Search

Trace impurity patterns are important nuclear forensic signatures in uranium ore concentrates (UOCs) and Certified Reference Materials (CRMs) are used to validate the analysis methods employed by end users. Herein, we discuss the certification campaign for three new UOC CRMs from the National Research Council Canada: UCLO-1 (https://doi.org/10.4224/crm.2020.uclo-1), UCHI-1 (https://doi.org/10.4224/crm.2020.uchi-1), and UPER-1 (https://doi.org/10.4224/crm.2020.uper-1). This study involved 15 laboratories from 10 countries, using sector-field and (triple) quadrupole inductively-coupled plasma mass spectrometry to analyze 64 trace element impurities. We discuss the importance of the acids used for sample digestion, difficulties analyzing in a high uranium matrix, and data combination and uncertainty evaluation for this large dataset.

A workshop titled “Beyond the Symptom: The Biology of Fatigue” was held virtually September 27-28, 2021. It was jointly organized by the Sleep Research Society and the Neurobiology of Fatigue Working Group of the NIH Blueprint Neuroscience Research Program. For access to the presentations and video recordings, see: https : //neuroscienceblueprint.nih.gov/about/event/beyond-symptom-biology-fatigue. The goals of this workshop were to bring together clinicians and scientists who use a variety of research approaches to understand fatigue in multiple conditions and to identify key gaps in our understanding of the biology of fatigue. This workshop summary distills key issues discussed in this workshop and provides a list of promising directions for future research on this topic. We do not attempt to provide a comprehensive review of the state of our understanding of fatigue, nor to provide a comprehensive reprise of the many excellent presentations. Rather, our goal is to highlight key advances and to focus on questions and future approaches to answering them.

Phosphoinositide-3-kinase γ (PI3Kγ) is highly expressed in immune cells and promotes the production and migration of inflammatory mediators. The inhibition of PI3Kγ has been shown to repolarize the tumor immune microenvironment to a more inflammatory phenotype, thereby controlling immune suppression in cancer. Herein, we report the structure-based optimization of an early lead series of pyrazolopyrimidine isoindolinones, which culminated in the discovery of highly potent and isoform-selective PI3Kγ inhibitors with favorable drug-like properties. X-ray cocrystal structure analysis, molecular docking studies, and detailed structure-activity relationship investigations resulted in the identification of the optimal amide and isoindolinone substituents to achieve a desirable combination of potency, selectivity, and metabolic stability. Preliminary in vitro studies indicate that inhibition of PI3Kγ with compound 56 results in a significant immune response by increasing pro-inflammatory cytokine gene expression in M1 macrophages.

Scaffolds for bone tissue applications have been an outstanding alternative to repair and regenerate bone tissue defects caused by traumas or illness. There are many methods available to fabricate porous scaffold such as solvent casting, gas bubble, phase separation, electrospinning, particle-leaching, among others. The particle-leaching technique has shown advantages in bone tissue regeneration applications, the main benefit of this technique is related to the porogen particle size and the porogen content in the manufacture of scaffolds. Tricalcium phosphate is one calcium phosphate that presented appropriated characteristic to be used for bone tissue engineering due to the chemical properties similar to the human bones. Scaffolds of tricalcium phosphate β phase were made using sugar particles. The porogen was varied in amounts of 50, 60 and 70 wt.% of two commercial sugars with the remainder of the composition made up of tricalcium phosphate powders. The pore sizes in all the scaffolds were in the range of 90 to 600 μm with an irregular pore morphology and the porosity was in the range of 63 to 77%.

A novel hoof disease of elk (Cervus elaphus) was described in southwestern Washington, US, in 2008 and was subsequently diagnosed in an adjacent area in northwestern Oregon in 2014. The disease, currently referred to as treponeme-associated hoof disease (TAHD), is characterized by lesions ranging from mild erosions, to severe ulcers with underrunning of the hoof capsule and heel-sole junction, to overgrown and avulsed hoof capsules. Histologically, lesions exhibit epithelial erosion or ulceration, suppurative inflammation, and the presence of argyrophilic spirochetes. We used data collected by the Washington Department of Fish and Wildlife and Oregon Department of Fish and Wildlife from 2008 to 2017 as reference for disease distribution. We then conducted enhanced surveillance in 2018-20 by obtaining 164 submissions from four US Pacific West states. We detected TAHD for the first time in Idaho and northern California, as well as in multiple counties in Washington and Oregon where it had not been previously reported. Given the unexpectedly broad disease distribution, continued surveillance is warranted to determine the full geographic extent of TAHD. From samples of 22 elk, we investigated 16S rRNA gene amplicon sequencing as a technique that could be used to supplement TAHD surveillance. Operational taxonomic units of the family Spirochaetaceae were identified in 10 of 12 histologically diagnosed TAHD-positive cases and two of 10 TAHD-negative cases. Phyla Spirochaetae (P0.008), Fusobacteria (P0.006), and Tenericutes (P0.01) were overrepresented in samples from TAHD-positive feet when compared with TAHD-negative elk. A unique spirochete, PT19, was detected in hooves of 11 elk and from at least one elk in each state. Results support the use of 16S rRNA gene amplicon sequencing as a reliable and informative tool to supplement investigations into distribution and etiology of this presumed polybacterial disease.

Little research regarding the influence of parental knowledge and attitudes about child development on parenting practices includes fathers. The wartime military provides a specific context for fathering with frequent separations, which may impact soldiers’ knowledge and attitudes about their young children’s development. The purpose of the current study is to explore how military fathers’ knowledge and attitudes about their young children’s development influence their parenting behaviors across the deployment cycle. Fifteen active duty U.S. Army fathers with young children completed qualitative interviews, which were coded and analyzed to identify major themes. Many fathers had accurate knowledge of typical development and adapted their parenting responsively. Some knew less and were unsure how to respond to their children’s behavior. Many believed separations did not negatively affect young children. This attitude may reduce concern about deployment’s impact and keep these fathers mission-focused, but may also lead to missed opportunities to prepare young children for transitions. Overall, these fathers wanted to be involved, responsive parents. While many faced challenges navigating parenting throughout the deployment cycle, nearly all described positive adaptation, often with support from the homefront parent. These findings suggest that efforts to enhance military fathers’ knowledge should be tied to their children’s developmental stages and needs, focusing on parenting within the military context. Practitioners can respect Army families’ cultural values by aligning family readiness as necessary to mission readiness.

Psoroptes are a non-burrowing, ectoparasitic, mange-causing mite that has been documented in American bighorn sheep populations throughout the 19th and 20th centuries; however, it was not seen on Canadian bighorn sheep until 2006. The aim of this study was to determine the potential source of the Psoroptes outbreak in Canadian bighorn sheep. Morphological and molecular analyses were used to compare mites recovered from outbreak-associated bighorn sheep, pet rabbits in Canada, and on historically infested bighorn sheep in the USA. The results revealed that Psoroptes acquired from the Canadian and outbreak-associated American bighorn sheep were morphologically more similar to those collected from rabbits than mites on historically infested bighorn sheep. Outer opisthosomal setae lengths measured an average of 81.7 μm (±7.7 μm) in outbreak associated bighorn mites, 88.9 μm (±12.0 μm) in rabbit mites and 151.2 μm (±16.6 μm) in historically infested bighorn mites. The opisthosomal lobe morphology of bighorn mites in the outbreak herds was also more similar to that of rabbit mites, previously described as P. cuniculi, than historically infested bighorn mites, which match previous descriptions of P. ovis. This finding was supported by DNA sequence data of the mitochondrial cytochrome B gene. This is the first report of Psoroptes of the rabbit ecotype on bighorn sheep. The morphological and molecular data therefore support the hypothesis that the source of Psoroptes outbreak in Canadian bighorn sheep represented a disease spillover event from rabbits rather than transmission from infested American bighorn sheep populations.

KCNQ1 (Kv7.1 or KvLQT1) is a voltage-gated potassium ion channel that is involved in the ventricular repolarization following an action potential in the heart. It forms a complex with KCNE1 in the heart and is the pore forming subunit of slow delayed rectifier potassium current (I

In this article, a methodology based on Discrete Element Method (DEM) and Finite Elements Method (FEM) combined with modified Approximate Periodic Boundary Condition (mAPBC) has been utilized to develop a cubic Representative Element Volume (RVE). The developed methodology has then been effectively utilized to estimate the elastic mechanical properties of open foams, validated for the case of Ti open-cell foams with non-regular distribution of spherical pores. The non-regular distribution of overlapping pores was generated by means of DEM, while the homogenized elastic constants for foams with 30–70 percentage porosity are computed using FEM based on a Small Lineal Perturbation Method (SLPM). The accuracy of the developed approach has been demonstrated through the comparison of the simulations obtained for different RVE sizes with experimental results and predictive models available in literature.

Youth-initiated mentoring (YIM) is an approach to mentor recruitment that represents a significant departure from how formal mentoring typically has been conceptualized and carried out, most notably by having youth identify their own mentors. Despite enthusiasm for YIM, implementation can require significant shifts in program practices. Given the limited resources with which most mentoring programs have to work, it is important to discern staff investment in YIM and what it takes for programs to implement this approach. This study explored YIM implementation at the organizational level through interviews with mentoring program staff (n = 11) and addressed motivations of mentoring program staff to implement YIM, how their programs implemented this approach, and their perceptions of the facilitators and barriers to successful YIM implementation.

Active-duty military fathers are frequently away from their families throughout their military career and are faced with readjusting to family and garrison life after each separation. For fathers of very young children, reintegration can have unique challenges due to the tremendous developmental progression occurring in early childhood and the impact of lengthy deployment separations. While much of the research on military families focuses on extreme negative experiences (e.g., reactions to war injuries and posttraumatic stress disorder), little is known about the common experiences of military families. This qualitative study explores the reintegration experiences of 15 active-duty U.S. Army fathers with a child under six in their home during the deployment. Homecoming experiences were coded and analyzed to distinguish four adjustment factors and five adaptation challenges. Most fathers described having mixed experiences during reintegration, with 93% referencing at least one factor making adjustment easier (e.g., communication with their spouse during deployment), and 80% referencing at least one factor making adjustment difficult (e.g., child’s initial hesitation or perceived rejection). Adjustment facilitators included: spending quality time with family, individual and family growth, quality communication during deployment, and the service member’s parental perspective taking. Challenges to adjustment included negative postdeployment reactions of children, difficulty readjusting to family and civilian life, and service member psychological changes. These findings expand our understanding of the reintegration experience of active-duty fathers with young children and identify common challenges and facilitators that can be addressed through culturally informed supportive services across the deployment cycle.

Bacteriophages have evolved with an efficient host cell lysis mechanism to terminate the infection cycle and release the new progeny virions at the optimum time, allowing adaptation with the changing host and environment. Among the lytic proteins, holin controls the first and rate-limiting step of host cell lysis by permeabilizing the inner membrane at an allele-specific time known as "holin triggering". Pinholin S21 is a prototype holin of phage Φ21 which makes many nanoscale holes and destroys the proton motive force, which in turn activates the signal anchor release (SAR) endolysin system to degrade the peptidoglycan layer of the host cell and destruction of the outer membrane by the spanin complex. Like many others, phage Φ21 has two holin proteins: active pinholin and antipinholin. The antipinholin form differs only by three extra amino acids at the N-terminus; however, it has a different structural topology and conformation with respect to the membrane. Predefined combinations of active pinholin and antipinholin fine-tune the lysis timing through structural dynamics and conformational changes. Previously, the dynamics and topology of active pinholin and antipinholin were investigated (Ahammad et al. JPCB 2019, 2020) using continuous wave electron paramagnetic resonance (CW-EPR) spectroscopy. However, detailed structural studies and direct comparison of these two forms of pinholin S21 are absent in the literature. In this study, the structural topology and conformations of active pinholin (S2168) and inactive antipinholin (S2168IRS) in DMPC (1,2-dimyristoyl-sn-glycero-3-phosphocholine) proteoliposomes were investigated using the four-pulse double electron-electron resonance (DEER) EPR spectroscopic technique to measure distances between transmembrane domains 1 and 2 (TMD1 and TMD2). Five sets of interlabel distances were measured via DEER spectroscopy for both the active and inactive forms of pinholin S21. Structural models of the active pinholin and inactive antipinholin forms in DMPC proteoliposomes were obtained using the experimental DEER distances coupled with the simulated annealing software package Xplor-NIH. TMD2 of S2168 remains in the lipid bilayer, and TMD1 is partially externalized from the bilayer with some residues located on the surface. However, both TMDs remain incorporated in the lipid bilayer for the inactive S2168IRS form. This study demonstrates, for the first time, clear structural topology and conformational differences between the two forms of pinholin S21. This work will pave the way for further studies of other holin systems using the DEER spectroscopic technique and will give structural insight into these biological clocks in molecular detail.

Nanosilica (NS) has shown significant beneficial effects on concrete. However, the utilization of NS to achieve its maximum benefits is limited by the agglomeration of nanoparticles, which is associated with production methods and the method of NS dispersion in concrete. In this study, the effects of the utilization of NS as a suspension in calcium hydroxide (CH) on the hydration characteristics and the microstructure of the cement pastes were investigated with different levels of cement replacements (1%, 2%, 4%, and 6% NS) at 2, 7, and 28 days. The hydration of the cement pastes was investigated by isothermal calorimetry, and the measurement of CH content by thermogravimetry. The microstructures were analyzed by scanning electron microscopy and by energy dispersive X-ray spectroscopic mapping. The microstructure of the pastes was characterized by analyzing the pore size and the pore size distribution using mercury intrusion porosimetry (MIP). The calorimetric studies indicated that the replacing cement by NS derived by this method leads to faster hydration up to 4% replacement. The CH contents could be reduced by the incorporation of NS. The pore structures revealed that the pastes with NS had become comparably denser than the pastes without NS. A positive insight into the durability characteristics was shown by the results of the MIP when using NS as suspensions.

Context. The Gaia-ESO Survey (GES) is a public, high-resolution spectroscopic survey, conducted with the multi-object spectrograph Fibre Large Array Multi Element Spectrograph (FLAMES) on the Very Large Telescope (European Southern Observatory, ESO, Cerro Paranal, Chile) from December 2011 to January 2018. Gaia-ESO has targeted all the main stellar components of the Milky Way, including thin and thick disc, bulge, and halo. In particular, a large sample of open clusters has been observed, from very young ones, just out of the embedded phase, to very old ones. Aims. The different kinds of clusters and stars targeted in them are useful to reach the main science goals of the open cluster part of GES, which are the study of the open cluster structure and dynamics, the use of open clusters to constrain and improve stellar evolution models, and the definition of Galactic disc properties (e.g., metallicity distribution). Methods. The Gaia-ESO Survey is organised in 19 working groups (WGs), each one being responsible for a task. We describe here the work of three of them, one in charge of the selection of the targets within each cluster or association (WG4), one responsible for defining the most probable candidate member stars (WG1), and another one in charge of the preparation of the observations (WG6). As the entire GES has been conducted before the second Gaia data release, we could not make use of the Gaia astrometry to define cluster member candidates. We made use of public and private photometry to select the stars to be observed with FLAMES, once brought on a common astrometric system (the one defined by 2MASS). Candidate target selection was based on ground-based proper motions, radial velocities, and X-ray properties when appropriate, for example, and it was mostly used to define the position of the clustersa evolutionary sequences in the colour-magnitude diagrams. Targets for GIRAFFE were then selected near the sequences in an unbiased way. We used known information on membership, when available, only for the few stars to be observed with UVES. Results. We collected spectra for 62 confirmed clusters in the main observing campaign (and a few more clusters were taken from the ESO archive). Among them are very young clusters, where the main targets are pre-main sequence stars, clusters with very hot and massive stars currently on the main sequence, intermediate-age and old clusters where evolved stars are the main targets. Our strategy of making the selection of targets as inclusive and unbiased as possible and of observing a significant and representative fraction of all possible targets permitted us to collect the largest, most accurate, and most homogeneous spectroscopic data set on open star clusters ever achieved. © 2022 ESO.

Background The Center for Epidemiologic Studies Depression-Revised (CESD-R) is a widely used tool to screen for depression in the general population. An Arabic version of the CESD-R has not yet been translated and validated. Thus, this article reports the findings of two studies that were conducted to examine the psychometric properties of the Arabic version of the CESD-R. Methods Both studies were conducted using cross-sectional designs among college students from two large universities in Jordan. A total of 988 students were recruited from University A and 251 from University B. Data were collected using self-report measures of depression, perceived stress, and quality of life. Exploratory factor analysis was performed followed by a series of confirmatory factor analyses to compare different versions of the Arabic CESD-R. Measurement invariance was performed across both samples and gender of participants. Results The analyses revealed that the goodness-of-fit indices for the 20-item version of the Arabic CESD-R are not supported. Alternatively, a shorter version (CESDR-12) was created and the results supported its reliability, validity, and measurement invariance. This version, compared to a 10-item version, is supported theoretically as the items are more reflective of the DSM-V criteria for diagnosing depression. Limitations The specificity and sensitivity of the CESDR-12 were not evaluated in this article. Conclusion The Arabic CESDR-12 is a reliable, valid tool to screen for depression. Considering the prevalence and potential consequences of depression among college students, this tool could be used to identify those at risk and provide timely counseling and interventions.

The selective inhibition of the lipid signaling enzyme PI3Kγ constitutes an opportunity to mediate immunosuppression and inflammation within the tumor microenvironment but is difficult to achieve due to the high sequence homology across the class I PI3K isoforms. Here, we describe the design of a novel series of potent PI3Kγ inhibitors that attain high isoform selectivity through the divergent projection of substituents into both the "selectivity" and "alkyl-induced" pockets within the adenosine triphosphate (ATP) binding site of PI3Kγ. These efforts have culminated in the discovery of 5-[2-amino-3-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrimidin-5-yl]-2-[(1S)-1-cyclopropylethyl]-7-(trifluoromethyl)-2,3-dihydro-1H-isoindol-1-one (4, IC50 = 0.064 μM, THP-1 cells), which displays >600-fold selectivity for PI3Kγ over the other class I isoforms and is a promising step toward the identification of a clinical development candidate. The structure-activity relationships identified throughout this campaign demonstrate that greater γ-selectivity can be achieved by inhibitors that occupy an "alkyl-induced" pocket and possess bicyclic hinge-binding motifs capable of forming more than one hydrogen bond to the hinge region of PI3Kγ.

Formal youth mentoring programs typically rely on volunteers to serve as mentors to young people, with training and guidance from agency staff. A fundamental program practice is to provide ongoing support and supervision to volunteer mentors by engaging in regular contact to monitor the progress of the mentoring relationship and offer guidance and encouragement. Using data from mentors (n = 504) in multiple mentoring programs (n = 55), the current study investigated how the amount of time devoted to these match support contacts was associated with mentor perceptions regarding the nature of their volunteer experience, specifically: the quality of supervision received, the mentoring agency’s organizational culture with respect to engaging volunteers, and satisfaction with their volunteer service experience. Mentors who had no staff support contacts gave the lowest ratings for quality of supervision, organizational culture, and service experience. Further, mentors who typically had the shortest support contacts (1 to 5 minutes) reported lower quality supervision, organizational culture, and service experience compared to mentors with longer support contacts. In most cases, the associations between staff support contact length and mentor-reported outcomes remained significant after controlling for the helpfulness of the support contacts and the frequency of using advice suggested during the contacts. These findings provide evidence that match support contacts are an important practice for youth mentoring programs and suggest that programs should encourage staff to spend time engaging in meaningful conversations beyond quick check-ins. Future research should examine how the content of support contacts influences volunteer mentoring experiences.

Highly committed mentors may be less likely to end their mentoring relationships with their mentees. Theory suggests commitment is predicted by relationship satisfaction, investment, and perceptions of available alternatives. Mentoring program practices may influence commitment, but little research has investigated potential mechanisms. Using data from 537 mentors representing 55 mentoring programs, this study examined a theoretical path model in which mentor perceptions of program practices, specifically setting expectations, prematch mentor training, and matching based on mentor preferences, predict mentor satisfaction, investment, perceptions of available alternatives, and ultimately, relationship commitment. As expected, commitment was associated positively with satisfaction and investment and negatively with available alternatives. Perceptions of the program setting clear expectations, the amount of prematch training, and matching by preferences predicted mentor commitment. These associations were mediated by relationship satisfaction, investment, and available alternatives, respectively. These findings identify program practices that can support mentor commitment.

During the in-situ nitridation of Si in the presence of CaO, MgO and Al2O3 formation of reaction bonded silicon nitride ceramics (RBSN) having various microstructures indicated the possibility of different nitridation mechanisms operating. Experimental evidence suggested that, whereas the morphology of pores was controlled by nitridation of Si(g) in CaO-RBSN and SiO(g) in Al2O3-RBSN, a combination of these two reactions occurred during the nitridation of the MgO-RBSN. By inhibiting the growth of whiskers and maximizing the α/β ratio, the CaO addition led to the formation of matte grains creating clean spherical cavities with d

The bacteriophage infection cycle plays a crucial role in recycling the world's biomass. Bacteriophages devise various cell lysis systems to strictly control the length of the infection cycle for an efficient phage life cycle. Phages evolved with lysis protein systems, which can control and fine-tune the length of this infection cycle depending on the host and growing environment. Among these lysis proteins, holin controls the first and rate-limiting step of host cell lysis by permeabilizing the inner membrane at an allele-specific time and concentration hence known as the simplest molecular clock. Pinholin S21 is the holin from phage Φ21, which defines the cell lysis time through a predefined ratio of active pinholin and antipinholin (inactive form of pinholin). Active pinholin and antipinholin fine-tune the lysis timing through structural dynamics and conformational changes. Previously we reported the structural dynamics and topology of active pinholin S2168. Currently, there is no detailed structural study of the antipinholin using biophysical techniques. In this study, the structural dynamics and topology of antipinholin S2168IRS in DMPC proteoliposomes is investigated using electron paramagnetic resonance (EPR) spectroscopic techniques. Continuous-wave (CW) EPR line shape analysis experiments of 35 different R1 side chains of S2168IRS indicated restricted mobility of the transmembrane domains (TMDs), which were predicted to be inside the lipid bilayer when compared to the N- and C-termini R1 side chains. In addition, the R1 accessibility test performed on 24 residues using the CW-EPR power saturation experiment indicated that TMD1 and TMD2 of S2168IRS were incorporated into the lipid bilayer where N- and C-termini were located outside of the lipid bilayer. Based on this study, a tentative model of S2168IRS is proposed where both TMDs remain incorporated into the lipid bilayer and N- and C-termini are located outside of the lipid bilayer. This work will pave the way for the further studies of other holins using biophysical techniques and will give structural insights into these biological clocks in molecular detail.

The ignition temperature of Mg–(1–3) wt% Ca binary alloys has been tested at two different heating rates: a low heating rate (LHR) of 25 °C/min and a high heating rate (HHR) of 45 °C/min under a constant flow of extra dry air at a rate of 0.9 L/min. At both heating rates, the ignition temperature increased with Ca in the alloy. For LHR sample, the ignition temperature increased from 655 °C at 0 wt% Ca to 861 °C at 3 wt% Ca. For HHR samples, the increase in ignition temperature was lower, from 658 to 787 °C as Ca increased from 0 to 3 wt%. It was observed that Ca-rich interdendritic regions, when molten, resist oxidation more than when they are solid, an effect that can be attributed to the ΔG (Gibbs energy change) of CaO formation from the molten and solid phases. Using a LHR results in a smooth oxide scale and a higher ignition temperature, which is related to the formation of extensive molten pools, while a HHR yielded an irregular oxidation and lower ignition temperature due to the early oxidation of solid intermetallics.

CD73 is an extracellular mediator of purinergic signaling. When upregulated in the tumor microenvironment, CD73 has been implicated in the inhibition of immune function through overproduction of adenosine. Traditional efforts to inhibit CD73 have involved antibody therapy or the development of small molecules, the most potent of which mimic the acidic and ionizable structure of the enzyme's natural substrate, adenosine 5'-monophosphate (AMP). Here, we report the systematic discovery of a novel class of non-nucleotide CD73 inhibitors that are more potent than all other nonphosphonate inhibitor classes reported to date. These efforts have culminated in the discovery of 4-({5-[4-fluoro-1-(2H-indazol-6-yl)-1H-1,2,3-benzotriazol-6-yl]-1H-pyrazol-1-yl}methyl)benzonitrile (73, IC50 = 12 nM) and 4-({5-[4-chloro-1-(2H-indazol-6-yl)-1H-1,2,3-benzotriazol-6-yl]-1H-pyrazol-1-yl}methyl)benzonitrile (74, IC50 = 19 nM). Cocrystallization of 74 with human CD73 demonstrates a competitive binding mode. These compounds show promise for the improvement of drug-like character via the attenuation of the acidity and low membrane permeability inherent to known nucleoside inhibitors of CD73.