Parainfluenza virus types 1–4 (PIV1–4) are highly infectious human pathogens, of which PIV3 is most commonly responsible for severe respiratory illness in newborns, elderly, and immunocompromised ...individuals. To obtain a vaccine effective against all four PIV types, we engineered mutations in each of the four PIV fusion (F) glycoproteins to stabilize their metastable prefusion states, as such stabilization had previously enabled the elicitation of high-titer neutralizing antibodies against the related respiratory syncytial virus. A cryoelectron microscopy structure of an engineered PIV3 F prefusion-stabilized trimer, bound to the prefusion-specific antibody PIA174, revealed atomic-level details for how introduced mutations improved stability as well as how a single PIA174 antibody recognized the trimeric apex of prefusion PIV3 F. Nine combinations of six newly identified disulfides and two cavity-filling mutations stabilized the prefusion PIV3 F immunogens and induced 200- to 500-fold higher neutralizing titers in mice than were elicited by PIV3 F in the postfusion conformation. For PIV1, PIV2, and PIV4, we also obtained stabilized prefusion Fs, for which prefusion versus postfusion titers were 2- to 20-fold higher. Elicited murine responses were PIV type-specific, with little cross-neutralization of other PIVs. In nonhuman primates (NHPs), quadrivalent immunization with prefusion-stabilized Fs from PIV1–4 consistently induced potent neutralizing responses against all four PIVs. For PIV3, the average elicited NHP titer from the quadrivalent immunization was more than fivefold higher than any titer observed in a cohort of over 100 human adults, highlighting the ability of a prefusion-stabilized immunogen to elicit especially potent neutralization.
Early Breast Cancer Therapy and Cardiovascular Injury Jones, Lee W., PhD; Haykowsky, Mark J., PhD; Swartz, Jonas J., BS ...
Journal of the American College of Cardiology,
10/2007, Letnik:
50, Številka:
15
Journal Article
Recenzirano
Odprti dostop
Early Breast Cancer Therapy and Cardiovascular Injury Lee W. Jones, Mark J. Haykowsky, Jonas J. Swartz, Pamela S. Douglas, John R. Mackey Although recent advances in curative-intent therapies are ...beginning to produce significant survival gains in early breast cancer, these improvements may ultimately be attenuated by increased risk of long-term cardiovascular mortality. This report reviews emerging evidence on the cardiovascular effects of breast cancer adjuvant therapy and proposes a new entity that we have labeled the “multiple-hit” hypothesis. The evidence that lifestyle modification, especially exercise therapy, may mitigate these adverse effects is also reviewed. These issues are of considerable practical importance for cardiovascular clinicians, as identification and intervention in those at high risk for cardiovascular complications may reduce a major cause of mortality in women with early breast cancer.
IMPORTANCE From January 1, 2003, through December 31, 2010, drug overdose deaths in Tennessee increased from 422 to 1059 per year. More of these deaths involved prescription opioids than heroin and ...cocaine combined. OBJECTIVE To assess the contribution of certain opioid-prescribing patterns to the risk of overdose death. DESIGN, SETTING, AND PARTICIPANTS We performed a matched case-control study that analyzed opioid prescription data from the Tennessee Controlled Substances Monitoring Program (TNCSMP) from January 1, 2007, through December 31, 2011, to identify risk factors associated with opioid-related overdose deaths from January 1, 2009, through December 31, 2010. Case patients were ascertained from death certificate data. Age- and sex-matched controls were randomly selected from among live patients in the TNCSMP. MAIN OUTCOMES AND MEASURES We defined a high-risk number of prescribers or pharmacies as 4 or more per year and high-risk dosage as a daily mean of more than 100 morphine milligram equivalents (MMEs) per year. The main outcome was opioid-related overdose death. RESULTS From January 1, 2007, through December 31, 2011, one-third of the population of Tennessee filled an opioid prescription each year, and opioid prescription rates increased from 108.3 to 142.5 per 100 population per year. Among all patients in Tennessee prescribed opioids during 2011, 7.6% used more than 4 prescribers, 2.5% used more than 4 pharmacies, and 2.8% had a mean daily dosage greater than 100 MMEs. Increased risk of opioid-related overdose death was associated with 4 or more prescribers (adjusted odds ratio aOR, 6.5; 95% CI, 5.1-8.5), 4 or more pharmacies (aOR, 6.0; 95% CI, 4.4-8.3), and more than 100 MMEs (aOR, 11.2; 95% CI, 8.3-15.1). Persons with 1 or more risk factor accounted for 55% of all overdose deaths. CONCLUSIONS AND RELEVANCE High-risk use of prescription opioids is frequent and increasing in Tennessee and is associated with increased overdose mortality. Use of prescription drug–monitoring program data to direct risk-reduction measures to the types of patients overrepresented among overdose deaths might reduce mortality associated with opioid abuse.
During May–September 2000–2001, physicochemical data were collected from 241 lakes in Missouri, Iowa, northeastern Kansas, and southern Minnesota U.S.A., to determine the environmental variables ...associated with high concentrations of the cyanobacterial hepatotoxin microcystin (MC). The study region represents a south–north latitudinal gradient in increasing trophic status, with total phosphorus (TP) and total nitrogen (TN) values ranging between 2–995 and 90–15870
μg/L, respectively. Particulate MC values, measured by ELISA, ranged from undetectable to 4500
ng/L and increased with increasing latitude. Despite latitudinal trends, environmental variables explained <50% of the variation in MC values. Inspection of MC–TN and MC–Secchi bivariate plots revealed distinctly nonlinear trends, suggesting optima for maximum MC values. Nonlinear interval maxima regression indicated that MC–TN maxima were characterized by a unimodal curve, with maximal (>2000
ng/L) MC values occurring between 1500 and 4000
μg/L TN. Above 8000
μg/L TN all MC values were <150
ng/L. MC–Secchi maxima were characterized by exponential decline, with maximal MC values occurring at Secchi depths <2.5
m. The development of empirical relationships between environmental variables and MC values is critical to effective lake management and minimization of human health risks associated with the toxin. This study indicates MC values are linked to the physicochemical environment; however, the relationships are not traditional linear models.
Photon upconversion is an elementary light-matter interaction process in which an absorbed photon is re-emitted at higher frequency after extracting energy from the medium. This phenomenon lies at ...the heart of optical refrigeration in solids1, where upconversion relies on anti-Stokes processes enabled either by rare-earth impurities2 or exciton-phonon coupling3. Here, we demonstrate a luminescence upconversion process from a negatively charged exciton to a neutral exciton resonance in monolayer WSe2, producing spontaneous anti-Stokes emission with an energy gain of 30 meV. Polarization-resolved measurements find this process to be valley selective, unique to monolayer semiconductors4. Since the charged exciton binding energy5 closely matches the 31 meV A1variant prime optical phonon6, 7, 8, 9, we ascribe the spontaneous excitonic anti-Stokes to doubly resonant Raman scattering, where the incident and outgoing photons are in resonance with the charged and neutral excitons, respectively. In addition, we resolve a charged exciton doublet with a 7 meV splitting, probably induced by exchange interactions, and show that anti-Stokes scattering is efficient only when exciting the doublet peak resonant with the phonon, further confirming the excitonic doubly resonant picture.
Van der Waals bound heterostructures constructed with two-dimensional materials, such as graphene, boron nitride and transition metal dichalcogenides, have sparked wide interest in device physics and ...technologies at the two-dimensional limit. One highly coveted heterostructure is that of differing monolayer transition metal dichalcogenides with type-II band alignment, with bound electrons and holes localized in individual monolayers, that is, interlayer excitons. Here, we report the observation of interlayer excitons in monolayer MoSe2-WSe2 heterostructures by photoluminescence and photoluminescence excitation spectroscopy. We find that their energy and luminescence intensity are highly tunable by an applied vertical gate voltage. Moreover, we measure an interlayer exciton lifetime of ~1.8 ns, an order of magnitude longer than intralayer excitons in monolayers. Our work demonstrates optical pumping of interlayer electric polarization, which may provoke further exploration of interlayer exciton condensation, as well as new applications in two-dimensional lasers, light-emitting diodes and photovoltaic devices.
In a study involving 51 patients with electronic-cigarette, or vaping, product use–associated lung injury in 16 states across the United States, vitamin E acetate was detected in samples of ...bronchoalveolar-lavage fluid from 94% of the patients but not in samples from a healthy comparator group.
Over the last two decades, lattice Boltzmann methods have become an increasingly popular tool to compute the flow in complex geometries such as porous media. In addition to single phase simulations ...allowing, for example, a precise quantification of the permeability of a porous sample, a number of extensions to the lattice Boltzmann method are available which allow to study multiphase and multicomponent flows on a pore scale level. In this article, we give an extensive overview on a number of these diffuse interface models and discuss their advantages and disadvantages. Furthermore, we shortly report on multiphase flows containing solid particles, as well as implementation details and optimization issues.
The quality of metaphase II oocytes deteriorates rapidly following ovulation as the result of an aging process associated with impaired fertilizing potential, disrupted developmental competence, and ...increased likelihood of embryonic resorption. Because oxidative stress accelerates the onset of apoptosis in oocytes and influences their capacity for fertilization, this study aimed to characterize the significance of such stress in the postovulatory aging of mouse oocytes in vitro. We investigated the ability of the potent antioxidant melatonin to arrest the aging process when used to supplement oocyte culture medium. This study demonstrated that oxidative stress may occur in oocytes after as little as 8 h in culture and coincides with the appearance of early apoptotic markers such as phosphatidylserine externalization, followed 16 h later by caspase activation (P < 0.05) and morphological evidence of oocyte senescence. Importantly, supplementation of oocyte culture medium with 1 mM melatonin was able to significantly relieve the time-dependent appearance of oxidative stress in oocytes (P < 0.05) and, as a result, significantly delay the onset of apoptosis (P < 0.05). Furthermore, melatonin supplementation extended the optimal window for fertilization of oocytes aged for 8 and 16 h in vitro (P < 0.05) and significantly improved the quality of the resulting embryos (P < 0.01). We conclude that melatonin may be a useful tool in a clinical setting to prevent the time-dependent deterioration of oocyte quality following prolonged culture in vitro.
We combine experiment and theory to investigate the cooperation or competition between organic and inorganic structure-directing agents (SDAs) for occupancy within microporous voids of chabazite ...(CHA) zeolites and to rationalize the effects of SDA siting on biasing the framework Al arrangement (Al–O(−Si–O) x –Al, x = 1–3) among CHA zeolites of essentially fixed composition (Si/Al = 15). CHA zeolites crystallized using mixtures of TMAda+ and Na+ contain one TMAda+ occluded per cage and Na+ co-occluded in an amount linearly proportional to the number of 6-MR paired Al sites, quantified by Co2+ titration. In contrast, CHA zeolites crystallized using mixtures of TMAda+ and K+ provide evidence that three K+ cations, on average, displace one TMAda+ from occupying a cage and contain predominantly 6-MR isolated Al sites. Moreover, CHA crystallizes from synthesis media containing more than 10-fold higher inorganic-to-organic ratios with K+ than with Na+ before competing crystalline phases form, providing a route to decrease the amount of organic SDA needed to crystallize high-silica CHA. Density functional theory calculations show that differences in the ionic radii of Na+ and K+ determine their preferences for siting in different CHA rings, which influences their energy to co-occlude with TMAda+ and stabilize different Al configurations. Monte Carlo models confirm that energy differences resulting from Na+ or K+ co-occlusion promote the formation of 6-MR and 8-MR paired Al arrangements, respectively. These results highlight opportunities to exploit using mixtures of organic and inorganic SDAs during zeolite crystallization in order to more efficiently use organic SDAs and influence framework Al arrangements.
PDF
