Measurement of the

The cross section of the ^{13}C(α,n)^{16}O reaction is needed for nuclear astrophysics and applications to a precision of 10% or better, yet inconsistencies among 50 years of experimental studies currently lead to an uncertainty of ≈15%. Using a state-of-the-art neutron detection array, we have performed a high resolution differential cross section study covering a broad energy range. These measurements result in a dramatic improvement in the extrapolation of the cross section to stellar energies potentially reducing the uncertainty to ≈5% and resolving long standing discrepancies in higher energy data.

EVALUATION OF SEXUAL FUNCTION IN TRANSGENDER AND GENDER DIVERSE INDIVIDUALS; A CALL FOR ACTION.

Sexual function is a key factor impacting all individuals' wellbeing, including the transgender and gender diverse (TGGD) population. Lack of validated sexual function evaluation tools for this community contributes to gaps in medical knowledge, barriers to proper assessment, interventions, and an understanding of sexual function expectations pre and post gender-affirming surgery (GAS). Current studies indicate beneficial individualized treatments for management of sexual dysfunction in TGGD individuals, while demonstrating the importance of applicable and validated sexual function assessments. In the evaluation of sexual function for these patients, it is essential to consider the social, mental, and physical components experienced by this community as well as all variations of sexual practices and preferences. Currently, due to the general lack of an index of assessment, providers and/or researchers are left to adapt one of the validated cisgender tools or create non-validated evaluation tools when assessing TGGD patients. Through the creation of unique validated sexual function tools, providers will be able to improve affirming patient care, reduce stigma, and ensure accurate sexual function evaluation.

Dynamical instability of 3D stationary and traveling planar dark solitons.

Here we revisit the topic of stationary and propagating solitonic excitations in self-repulsive three-dimensional (3D) Bose-Einstein condensates by quantitatively comparing theoretical analysis and associated numerical computations with our experimental results. Motivated by numerous experimental efforts, including our own herein, we use fully 3D numerical simulations to explore the existence, stability, and evolution dynamics of planar dark solitons. This also allows us to examine their instability-induced decay products including solitonic vortices and vortex rings. In the trapped case and with no adjustable parameters, our numerical findings are in correspondence with experimentally observed coherent structures. Without a longitudinal trap, we identify numerically exact traveling solutions and quantify how their transverse destabilization threshold changes as a function of the solitary wave speed.

Dynamically Induced Symmetry Breaking and Out-of-Equilibrium Topology in a 1D Quantum System.

Nontrivial topology in lattices is characterized by invariants-such as the Zak phase for one-dimensional (1D) lattices-derived from wave functions covering the Brillouin zone. We realize the 1D bipartite Rice-Mele (RM) lattice using ultracold ^{87}Rb and focus on lattice configurations possessing various combinations of chiral, time-reversal, and particle-hole symmetries. We quench between configurations and use a form of quantum state tomography, enabled by diabatically tuning lattice parameters, to directly follow the time evolution of the Zak phase as well as a chiral winding number. The Zak phase evolves continuously; however, when chiral symmetry transiently appears in the out-of-equilibrium system, the chiral winding number becomes well defined and can take on any integer value. When quenching between two configurations obeying the same three symmetries, the Zak phase is time independent; we confirm the dynamically induced symmetry breaking predicted in [McGinley and Cooper, Phys. Rev. Lett. 121, 090401 (2018)PRLTAO0031-900710.1103/PhysRevLett.121.090401] that chiral symmetry is periodically restored, at which times the winding number changes by ±2, yielding values that are not present in the native RM Hamiltonian.

Floquet Engineering Topological Dirac Bands.

We experimentally realized a time-periodically modulated 1D lattice for ultracold atoms featuring a pair of linear bands, each with a Floquet winding number. These bands are spin-momentum locked and almost perfectly linear everywhere in the Brillouin zone: a near-ideal realization of the 1D Dirac Hamiltonian. We characterized the Floquet winding number using a form of quantum state tomography, covering the Brillouin zone and following the micromotion through one Floquet period. Last, we altered the modulation timing to lift the topological protection, opening a gap at the Dirac point that grew in proportion to the deviation from the topological configuration.

Creating solitons with controllable and near-zero velocity in Bose-Einstein condensates.

Established techniques for deterministically creating dark solitons in repulsively interacting atomic Bose-Einstein condensates (BECs) can only access a narrow range of soliton velocities. Because velocity affects the stability of individual solitons and the properties of soliton-soliton interactions, this technical limitation has hindered experimental progress. Here we create dark solitons in highly anisotropic cigar-shaped BECs with arbitrary position and velocity by simultaneously engineering the amplitude and phase of the condensate wave function, improving upon previous techniques which explicitly manipulated only the condensate phase. The single dark soliton solution present in true one-dimensional (1D) systems corresponds to the kink soliton in anisotropic three-dimensional systems and is joined by a host of additional dark solitons, including vortex ring and solitonic vortex solutions. We readily create dark solitons with speeds from zero to half the sound speed. The observed soliton oscillation frequency suggests that we imprinted solitonic vortices, which for our cigar-shaped system are the only stable solitons expected for these velocities. Our numerical simulations of 1D BECs show this technique to be equally effective for creating kink solitons when they are stable. We demonstrate the utility of this technique by deterministically colliding dark solitons with domain walls in two-component spinor BECs.

Population Modeling Integrating Pharmacokinetics, Pharmacodynamics, Pharmacogenetics, and Clinical Outcome in Patients With Sunitinib-Treated Cancer.

The tyrosine kinase inhibitor sunitinib is used as first-line therapy in patients with metastasized renal cell carcinoma (mRCC), given in fixed-dose regimens despite its high variability in pharmacokinetics (PKs). Interindividual variability of drug exposure may be responsible for differences in response. Therefore, dosing strategies based on pharmacokinetic/pharmacodynamic (PK/PD) models may be useful to optimize treatment. Plasma concentrations of sunitinib, its active metabolite SU12662, and the soluble vascular endothelial growth factor receptors sVEGFR-2 and sVEGFR-3, were measured in 26 patients with mRCC within the EuroTARGET project and 21 patients with metastasized colorectal cancer (mCRC) from the C-II-005 study. Based on these observations, PK/PD models with potential influence of genetic predictors were developed and linked to time-to-event (TTE) models. Baseline sVEGFR-2 levels were associated with clinical outcome in patients with mRCC, whereas active drug PKs seemed to be more predictive in patients with mCRC. The models provide the basis of PK/PD-guided strategies for the individualization of anti-angiogenic therapies.

Doripenem Treatment during Continuous Renal Replacement Therapy.

Doripenem is a broad-spectrum parenteral carbapenem with enhanced activity against Pseudomonas aeruginosa. While the initial dosing recommendation for renally competent patients and patients undergoing continuous renal replacement therapy (cRRT) was 500 mg every 8 h (q8h), the dose for renally competent patients was updated to 1 g q8h in June 2012. There are no updated data for the dosing of patients on continuous renal replacement therapy. The original dosing regimen for cRRT patients was based on nonseptic patients, while newer publications chose comparatively low target concentrations for a carbapenem. Thus, there is an urgent need for updated recommendations for dosing during cRRT. In the trial presented here, we included 13 oliguric septic patients undergoing cRRT in an intensive care setting. Five patients each were treated with hemodiafiltration or hemodialysis, while three patients received hemofiltration treatment. All patients received 1 g doripenem every 8 h. Doripenem concentrations in the plasma and ultrafiltrate were measured over 48 h. The mean hemofilter clearance was 36.53 ml/min, and the mean volume of distribution was 59.26 liters. The steady-state trough levels were found at 8.5 mg/liter, with no considerable accumulation. Based on pharmacokinetic and pharmacodynamic considerations, we propose a regimen of 1 g q8h, which may be combined with a loading dose of 1.5 to 2 g for critically ill patients. (This study has been registered with EudraCT under registration no. 2009-018010-18 and at ClinicalTrials.gov under registration no. NCT02018939.).

Evaluation of single-cell biomechanics as potential marker for oral squamous cell carcinomas: a pilot study.

OBJECTIVES: Early detection of oral cancer is a major health issue. The objective of this pilot study was to analyze the deformability of healthy and cancer cells using a microfluidic optical stretcher (OS). MATERIAL AND METHODS: Different cancer cell lines, primary oral cancer cells, and their healthy counterparts were cultivated and characterized, respectively. A measurable deformation of the cells along the optical axis was detected, caused by surface stress, which is optically induced by the laser power. RESULTS: All cells revealed a viscoelastic extension behavior and showed a characteristic deformation response under laser light exposure. The CAL-27/-33 cells exhibited the highest relative deformation. All other cells achieved similar values, but on a lower level. The cytoskeleton reacts sensitively of changing environmental conditions, which may be influenced by growth behavior of the cancer specimens. Nevertheless, the statistical analysis showed significant differences between healthy and cancer cells. CONCLUSION: Generally, malignant and benign cells showed significantly different mechanical behavior. Cancer-related changes influence the composition of the cytoskeleton and thus affect the deformability, but this effect may be superimposed by cell cultivation conditions or cell doubling time. These influences had to be substituted by brush biopsies to minimize confounders in pursuing investigations.

Analysis of multiple physical parameters for mechanical phenotyping of living cells.

Since the cytoskeleton is known to regulate many cell functions, an increasing amount of effort to characterize cells by their mechanical properties has occured. Despite the structural complexity and dynamics of the multicomponent cytoskeleton, mechanical measurements on single cells are often fit to simple models with two to three parameters, and those parameters are recorded and reported. However, different simple models are likely needed to capture the distinct mechanical cell states, and additional parameters may be needed to capture the ability of cells to actively deform. Our new approach is to capture a much larger set of possibly redundant parameters from cells' mechanical measurement using multiple rheological models as well as dynamic deformation and image data. Principal component analysis and network-based approaches are used to group parameters to reduce redundancies and develop robust biomechanical phenotyping. Network representation of parameters allows for visual exploration of cells' complex mechanical system, and highlights unexpected connections between parameters. To demonstrate that our biomechanical phenotyping approach can detect subtle mechanical differences, we used a Microfluidic Optical Cell Stretcher to mechanically stretch circulating human breast tumor cells bearing genetically-engineered alterations in c-src tyrosine kinase activation, which is known to influence reattachment and invasion during metastasis.

Clinical efficacy of moxifloxacin versus comparator therapies for community-acquired pneumonia caused by Legionella spp.

The aim of this study was to compare outcomes for patients with community-acquired pneumonia (CAP) caused by Legionella spp. following treatment with moxifloxacin or a range of comparator antimicrobial agents. Data were pooled from four sequential I.V./P.O. trials of moxifloxacin in the treatment of CAP. Comparators were ceftriaxone +/- erythromycin, amoxicillin/clavulanate +/- clarithromycin, trovafloxacin, levofloxacin, or ceftriaxone + levofloxacin. Legionella infection was diagnosed by culture, urine antigen testing and/or serology. Clinical success rates for the efficacy-valid (per protocol) populations were recorded at the test-of-cure visit (5-30 days post-therapy). Severity of CAP was determined using the modified American Thoracic Society criteria.Of 1786 efficacy-valid patients, 33 (1.8%) had documented infection with Legionella spp. (moxifloxacin: n=13; comparator: n=20). Of these, 30 cases were identified by serology and/or urine antigen detection and 3 by respiratory culture. The success rate of moxifloxacin vs. comparator therapy was 92.3% vs. 80.0% for the I.V./P.O. trials.Sequential (I.V./P.O.) moxifloxacin demonstrated clinical efficacy that was at least as good as that of comparator treatments for the treatment of CAP due to Legionella.

Some epidermolysis bullosa acquisita sera react with epitopes within the triple-helical collagenous domain as indicated by immunoelectron microscopy.

BACKGROUND: Epidermolysis bullosa acquisita (EBA) autoantibodies recognize epitopes predominantly within the N-terminal noncollagenous (NC)-1 domain of type VII collagen. Recently, some EBA cases with reactivity to other domains, i.e. the triple-helical (T-H) collagenous domain and the NC-2 domain, have been reported. OBJECTIVES: To investigate the ultrastructural localization of epitopes for sera from five patients with EBA that were unreactive by immunoblotting with the NC-1, NC-2 and collagenous domains of type VII collagen. METHODS: Immunogold postembedding indirect immunoelectron microscopy was performed using normal human skin and type VII collagen-deficient skin as substrates. RESULTS: Postembedding indirect immunoelectron microscopy revealed that the five EBA sera showed immunoreactivity in the dermis, mainly located 0-400 nm below the lamina densa. IgG labelling was not observed in type VII collagen-deficient skin from a patient with recessive dystrophic epidermolysis bullosa. The distribution histogram found in this study was different from those of sera that reacted with the NC-1 and/or NC-2 domains, and was similar to those of sera reacting with the T-H collagenous domain. CONCLUSIONS: Our results suggest that epitopes within the T-H collagenous domain of type VII collagen are recognized by IgG antibodies from some EBA sera. These antibodies appear to be found in patients with inflammatory-type EBA.

Severe fetal hydrocephalus with and without neural tube defect: a comparative study.

OBJECTIVE: To describe the main perinatal and 1-year outcomes in babies with a prenatal ultrasonographic diagnosis of severe hydrocephalus according to the presence or absence of a neural tube defect (NTD) in a country where abortion is illegal. METHOD: The study population consisted of cases referred to and delivered at Hospital de Clínicas de Porto Alegre, diagnosed between January 1993 and December 2001. The diagnosis of severe hydrocephalus was based on a lateral ventricular atrium diameter > or =15 mm in at least one hemisphere. RESULTS: Sixty cases were ascertained: 28 with NTD (group 1) and 32 without NTD (group 2). The groups were similar in terms of maternal and child variables at birth and hospitalization days during the 1st year of life. The mortality (including intrauterine deaths and deaths of babies with malformations incompatible with life that characterize a very poor prognosis) until 1 year of age was 36% in group 1 and 59% in group 2 (p = 0.077). The rate of cardiac malformations was higher in the group without NTD (p = 0.015). The length of hospital stay after birth (1st admission) was significantly higher in the group with NTD (p = 0.007). CONCLUSIONS: The morbidity was higher in the group with NTD, possibly due to the higher number of surgical interventions in the central nervous system. However, the mortality was higher in the group without NTD, possibly due to the presence of other associated malformations, especially congenital heart disease. Further studies should focus on neurological function and quality of life of the children and their families at the end of the 1st year and after 2 or 6 years of age.

Cell cycle and biochemical effects of PD 0183812. A potent inhibitor of the cyclin D-dependent kinases CDK4 and CDK6.

Progression through the G1 phase of the cell cycle requires phosphorylation of the retinoblastoma gene product (pRb) by the cyclin D-dependent kinases CDK4 and CDK6, whose activity can specifically be blocked by the CDK inhibitor p16(INK4A). Misregulation of the pRb/cyclin D/p16(INK4A) pathway is one of the most common events in human cancer and has lead to the suggestion that inhibition of cyclin D-dependent kinase activity may have therapeutic value as an anticancer treatment. Through screening of a chemical library, we initially identified the [2,3-d]pyridopyrimidines as inhibitors of CDK4. Chemical modification resulted in the identification of PD 0183812 as a potent and highly selective inhibitor of both CDK4 and CDK6 kinase activity, which is competitive with ATP. Flow cytometry experiments showed that of the cell lines tested, only those expressing pRb demonstrated a G1 arrest when treated with PD 0183812. This arrest correlated in terms of incubation time and potency with a loss of pRb phosphorylation and a block in proliferation, which was reversible. These results suggest a potential use of this chemical class of compounds as therapeutic agents in the treatment of tumors with functional pRb, possessing cell cycle aberrations in other members of the pRb/cyclin D/p16(INK4A) pathway.

Pyrido[2,3-d]pyrimidin-7-one inhibitors of cyclin-dependent kinases.

The identification of 8-ethyl-2-phenylamino-8H-pyrido[2, 3-d]pyrimidin-7-one (1) as an inhibitor of Cdk4 led to the initiation of a program to evaluate related pyrido[2, 3-d]pyrimidin-7-ones for inhibition of cyclin-dependent kinases (Cdks). Analysis of more than 60 analogues has identified some clear SAR trends that may be exploited in the design of more potent Cdk inhibitors. The most potent Cdk4 inhibitors reported in this study inhibit Cdk4 with IC(50) = 0.004 microM ([ATP] = 25 microM). X-ray crystallographic analysis of representative compounds bound to the related kinase, Cdk2, reveals that they occupy the ATP binding site. Modest selectivity between Cdks is exhibited by some compounds, and Cdk4-selective inhibitors block pRb(+) cells in the G(1)-phase of the cell division cycle.

Motor cortex disinhibition in acute stroke.

OBJECTIVES: To test whether a disinhibition occurs in the human motor cortex after stroke. METHODS: Patients with a mild to moderate hemiparesis after an acute unilateral ischemic stroke were compared with age-matched healthy controls. We used paired transcranial magnetic stimuli (TMS) to investigate intracortical inhibition and facilitation. Single TMS were applied to obtain a cortical silent period. RESULTS: Intracortical inhibition was significantly reduced in the affected hemisphere at interstimulus intervals of 2, 3 and 4 ms. The cortical silent period was significantly prolonged when compared to the unaffected hemisphere of the patients and to the control group. Motor cortex disinhibition observed in stroke patients was associated either with minimal impairment at the onset of symptoms or with rapidly improving motor functions. CONCLUSIONS: Motor cortex disinhibition occurs in humans after stroke. We suggest that this disinhibition is indicative of compensatory mechanisms, which are involved in recovery-related reorganization.

Oxidized low-density lipoprotein inhibits the binding of monoclonal antibody to platelet glycoprotein IIB-IIIA.

Previous studies have shown that oxidized low-density lipoprotein (LDL) induces platelet activation more effectively than native LDL. To achieve a better understanding of the mechanism underlying the activation of human platelets by oxidized LDL, the present study relates the effect of oxidized LDL to changes of binding characteristics for glycoprotein (GP) IIb-IIIa. Washed human platelets were treated by monoclonal antibody against GP IIb-IIIa, and the ligand-receptor complexes were revealed by immunocytochemical techniques on the ultrastructural level. The localization of the antiglycoprotein IIb-IIIa was time-dependent. After binding to the platelet surface membrane and open canalicular system, the surface-membrane labeling decreased during longer incubation periods. Preincubation with oxidized LDL inhibited the binding of antiglycoprotein IIb-IIIa. Our findings suggest that GP IIb-IIIa acts as a receptor for oxidized LDL. The binding of oxidized LDL to the GP IIb-IIIa might be the first step in platelet activation by plasma lipoproteins.

PAK4, a novel effector for Cdc42Hs, is implicated in the reorganization of the actin cytoskeleton and in the formation of filopodia.

The GTPases Rac and Cdc42Hs control diverse cellular functions. In addition to being mediators of intracellular signaling cascades, they have important roles in cell morphogenesis and mitogenesis. We have identified a novel PAK-related kinase, PAK4, as a new effector molecule for Cdc42Hs. PAK4 interacts only with the activated form of Cdc42Hs through its GTPase-binding domain (GBD). Co-expression of PAK4 and the constitutively active Cdc42HsV12 causes the redistribution of PAK4 to the brefeldin A-sensitive compartment of the Golgi membrane and the subsequent induction of filopodia and actin polymerization. Importantly, the reorganization of the actin cytoskeleton is dependent on PAK4 kinase activity and on its interaction with Cdc42Hs. Thus, unlike other members of the PAK family, PAK4 provides a novel link between Cdc42Hs and the actin cytoskeleton. The cellular locations of PAK4 and Cdc42Hs suggest a role for the Golgi in cell morphogenesis.