cssi/SciSciGPT-SciSciNet huggingface dataset:
Novel factor VIII variants with a modified furin cleavage site improve the efficacy of gene therapy for hemophilia A

Essentials Factor (F) VIII is an inefficiently expressed protein. Furin deletion FVIII variants were purified and characterized using in vitro and in vivo assays. These minimally modified novel FVIII variants have enhanced function. These variants provide a strategy for increasing FVIII expression in hemophilia A gene therapy. SummaryBackground The major challenge for developing gene-based therapies for hemophilia A is that human factor VIII (hFVIII) has intrinsic properties that result in inefficient biosynthesis. During intracellular processing, hFVIII is predominantly cleaved at a paired basic amino acid cleaving enzyme (PACE) or furin cleavage site to yield a heterodimer that is the major form of secreted protein. Previous studies with B-domain-deleted (BDD) canine FVIII and hFVIII-R1645H, both differing from hFVIII by a single amino acid at this site, suggested that these proteins are secreted mainly in a single polypeptide chain (SC) form and exhibit enhanced function. Objective We hypothesized that deletion(s) of the furin site modulates FVIII biology and may enhance its function. Methods A series of recombinant hFVIII-furin deletion variants were introduced into hFVIII-BDD [Δ1645, 1645-46(Δ2), 1645-47(Δ3), 1645-48(Δ4), or Δ1648] and characterized. Results In vitro, recombinant purified Δ3 and Δ4 were primarily SC and, interestingly, had 2-fold higher procoagulant activity compared with FVIII-BDD. In vivo, the variants also have improved hemostatic function. After adeno-associated viral (AAV) vector delivery, the expression of these variants is 2–4-fold higher than hFVIII-BDD. Protein challenges of each variant in mice tolerant to hFVIII-BDD showed no anti-FVIII immune response. Conclusions These data suggest that the furin deletion hFVIII variants are superior to hFVIII-BDD without increased immunogenicity. In the setting of gene-based therapeutics, these novel variants provide a unique strategy to increase FVIII expression, thus lowering the vector dose, a critical factor for hemophilia A gene therapy.
One session is enough: Pastoral counseling for African American families

Abstract The author proposes a model of pastoral counseling that can be utilized with African American parishioners. The model utilizes elements of brief therapy, African American culture, and spirituality as a means of developing solutions in time-critical situations. Due to the particularity of the African American context, significant emphasis is offered on the theological underpinnings that frame African American future orientation.
Antibody-mediated inhibition of EGFR reduces phosphate excretion and induces hyperphosphatemia and mild hypomagnesemia in mice.

Abstract Monoclonal antibody therapies targeting the EGF receptor (EGFR) frequently result in hypomagnesemia in human patients. In contrast, EGFR tyrosine kinase inhibitors do not affect Mg 2+ balance in patients and only have a mild effect on Mg 2+ homeostasis in rodents at elevated doses. EGF has also been shown to affect phosphate (P i ) transport in rat and rabbit proximal convoluted tubules (PCT), but evidence from studies targeting EGFR and looking at P i excretion in whole animals is still missing. Thus, the role of EGF in regulating reabsorption of Mg 2+ and/or P i in the kidney remains controversial. Here, we inject mice with the anti‐EGFR monoclonal antibody ME‐1 for 2 weeks and observe a significant increase in serum P i and mild hypomagnesemia, but no changes in P i or Mg 2+ excretion. In contrast, a single injection of ME‐1 resulted in hyperphosphatemia and a significant reduction in P i excretion 2 days after treatment, while no changes in serum Mg 2+ or Mg 2+ excretion were observed. Dietary Mg 2+ deprivation is known to trigger a rapid Mg 2+ conservation response in addition to hyperphosphatemia and hyperphosphaturia. Interestingly, one dose of ME‐1 did not significantly modify the response of mice to 2 days of Mg 2+ deprivation. These data show that EGFR plays a significant role in regulating P i reabsorption in the kidney PCT, but suggest only a minor role in long‐term regulation of Mg 2+ transport in the distal convoluted tubule.
Asynchronous invocation of adaptations in electronic structure calculations

Modern quantum chemistry deals with electronic structure calculations of unprecedented complexity and accuracy. They demand full power of high-performance computing and must be in tune with the given architecture for superior efficiency. To make such applications resource-aware, it is desirable to enable their static and dynamic adaptations using some external software (middleware), which may monitor both system availability and application needs, rather than mix science with system-related calls inside the application.This paper investigates models of application interlinking with middleware based on the example of the computational chemistry package GAMESS and middleware NICAN. The existing synchronous model is limited by the possible delays due to the middleware processing time under the sustainable runtime system conditions. Proposed asynchronous and hybrid models aim at overcoming this limitation. The experiments contribute to gaining an insight into a choice of the model.
Mössbauer Studies of Ternary Hydrides

The formation of ternary hydrides is often accompanied by significant changes in the structural, electronic and magnetic properties of the binary host intermetallic. Since Mossbauer spectroscopy is in essence a technique which probes the local structural, electronic and magnetic properties of the employed isotope, we used this technique to study the changes which occur in the ternary hydrides. Data from 57Fe, 161Dy, 166Er will be discussed and compared with results from other techniques.
Identification of Fkh1 and Fkh2 binding site variants associated with dynamically bound DNA elements including replication origins.

Forkhead Box (Fox) DNA binding proteins control multiple genome activities, including transcription, replication, and repair. These activities are organized spatially and temporally in the nucleus,...
Getting Along or Going Alone: Understanding Collaboration Between Local Governments and NGOs in Bolivia

What explains mayors’ collaboration with nongovernmental organizations in delivering public goods and services? While some successful collaborations are established, in other cases the call for NGOs to coordinate with governments goes unheeded. Collaboration minimizes the duplication of effort, maximizes information sharing, and builds capacity. Given the scholarly consensus on the importance of collaboration, we know little about it at local levels, where it may matter most. This article focuses on Bolivia, a country with deep decentralization reforms and an active NGO sector. It utilizes survey data on mayors from 2007 to provide insight into the variation in NGO–local government collaboration across a country. It argues that political context is important: mayoral turnover, greater community group engagement, and more municipal resources deter collaboration. The findings illustrate the strategic interplay between state and nonstate actors and explain the uneven geographies of partnerships in governance.
The role of environmental driving factors in historical and projected carbon dynamics of wetland ecosystems in Alaska.

Wetlands are critical terrestrial ecosystems in Alaska, covering ~177,000 km2 , an area greater than all the wetlands in the remainder of the United States. To assess the relative influence of changing climate, atmospheric carbon dioxide (CO2 ) concentration, and fire regime on carbon balance in wetland ecosystems of Alaska, a modeling framework that incorporates a fire disturbance model and two biogeochemical models was used. Spatially explicit simulations were conducted at 1-km resolution for the historical period (1950-2009) and future projection period (2010-2099). Simulations estimated that wetland ecosystems of Alaska lost 175 Tg carbon (C) in the historical period. Ecosystem C storage in 2009 was 5,556 Tg, with 89% of the C stored in soils. The estimated loss of C as CO2 and biogenic methane (CH4 ) emissions resulted in wetlands of Alaska increasing the greenhouse gas forcing of climate warming. Simulations for the projection period were conducted for six climate change scenarios constructed from two climate models forced under three CO2 emission scenarios. Ecosystem C storage averaged among climate scenarios increased 3.94 Tg C/yr by 2099, with variability among the simulations ranging from 2.02 to 4.42 Tg C/yr. These increases were driven primarily by increases in net primary production (NPP) that were greater than losses from increased decomposition and fire. The NPP increase was driven by CO2 fertilization (~5% per 100 parts per million by volume increase) and by increases in air temperature (~1% per °C increase). Increases in air temperature were estimated to be the primary cause for a projected 47.7% mean increase in biogenic CH4 emissions among the simulations (~15% per °C increase). Ecosystem CO2 sequestration offset the increase in CH4 emissions during the 21st century to decrease the greenhouse gas forcing of climate warming. However, beyond 2100, we expect that this forcing will ultimately increase as wetland ecosystems transition from being a sink to a source of atmospheric CO2 because of (1) decreasing sensitivity of NPP to increasing atmospheric CO2 , (2) increasing availability of soil C for decomposition as permafrost thaws, and (3) continued positive sensitivity of biogenic CH4 emissions to increases in soil temperature.
Book review: Just One Child: Science and Policy in Deng's China

Just One Child: Science and Policy in Deng's China is an important work by anthropologist and science studies scholar Susan Greenhalgh, based on more than two decades of research on population poli...
SYMMETRIES: SOME RECENT THEORETICAL WORK

Publisher Summary This chapter reviews the theoretical developments in the understanding of quantum mechanical symmetries as they pertain to few particle systems. It discusses the space-time symmetries such as parity and time reversal invariance, and internal charge symmetries. It describes the parity violation (PV) in non-leptonic or hadronic systems. Recent experiments in heavy nuclei leave little room for doubt that a weak parity-violating force exists between nucleons. However, the standard Cabibbo theory of weak interactions applied in its simplest form predicts a violation that is more than an order of magnitude smaller than observations. There remain uncertainties in the nuclear part of the calculated asymmetries. However, the improved nuclear models that have been used over the past two years make it doubtful that the fault lies there. Nevertheless, PV experiments in few hadron systems allow one to test this assumption. The single particle exchange models do not give any PV force between two neutrons or two protons. The chapter discusses a proposed experiment that would not only test these predictions but also would measure the two pion and other two particle exchange contributions to the PV nuclear force.
Moderate hypoxia (10 kPa) extends lifespan with adult but not juvenile exposure in the fruitfly, Drosophila melanogaster

Oxygen provides the substrate for most ATP production but also serves as the source of reactive oxygen species that promote aging. Multiple invertebrate studies have shown that pure oxygen atmosphe...
Acute Kidney Injury, Sodium Disorders, and Hypercalcemia in the Aging Kidney:: Diagnostic and Therapeutic Management Strategies in Emergency Medicine

This article summarizes the current literature regarding the structural and functional changes of the aging kidney and describes how these changes make the older patient more susceptible to acute kidney injury and fluid and electrolyte disorders. It discusses the clinical manifestations, evaluation, and management of hyponatremia and shows how the management of hypernatremia in geriatric patients involves addressing the underlying cause and safely correcting the hypernatremia. The current literature regarding evaluation and management of hypercalcemia in older patients is summarized. The management of severe hypercalcemia is discussed in detail. The evaluation and management of acute kidney injury is described.
Perceived Barriers to Treatment Participation and Treatment Acceptability Among Antisocial Children and Their Families

This study examined the role of perceived barriers to participation in treatment and the acceptability of treatment among children and parents. Children (N = 144, ages 6–14) referred for outpatient treatment for oppositional, aggressive, and antisocial behavior and their families participated. The main findings were that: (a) perceived barriers to participation in treatment predicted treatment acceptability as rated by children and parents; (b) the effect was not accounted for by socioeconomic disadvantage, parent psychopathology and stress, and severity of child dysfunction; and (c) treatment acceptability was related to therapeutic change in the children over the course of therapy but the relation was small. Overall, the findings indicate that families vary considerably in the barriers they perceive in coming to treatment and that these barriers influence the extent to which they and their children evaluate the acceptability of the treatments they receive. The implications of treatment acceptability for evaluation and delivery of psychotherapy are discussed.
Why do phylogenomic analyses of early animal evolution continue to disagree? Sites in different structural environments yield different answers

Phylogenomics has revolutionized the study of evolutionary relationships. However, genome-scale data have not been able to resolve all relationships in the tree of life. This could reflect the poor-fit of the models used to analyze heterogeneous datasets; that heterogeneity is likely to have many explanations. However, it seems reasonable to hypothesize that the different patterns of selection on proteins based on their structures might represent a source of heterogeneity. To test that hypothesis, we developed an efficient pipeline to divide phylogenomic datasets that comprise proteins into subsets based on secondary structure and relative solvent accessibility. We then tested whether amino acids in different structural environments had different signals for the deepest branches in the metazoan tree of life. Sites located in different structural environments did support distinct tree topologies. The most striking difference in phylogenetic signal reflected relative solvent accessibility; analyses of sites on the surface of proteins yielded a tree that placed ctenophores sister to all other animals whereas sites buried inside proteins yielded a tree with a sponge-ctenophore clade. These differences in phylogenetic signal were not ameliorated when we repeated our analyses using the site-heterogeneous CAT model, a mixture model that is often used for analyses of protein datasets. In fact, analyses using the CAT model actually resulted in rearrangements that are unlikely to represent evolutionary history. These results provide striking evidence that it will be necessary to achieve a better understanding the constraints due to protein structure to improve phylogenetic estimation.
Abstract 254: Utilization and Outcomes of Early Respiratory Support in 6.5 Million Acute Heart Failure Hospitalizations

Background: Patients with acute heart failure (AHF) often require non-invasive ventilation (NIV) via facemask or invasive mechanical ventilation (IMV) via endotracheal tube, yet the incidence and p...
The A.I. Impacts on the Process of the Division of Labor

Abstract In this paper we explore the socio-economic processes which make the emergence of artificial intelligence possible, as well as the reverse effects of artificial intelligence on the very processes which brought it about. Their mutual and circular interdependency is by no means accidental or spurious: artificial intelligence, with its re-integrative impacts on human labor and knowledge, could only emerge at the end of the process of specialization, and can only accelerate bringing this end to its completion. We study the process of division of labor and division of knowledge, point to their inevitable slowdown, ultimate reversal, and unprecedented and fundamental impacts. We conceive of artificial intelligence as a form of "high technology" which is properly embedded in an increasingly knowledge-oriented society. Its scientific subarea - mimicking human intelligence - is of much less importance or impact. Studying the socio-economic framework of artificial intelligence its necessary not only for justifying the ongoing research, but mainly for opening new directions, new frames of reference, and new areas of application
Cross-linker-Modulated Nanogel Flexibility Correlates with Tunable Targeting to a Sterically Impeded Endothelial Marker

Deformability of injectable nanocarriers impacts rheological behavior, drug loading, and affinity target adhesion. Here, we present atomic force microscopy (AFM) and spectroscopy measurements of nanocarrier Young's moduli, tune the moduli of deformable nanocarriers with cross-linkers, and demonstrate vascular targeting behavior that correlates with Young's modulus. Homobifunctional cross-linkers were introduced into lysozyme-dextran nanogels (NGs). Single particle-scale AFM measurements determined NG moduli varying from ∼50-150 kPa for unmodified NGs or NGs with a short hydrophilic cross-linker (2,2'-(ethylenedioxy)bis(ethylamine), EOD) to ∼350 kPa for NGs modified with a longer hydrophilic cross-linker (4,9-dioxa-1,12-dodecanediamine, DODD) to ∼10 MPa for NGs modified with a longer hydrophobic cross-linker (1,12-diaminododecane, DAD). Cross-linked NGs were conjugated to antibodies for plasmalemma vesicle associated protein (PLVAP), a caveolar endothelial marker that cannot be accessed by rigid particles larger than ∼100 nm. In previous work, 150 nm NGs effectively targeted PLVAP, where rigid particles of similar diameter did not. EOD-modified NGs targeted PLVAP less effectively than unmodified NGs, but more effectively than DODD or DAD modified NGs, which both yielded low levels of targeting, resembling results previously obtained with polystyrene particles. Cross-linked NGs were also conjugated to antibodies against intracellular adhesion molecule-1 (ICAM-1), an endothelial marker accessible to large rigid particles. Cross-linked NGs and unmodified NGs targeted uniformly to ICAM-1. We thus demonstrate cross-linker modification of NGs, AFM determination of NG mechanical properties varying with cross-linker, and tuning of specific sterically constrained vascular targeting behavior in correlation with cross-linker-modified NG mechanical properties.
Genomics of major depressive disorder

Abstract Progress is now being made in identifying specific genetic factors that predispose people to major depressive disorder (MDD), using the genome-wide association study (GWAS) method to study common DNA sequence variants. This chapter summarizes epidemiological findings relevant to genetics of MDD and its overlap with other psychiatric disorders. The principles of GWAS and other genetic approaches are described, along with current analytic strategies to detect association to single genetic variants, and to use genome-wide data to evaluate heritability, overlap of genetic factors with other disorders, and genetic pathways (sets of genes with known functional relationships) that may be involved in risk. We then review findings of recent GWAS meta-analyses of multiple cohorts, resulting in samples exceeding 100,000 cases in the largest analyses, for example, the Psychiatric Genomics Consortium analysis that detected 44 independent significantly-associated genetic loci. Genes with roles in brain function predominate the list of individual associations and of significant pathways, but there is also representation of the immune system. Genome-wide, common variants explain 8%–30% of the risk of MDD (compared with 35%–40% according to twin studies), with a tendency for studies of more severely ill, “clinical” cases to have a higher common-variant heritability. Genetic risk factors for MDD overlap substantially with those for anxiety disorders and trait neuroticism, and significantly with ADHD, autism schizophrenia, bipolar disorder, and obesity. Based on current knowledge and studies of other disorders, it is likely that GWAS analyses of even larger samples will greatly increase the number of specific associations and enhance our knowledge of relevant genetic mechanisms. The evidence for genetic overlap among current diagnostic categories suggests that genetic data may ultimately contribute to a reformulation of diagnostic approaches, but given how little we know about which genetic factors underlie the important differences among these disorders, genetic data do not yet support a radical restructuring of diagnostic methods for clinical practice and research.
The 'nature' of fisheries governance: narratives of environment, politics, and power and their implications for changing seascapes

This article responds to recent calls for more engagement from political ecologists in ocean and coastal governance concerns, and employs a controversy over the practice of gill netting in North Carolina as a lens into questions about how narratives of nature and power affect fisheries policymaking processes. The article analyzes commercial and recreational fisher narratives about marine 'nature,' including perceptions of resource health, expressions of blame or responsibility, and storylines about the different roles of fishers and managers in the process of governing fisheries. The article focuses particularly on how fishers perceive the politics of fisheries management and where they believe power lies in negotiations about the 'right' ways to steward and allocate fishery resources. Fisher narratives are then compared to those of fishery regulators themselves. The article asks how the perceptions of different groups about politics and power in fisheries management affect their levels of trust and engagement with each other and with the policymaking process. It offers insights into the complex negotiations over the meaning of terms like 'conservation,' 'endangered,' and 'livelihood,' and analyzes the implications of these narratives for stimulating material changes in the coastal seascape and the lives of fishers. Key Words: political ecology, governance, fisheries, nature, narrative analysis
Engineered Pseudomonas putida KT2440 co-utilizes galactose and glucose.

Efficient conversion of plant biomass to commodity chemicals is an important challenge that needs to be solved to enable a sustainable bioeconomy. Deconstruction of biomass to sugars and lignin yields a wide variety of low molecular weight carbon substrates that need to be funneled to product. Pseudomonas putida KT2440 has emerged as a potential platform for bioconversion of lignin and the other components of plant biomass. However, P. putida is unable to natively utilize several of the common sugars in hydrolysate streams, including galactose. In this work, we integrated a De Ley–Doudoroff catabolic pathway for galactose catabolism into the chromosome of P. putida KT2440, using genes from several different organisms. We found that the galactonate catabolic pathway alone (DgoKAD) supported slow growth of P. putida on galactose. Further integration of genes to convert galactose to galactonate and to optimize the transporter expression level resulted in a growth rate of 0.371 h−1. Additionally, the best-performing strain was demonstrated to co-utilize galactose with glucose. We have engineered P. putida to catabolize galactose, which will allow future engineered strains to convert more plant biomass carbon to products of interest. Further, by demonstrating co-utilization of glucose and galactose, continuous bioconversion processes for mixed sugar streams are now possible.
Aligned and Conductive 3D Collagen Scaffolds for Skeletal Muscle Tissue Engineering

Skeletal muscle is characterized by its three-dimensional (3D) anisotropic architecture composed of highly aligned, organized, and electrically excitable muscle fibers that enable normal locomotion. Biomaterial-based tissue engineering approaches to repair skeletal muscle injuries are limited due to difficulties in combining 3D structural alignment (to guide cell/matrix organization) and electrical conductivity (to enable electrically excitable myotube assembly and maturation). In this work we successfully produced aligned and electrically conductive 3D collagen scaffolds using a freeze-drying approach. Conductive polypyrrole (PPy) microparticles were synthesized and directly mixed into a suspension of type I collagen and chondroitin sulfate followed by directional lyophilization. Scanning electron microscopy (SEM), energy-dispersive spectroscopy (EDS), and confocal microscopy analyses showed that directional solidification resulted in scaffolds with longitudinally aligned macropores (transverse plane: 155 ± 27 μm, longitudinal plane: 218 ± 49 μm) with homogeneously-distributed PPy content. Chronopotentiometry verified that PPy incorporation resulted in a five-fold increase in conductivity when compared to non-PPy containing collagen scaffolds without detrimentally affecting C2C12 mouse myoblast metabolic activity. Furthermore, the aligned scaffold microstructure provided contact guidance cues that directed myoblast growth and organization. Incorporation of PPy also promoted enhanced myotube formation and maturation as measured by myosin heavy chain (MHC) expression and number of nuclei per myotube. Together these data suggest that aligned and conductive 3D collagen scaffolds could be useful for skeletal muscle tissue engineering.
Quantitative Assessment of Ventriculostomy-Related Hemorrhage: A Volume-Based Classification System to Predict New Neurological Symptoms.

Background Hemorrhage is one of the most feared complications following ventriculostomy placement. Current studies have assessed factors associated with increased risk of ventriculostomy-related hemorrhage (VRH). However, the clinical significance of VRH has not been determined. Objective To correlate quantitative volumetric measurements of VRH with new neurological symptoms. Methods A retrospective review of our institutional database of ventriculostomy patients during the last decade was performed. Patients' demographics and procedural details such as indication, number of passes and position of the catheter were recorded. VRH volume was quantified on noncontrast head computed tomography using the Picture Archiving Communication System (Carestream Vue®, Rochester, New York) semi-automated livewire segmentation tool. Patients with new neurological symptoms within 48 h of VRH were considered symptomatic. Several clinical confounders were ruled out. Logistic regression analyses were performed. The best volumetric cut-offs in predicting symptomatic VRH were determined through receiver operating characteristic (ROC) curve analysis. Results A total of 3090 patients underwent ventriculostomy procedures and 179 (∼6%) developed VRH. A total of 41 (1.06%) patients with VRH developed new neurological symptoms. Only 12 (0.39%) were attributable to a new VRH. Multivariable logistic regression showed that volume of the hemorrhage (OR 1.17, P = .006) is the only significant predictor of symptomatic VRH. ROC curve analysis demonstrated that VRH volume 7.59 cc has 95.5% specificity to predict symptomatic VRH. Conclusion Approximately 6% of patients developed postprocedural VRH, but only 0.4% were symptomatic. VRH volumes 7.5 cc may predict development of new neurological deficits.
Transcriptional silencing of ALDH2 in acute myeloid leukemia confers a dependency on Fanconi anemia proteins

Hundreds of genes become aberrantly silenced in acute myeloid leukemia (AML), with most of these epigenetic changes being of unknown functional consequence. Here, we demonstrate how gene silencing can lead to an acquired dependency on the DNA repair machinery in AML. We make this observation by profiling the essentiality of the ubiquitin conjugation and ligation machinery in cancer cell lines using domain-focused CRISPR screening, which revealed Fanconi anemia (FA) proteins UBE2T (an E2) and FANCL (an E3) as unique dependencies in AML. We demonstrate that these dependencies are due to a synthetic lethal interaction between FA proteins and Aldehyde Dehydrogenase 2 (ALDH2), which function in parallel pathways to counteract the genotoxic effects of endogenous aldehydes. We provide evidence that DNA hypermethylation and transcriptional silencing of ALDH2 occur in a recurrent manner in human AML patient samples, which is sufficient to confer FA pathway dependency in this disease. Taken together, our study suggests that targeting of the ubiquitination reaction catalyzed by FA proteins can eliminate ALDH2-deficient AML.
Loss of G-Protein Pathway Suppressor 2 Promotes Tumor Growth Through Activation of AKT Signaling

G Protein Suppressor 2 (GPS2) is a multifunctional protein that exerts important roles in inflammation and metabolism in adipose, liver, and immune cells. GPS2 has recently been identified as a significantly mutated gene in breast cancer and other malignancies and proposed to work as a putative tumor suppressor. However, molecular mechanisms by which GPS2 prevents cancer development and/or progression are largely unknown. Here, we have profiled the phenotypic changes induced by GPS2 depletion in MDA-MB-231 triple negative breast cancer cells and investigated the underlying molecular mechanisms. We found that GPS2-deleted MDA-MB-231 cells exhibited increased proliferative, migratory, and invasive properties in vitro, and conferred greater tumor burden in vivo in an orthotopic xenograft mouse model. Transcriptomic, proteomic and phospho-proteomic profiling of GPS2-deleted MBA-MB-231 revealed a network of altered signals that relate to cell growth and PI3K/AKT signaling. Overlay of GPS2-regulated gene expression with MDA-MB-231 cells modified to express constitutively active AKT showed significant overlap, suggesting that sustained AKT activation is associated with loss of GPS2. Accordingly, we demonstrate that the pro-oncogenic phenotypes associated with GPS2 deletion are rescued by pharmacological inhibition of AKT with MK2206. Collectively, these observations confirm a tumor suppressor role for GPS2 and reveal that loss of GPS2 promotes breast cancer cell proliferation and tumor growth through uncontrolled activation of AKT signaling. Moreover, our study points to GPS2 as a potential biomarker for a subclass of breast cancers that would be responsive to PI3K-class inhibitor drugs.
Patterns of care and treatment outcomes in locoregional squamous cell carcinoma of the prostate.

260Background: Primary pure prostate squamous cell carcinoma (PSCC) is a rare, aggressive disease accounting for less than 0.5-1% of prostate cancer diagnoses. PSCC is a distinct entity from adenoc...
Effects of intraventricular hemorrhage on white matter microstructural changes at term and early developmental outcomes in infants born very preterm

Very preterm (VPT) infants are at high risk for motor and behavioral deficits. We investigated microstructural differences using diffusion tensor imaging (DTI) among VPT infants with different grades of intraventricular hemorrhage (IVH), their association with early motor function and temperament ratings, and the potential moderating effect of IVH severity on the above structure-function relations. Fifty-seven VPT (≤32 weeks gestational age) infants with IVH (Low Grade (Papile grading I/II): 42; High Grade (III/IV): 15) were studied. DTI was acquired between 39 and 44 weeks postmenstrual age and was analyzed using the tract-based spatial statistics approach. Early motor function and temperament were assessed at 3-month corrected age based on the Hammersmith Infant Neurological Examination (HINE) and Infant Behavioral Questionnaire – Revised, Short Version (IBQ-R-S), respectively. Significantly lower fractional anisotropy and higher mean, axial, and/or radial diffusivity were found in VPT infants with High Grade IVH compared to Low Grade IVH (p < 0.05). Significant associations were found between DTI metrics and motor function in both IVH groups and between DTI and Fear temperament ratings in the High Grade IVH Group (all p < 0.05). IVH severity had a significant moderating effect on the relation between DTI and motor and Fear ratings (p < 0.05). DTI is a sensitive neuroimaging biomarker providing a refined understanding of the impact and location of differing severities of IVH on the developing white matter of VPT infants. Early motor and behavioral outcomes are associated with microstructural changes that are influenced by severity of IVH.
Physiologically Relevant Free Ca2+ Ion Concentrations Regulate STRA6-Calmodulin Complex Formation via the BP2 Region of STRA6.

The interaction of calmodulin (CaM) with the receptor for retinol uptake, STRA6, involves an α-helix termed BP2 that is located on the intracellular side of this homodimeric transporter (Chen et al., 2016 [1]). In the absence of Ca2+, NMR data showed that a peptide derived from BP2 bound to the C-terminal lobe (C-lobe) of Mg2+-bound CaM (MgCaM). Upon titration of Ca2+ into MgCaM-BP2, NMR chemical shift perturbations (CSPs) were observed for residues in the C-lobe, including those in the EF-hand Ca2+-binding domains, EF3 and EF4 (CaKD = 60 ± 7 nM). As higher concentrations of free Ca2+ were achieved, CSPs occurred for residues in the N-terminal lobe (N-lobe) including those in EF1 and EF2 (CaKD = 1000 ± 160 nM). Thermodynamic and kinetic Ca2+ binding studies showed that BP2 addition increased the Ca2+-binding affinity of CaM and slowed its Ca2+ dissociation rates (koff) in both the C- and N-lobe EF-hand domains, respectively. These data are consistent with BP2 binding to the C-lobe of CaM at low free Ca2+ concentrations (<100 nM) like those found at resting intracellular levels. As free Ca2+ levels approach 1000 nM, which is typical inside a cell upon an intracellular Ca2+-signaling event, BP2 is shown here to interact with both the N- and C-lobes of Ca2+-loaded CaM (CaCaM-BP2). Because this structural rearrangement observed for the CaCaM-BP2 complex occurs as intracellular free Ca2+ concentrations approach those typical of a Ca2+-signaling event (CaKD = 1000 ± 160 nM), this conformational change could be relevant to vitamin A transport by full-length CaCaM-STRA6.
Taste loss as a distinct symptom of COVID-19: A systematic review and meta-analysis

Chemosensory scientists have been skeptical that reports of COVID-19 taste loss are genuine, in part because before COVID-19, taste loss was rare and often confused with smell loss. Therefore, to establish the predicted prevalence rate of taste loss in COVID-19 patients, we conducted a systematic review and meta-analysis of 376 papers published in 2020-2021, with 241 meeting all inclusion criteria. Additionally, we explored how methodological differences (direct vs. self-report measures) may affect these estimates. We hypothesized that direct prevalence measures of taste loss would be the most valid because they avoid the taste/smell confusion of self-report. The meta-analysis showed that, among 138,897 COVID-19-positive patients, 39.2% reported taste dysfunction (95% CI: 35.34-43.12%), and the prevalence estimates were slightly but not significantly higher from studies using direct (n = 18) versus self-report (n = 223) methodologies (Q = 0.57, df = 1, p = 0.45). Generally, males reported lower rates of taste loss than did females and taste loss was highest in middle-aged groups. Thus, taste loss is a bona fide symptom COVID-19, meriting further research into the most appropriate direct methods to measure it and its underlying mechanisms.
Legal and Legislative Considerations

The law that binds schizophrenic persons has seldom been prescribed or controlled by their authority. In this respect, schizophrenic persons have had, at least until the 1970s, less authority than many criminals, especially criminals of the white-collar variety, who may have powerful influences on both statutory and case law. Schizophrenic persons also have less authority to make and to carry out law than their families, or nearly anyone else in society. This chapter addresses legal and legislative considerations regarding severely mentally disturbed persons, with particular attention to those labeled schizophrenic and with emphasis on the sense and nonsense of the most relevant and important laws.
Susceptibility-weighted imaging in stroke-like migraine attacks after radiation therapy syndrome

Stroke-like migraine attacks after radiation therapy (SMART) syndrome has a characteristic clinical presentation and postcontrast T1WI MRI appearance. Susceptibility-weighted imaging (SWI) may help distinguish SMART from other disorders that may have a similar postcontrast MRI appearance. The MRI examinations of four patients with SMART syndrome are described herein, each of which included SWI, FLAIR, DWI, and postcontrast T1WI on the presenting and follow-up MRI examinations. In each, the initial SWI MRI demonstrated numerous susceptibility hypointensities <5 mm in size throughout the cerebrum, particularly within the periventricular white matter (PVWM), presumably related to radiation-induced cavernous hemangiomas (RICHs). By follow-up MRI, each postcontrast examination had demonstrated resolution of the gyriform enhancement on T1WI, without susceptibility hypointensities on SWI within those previously enhancing regions. These preliminary findings suggest that SWI may help identify SMART syndrome or at least help discriminate it from other disorders, by the findings of numerous susceptibility hypointensities on SWI likely representing RICHs, gyriform enhancement on T1WI, and postsurgical findings or appropriate clinical history.
Metabolism and biliary excretion of phenanthridinium salts—I

Abstract The nature of the biliary metabolites of three phenanthridinium salts—3,8-diamino-6- p -aminophenyl-5-methylphenanthridinium chlori (150C47), 3,8-diamino-6-phenyl-5-ethylphenanthridinium bromide (ethidium), and 2-amino-6- p -carbethoxyaminophenyl-5-methylphenanthridinium sulfate (carbidium) —has been investigated in rats with ligated renal pedicles. Up to 50 per cent of a small intravenous dose of each of these compounds may be excreted in the bile of rats with ligated renal pedicles in 1 hr depending on the dose and individual variation. At the dose selected, about 15 per cent of the dose was excreted in the first hour after injection. Sixty-five percent of a 15 mg/kg dose of 150C47 was recovered in the bile in 11–21 hr; 85 percent of this total was excreted within 5 hr. Of the material recovered, approximately 15 per cent was unchanged 150C47. The major metabolite present in bile was a monoacetyl amino conjugate and this accounted for about 50 per cent of the material recovered. Two other metabolites were also shown to be present and these are also believed to be acetyl conjugates. One of these is probably a diacetylated compound and accounted for about 25 per cent of the material recovered. The other accounted for the remaining 10 per cent. During the first hour after injection, the material was almost entirely in the form of the major metabolite plus the unchanged compound. After injection of the major monoacetyl metabolite, only the injected monoacetyl compound and the diacetylated one could be detected in bile, and the rate of excretion exceeded the rate of excretion of all forms of 150C47 in control rats given the same dose of 150C47. Of a 15 mg/kg dose of ethidium, 50–55 per cent was recovered in the bile in 16–18 hr. Unchanged ethidium accounted for 20–25 per cent of the material present. Two metabolites were found and these are both believed to be monoacetyl amino conjugates. They accounted for 65–70 per cent and 10 per cent of the material recovered; 85–90 per cent of this total was excreted within 5 hr. Carbidium is excreted in bile as the unchanged compound and its acetyl conjugate. Only one acetyl conjugate is possible for this compound and it was the only metabolite found in bile. Of a dose of 15 mg/kg, 60–65 per cent was recovered in 10–16 hr. About 20 per cent of the material recovered was unchanged carbidium; the remaining 80 per cent was the acetyl derivative. During the first hour after injection, 55 per cent of the material excreted was unchanged carbidium.
Sub-Doppler Spectroscopy

The Doppler effect has long been one of the principal problems in high resolution spectroscopy of atoms and molecules. Atoms moving towards an observer appear to emit or absorb light at shorter wavelengths than atoms at rest, and atoms moving away appear to emit at longer wavelengths. In a gas, with atoms moving at random in different directions, the lines appear blurred, and important details in line shape and structure are often obscured.
Epidermal Sensor Paradigm: Inner Layer Tissue Monitoring

The relevant properties of the human body from the very high frequency (VHF) to the X band are studied and dominant propagation modes around the body are discussed in this chapter. Based on these data, approximate human torso models are built for each propagation mode using multiple concentric cylinders emulating the skin, muscle, organ, and the like. After this study, a simpler two-layer model of the human body is proposed for efficient calculations without loss of accuracy and used in the analysis of the epidermal sensor. The radio frequency (RF) properties of human body tissues affect propagation, reflection, attenuation, and other behaviors of electromagnetic fields around the body. Body-centric wireless communications can be divided into three types based on the interaction between the body and the EM field. In each case, different propagation modes are dominant.
On the Global and Linear Convergence of the Generalized Alternating Direction Method of Multipliers

The formulation $$\begin{aligned} \min _{x,y} ~f(x)+g(y),\quad \text{ subject } \text{ to } Ax+By=b, \end{aligned}$$minx,yf(x)+g(y),subjecttoAx+By=b,where f and g are extended-value convex functions, arises in many application areas such as signal processing, imaging and image processing, statistics, and machine learning either naturally or after variable splitting. In many common problems, one of the two objective functions is strictly convex and has Lipschitz continuous gradient. On this kind of problem, a very effective approach is the alternating direction method of multipliers (ADM or ADMM), which solves a sequence of f/g-decoupled subproblems. However, its effectiveness has not been matched by a provably fast rate of convergence; only sublinear rates such as O(1 / k) and $$O(1/k^2)$$O(1/k2) were recently established in the literature, though the O(1 / k) rates do not require strong convexity. This paper shows that global linear convergence can be guaranteed under the assumptions of strong convexity and Lipschitz gradient on one of the two functions, along with certain rank assumptions on A and B. The result applies to various generalizations of ADM that allow the subproblems to be solved faster and less exactly in certain manners. The derived rate of convergence also provides some theoretical guidance for optimizing the ADM parameters. In addition, this paper makes meaningful extensions to the existing global convergence theory of ADM generalizations.
The influence of riparian vegetation and season on stream metabolism of Valley Creek, Minnesota

Climate change will undoubtedly influence stream ecosystems by affecting water temperature, discharge, and riparian vegetation phenology. It has been suggested that increasing the extent of riparian buffers may help to mitigate these impacts and contribute to ecosystem resilience. Measures of stream metabolism are one way to examine the changes in ecosystem function as they respond to climate change and management strategies used to respond to these impacts. In this study we examine the influence of riparian vegetation (open vs. forest) and season on ecosystem metabolism in a small stream in MN, USA. The stream was heterotrophic regardless of the type of riparian vegetation but the presence of a forested buffer depressed gross primary production (GPP) and also resulted in lower (less negative) ecosystem respiration (ER) and net ecosystem production (NEP). We also found significant daily and seasonal variation in GPP, ER, and NEP. Stream metabolism was more variable in the fall than in the summer. The stud...
SUM RULES FOR MESONS. I. THE EXISTENCE OF OPPOSITE PARITY STATES.

Abstract By investigating matrix elements of current commutation rules taken between the vacuum and one-meson states (o−, 1−), we show the need for opposite-parity meson states (0+, 1+), even in the presence of SU(3) × SU(3) symmetry-breaking effects. We obtain sum rules for these 0+ and 1+ states under the assumption that they appear as resonances and under the assumption that they appear as an enhancement in the scattering amplitude near threshold. Our results indicate that these opposite parity states appear either as threshold-scattering enhancements or as resonances close to threshold. When the sum rules are used to calculate the contributions from the 0+ and 1+ intermediate states to the meson-meson forward-scattering sum rules, i.e., πK and πϱ scattering, we find that these contributions completely saturate these sum rules.
Separation of Clonogenic Tumor Cells from Small Cell Lung Cancer Bone Marrow and Small Cell Lung Cancer Cell Lines

One of the major obstacles to successful autologous bone marrow transplantation is tumor contamination of the marrow. We attempted to separate tumor cells from the marrow of patients with small cell lung cancer by layering bone marrow on a discontinuous albumin gradient and then assessing hematopoietic potential (CFUc) and clonogenic tumor cells (TCFUc) by standard techniques. In the six of seven patients whose bone marrow grew tumor colonies, 75 to 80% of CFUc could be found in Fraction 3 of the gradient; while 80 to 90% of TCFUc could be found in light-density Fraction 1 + 2. Furthermore, we observed tumor colony growth in Fraction 1 + 2 in some patients whose unfractionated bone marrow failed to grow tumor colonies. In separate experiments, we layered five cell lines established in patients with small cell lung cancer on the gradient and found that cells from four of the five lines also migrated to Fraction 1 + 2, and TCFUc from these lines were observed in Fractions 1 + 2 in three of four lines tested. We conclude that gradient fractionation may be one way of removing clonogenic tumor cells from the bone marrow of small cell lung cancer patients prior to autologous transplantation.
Changing fluvial systems

Change in fluvial systems has interested geomorphologists for several decades, but awareness of change dates back much further to the ancient Greeks. This paper introduces seven articles that focus on aspects of temporal and/or spatial change in rivers in the central and southeastern United States of America. Timescales examined span from the late Pleistocene through historical and into modern times. Spatial scales investigated range from small watersheds to the juncture between two of the larger rivers in North America. Natural drivers of change discussed include sea-level rise which followed the last glacial maxima and influenced drainage connections, avulsions, and lateral migration which influenced channel position and caused stream capture; and transitions across geomorphic provinces with differing bedrock and structure. Human-induced drivers of change include land use alterations such as settlement and logging which influenced sediment input and channel form, artificial cut-offs, removal of log raft...