelchair wheels have been developed allowing the user to pull backwards on the rims to move forward. Theoretically, this utilizes larger muscle groups compared to conventional propulsion preventing repetitive stress injuries. This study compared the gross mechanical efficiency (GME), perceived effort and energy expenditure of propelling the wheelchair using two types of these geared wheels and standard forward propulsion wheels. A within participants repeated measures design was used. Participants' energy expenditure and perceived exertion were measured...
May 17, 2018: Assistive Technology: the Official Journal of RESNA
https://www.readbyqxmd.com/read/29771569/prestige-in-a-large-scale-social-group-predicts-longitudinal-changes-in-testosterone
#14
Joey T Cheng, Olga Kornienko, Douglas A Granger
In many social species, organisms adaptively fine-tune their competitive behavior in response to previous experiences of social status: Individuals who have prevailed in the past preferentially compete in the future, whereas those who have suffered defeat tend to defer and submit. A growing body of evidence suggests that testosterone functions as a "competition hormone" that coordinates this behavioral plasticity through its characteristic rise and fall following victory and defeat. Although well demonstrated in competitions underpinned by dominance (fear-based status derived from force and intimidation), this pattern has not been examined in status contests that depend solely on prestige-respect-based status derived from success, skills, and knowledge in locally valued domains, devoid of fear or antagonism...
June 2018: Journal of Personality and Social Psychology
https://www.readbyqxmd.com/read/29771512/discovery-of-a-diazo-forming-enzyme-in-cremeomycin-biosynthesis
#15
Abraham J Waldman, Emily P Balskus
The molecular architectures and potent bioactivities of diazo-containing natural products have attracted the interest of synthetic and biological chemists. Despite this attention, the biosynthetic enzymes involved in diazo group construction have not been identified. Here, we show the ATP-dependent enzyme CreM installs the diazo group in cremeomycin via late-stage N-N bond formation using nitrite. This finding should inspire efforts to use diazo-forming enzymes in biocatalysis and synthetic biology and enable genome-based discovery of new diazo-containing metabolites...
May 17, 2018: Journal of Organic Chemistry
https://www.readbyqxmd.com/read/29771491/modification-of-side-chains-of-conjugated-molecules-and-polymers-for-charge-mobility-enhancement-and-sensing-functionality
#16
Zitong Liu, Guanxin Zhang, Deqing Zhang
Organic semiconductors have received increasing attentions in recent years because of their promising applications in various optoelectronic devices. The key performance metric for organic semiconductors is charge carrier mobility, which is governed by the electronic structures of conjugated backbones and intermolecular/interchain π-π interactions and packing in both microscopic and macroscopic levels. For this reason, more efforts have been paid to the design and synthesis of conjugated frameworks for organic semiconductors with high charge mobilities...
May 17, 2018: Accounts of Chemical Research
https://www.readbyqxmd.com/read/29771460/targeting-prostate-cancer-prostate-specific-membrane-antigen-based-diagnosis-and-therapy
#17
REVIEW
Till Wüstemann, Uwe Haberkorn, John Babich, Walter Mier
The high incidence rates of prostate cancer (PCa) raise demand for improved therapeutic strategies. Prostate tumors specifically express the prostate-specific membrane antigen (PSMA), a membrane-bound protease. As PSMA is highly overexpressed on malignant prostate tumor cells and as its expression rate correlates with the aggressiveness of the disease, this tumor-associated biomarker provides the possibility to develop new strategies for diagnostics and therapy of PCa. Major advances have been made in PSMA targeting, ranging from immunotherapeutic approaches to therapeutic small molecules...
May 17, 2018: Medicinal Research Reviews
https://www.readbyqxmd.com/read/29771363/multiple-sequence-alignment-averaging-improves-phylogeny-reconstruction
#18
Haim Ashkenazy, Itamar Sela, Eli Levy Karin, Giddy Landan, Tal Pupko
The classic methodology of inferring a phylogenetic tree from sequence data is composed of two steps. First, a multiple sequence alignment (MSA) is computed. Then, a tree is reconstructed assuming the MSA is correct. Yet, inferred MSAs were shown to be inaccurate and alignment errors reduce tree inference accuracy. It was previously proposed that filtering unreliable alignment regions can increase the accuracy of tree inference. However, it was also demonstrated that the benefit of this filtering is often obscured by the resulting loss of phylogenetic signal...
May 15, 2018: Systematic Biology
https://www.readbyqxmd.com/read/29771317/exon-skipping-advances-for-duchenne-muscular-dystrophy
#19
Lucía Echevarría, Philippine Aupy, Aurélie Goyenvalle
Duchenne muscular dystrophy (DMD) is a fatal genetic disorder characterized by progressive muscle wasting that has currently no cure. Exon-skipping strategy represents one of the most promising therapeutic approaches that aims to restore expression of a shorter but functional dystrophin protein. The antisense field has remarkably progress over the last years with recent accelerated approval of the first ASO-based therapy for DMD, Exondys 51, though the therapeutic benefit remains to be proven in patients. Despite clinical advances, the poor effective delivery to target all muscle remains the main hurdle for antisense drug therapy...
May 16, 2018: Human Molecular Genetics
https://www.readbyqxmd.com/read/29771306/drug-screening-for-human-genetic-diseases-using-ipsc-models
#20
Matthew S Elitt, Lilianne Barbar, Paul J Tesar
Induced pluripotent stem cells (iPSCs) enable the generation of previously unattainable, scalable quantities of disease-relevant tissues from patients suffering from essentially any genetic disorder. This cellular material has proven instrumental for drug screening efforts on these disorders, and has facilitated the identification of novel therapeutics for patients. Here we will review the foundational technologies that have enabled iPSCs, the power and limitations of iPSC-based compound screens along with screening guidelines, and recent examples of screening efforts...
May 16, 2018: Human Molecular Genetics
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