The pathophysiologic causes of obstructive sleep apnea (OSA) likely vary among patients but have not been well characterized.
To define carefully the proportion of key anatomic and nonanatomic ...contributions in a relatively large cohort of patients with OSA and control subjects to identify pathophysiologic targets for future novel therapies for OSA.
Seventy-five men and women with and without OSA aged 20-65 years were studied on three separate nights. Initially, the apnea-hypopnea index was determined by polysomnography followed by determination of anatomic (passive critical closing pressure of the upper airway Pcrit) and nonanatomic (genioglossus muscle responsiveness, arousal threshold, and respiratory control stability; loop gain) contributions to OSA.
Pathophysiologic traits varied substantially among participants. A total of 36% of patients with OSA had minimal genioglossus muscle responsiveness during sleep, 37% had a low arousal threshold, and 36% had high loop gain. A total of 28% had multiple nonanatomic features. Although overall the upper airway was more collapsible in patients with OSA (Pcrit, 0.3 -1.5 to 1.9 vs. -6.2 -12.4 to -3.6 cm H2O; P <0.01), 19% had a relatively noncollapsible upper airway similar to many of the control subjects (Pcrit, -2 to -5 cm H2O). In these patients, loop gain was almost twice as high as patients with a Pcrit greater than -2 cm H2O (-5.9 -8.8 to -4.5 vs. -3.2 -4.8 to -2.4 dimensionless; P = 0.01). A three-point scale for weighting the relative contribution of the traits is proposed. It suggests that nonanatomic features play an important role in 56% of patients with OSA.
This study confirms that OSA is a heterogeneous disorder. Although Pcrit-anatomy is an important determinant, abnormalities in nonanatomic traits are also present in most patients with OSA.
Generating compatible and competitive materials that are environmentally sustainable and economically viable is paramount for the success of additive manufacturing using renewable materials. We ...report the successful application of renewable, modified lignin-containing photopolymer resins in a commercial stereolithography system. Resins were fabricated within operable ranges for viscosity and cure properties, using up to 15% modified lignin by weight. A 4-fold increase in ductility in cured parts with higher lignin concentration is noted compared to commercial stereolithography resins. Excellent print quality was seen in modified lignin resins, with good layer fusion, high surface definition, and visual clarity. These materials can be used to generate new products for additive manufacturing applications and help fill vacant material property spaces, where ductility, sustainability, and application costs are critical.
Summary The Ebola virus disease outbreak in West Africa was unprecedented in both its scale and impact. Out of this human calamity has come renewed attention to global health security—its definition, ...meaning, and the practical implications for programmes and policy. For example, how does a government begin to strengthen its core public health capacities, as demanded by the International Health Regulations? What counts as a global health security concern? In the context of the governance of global health, including WHO reform, it will be important to distil lessons learned from the Ebola outbreak. The Lancet invited a group of respected global health practitioners to reflect on these lessons, to explore the idea of global health security, and to offer suggestions for next steps. Their contributions describe some of the major threats to individual and collective human health, as well as the values and recommendations that should be considered to counteract such threats in the future. Many different perspectives are proposed. Their common goal is a more sustainable and resilient society for human health and wellbeing.
The role of the alkali metal cations in halide perovskite solar cells is not well understood. Using synchrotron-based nano-x-ray fluorescence and complementary measurements, we found that the halide ...distribution becomes homogenized upon addition of cesium iodide, either alone or with rubidium iodide, for substoichiometric, stoichiometric, and overstoichiometric preparations, where the lead halide is varied with respect to organic halide precursors. Halide homogenization coincides with long-lived charge carrier decays, spatially homogeneous carrier dynamics (as visualized by ultrafast microscopy), and improved photovoltaic device performance. We found that rubidium and potassium phase-segregate in highly concentrated clusters. Alkali metals are beneficial at low concentrations, where they homogenize the halide distribution, but at higher concentrations, they form recombination-active second-phase clusters.
Lake Analyzer is a numerical code coupled with supporting visualization tools for determining indices of mixing and stratification that are critical to the biogeochemical cycles of lakes and ...reservoirs. Stability indices, including Lake Number, Wedderburn Number, Schmidt Stability, and thermocline depth are calculated according to established literature definitions and returned to the user in a time series format. The program was created for the analysis of high-frequency data collected from instrumented lake buoys, in support of the emerging field of aquatic sensor network science. Available outputs for the Lake Analyzer program are: water temperature (error-checked and/or down-sampled), wind speed (error-checked and/or down-sampled), metalimnion extent (top and bottom), thermocline depth, friction velocity, Lake Number, Wedderburn Number, Schmidt Stability, mode-1 vertical seiche period, and Brunt-Väisälä buoyancy frequency. Secondary outputs for several of these indices delineate the parent thermocline depth (seasonal thermocline) from the shallower secondary or diurnal thermocline. Lake Analyzer provides a program suite and best practices for the comparison of mixing and stratification indices in lakes across gradients of climate, hydro-physiography, and time, and enables a more detailed understanding of the resulting biogeochemical transformations at different spatial and temporal scales.
Zinc (Zn) is an essential micronutrient and cofactor for up to 10% of proteins in living organisms. During Zn limitation, specialized enzymes called metallochaperones are predicted to allocate Zn to ...specific metalloproteins. This function has been putatively assigned to G3E GTPase COG0523 proteins, yet no Zn metallochaperone has been experimentally identified in any organism. Here, we functionally characterize a family of COG0523 proteins that is conserved across vertebrates. We identify Zn metalloprotease methionine aminopeptidase 1 (METAP1) as a COG0523 client, leading to the redesignation of this group of COG0523 proteins as the Zn-regulated GTPase metalloprotein activator (ZNG1) family. Using biochemical, structural, genetic, and pharmacological approaches across evolutionarily divergent models, including zebrafish and mice, we demonstrate a critical role for ZNG1 proteins in regulating cellular Zn homeostasis. Collectively, these data reveal the existence of a family of Zn metallochaperones and assign ZNG1 an important role for intracellular Zn trafficking.
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•The N terminus of ZNG1 interacts with the zinc finger of METAP1•ZNG1 promotes METAP1 activity in a GTP-hydrolysis- and Zn-dependent manner•Loss of ZNG1 impairs mitochondrial function and cellular proliferation•Zng1 mutant animals are sensitive to Zn starvation and inhibition of METAP activity
ZNG1 is a putative Zn metallochaperone that supports the activity of Zn-dependent proteins in vertebrates, thereby maintaining Zn homeostasis and cellular integrity.
An anatomically narrow/highly collapsible upper airway is the main cause of obstructive sleep apnea (OSA). Upper airway muscle activity contributes to airway patency and, like apnea severity, can be ...sleep stage dependent. Conversely, existing data derived from a small number of participants suggest that upper airway collapsibility, measured by the passive pharyngeal critical closing pressure (Pcrit) technique, is not sleep stage dependent. This study aimed to determine the effect of sleep stage on Pcrit and upper airway muscle activity in a larger cohort than previously tested.
Pcrit and/or muscle data were obtained from 72 adults aged 20-64 y with and without OSA.Pcrit was determined via transient reductions in continuous positive airway pressure (CPAP) during N2, slow wave sleep (SWS) and rapid eye movement (REM) sleep. Genioglossus and tensor palatini muscle activities were measured: (1) awake with and without CPAP, (2) during stable sleep on CPAP, and (3) in response to the CPAP reductions used to quantify Pcrit.
Pcrit was 4.9 ± 1.4 cmH2O higher (more collapsible) during REM versus SWS (P = 0.012), 2.3 ± 0.6 cmH2O higher during REM versus N2 (P < 0.001), and 1.6 ± 0.7 cmH2O higher in N2 versus SWS (P = 0.048). Muscle activity decreased from wakefulness to sleep and from SWS to N2 to REM sleep for genioglossus but not for tensor palatini. Pharyngeal muscle activity increased by ∼50% by breath 5 following CPAP reductions.
Upper airway collapsibility measured via the Pcrit technique and genioglossus muscle activity vary with sleep stage. These findings should be taken into account when performing and interpreting "passive" Pcrit measurements.
Identification of pathogenic germline alterations (PGAs) has important clinical and therapeutic implications in pancreas cancer. We performed comprehensive germline testing (GT) in an unselected ...prospective cohort of patients with exocrine pancreatic neoplasms with genotype and phenotype association to facilitate identification of prognostic and/or predictive biomarkers and examine potential therapeutic implications.
Six hundred fifteen unselected patients with exocrine pancreatic neoplasms were prospectively consented for somatic tumor and matched sample profiling for 410-468 genes. GT for PGAs in 76 genes associated with cancer susceptibility was performed in an "identified" manner in 356 (57.9%) patients and in an "anonymized" manner in 259 (42.1%) patients, using an institutional review board-approved protocol. Detailed clinical and pathological features, response to platinum, and overall survival (OS) were collected for the identified cohort. OS was analyzed with Kaplan-Meier curves.
PGAs were present in 122 (19.8%) of 615 patients involving 24 different genes, including BRCA1/2, ATM, PALB2, and multiple additional genes associated with the DNA damage response pathway. Of 122 patients with germline alterations, 41.8% did not meet current guidelines for GT. The difference in median OS was not statistically significant between patients with and without PGA (50.8 months, 95% confidence interval = 34.5 to not reached, two-sided P = .94). Loss of heterozygosity was found in 60.0% of BRCA1/2.
PGAs frequently occur in pancreas exocrine neoplasms and involve multiple genes beyond those previously associated with hereditary pancreatic cancer. These PGAs are therapeutically actionable in about 5% to 10% of patients. These data support routinely offering GT in all pancreatic ductal adenocarcimona patients with a broad panel of known hereditary cancer predisposition genes.
The purpose of this study was to examine sex-specific differences in the blood glucose (BG) response to recurrent aerobic exercise in type 1 diabetes rats. Specifically, we examined the role of peak ...estrogen (E2) concentrations during proestrus on BG response to prolonged repetitive aerobic exercise. To do so, nineteen Sprague-Dawley rats were assigned to four exercised groups: control female (CXF; n = 5), control male (CXM; n = 5), diabetic female (DXF, n = 5) and diabetic male (DXM, n = 4). Diabetes was induced in DX groups via subcutaneous multiple injections of low dose streptozotocin (20mg/day for 7 days). After four days of exercise, muscle and liver glycogen content, liver gluconeogenic enzyme content, muscle Beta oxidation activity and BG responses to exercise were compared. The final bout of exercise took place during proestrus when E2 concentrations were at their highest in the female rats. During days 1–3 DXM had significantly lower BG concentrations during exercise than DXF. While both T1DM and non-T1DM females demonstrated higher hepatic G6Pase expression and muscle beta oxidation activity levels on day 4 exercise, no differences in BG response between the male and female T1DM rats were evident. Further, no differences in liver and muscle glycogen content following day 4 of exercise were seen between the sexes. These results would suggest that heightened E2 levels during proestrus may not be an important factor governing glucose counter regulatory response to exercise in female T1DM rats. Rather, the pre-exercise blood glucose levels are likely to be a large determinant of the blood glucose response to exercise in both male and female rats.
The mechanical properties of π-conjugated (semiconducting) polymers are a key determinant of the stability and manufacturability of devices envisioned for applications in energy and healthcare. These ...propertiesincluding modulus, extensibility, toughness, and strengthare influenced by the morphology of the solid film, which depends on the method of processing. To date, the majority of work done on the mechanical properties of semiconducting polymers has been performed on films deposited by spin coating, a process not amenable to the manufacturing of large-area films. Here, we compare the mechanical properties of thin films of regioregular poly(3-heptylthiophene) (P3HpT) produced by three scalable deposition processesinterfacial spreading, solution shearing, and spray coatingand spin coating (as a reference). Our results lead to four principal conclusions. (1) Spray-coated films have poor mechanical robustness due to defects and inhomogeneous thickness. (2) Sheared films show the highest modulus, strength, and toughness, likely resulting from a decrease in free volume. (3) Interfacially spread films show a lower modulus but greater fracture strain than spin-coated films. (4) The trends observed in the tensile behavior of films cast using different deposition processes held true for both P3HpT and poly(3-butylthiophene) (P3BT), an analogue with a higher glass transition temperature. Grazing incidence X-ray diffraction and ultraviolet–visible spectroscopy reveal many notable differences in the solid structures of P3HpT films generated by all four processes. While these morphological differences provide possible explanations for differences in the electronic properties (hole mobility), we find that the mechanical properties of the film are dominated by the free volume and surface topography. In field-effect transistors, spread films had mobilities more than 1 magnitude greater than any other films, likely due to a relatively high proportion of edge-on texturing and long coherence length in the crystalline domains. Overall, spread films offer the best combination of deformability and charge-transport properties.
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