From Wrinkles to Creases in Elastomers: The Instability and Imperfection-Sensitivity of Wrinkling

The stability of the wrinkling mode experienced by a compressed half-space of neo-Hookean material is investigated using analytical and numerical methods to study the post-bifurcation behaviour of periodic solutions. It is shown that wrinkling is highly unstable owing to the nonlinear interaction among the multiple modes associated with the critical compressive state. Concomitantly, wrinkling is sensitive to exceedingly small initial imperfections that significantly reduce the compressive strain at which the instability occurs. The study provides insight into the connection between wrinkling and an alternative surface mode, the finite amplitude crease or sulcus. The shape of the critical combination of wrinkling modes has the form of an incipient crease, and a tiny initial imperfection can trigger a wrinkling instability that collapses into a crease.Engineering and Applied Science

Wrinkling Phenomena in Neo-Hookean Film/Substrate Bilayers

Wrinkling modes are determined for a two-layer system comprised of a neo-Hookean film bonded to an infinitely deep neo-Hookean substrate with the entire bilayer undergoing compression. The full range of the film/substrate modulus ratio is considered from the limit of a traction-free homogeneous substrate to very stiff films on compliant substrates. The role of substrate prestretch is considered wherein an unstretched film is bonded to a prestretched substrate with wrinkling arising as the stretch in the substrate is relaxed. An exact bifurcation analysis reveals the critical strain in the film at the onset of wrinkling. Numerical simulations carried out within a finite element framework uncover advanced post-bifurcation modes including period-doubling, folding and a newly identified mountain ridge mode.Engineering and Applied Science

Localized Ridge Wrinkling of Stiff Films on Compliant Substrates

Wrinkling of thin stiff films on thick compliant elastomeric substrates subject to plane strain compression is considered for cases in which the substrate is pre-stretched prior to film attachment. Advanced wrinkling modes are investigated that evolve as the systems are compressed beyond the onset of the primary sinusoidal wrinkling mode. If the substrate pre-stretch is greater than about 40%, an advanced mode in the form of a series of well-spaced ridges separated by relatively flat film is observed in the simulations. Our experiments reveal a localization mode in the form of alternating packets of large and small amplitude wrinkles, but not ridges, while ridge formation has been observed in other recent experiments. Measurements of undulation amplitudes have been made for wrinkle fields of stiff films formed by oxidation of the surface of pre-stretched PDMS substrates. Simulations have been performed with a finite element model and an analytical film/substrate model. The formation of the ridge mode is a consequence of the altered nonlinearity of the substrate produced by the pre-stretch. The role of the tangential substrate stiffness in suppressing localization at the ridges is also highlighted. If there is no substrate pre-stretch, or if the substrate is pre-compressed, the primary sinusoidal mode gives way to an entirely different sequence of advanced modes usually entailing period doubling followed by folding. The nature of substrate nonlinearity that leads to ridges or folds is discussed.Engineering and Applied Science

Interactions of IgG1 CH2 and CH3 Domains with FcRn

Antibody fragments are emerging as promising biopharmaceuticals because of their relatively small size and other unique properties. However, when compared to full-size antibodies, most of the current antibody fragments of VH or VL display greatly reduced half-lives. A promising approach to overcome this problem is through the development of novel antibody fragments based on IgG Fc region, which contributes to the long half-life of IgG through its unique pH-dependent association with the neonatal Fc receptor (FcRn). The IgG Fc region comprises two CH2 and two CH3 domains. In this report, we present a comparative study of the FcRn binding capability of the CH2 and CH3 domains. The stability and aggregation resistance of these domains were also investigated and compared. We found that monomeric CH2 and CH3 domains exhibited the pH-dependent FcRn binding while the dimeric forms of CH2 and CH3 domains did not. Although all of these domains had high serum stability, they had aggregation tendencies as measured by dynamic light scattering. By providing a better understanding of the structure-activity relationship of the Fc fragment, these results guide further approaches to generate novel Fc-based small-size antibody fragments that possess pH-dependent FcRn binding capability, desired in vivo half-lives and other favorable biophysical properties for their drugability

Three-dimensional correlated-fermion phase separation from analysis of the geometric mean of the individual susceptibilities

A quasi-Gaussian approximation scheme is formulated to study the strongly correlated imbalanced fermions thermodynamics, where the mean-field theory is not applicable. The non-Gaussian correlation effects are understood to be captured by the statistical geometric mean of the individual susceptibilities. In the three-dimensional unitary fermions ground state, an {\em universal} non-linear scaling transformation relates the physical chemical potentials with the individual Fermi kinetic energies. For the partial polarization phase separation to full polarization, the calculated critical polarization ratio is $P_C={[1-(1-\xi)^{6/5}]}/{[1+(1-\xi)^{6/5}]}\doteq 0.34$. The $\xi=4/9$ defines the ratio of the symmetric ground state energy density to that of the ideal fermion gas.Comment: Minor changes with typos correcte

207-nm UV Light—A Promising Tool for Safe Low-Cost Reduction of Surgical Site Infections. II: In-Vivo Safety Studies

Background UVC light generated by conventional germicidal lamps is a well-established anti-microbial modality, effective against both bacteria and viruses. However, it is a human health hazard, being both carcinogenic and cataractogenic. Earlier studies showed that single-wavelength far-UVC light (207 nm) generated by excimer lamps kills bacteria without apparent harm to human skin tissue in vitro. The biophysical explanation is that, due to its extremely short range in biological material, 207 nm UV light cannot penetrate the human stratum corneum (the outer dead-cell skin layer, thickness 5–20 μm) nor even the cytoplasm of individual human cells. By contrast, 207 nm UV light can penetrate bacteria and viruses because these cells are physically much smaller. Aims To test the biophysically-based hypothesis that 207 nm UV light is not cytotoxic to exposed mammalian skin in vivo. Methods Hairless mice were exposed to a bactericidal UV fluence of 157 mJ/cm2 delivered by a filtered Kr-Br excimer lamp producing monoenergetic 207-nm UV light, or delivered by a conventional 254-nm UV germicidal lamp. Sham irradiations constituted the negative control. Eight relevant cellular and molecular damage endpoints including epidermal hyperplasia, pre-mutagenic UV-associated DNA lesions, skin inflammation, and normal cell proliferation and differentiation were evaluated in mice dorsal skin harvested 48 h after UV exposure. Results While conventional germicidal UV (254 nm) exposure produced significant effects for all the studied skin damage endpoints, the same fluence of 207 nm UV light produced results that were not statistically distinguishable from the zero exposure controls. Conclusions As predicted by biophysical considerations and in agreement with earlier in vitro studies, 207-nm light does not appear to be significantly cytotoxic to mouse skin. These results suggest that excimer-based far-UVC light could potentially be used for its anti-microbial properties, but without the associated hazards to skin of conventional germicidal UV lamps

Exposure to the Chinese Famine in Early Life and the Risk of Hyperglycemia and Type 2 Diabetes in Adulthood

OBJECTIVE: Early developmental adaptations in response to undernutrition may play an essential role in susceptibility to type 2 diabetes, particularly for those experiencing a “mismatched rich nutritional environment” in later life. We examined the associations of exposure to the Chinese famine (1959–1961) during fetal life and childhood with the risk of hyperglycemia and type 2 diabetes in adulthood. RESEARCH DESIGN AND METHODS: We used the data for 7,874 rural adults born between 1954 and 1964 in selected communities from the cross-sectional 2002 China National Nutrition and Health Survey. Hyperglycemia was defined as fasting plasma glucose ≥6.1 mmol/l and/or 2-h plasma glucose ≥7.8 mmol/l and/or a previous clinical diagnosis of type 2 diabetes. RESULTS: Prevalences of hyperglycemia among adults in nonexposed, fetal exposed, early-childhood, mid-childhood, and late-childhood exposed cohorts were 2.4%, 5.7%, 3.9%, 3.4%, and 5.9%, respectively. In severely affected famine areas, fetal-exposed subjects had an increased risk of hyperglycemia compared with nonexposed subjects (odds ratio = 3.92; 95% CI: 1.64–9.39; $P$ = 0.002); this difference was not observed in less severely affected famine areas (odds ratio = 0.57; 95% CI: 0.25–1.31; P = 0.185). The odds ratios were significantly different between groups from the severe and less severe famine areas ($P$ for interaction = 0.001). In severely affected famine areas, fetal-exposed subjects who followed an affluent/Western dietary pattern (odds ratios = 7.63; 95% CI: 2.41–24.1; $P$ = 0.0005) or who had a higher economic status in later life experienced a substantially elevated risk of hyperglycemia (odds ratios = 6.20; 95% CI: 2.08–18.5; $P$ = 0.001). CONCLUSIONS: Fetal exposure to the severe Chinese famine increases the risk of hyperglycemia in adulthood. This association appears to be exacerbated by a nutritionally rich environment in later life

Reversal of Cancer Cachexia and Muscle Wasting by ActRIIB Antagonism Leads to Prolonged Survival

SummaryMuscle wasting and cachexia have long been postulated to be key determinants of cancer-related death, but there has been no direct experimental evidence to substantiate this hypothesis. Here, we show that in several cancer cachexia models, pharmacological blockade of ActRIIB pathway not only prevents further muscle wasting but also completely reverses prior loss of skeletal muscle and cancer-induced cardiac atrophy. This treatment dramatically prolongs survival, even of animals in which tumor growth is not inhibited and fat loss and production of proinflammatory cytokines are not reduced. ActRIIB pathway blockade abolished the activation of the ubiquitin-proteasome system and the induction of atrophy-specific ubiquitin ligases in muscles and also markedly stimulated muscle stem cell growth. These findings establish a crucial link between activation of the ActRIIB pathway and the development of cancer cachexia. Thus ActRIIB antagonism is a promising new approach for treating cancer cachexia, whose inhibition per se prolongs survival.PaperCli

Relaxation of the one child policy and trends in caesarean section rates and birth outcomes in China between 2012 and 2016: observational study of nearly seven million health facility births.

OBJECTIVE: To examine how the relaxation of the one child policy and policies to reduce caesarean section rates might have affected trends over time in caesarean section rates and perinatal and pregnancy related mortality in China. DESIGN: Observational study. SETTING: China's National Maternal Near Miss Surveillance System (NMNMSS). PARTICIPANTS: 6 838 582 births at 28 completed weeks or more of gestation or birth weight ≥1000 g in 438 hospitals in the NMNMSS between 2012 and 2016. MAIN OUTCOME MEASURES: Obstetric risk was defined using a modified Robson classification. The main outcome measures were changes in parity and age distributions and relative frequency of each Robson group, crude and adjusted trends over time in caesarean section rates within each risk category (using Poisson regression with a robust variance estimator), and trends in perinatal and pregnancy related mortality over time. RESULTS: Caesarean section rates declined steadily between 2012 and 2016 (crude relative risk 0.91, 95% confidence interval 0.89 to 0.93), reaching an overall hospital based rate of 41.1% in 2016. The relaxation of the one child policy was associated with an increase in the proportion of multiparous births (from 34.1% in 2012 to 46.7% in 2016), and births in women with a uterine scar nearly doubled (from 9.8% to 17.7% of all births). Taking account of these changes, the decline in caesarean sections was amplified over time (adjusted relative risk 0.82, 95% confidence interval 0.81 to 0.84). Caesarean sections declined noticeably in nulliparous women (0.75, 0.73 to 0.77) but also declined in multiparous women without a uterine scar (0.65, 0.62 to 0.77). The decrease in caesarean section rates was most pronounced in hospitals with the highest rates in 2012, consistent with the government's policy of targeting hospitals with the highest rates. Perinatal mortality declined from 10.1 to 7.2 per 1000 births over the same period (0.87, 0.83 to 0.91), and there was no change in pregnancy related mortality over time. CONCLUSIONS: China is the only country that has succeeded in reverting the rising trends in caesarean sections. China's success is remarkable given that the changes in obstetric risk associated with the relaxation of the one child policy would have led to an increase in the need for caesarean sections. China's experience suggests that change is possible when strategies are comprehensive and deal with the system level factors that underpin overuse as well as the various incentives at work during a clinical encounter