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This article proposed a new fixed-time trajectory tracking control strategy based on the disturbance observer (DOB) for a tilt trirotor unmanned aerial vehicle (TTUAV), which is subject to unknown external disturbances. To facilitate the TTUAV's trajectory tracking controller design, the dynamic model of the TTUAV is divided into two subsystems, the position subsystem (outer-loop) and the attitude subsystem (inner-loop). For the dynamics of the TTUAV's outer loop, the unknown external disturbances consist of the unknown wind disturbances, the unknown aerodynamic frictions forces, the lateral force generated by the rear servo, and the states coupling between the outer loop and the inner loop. Then, a nonlinear DOB is designed to estimate the unknown external disturbances, and a nonsingular terminal sliding-mode controller (NTSMC) is further developed to drive the TTUAV's position tracking errors to zero in a fixed time. For the dynamics of the TTUAV's inner loop, the unknown external disturbances are mainly introduced by the aerodynamic frictions torques. Then, a modified sliding mode controller is designed to reject the unknown external disturbances, and to ensure that the attitude tracking errors converge to zero exponentially. In addition, a composite stability analysis based on Lyapunov stability theory is provided to guarantee the fixed-time convergence of the closed-loop dynamics of the TTUAV. Finally, the results of the real-time experiments are presented to verify the effectiveness of the proposed control strategy.

The Cancer/Testis Antigen (CTA) genes comprise a group of genes whose expression under physiological conditions is restricted to the testis but is activated in many human cancers. Depending on the particular expression pattern, the CTA genes are speculated to play a role in spermatogenesis, but evidence is limited thus far. Here, we reported patients with a hemizygous nonsense mutation in cancer-testis antigen 55 (CT55) suffering from male infertility with extreme disruption in sperm production, morphology, and locomotion. Specifically, the insufficiency of sperm individualization, excessive residue of unnecessary cytoplasm, and defects in acrosome development were evident in the spermatozoa of the patients. Furthermore, mouse models with depletion of Ct55showed accelerated infertility with age, mimicking the defects in sperm individualization, unnecessary cytoplasm removal, and meanwhile exhibiting the disrupted cumulus-oocyte complex penetration. Mechanistically, our functional experiments uncovered CT55 as a new autophagic manipulator to regulate spermatogenesis via selectively interacting with LAMP2 and GABARAP (which are key regulators in the autophagy process) and further fine-tuning their expression. Therefore, our findings revealed CT55as a novel CTA gene involved in spermatogenesis due to its unprecedented autophagy activity.

ABSTRACTThe injectable progestin depot-medroxyprogesterone acetate (DMPA) is a popular contraceptive choice in sub-Saharan Africa although mouse models indicate it weakens genital epithelial integrity and barrier function and increases susceptibility to genital infection. The intravaginal ring NuvaRing® is another contraceptive option that like DMPA suppresses hypothalamic pituitary ovarian (HPO) axis function with local release of progestin (etonogestrel) and estrogen (ethinyl estradiol). As we previously reported that treating mice with DMPA and estrogen averts the loss of genital epithelial integrity and barrier function induced by DMPA alone, in the current investigation we compared genital levels of the cell-cell adhesion molecule desmoglein-1 (DSG1) and genital epithelial permeability in rhesus macaques (RM) treated with DMPA or a NuvaRing®re-sized for RM (N-IVR). While these studies demonstrated comparable inhibition of the HPO axis with DMPA or N-IVR, DMPA induced significantly lower genital DSG1 levels and greater tissue permeability to intravaginally administered low molecular mass molecules. By identifying greater compromise of genital epithelial integrity and barrier function in RM administered DMPA vs. N-IVR, our results add to the growing body of evidence that indicate DMPA weakens a fundamental mechanism of anti-pathogen host defense in the female genital tract.

Poly[lactic-co-(glycolic acid)] (PLGA) is arguably one of the most versatile synthetic copolymers used for biomedical applications. In vivo delivery of multiple substances including cells, pharmaceutical compounds, and antigens has been achieved by using PLGA-based micro-/nanoparticles although, presently, the exact biological impact of PLGA particles on the immune system remains controversial. Type 1 diabetes (T1D) is one subtype of diabetes characterized by the attack of immune cells against self-insulin-producing pancreatic islet cells. Considering the autoimmune etiology of T1D and the recent use of PLGA particles for eliciting desired immune responses in various aspects of immunotherapy, for the present study, a combination of Ins29–23peptide (a known autoantigen of T1D) and PLGA microparticles was selected for T1D prevention assessment in nonobese diabetic (NOD) mice, a well-known animal model with spontaneous development of T1D. Thus, inoculation of PLGA microparticles + Ins29–23completely prevented T1D development, significantly better than untreated controls and mice treated by either PLGA microparticles or Ins29–23per se. Subsequent mechanistic investigation further revealed a facilitative role of PLGA microparticles in immune tolerance induction. In summary, our data demonstrate an adjuvant potential of PLGA microparticles in tolerance induction and immune remodulation for effective prevention of autoimmune diseases such as T1D.

ABSTRACTThe bipolar voltage comparator LM139 were exposed to ionizing radiation with a high-dose-rate of 10 rad(Si)/s and a low-dose-rate of 0.01 rad(Si)/s; then, pulsed laser single-event-transient (SET) testing was performed. The experimental results show that the SET phenomenon of LM139 after low-dose-rate irradiation of 0.01 rad(Si)/s is obviously different from the SET phenomenon of LM139 after high-dose-rate irradiation of 10 rad(Si)/s. After irradiation with the low-dose-rate, the comparator LM139 has Enhanced Low Dose Rate Sensitivity (ELDRS) in terms of the total dose effect, and the SET was further influenced by ELDRS. The greater gain degradation of the internal transistor in LM139 with low-dose-rate irradiation is the direct cause of this phenomenon.

Observations of vertical ion drift velocities (Vz) at the topside of the ionosphere by Defense Meteorological Satellite Program (DMSP) satellites have been accumulated over decades and provide us a unique opportunity to study the vertical ion drifts through the ionosphere on different temporal and spatial scales. In this paper, Vzdata of F13, which are of high quality, are taken as the reference to rescale the measurements of DMSP F11, F12, F14, F15, and F16 at high latitudes from 50°N/S to 90°N/S, which show significant differences from each other in magnitudes. Through rescaling, all Vzdata of F11–F16 are in a similar order of magnitudes. Moreover, their spatial and temporal distributions resemble each other on average and are consistent with the excepted averaged behaviors reported in previous studies. Thus, the rescaling is basically effective, which provides an opportunity to construct a data set of Vzfrom 1995 to 2014 that covers nearly two solar cycles for further statistical analysis. Meanwhile, it should be noted that the rescaling results are qualitative/semiqualitative with some uncertainty, which needs more detailed discussion and analysis in future studies. Rescaling vertical ion drift velocities of DMSP F11, F12, F14, F15, and F16, respectively, by taking F13 data as the reference is discussedThe rescaled data of different satellites are in similar magnitudes on average and show reasonable spatial and temporal distributionsA long‐term data set of vertical ion drift velocities from 1995 to 2014 are constructed based on the rescaled data of DMSP F11–F16

To solve the problem of low interfacial bonding strength caused by the violent reaction of the titanium/stainless steel interface, the corrugated rolling-flat rolling (CFR) process was used to introduce inhomogeneous plastic deformation, and the titanium/stainless steel was prepared. The interface morphology and strain distribution characteristics of flat rolling (FR) and CFR titanium/stainless steel were studied in comparison. The effect of the inhomogeneous plastic deformation on interfacial microstructure and properties was investigated, and the intrinsic mechanism was revealed. The results show that FR titanium/stainless steel interface is relatively flat and exists in a large number of continuous intermetallic compounds. The interfacial bonding strength is at a low level. In CFR titanium/stainless steel, the interface shows a wave-shape and has few intermetallic compounds. The interfacial bonding strength of the peak, waist and trough are all above 240 MPa. The continuous intermetallic compounds of FR titanium/stainless steel split the interface, leading to low interfacial bonding strength. In the CFR process, the strong inhomogeneous plastic deformation effect reduces the generation of continuous intermetallic compounds at the interface. Meanwhile, the increase of deformation storage energy improves the interfacial metallurgical bonding effect. In combination with the effect of a larger interfacial contact area, a high level of interfacial bonding strength is achieved. The CFR process is an effective way to prepare titanium/stainless steel with excellent interfacial bonding strength.

We previously reported, on the basis of a genome-wide association study for aromatase inhibitor-induced musculoskeletal symptoms, that single-nucleotide polymorphisms (SNPs) near the T-cell leukemia/lymphoma 1A (TCL1A) gene were associated with aromatase inhibitor-induced musculoskeletal pain and with estradiol (E2)-induced TCL1A expression. Furthermore, variation in TCL1A expression influenced the downstream expression of proinflammatory cytokines and cytokine receptors. Specifically, the top hit genome-wide association study SNP, rs11849538, created a functional estrogen response element (ERE) that displayed estrogen receptor (ER) binding and increased E2 induction of TCL1A expression only for the variant SNP genotype. In the present study, we pursued mechanisms underlying the E2-SNP-dependent regulation of TCL1A expression and, in parallel, our subsequent observations that SNPs at a distance from EREs can regulate ERα binding and that ER antagonists can reverse phenotypes associated with those SNPs. Specifically, we performed a series of functional genomic studies using a large panel of lymphoblastoid cell lines with dense genomic data that demonstrated that TCL1ASNPs at a distance from EREs can modulate ERα binding and expression of TCL1A as well as the expression of downstream immune mediators. Furthermore, 4-hydroxytamoxifen or fulvestrant could reverse these SNP-genotype effects. Similar results were found for SNPs in the IL17Acytokine and CCR6chemokine receptor genes. These observations greatly expand our previous results and support the existence of a novel molecular mechanism that contributes to the complex interplay between estrogens and immune systems. They also raise the possibility of the pharmacological manipulation of the expression of proinflammatory cytokines and chemokines in a SNP genotype-dependent fashion.

Temperature data from SABER/TIMED and Empirical Orthogonal Function (EOF) analysis are taken to examine possible modulations of the temperature migrating diurnal tide (DW1) by latitudinal gradients of zonal mean zonal wind ($$\overline \zeta $$). The result shows that $$\overline \zeta $$increases with altitudes and displays clearly seasonal and interannual variability. In the upper mesosphere and lower thermosphere (MLT), at the latitudes between 20°N and 20°S, when $$\overline \zeta $$strengthens (weakens) at equinoxes (solstices) the DW1 amplitude increases (decreases) simultaneously. Stronger maximum in March-April equinox occurs in both $$\overline \zeta $$and the DW1 amplitude. Besides, a quasi-biennial oscillation of DW1 is also found to be synchronous with $$\overline \zeta $$. The resembling spatial-temporal features suggest that $$\overline \zeta $$in the upper tropic MLT probably plays an important role in modulating semiannual, annual, and quasi-biennial oscillations in DW1 at the same latitude and altitude. In addition, $$\overline \zeta $$in the mesosphere possibly affects the propagation of DW1 and produces SAO of DW1 in the lower thermosphere. Thus, SAO of DW1 in the upper MLT may be a combined effect of $$\overline \zeta $$both in the mesosphere and in the upper MLT, which models studies should determine in the future.

Ten years of SABER/TIMED temperature data are used to analyze the global structure and seasonal variations of the migrating 6-h tide from the stratosphere to the lower thermosphere. The amplitudes of the migrating 6-h tide increase with altitudes. In the stratosphere, the migrating 6-h tide peaks around 35°N/S. The climatologically annual mean of the migrating 6-h tide clearly shows the manifestation of the (4, 6) Hough mode between 70 and 90 km that peaks at the equator and near 35°N/S. Above 90 km, the 6-h tide shows more than one Hough mode with the (4, 6) mode being the dominant one. The migrating 6-h tide is stronger in the southern hemisphere. Annual, semiannual, 4-, and 3-month oscillations are the four dominant seasonal variations of the tidal amplitude. In the stratosphere and stratopause, the spring enhancement of the 6-h tide at middle latitudes is the most conspicuous feature. From the mesosphere to the lower thermosphere, the tidal amplitude at low latitudes is gradually in the scale of that at middle latitudes and exhibits different temporal variations at different altitudes and latitudes. Both ozone heating in the stratosphere and the background atmosphere probably affect the generation and the seasonal variations of the migrating 6-h tide. In addition, the non-linear interaction between different tidal harmonics is another possible mechanism.

Type 1 diabetes (T1D) is an autoimmune subtype of diabetes, mainly caused by the immune attack of self-insulin-producing cells. Immune modulation that delays the onset of T1D is able to reduce diabetic complications and mortality. We have previously reported that mannosylated sodium alginate nanoparticles (MAN-ALG) exhibited excellent dendritic cell targeting and in vivo antigen delivery efficacy. To investigate the role of MAN-ALG in an autoimmune context, we loaded the MAN-ALG with Ins29–23, a T1D autoantigen [MAN-ALG(PEP)], for T1D immune tolerance induction in nonobese diabetic (NOD) mice. We observed the delayed onset of T1D occurrence and some degree of blood glucose reduction accompanied by a larger islet area, attributable to augmented T-regulatory cell proportion in mice treated with MAN-ALG(PEP). However, MAN-ALG was also found to elicit lysosomal escape and cross-presentation of Ins29–23in bone marrow-derived dendritic cells, leading to the immune activation of Ins29–23-recognizing T cells and destruction of Ins29–23-expressing islet cells. This dual impact resulted in delayed but a nonpreventive effect of MAN-ALG(PEP) on the T1D onset in NOD mice. Considering the potent immune stimulatory property of MAN-ALG, cautions should be implemented when using alginate-based biomaterials in an autoimmune context. Moreover, it is also noted that regarding the in vivo outcome of immune therapies, biomaterial-based delivery systems and their detailed role on immune regulation need to be examined.

Hidradenitis suppurativa is a chronic skin disease with a significant genetic component and prevalence from 0.5% to 4%. Adalimumab is the only treatment approved by either the European Medicines Agency or the U.S. Food and Drug Administration for the management of moderate to severe hidradenitis suppurativa. To identify genetic variants associated with adalimumab response, we performed a genome-wide association study (GWAS) from the most extensive two phase 3 hidradenitis suppurativa clinical trials (PIONEER I and II) to date. Through direct genotyping and imputation, we tested almost 7 million genetic variants with minor allele frequency > 5% and identified one single linkage disequilibrium block, located in the intron of the BCL2gene, which reached genome-wide significance (lead single-nucleotide polymorphism, rs59532114; P = 2.35E–08). Bioinformatic analysis and functional genomics experiments suggested a correlation of the most strongly associated single-nucleotide polymorphism minor allele with increased BCL2gene and protein expressions in hair follicle tissues. In reciprocal knockdown experiments, we found that BCL2is down-regulated by TNFinhibition. These results highlight a pathway that involves BCL2in response to adalimumab. Further work is required to determine how this pathway influences adalimumab effectiveness in patients with hidradenitis suppurativa.

Based on the measurements from Defense Meteorological Satellite Program (DMSP) F12, F13, and F15 satellites in 1995–2014, we report significant hemispheric asymmetries in vertical ion drift velocity (Vz) at dawn (0500–0700 solar local time) in geomagnetic and geographic coordinates. Vzis distributed in 0300–0900 magnetic local time sector in both the northern (NH) and southern (SH) hemispheres. The north‐south asymmetries are persistent no matter under what kind of seasonal, solar activity, and IMF conditions. In the polar cap, downward Vzis stronger in the SH. Such difference shows clear IMF BYdependence and is more significant in the local winter and/or under low solar activity conditions. In the geomagnetic coordinates, the auroral zone is dominated by upward Vzin the NH but by downward Vzin the SH statistically. In the geographic coordinates, the geographic longitudinal variation of Vzis more pronounced in the SH. The seasonal variations of high‐latitude Vzare different in the NH and SH. The average asymmetric feature of Vzlargely depends on the occurrence and magnitude of ion upflow/outflow, which are modulated by the combined effects of the asymmetric magnetic field configuration between the two hemispheres, and the dynamic processes in the tightly coupled ionosphere‐thermosphere system, and their (probably nonlinear) interactions with each other. There is obvious north-south asymmetry in the vertical ion drift in the topside ionosphere at dawn in geomagnetic and geographic coordinateThe hemispheric asymmetries depend on seasonal, solar activity, and IMF orientationThe asymmetries may be caused by magnetic field configuration and dynamic processes in the ionosphere/thermosphere, and their interactions