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1.
Mol Imaging Biol ; 24(1): 157-166, 2022 02.
Artigo em Inglês | MEDLINE | ID: mdl-34542805

RESUMO

PURPOSE: In this study we compared the recently developed TSPO tracer [18F]F-DPA, with [18F]DPA-714 and [11C]PBR28 by performing in vivo PET imaging on the same Alzheimer's disease mouse model APP/PS1-21 (TG) and wild-type (WT) mice with all three radiotracers. PROCEDURES: To compare the radiotracer uptake, percentage of injected dose/mL (%ID/mL), standardized uptake value ratios to cerebellum (SUVRCB), and voxel-wise analyses were performed. RESULTS: The peak uptake of [18F]F-DPA was higher than 4.3% ID/mL, while [18F]DPA-714 reached just over 3% ID/mL, and [11C]PBR28 was over 4% ID/mL in only one brain region in the WT mice. The peak/60-min uptake ratios of [18F]F-DPA were significantly higher (p < 0.001) than those of [18F]DPA-714 and [11C]PBR28. The differences in [18F]F-DPA SUVRCB between WT and TG mice were highly significant (p < 0.001) in the three studied time periods after injection. [18F]DPA-714 uptake was significantly higher in TG mice starting in the 20-40-min timeframe and increased thereafter, whereas [11C]PBR28 uptake became significant at 10-20 min (p < 0.05). The voxel-wise analysis confirmed the differences between the radiotracers. CONCLUSIONS: [18F]F-DPA displays higher brain uptake, higher TG-to-WT SUVRCB ratios, and faster clearance than [18F]DPA-714 and [11C]PBR28, and could prove useful for detecting low levels of inflammation and allow for shorter dynamic PET scans.


Assuntos
Doença de Alzheimer , Doença de Alzheimer/diagnóstico por imagem , Animais , Encéfalo/diagnóstico por imagem , Camundongos , Tomografia por Emissão de Pósitrons/métodos , Pirazóis , Pirimidinas
2.
Materials (Basel) ; 15(20)2022 Oct 20.
Artigo em Inglês | MEDLINE | ID: mdl-36295411

RESUMO

Flip-chip bonding is a key packaging technology to achieve the smallest form factor possible. Using copper as a direct under-bump metal and performing bonding under little force and at a low temperature eliminates the processing step for the deposition of a suitable wetting metal and offers an economical solution for electronic chip packaging. In this paper, various samples with copper and nickel-gold surface finishes are used to apply an in-house solder bumping, flip-chip bonding and reflow process to exhibit the bump-bond feasibility. Native oxides are reduced using process gases, and copper surface protection and solder wetting are achieved using copper formate. Lead-free 40 µm solder balls were bumped on 80 µm copper pads and 120 µm copper pillars to demonstrate a full intermetallic Cu-Cu bond as a base study for stacking applications. Using a low-force bonding technique, various chips with different dimensions were bonded at 0.5-16 MPa, followed by a reflow step at a maximum temperature of 270 °C. Then, 30 µm solder balls are utilized to bump the samples with NiAu and Cu bond pads at 50 µm pitch. A mean shear strength of 44 MPa was obtained for the 30 µm Cu samples. To the best of our knowledge, 30 µm solder bumping directly on the copper pads by producing copper formate is a novel research contribution.

4.
Toxics ; 10(8)2022 Jul 28.
Artigo em Inglês | MEDLINE | ID: mdl-36006103

RESUMO

Suicide by helium inhalation has become increasingly common in the last few decades in Europe and the US because it produces a quick and painless death. Inhaled-gas suicides can easily be assessed through death scene investigation and autopsy. However, helium is a colorless and odorless inert gas that unfortunately cannot be detected using standard toxicological analysis. A successful gas analysis was performed following the suicide of a 17-year-old female. For the detection of helium, central/peripheral blood samples and gaseous samples from the esophagus, stomach, and upper and lower respiratory airways (from the trachea and the primary left and right bronchia) were collected with a gastight syringe, ensuring minimal dilution. Qualitative analyses were positive in all gaseous samples. Quantitative analyses were performed using a special gas-inlet system with a vacuum by which the sample can be transferred to a mass spectrometer, reducing the risk of contamination. Helium concentrations were 20.16% from the trachea, 12.33% from the right lung, and 1.5% from the stomach. Based on the high levels of helium, the cause and manner of death were assessed as asphyxia suicide by inhalation of helium. Therefore, toxicological analyses should always be applied in order to gain evidence of inhaled gas in gaseous samples.

5.
Adv Mater ; 34(35): e2202971, 2022 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-35817958

RESUMO

Devices with tunable magnetic noncollinearity are important components of superconducting electronics and spintronics, but they typically require epitaxial integration of several complex materials. The spin-polarized neutron reflectometry measurements on La1-x Srx MnO3 homojunction arrays with modulated Sr concentration reported herein have led to the discovery of magnetic fan structures with highly noncollinear alignment of Mn spins and an emergent periodicity twice as large as the array's unit cell. The neutron data show that these magnetic superstructures can be fully long-range ordered, despite the gradual modulation of the doping level created by charge transfer and chemical intermixing. The degree of noncollinearity can be effectively adjusted by low magnetic fields. Notwithstanding their chemical and structural simplicity, oxide homojunctions thus show considerable promise as a platform for tunable complex magnetism and as a powerful design element of spintronic devices.

6.
Microbiol Spectr ; 10(3): e0070222, 2022 06 29.
Artigo em Inglês | MEDLINE | ID: mdl-35652638

RESUMO

Human toxoplasmosis is a life-threatening disease caused by the apicomplexan parasite Toxoplasma gondii. Rapid replication of the tachyzoite is associated with symptomatic disease, while suppressed division of the bradyzoite is responsible for chronic disease. Here, we identified the T. gondii cell cycle mechanism, the G1 restriction checkpoint (R-point), that operates the switch between parasite growth and differentiation. Apicomplexans lack conventional R-point regulators, suggesting adaptation of alternative factors. We showed that Cdk-related G1 kinase TgCrk2 forms alternative complexes with atypical cyclins (TgCycP1, TgCycP2, and TgCyc5) in the rapidly dividing developmentally incompetent RH and slower dividing developmentally competent ME49 tachyzoites and bradyzoites. Examination of cyclins verified the correlation of cyclin expression with growth dependence and development capacity of RH and ME49 strains. We demonstrated that rapidly dividing RH tachyzoites were dependent on TgCycP1 expression, which interfered with bradyzoite differentiation. Using the conditional knockdown model, we established that TgCycP2 regulated G1 duration in the developmentally competent ME49 tachyzoites but not in the developmentally incompetent RH tachyzoites. We tested the functions of TgCycP2 and TgCyc5 in alkaline induced and spontaneous bradyzoite differentiation (rat embryonic brain cells) models. Based on functional and global gene expression analyses, we determined that TgCycP2 also regulated bradyzoite replication, while signal-induced TgCyc5 was critical for efficient tissue cyst maturation. In conclusion, we identified the central machinery of the T. gondii restriction checkpoint comprised of TgCrk2 kinase and three atypical T. gondii cyclins and demonstrated the independent roles of TgCycP1, TgCycP2, and TgCyc5 in parasite growth and development. IMPORTANCE Toxoplasma gondii is a virulent and abundant human pathogen that puts millions of silently infected people at risk of reactivation of the chronic disease. Encysted bradyzoites formed during the chronic stage are resistant to current therapies. Therefore, insights into the mechanism of tissue cyst formation and reactivation are major areas of investigation. The fact that rapidly dividing parasites differentiate poorly strongly suggests that there is a threshold of replication rate that must be crossed to be considered for differentiation. We discovered a cell cycle mechanism that controls the T. gondii growth-rest switch involved in the conversion of dividing tachyzoites into largely quiescent bradyzoites. This switch operates the T. gondii restriction checkpoint using a set of atypical and parasite-specific regulators. Importantly, the novel T. gondii R-point network was not present in the parasite's human and animal hosts, offering a wealth of new and parasite-specific drug targets to explore in the future.


Assuntos
Toxoplasma , Toxoplasmose , Animais , Ciclo Celular , Diferenciação Celular , Ciclinas/metabolismo , Humanos , Ratos , Toxoplasma/genética
7.
Artigo em Inglês | MEDLINE | ID: mdl-35703571

RESUMO

A significant body of research has demonstrated that mentoring relationships support positive youth development. The quality of the mentoring relationship has been identified as a predictor of positive youth outcomes. However, limited research has examined how engagement in a mentoring program may be related to youth depressive symptoms specifically. The current study utilized a sample of 2003 youth participating in mentoring programs across the country (Mage = 12.32, SD = 1.42, 55.1% female) from diverse racial and ethnic backgrounds (39.1% Black, 23.6% White, 22.1% Hispanic, 3.3% Native American or Alaskan Native, .4% Asian or Pacific Islander, 1.8% other, and 9.7% Multi-Ethnic) to investigate associations between youth depressive symptoms and mentoring relationship quality. Results revealed that: (1) mean depressive symptoms decreased after participation in a mentoring program; (2) several, but not all, relationship quality indicators predicted change in depressive symptoms; (3) baseline levels of depressive symptoms negatively predicted indicators of relationship quality; and (4) associations between several relationship quality indicators and follow-up depressive symptoms differed by baseline levels of depressive symptoms. These findings highlight the potential benefits of mentoring programs to youth and the need to provide mentors with support around building relationships with youth, especially those experiencing depressive symptoms.

8.
Proc Natl Acad Sci U S A ; 119(21): e2117699119, 2022 05 24.
Artigo em Inglês | MEDLINE | ID: mdl-35576469

RESUMO

Mechanization has greatly contributed to the success of modern agriculture, with vastly expanded food production capabilities achieved by the higher capacity of farm machinery. However, the increase in capacity has been accompanied by higher vehicle weights that increase risks of subsoil compaction. We show here that while surface contact stresses remained nearly constant over the course of modern mechanization, subsoil stresses have propagated into deeper soil layers and now exceed safe mechanical limits for soil ecological functioning. We developed a global map for delineating subsoil compaction susceptibility based on estimates of mechanization level, mean tractor size, soil texture, and climatic conditions. The alarming trend of chronic subsoil compaction risk over 20% of arable land, with potential loss of productivity, calls for a more stringent design of farm machinery that considers intrinsic subsoil mechanical limits. As the total weight of modern harvesters is now approaching that of the largest animals that walked Earth, the sauropods, a paradox emerges of potential prehistoric subsoil compaction. We hypothesize that unconstrained roaming of sauropods would have had similar adverse effects on land productivity as modern farm vehicles, suggesting that ecological strategies for reducing subsoil compaction, including fixed foraging trails, must have guided these prehistoric giants.


Assuntos
Produção Agrícola , Veículos Automotores , Solo , Fazendas , Propriedades de Superfície
9.
Mol Imaging Biol ; 24(4): 641-650, 2022 08.
Artigo em Inglês | MEDLINE | ID: mdl-35303205

RESUMO

PURPOSE: Recent studies have linked activated spinal glia to neuropathic pain. Here, using a positron emission tomography (PET) scanner with high spatial resolution and sensitivity, we evaluated the feasibility and sensitivity of N,N-diethyl-2-(2-(4-([18F]fluoro)phenyl)-5,7-dimethylpyrazolo[1,5-a] pyrimidin-3-yl)acetamide ([18F]F-DPA) imaging for detecting spinal cord microglial activation after partial sciatic nerve ligation (PSNL) in rats. PROCEDURES: Neuropathic pain was induced in rats (n = 20) by PSNL, and pain sensation tests were conducted before surgery and 3 and 7 days post-injury. On day 7, in vivo PET imaging and ex vivo autoradiography were performed using [18F]F-DPA or [11C]PK11195. Ex vivo biodistribution and PET imaging of the removed spinal cord were carried out with [18F]F-DPA. Sham-operated and PK11195-pretreated animals were also examined. RESULTS: Mechanical allodynia was confirmed in the PSNL rats from day 3 through day 7. Ex vivo autoradiography showed a higher lesion-to-background uptake with [18F]F-DPA compared with [11C]PK11195. Ex vivo PET imaging of the removed spinal cord showed [18F]F-DPA accumulation in the inflammation site, which was immunohistochemically confirmed to coincide with microglia activation. Pretreatment with PK11195 eliminated the uptake. The SUV values of in vivo [18F]F-DPA and [11C]PK11195 PET were not significantly increased in the lesion compared with the reference region, and were fivefold higher than the values obtained from the ex vivo data. Ex vivo biodistribution revealed a twofold higher [18F]F-DPA uptake in the vertebral body compared to that seen in the bone from the skull. CONCLUSIONS: [18F]F-DPA aided visualization of the spinal cord inflammation site in PSNL rats on ex vivo autoradiography and was superior to [11C]PK11195. In vivo [18F]F-DPA PET did not allow for visualization of tracer accumulation even using a high-spatial-resolution PET scanner. The main reason for this result was due to insufficient SUVs in the spinal cord region as compared with the background noise, in addition to a spillover from the vertebral body.


Assuntos
Microglia , Neuralgia , Animais , Radioisótopos de Flúor , Microglia/patologia , Neuralgia/diagnóstico por imagem , Neuralgia/patologia , Tomografia por Emissão de Pósitrons/métodos , Pirazóis , Pirimidinas , Ratos , Medula Espinal/diagnóstico por imagem , Distribuição Tecidual
10.
Adv Sci (Weinh) ; 9(8): e2105432, 2022 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-35289133

RESUMO

The synthesis of hierarchically porous materials usually requires complex experimental procedures, often based around extensive trial and error approaches. One common synthesis strategy is the sol-gel method, although the relation between synthesis parameters, material structure and function has not been widely explored. Here, in situ 2D hard X-ray ptychography (XRP) and 3D ptychographic X-ray computed tomography (PXCT) are applied to monitor the development of hierarchical porosity in Ni/Al2 O3 and Al2 O3 catalysts with connected meso- and macropore networks. In situ XRP allows to follow textural changes of a dried gel Ni/Al2 O3 sample as a function of temperature during calcination, activation and CO2 methanation reaction. Complementary PXCT studies on dried gel particles of Ni/Al2 O3 and Al2 O3 provide quantitative information on pore structure, size distribution, and shape with 3D spatial resolution approaching 50 nm, while identical particles are imaged ex situ before and after calcination. The X-ray imaging results are correlated with N2 -sorption, Hg porosimetry and He pycnometry pore characterization. Hard X-ray nanotomography is highlighted to derive fine structural details including tortuosity, branching nodes, and closed pores, which are relevant in understanding transport phenomena during chemical reactions. XRP and PXCT are enabling technologies to understand complex synthesis pathways of porous materials.

11.
Blood ; 139(19): 2942-2957, 2022 05 12.
Artigo em Inglês | MEDLINE | ID: mdl-35245372

RESUMO

The hematopoietic stem cells (HSCs) that produce blood for the lifetime of an animal arise from RUNX1+ hemogenic endothelial cells (HECs) in the embryonic vasculature through a process of endothelial-to-hematopoietic transition (EHT). Studies have identified inflammatory mediators and fluid shear forces as critical environmental stimuli for EHT, raising the question of how such diverse inputs are integrated to drive HEC specification. Endothelial cell MEKK3-KLF2/4 signaling can be activated by both fluid shear forces and inflammatory mediators, and it plays roles in cardiovascular development and disease that have been linked to both stimuli. Here we demonstrate that MEKK3 and KLF2/4 are required in endothelial cells for the specification of RUNX1+ HECs in both the yolk sac and dorsal aorta of the mouse embryo and for their transition to intraaortic hematopoietic cluster (IAHC) cells. The inflammatory mediators lipopolysaccharide and interferon-γ increase RUNX1+ HECs in an MEKK3-dependent manner. Maternal administration of catecholamines that stimulate embryo cardiac function and accelerate yolk sac vascular remodeling increases EHT by wild-type but not MEKK3-deficient endothelium. These findings identify MEKK-KLF2/4 signaling as an essential pathway for EHT and provide a molecular basis for the integration of diverse environmental inputs, such as inflammatory mediators and hemodynamic forces, during definitive hematopoiesis.


Assuntos
Subunidade alfa 2 de Fator de Ligação ao Core , Hemangioblastos , Hematopoese , Animais , Diferenciação Celular , Subunidade alfa 2 de Fator de Ligação ao Core/metabolismo , Endotélio/metabolismo , Hemangioblastos/citologia , Hemangioblastos/metabolismo , Hemodinâmica , Mediadores da Inflamação/metabolismo , Fatores de Transcrição Kruppel-Like/genética , Fatores de Transcrição Kruppel-Like/metabolismo , MAP Quinase Quinase Quinase 3/metabolismo , Camundongos
12.
PLoS One ; 17(1): e0262656, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-35051208

RESUMO

SARS-CoV-2, the cause of COVID-19, requires reliable diagnostic methods to track the circulation of this virus. Following the development of RT-qPCR methods to meet this diagnostic need in January 2020, it became clear from interlaboratory studies that the reported Ct values obtained for the different laboratories showed high variability. Despite this the Ct values were explored as a quantitative cut off to aid clinical decisions based on viral load. Consequently, there was a need to introduce standards to support estimation of SARS-CoV-2 viral load in diagnostic specimens. In a collaborative study, INSTAND established two reference materials (RMs) containing heat-inactivated SARS-CoV-2 with SARS-CoV-2 RNA loads of ~107 copies/mL (RM 1) and ~106 copies/mL (RM 2), respectively. Quantification was performed by RT-qPCR using synthetic SARS-CoV-2 RNA standards and digital PCR. Between November 2020 and February 2021, German laboratories were invited to use the two RMs to anchor their Ct values measured in routine diagnostic specimens, with the Ct values of the two RMs. A total of 305 laboratories in Germany were supplied with RM 1 and RM 2. The laboratories were requested to report their measured Ct values together with details on the PCR method they used to INSTAND. This resultant 1,109 data sets were differentiated by test system and targeted gene region. Our findings demonstrate that an indispensable prerequisite for linking Ct values to SARS-CoV-2 viral loads is that they are treated as being unique to an individual laboratory. For this reason, clinical guidance based on viral loads should not cite Ct values. The RMs described were a suitable tool to determine the specific laboratory Ct for a given viral load. Furthermore, as Ct values can also vary between runs when using the same instrument, such RMs could be used as run controls to ensure reproducibility of the quantitative measurements.


Assuntos
Teste de Ácido Nucleico para COVID-19/métodos , COVID-19/diagnóstico , Testes Diagnósticos de Rotina/métodos , RNA Viral/genética , Reação em Cadeia da Polimerase Via Transcriptase Reversa/métodos , SARS-CoV-2/genética , Carga Viral/métodos , COVID-19/epidemiologia , COVID-19/virologia , Genes Virais , Alemanha/epidemiologia , Humanos , Reprodutibilidade dos Testes
13.
Eur Urol Oncol ; 5(3): 321-327, 2022 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-33422560

RESUMO

BACKGROUND: Prostate-specific antigen (PSA)-based detection of prostate cancer (PCa) often leads to negative biopsy results or detection of clinically insignificant PCa, more frequently in the PSA range of 2-10 ng/ml, in men with increased prostate volume and normal digital rectal examination (DRE). OBJECTIVE: This study evaluated the accuracy of Proclarix, a novel blood-based diagnostic test, to help in biopsy decision-making in this challenging patient population. DESIGN, SETTING, AND PARTICIPANTS: Ten clinical sites prospectively enrolled 457 men presenting for prostate biopsy with PSA between 2 and 10 ng/ml, normal DRE, and prostate volume ≥35 cm3. Transrectal ultrasound-guided and multiparametric magnetic resonance imaging (mpMRI)-guided biopsy techniques were allowed. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: Serum samples were tested blindly at the end of the study. Diagnostic performance of Proclarix risk score was established in correlation to systematic biopsy outcome and its performance compared with %free PSA (%fPSA) and the European Randomised Study of Screening for Prostate Cancer (ERSPC) risk calculator (RC) as well as Proclarix density compared with PSA density in men undergoing mpMRI. RESULTS AND LIMITATIONS: The sensitivity of Proclarix risk score for clinically significant PCa (csPCa) defined as grade group (GG) ≥2 was 91% (n = 362), with higher specificity than both %fPSA (22% vs 14%; difference = 8% [95% confidence interval {CI}, 2.6-14%], p = 0.005) and RC (22% vs 15%; difference = 7% [95% CI, 0.7-12%], p = 0.028). In the subset of men undergoing mpMRI-fusion biopsy (n = 121), the specificity of Proclarix risk score was significantly higher than PSA density (26% vs 8%; difference = 18% [95% CI, 7-28%], p < 0.001), and at equal sensitivity of 97%, Proclarix density had an even higher specificity of 33% [95% CI, 23-43%]. CONCLUSIONS: In a routine use setting, Proclarix accurately discriminated csPCa from no or insignificant PCa in the most challenging patients. Proclarix represents a valuable rule-out test in the diagnostic algorithm for PCa, alone or in combination with mpMRI. PATIENT SUMMARY: Proclarix is a novel blood-based test with the potential to accurately rule out clinically significant prostate cancer, and therefore to reduce the number of unneeded biopsies.


Assuntos
Imageamento por Ressonância Magnética Multiparamétrica , Neoplasias da Próstata , Humanos , Biópsia Guiada por Imagem/métodos , Masculino , Estudos Prospectivos , Antígeno Prostático Específico , Neoplasias da Próstata/patologia
14.
Protein Sci ; 31(2): 422-431, 2022 02.
Artigo em Inglês | MEDLINE | ID: mdl-34761455

RESUMO

Human eyes absent (EYA) proteins possess Tyr phosphatase activity, which is critical for numerous cancer and metastasis promoting activities, making it an attractive target for cancer therapy. In this work, we demonstrate that the inhibitor-bound form of EYA2 does not favour binding to Mg2+ , which is indispensable for the Tyr phosphatase activity. We further describe characterization and optimization of this class of allosteric inhibitors. A series of analogues were synthesized to improve potency of the inhibitors and to elucidate structure-activity relationships. Two co-crystal structures confirm the binding modes of this class of inhibitors. Our medicinal chemical, structural, biochemical, and biophysical studies provide insight into the molecular interactions of EYA2 with these allosteric inhibitors. The compounds derived from this study are useful for exploring the function of the Tyr phosphatase activity of EYA2 in normal and cancerous cells and serve as reference compounds for screening or developing allosteric phosphatase inhibitors. Finally, the co-crystal structures reported in this study will aid in structure-based drug discovery against EYA2.


Assuntos
Peptídeos e Proteínas de Sinalização Intracelular , Proteínas Nucleares , Proteínas Tirosina Fosfatases , Inibidores Enzimáticos/química , Humanos , Peptídeos e Proteínas de Sinalização Intracelular/antagonistas & inibidores , Peptídeos e Proteínas de Sinalização Intracelular/química , Proteínas Nucleares/antagonistas & inibidores , Proteínas Nucleares/química , Proteínas Tirosina Fosfatases/antagonistas & inibidores , Proteínas Tirosina Fosfatases/química , Relação Estrutura-Atividade
15.
J Community Psychol ; 50(3): 1579-1596, 2022 04.
Artigo em Inglês | MEDLINE | ID: mdl-34735021

RESUMO

This study sought to examine how social class bias may be enacted by mentors and mentoring program staff within community-based youth mentoring relationships and how these biases may influence the mentoring relationship. A narrative thematic analysis was conducted with interviews from mentors, mentees' parents/caregivers, and mentoring program staff representing 36 matches participating in a larger, prospective, mixed-methods study examining factors associated with early match closures. Findings indicate that although some mentors were able to partner with the youth and family to effectively navigate challenges related to the family's economic circumstances, other mentors and some mentoring program staff held deficit views of the youth and their family that appeared to be at least partially rooted in negative social class-based assumptions about attitudes and behaviors. Specifically, we observed tendencies on the part of some mentors and program staff toward (a) deficit-based views of families and youth, (b) individual-level attributions for the family's economic circumstances and blaming of caregivers, and (c) perceiving mentors as being underappreciated by the youth's caregiver. These deficit perspectives contributed to the minimization of parent/caregiver voice in the mentoring process and negative interpretations of parent/caregiver and, in some cases, youth attitudes and behaviors.


Assuntos
Tutoria , Adolescente , Viés , Humanos , Relações Interpessoais , Mentores , Avaliação de Programas e Projetos de Saúde , Estudos Prospectivos , Pesquisa Qualitativa , Classe Social
16.
Sci Total Environ ; 807(Pt 1): 150763, 2022 Feb 10.
Artigo em Inglês | MEDLINE | ID: mdl-34619198

RESUMO

The use of heavy farm machinery has resulted in widespread soil compaction in many regions of the world. Compacted soil limits the access of crops to soil water and nutrients and is expected to reduce crop productivity, but the influence of weather conditions on the interactions between compacted soil and crop productivity is unclear. Furthermore, early vigor has been regarded as a promising trait for improving the yield of crops grown under edaphic stress such as soil compaction. We aimed to assess the combined effects of soil compaction and contrasting weather conditions on growth and grain yield of spring wheat, and to evaluate the association between early vigor and grain yield under temporal variations of the soil physical conditions. Nine spring wheat genotypes were grown on compacted and non-compacted soils during two cropping seasons with contrasting weather conditions in Central Sweden. Compared to the non-compacted treatment, soil compaction increased the relative growth rate of shoot biomass from sowing to stem elongation, and from stem elongation to flowering in the drier year (2018), but decreased the same traits in the wetter year (2019). The contrasting effects of soil compaction on shoot growth in the two years could be explained by soil moisture and penetration resistance associated with the interactive effects of soil compaction and weather condition. Higher early vigor, here indicated by higher relative growth rate from sowing to stem elongation, was associated with reduced grain yield under the progressively drying and hardening soil conditions during the entire cropping season of both years. We conclude that the interactive effects of soil physical and weather conditions need to be considered when evaluating the impact of soil compaction on crop growth and productivity. The potential of early vigor to increase grain yield is strongly influenced by the temporal dynamics of soil physical conditions.


Assuntos
Solo , Triticum , Produtos Agrícolas , Grão Comestível , Tempo (Meteorologia)
17.
Chronic Obstr Pulm Dis ; 9(1): 55-67, 2022 Jan 27.
Artigo em Inglês | MEDLINE | ID: mdl-34915603

RESUMO

RATIONALE: Large gaps exist between guideline-recommended outpatient chronic obstructive pulmonary disease (COPD) care and clinical practice. Seeking to design effective interventions, we identified patient and primary care provider (PCP) characteristics associated with receiving evidence-based COPD care. METHODS: We performed an observational study of adults aged ≥ 40 years with clinically diagnosed COPD who received care at 2 University of Washington-affiliated primary care clinics between June 1, 2011, and June 1, 2013. Our primary outcome was the proportion of evidence-based outpatient COPD quality measures received through primary or pulmonary care. Among all patients, we assessed spirometry completion, respiratory symptom identification, smoking status ascertainment, oxygen saturation measurement, and guideline-concordant inhaled therapy prescription. We also determined confirmation of airflow obstruction, oxygen prescription, smoking cessation intervention, and pulmonary rehabilitation referral if eligible. We used multivariable mixed effects linear regression to estimate the association of patient and PCP characteristics with the primary outcome. RESULTS: Among 641 patients, 382 were male (59.6%) with mean age 63.6 (standard deviation [SD] 10.6) years. Most patients currently smoked (N=386, 60.2%). Patients saw 150 unique PCPs during 5.3 (SD 3.2) PCP visits, with 107 completing pulmonary referrals (16.7%). Patients received 67.5% (SD 18.4%) of eligible (median 7 [interquartile range 6-7]) evidence-based quality measures. After adjustment, pulmonary referral was associated with a higher receipt of outpatient quality measures (ß117.7%, 95% confidence interval: 12.6%, 22.7%). Patient demographics, comorbidities, and PCP identity/characteristics were not associated with outpatient care quality. CONCLUSIONS: The quality of outpatient COPD care was suboptimal. Future studies should investigate if engaging pulmonologists in COPD management improves care quality.

18.
J Cell Sci ; 134(24)2021 12 15.
Artigo em Inglês | MEDLINE | ID: mdl-34817055

RESUMO

Wnt signaling is essential for normal development and is a therapeutic target in cancer. The enzyme PORCN, or porcupine, is a membrane-bound O-acyltransferase (MBOAT) that is required for the post-translational modification of all Wnts, adding an essential mono-unsaturated palmitoleic acid to a serine on the tip of Wnt hairpin 2. Inherited mutations in PORCN cause focal dermal hypoplasia, and therapeutic inhibition of PORCN slows the growth of Wnt-dependent cancers. Based on homology to mammalian MBOAT proteins, we developed and validated a structural model of human PORCN. The model accommodates palmitoleoyl-CoA and Wnt hairpin 2 in two tunnels in the conserved catalytic core, shedding light on the catalytic mechanism. The model predicts how previously uncharacterized human variants of uncertain significance can alter PORCN function. Drugs including ETC-159, IWP-L6 and LGK-974 dock in the PORCN catalytic site, providing insights into PORCN pharmacologic inhibition. This structural model enhances our mechanistic understanding of PORCN substrate recognition and catalysis, as well as the inhibition of its enzymatic activity, and can facilitate the development of improved inhibitors and the understanding of disease-relevant PORCN mutants. This article has an associated First Person interview with the joint first authors of the paper.


Assuntos
Hipoplasia Dérmica Focal , Preparações Farmacêuticas , Aciltransferases/genética , Animais , Domínio Catalítico , Humanos , Proteínas de Membrana/genética , Modelos Estruturais
19.
Bioorg Med Chem ; 49: 116437, 2021 11 01.
Artigo em Inglês | MEDLINE | ID: mdl-34600239

RESUMO

AXL is a member of the TAM (TYRO3, AXL, MER) subfamily of receptor tyrosine kinases. It is upregulated in a variety of cancers and its overexpression is associated with poor disease prognosis and acquired drug resistance. Utilizing a fragment-based lead discovery approach, a new indazole-based AXL inhibitor was obtained. The indazole fragment hit 11, identified through a high concentration biochemical screen, was expeditiously improved to fragment 24 by screening our in-house expanded library of fragments (ELF) collection. Subsequent fragment optimization guided by docking studies provided potent inhibitor 54 with moderate exposure levels in mice. X-ray crystal structure of analog 50 complexed with the I650M mutated kinase domain of Mer revealed the key binding interactions for the scaffold. The good potency coupled with reasonable kinase selectivity, moderate in vivo exposure levels, and availability of structural information for the series makes it a suitable starting point for further optimization efforts.


Assuntos
Descoberta de Drogas , Indazóis/farmacologia , Inibidores de Proteínas Quinases/farmacologia , Proteínas Proto-Oncogênicas/antagonistas & inibidores , Receptores Proteína Tirosina Quinases/antagonistas & inibidores , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Relação Dose-Resposta a Droga , Humanos , Indazóis/síntese química , Indazóis/química , Modelos Moleculares , Estrutura Molecular , Inibidores de Proteínas Quinases/síntese química , Inibidores de Proteínas Quinases/química , Proteínas Proto-Oncogênicas/metabolismo , Receptores Proteína Tirosina Quinases/metabolismo , Relação Estrutura-Atividade
20.
J Exp Med ; 218(11)2021 11 01.
Artigo em Inglês | MEDLINE | ID: mdl-34617969

RESUMO

Glioblastoma ranks among the most lethal of primary brain malignancies, with glioblastoma stem cells (GSCs) at the apex of tumor cellular hierarchies. Here, to discover novel therapeutic GSC targets, we interrogated gene expression profiles from GSCs, differentiated glioblastoma cells (DGCs), and neural stem cells (NSCs), revealing EYA2 as preferentially expressed by GSCs. Targeting EYA2 impaired GSC maintenance and induced cell cycle arrest, apoptosis, and loss of self-renewal. EYA2 displayed novel localization to centrosomes in GSCs, and EYA2 tyrosine (Tyr) phosphatase activity was essential for proper mitotic spindle assembly and survival of GSCs. Inhibition of the EYA2 Tyr phosphatase activity, via genetic or pharmacological means, mimicked EYA2 loss in GSCs in vitro and extended the survival of tumor-bearing mice. Supporting the clinical relevance of these findings, EYA2 portends poor patient prognosis in glioblastoma. Collectively, our data indicate that EYA2 phosphatase function plays selective critical roles in the growth and survival of GSCs, potentially offering a high therapeutic index for EYA2 inhibitors.


Assuntos
Neoplasias Encefálicas/metabolismo , Glioblastoma/metabolismo , Peptídeos e Proteínas de Sinalização Intracelular/metabolismo , Células-Tronco Neoplásicas/metabolismo , Proteínas Nucleares/metabolismo , Proteínas Tirosina Fosfatases/metabolismo , Animais , Encéfalo/metabolismo , Morte Celular/fisiologia , Diferenciação Celular/fisiologia , Linhagem Celular Tumoral , Feminino , Regulação Neoplásica da Expressão Gênica/fisiologia , Humanos , Masculino , Camundongos , Células-Tronco Neurais/metabolismo
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