Systemic Inflammation Disrupts Circadian Rhythms and Diurnal Neuroimmune Dynamics.

Circadian rhythms regulate physiological processes in approximately 24 h cycles, and their disruption is associated with various diseases. Inflammation may perturb circadian rhythms, though these interactions remain unclear. This study examined whether systemic inflammation induced by an intraperitoneal injection of lipopolysaccharide (LPS) could alter central and peripheral circadian rhythms and diurnal neuroimmune dynamics. Mice were randomly assigned to two groups: the saline control group and the LPS group. The diurnal expression of circadian clock genes and inflammatory cytokines were measured in the hypothalamus, hippocampus, and liver. Diurnal dynamic behaviors of microglia were also assessed. Our results revealed that the LPS perturbed circadian gene oscillations in the hypothalamus, hippocampus, and liver. Furthermore, systemic inflammation induced by the LPS could trigger neuroinflammation and perturb the diurnal dynamic behavior of microglia in the hippocampus. These findings shed light on the intricate link between inflammation and circadian disruption, underscoring their significance in relation to neurodegenerative diseases.

Spectroscopy and efficient dual-wavelength laser performances of a Nd:GYSAG crystal.

We reported on the spectral properties and dual-wavelength laser performances of a novel, to the best of our knowledge, Nd:Gd1.8Y1.2ScAl4O12 (Nd:GYSAG) crystal for the first time. The absorption spectra, emission spectra, and fluorescence lifetime were systematically investigated. Further, a continuous-wavelength (CW) laser output power up to 5.02 W was obtained under an absorbed pump power of 9.45 W with slope and optical-to-optical efficiencies of 59.4% and 53.1%, respectively, at 1061.2 and 1063.2 nm. A stable passively Q-switched (PQS) laser employing Cr:YAG as a saturable absorber (SA) was realized. The maximum average output power of 0.756 W with a slope of near 34.4% was obtained with the pulse width, pulse energy, and peak power of 14.0 ns, 128.1 µJ, and 9.15 kW, respectively. The results indicate that the Nd:GYSAG crystal is an excellent laser medium for generating a high-efficiency dual-wavelength laser and has potential in terahertz (THz) laser generation.

SESAM mode-locked Yb:GdScO3 laser.

We report on the investigation of continuous-wave (CW) and SEmiconductor Saturable Absorber Mirror (SESAM) mode-locked operation of a Yb:GdScO3 laser. Using a single-transverse-mode, fiber-coupled InGaAs laser diode at 976 nm as a pump source, the Yb:GdScO3 laser delivers 343 mW output power at 1062 nm in the CW regime, which corresponds to a slope efficiency of 52%. Continuous tuning is possible across a wavelength range of 84 nm (1027-1111 nm). Using a commercial SESAM to initiate mode-locking and stabilize soliton-type pulse shaping, the Yb:GdScO3 laser produces pulses as short as 42 fs at 1065.9 nm, with an average output power of 40 mW at 66.89 MHz. To the best of our knowledge, this is the first demonstration of passively mode-locking with Yb:GdScO3 crystal.

Structures and Properties of High-Concentration Doped Th:CaF2 Single Crystals for Solid-State Nuclear Clock Materials.

Thorium-doped vacuum ultraviolet (VUV) transparent crystals is a promising candidate for establishing a solid-state nuclear clock. Here, we report the research results on high-concentration doping of 232Th:CaF2 single crystals. The structures, defects, and VUV transmittance performances of highly doped Th:CaF2 crystals are investigated by theoretical and experimental methods. The defect configurations formed by Th and the charge compensation mechanism (Ca vacancy or interstitial F atoms) located at its first nearest neighbor position are mainly considered and studied. The preferred defect configuration is identified according to the doping concentration dependence of structural changes caused by the defects and the formation energies of the defects at different Ca or F chemical potentials. The cultivated Th:CaF2 crystals maintain considerable high VUV transmittance levels while accommodating high doping concentrations, showcasing an exceptional comprehensive performance. The transmittances of 1-mm-thick samples with doping concentrations of 1.91 × 1020 and 2.76 × 1020 cm-3 can reach ∼62% and 53% at 150 nm, respectively. The VUV transmittance exhibits a weak negative doping concentration dependence. The system factors that may cause distortion and additional deterioration of the VUV transmittance are discussed. Balancing and controlling the impacts of various factors will be of great significance for fully exploiting the advantages of Th:CaF2 and other Th-doped crystals for a solid-state nuclear optical clock.

Emission cross section redetermination of Nd:LuAG crystals.

The emission cross section of Nd:LuAG was evaluated using two different methods: the Füchtbauer-Ladenburg equation and the threshold-slope measurements; similar results were obtained with both methods. All measurements and calculations were compared with those of Nd:YAG to reduce uncertainty. Detailed spectroscopic properties of Nd:LuAG were demonstrated. The results showed that the peak emission cross section of Nd:LuAG is approximately 20 × 10-20 cm2, approximately 2/3 the emission cross section of Nd:YAG, instead of the previously reported 9.67 × 10-20 cm2. Additionally, the corresponding saturation flux is 0.9 J/cm2. Therefore, the energy storage capacity of Nd:LuAG is not significantly improved, and it is not sufficient for large-scale amplifiers.

National debt management and business sustainability in Africa's largest economy: A focus on the private sector.

In many developing economies, high and increasing public debt profile constitutes an essential means of financial risk. An appropriate debt management is germane for survival of business and good international reputation though its effect on private sector credit mobilization had been seldomly investigated. This study seeks to know whether strategic debt management approach exacts a significant effect on the Nigerian private sector and Africa at large resulting to higher credit availability for sustainable enterprise establishment. The study used a time-series observation spanning from 1981-2021. The method of data analysis employed the unit root test for stationarity. Johansen cointegration and vector error correction approach. The result of the unit root test indicates the series were all stationary after first difference and thus were integrated of order1. The Johansen cointegration test support the existence of a cointegrating series between the private credit and its determinants. More empirical evidence from the study shows that proper debt management and increase revenue generation through net taxes on products accounted for 0.93 and 1.32% increase in private sector credit mobilization, while total external debt stock was responsible for a significant negative influence of 0.60% on private sector credit mobilization. The study recommends that the government should always be proactive in their strategic and innovative approach to debt management, revenue generation and sources of funds. This will help not only to avoid crowding out of the private sector but will enhance adequate credit mobilization for effective operations of the private sector.

Erbium-ytterbium codoped thin-film lithium niobate integrated waveguide amplifier with a 27†dB internal net gain.

A photonic integrated waveguide amplifier fabricated on erbium-ytterbium (Er-Yb) codoped thin-film lithium niobate (TFLN) has been investigated in this work. A small-signal internal net gain of 27 dB is achieved at a signal wavelength of 1532 nm in the fabricated Er-Yb TFLN waveguide amplifier pumped by a diode laser at ≈980 nm. Experimental characterizations reveal the suitability of waveguide fabrication by the photolithography-assisted chemo-mechanical etching (PLACE) technique and also the gain in an Yb-sensitized-Er material. The demonstrated high-gain chip-scale TFLN amplifier is promising for interfacing with established lithium niobate integrated devices, greatly extending the spectrum of TFLN photonic applications.

Spectral broadening of a mixed Nd: CYGA crystal with tunable laser operation beyond 1100†nm.

A broader emission band of the novel Nd: CaY0.9Gd0.1AlO4 (Nd: CYGA) mixed crystal was proved by the introduction of Gd3+ ions in Nd: CaYAlO4 (Nd: CYA) crystal, and a diode-pump tunable Nd: CYGA laser operation was achieved successfully. Due to the broad emission spectrum with the full width at half maximum (FWHM) of 23 nm, a tuning range of 32 nm from 1075 nm to 1107 nm was achieved, and the results were considered to be the first time for Nd-doped crystals to be tuned to such a long wavelength at 1107 nm, which promotes the further development of near-infrared tunable lasers. The maximum output power was 1.05 W at the center wavelength of 1081.4 nm, corresponding to the slope efficiency of 26.6%. Furthermore, we also demonstrated a continuous-wave 1105 nm laser with the output power of 53 mW. Our work indicates that Nd: CYGA crystal is a potential Nd-doped gain medium for generating all-solid-state near-infrared lasers.

Therapeutic aptamer targeting sclerostin loop3 for promoting bone formation without increasing cardiovascular risk in osteogenesis imperfecta mice.

Rationale: Sclerostin inhibition demonstrated bone anabolic potential in osteogenesis imperfecta (OI) mice, whereas humanized therapeutic sclerostin antibody romosozumab for postmenopausal osteoporosis imposed clinically severe cardiac ischemic events. Therefore, it is desirable to develop the next generation sclerostin inhibitors to promote bone formation without increasing cardiovascular risk for OI. Methods and Results: Our data showed that sclerostin suppressed inflammatory responses, prevented aortic aneurysm (AA) and atherosclerosis progression in hSOSTki.Col1a2+/G610C.ApoE-/- mice. Either loop2&3 deficiency or inhibition attenuated sclerostin's suppressive effects on expression of inflammatory cytokines and chemokines in vitro, whilst loop3 deficiency maintained the protective effect of sclerostin on cardiovascular system both in vitro and in vivo. Moreover, loop3 was critical for sclerostin's antagonistic effect on bone formation in Col1a2+/G610C mice. Accordingly, a sclerostin loop3-specific aptamer aptscl56 was identified by our lab. It could recognize both recombinant sclerostin and sclerostin in the serum of OI patients via targeting loop3. PEG40k conjugated aptscl56 (Apc001PE) demonstrated to promote bone formation, increase bone mass and improve bone microarchitecture integrity in Col1a2+/G610C mice via targeting loop3, while did not show influence in inflammatory response, AA and atherosclerosis progression in Col1a2+/G610C.ApoE-/- mice with Angiotensin II infusion. Further, Apc001PE had no influence in the protective effect of sclerostin on cardiovascular system in hSOSTki.Col1a2+/G610C.ApoE-/- mice, while it inhibited the antagonistic effect of sclerostin on bone formation in hSOSTki.Col1a2+/G610C mice via targeting loop3. Apc001PE was non-toxic to healthy rodents, even at ultrahigh dose. Apc001PE for OI was granted orphan drug designation by US-FDA in 2019 (DRU-2019-6966). Conclusion: Sclerostin loop3-specific aptamer Apc001PE promoted bone formation without increasing cardiovascular risk in OI mice.

Targeting loop3 of sclerostin preserves its cardiovascular protective action and promotes bone formation.

Sclerostin negatively regulates bone formation by antagonizing Wnt signalling. An antibody targeting sclerostin for the treatment of postmenopausal osteoporosis was approved by the U.S. Food and Drug Administration, with a boxed warning for cardiovascular risk. Here we demonstrate that sclerostin participates in protecting cardiovascular system and inhibiting bone formation via different loops. Loop3 deficiency by genetic truncation could maintain sclerostin's protective effect on the cardiovascular system while attenuating its inhibitory effect on bone formation. We identify an aptamer, named aptscl56, which specifically targets sclerostin loop3 and use a modified aptscl56 version, called Apc001PE, as specific in vivo pharmacologic tool to validate the above effect of loop3. Apc001PE has no effect on aortic aneurysm and atherosclerotic development in ApoE-/- mice and hSOSTki.ApoE-/- mice with angiotensin II infusion. Apc001PE can promote bone formation in hSOSTki mice and ovariectomy-induced osteoporotic rats. In summary, sclerostin loop3 cannot participate in protecting the cardiovascular system, but participates in inhibiting bone formation.

Drug Discovery of DKK1 Inhibitors.

Dickkopf-1 (DKK1) is a well-characterized Wnt inhibitor and component of the Wnt/ß-catenin signaling pathway, whose dysregulation is associated with multiple abnormal pathologies including osteoporosis, Alzheimer's disease, diabetes, and various cancers. The Wnt signaling pathway has fundamental roles in cell fate determination, cell proliferation, and survival; thus, its mis-regulation can lead to disease. Although DKK1 is involved in other signaling pathways, including the ß-catenin-independent Wnt pathway and the DKK1/CKAP4 pathway, the inhibition of DKK1 to propagate Wnt/ß-catenin signals has been validated as an effective way to treat related diseases. In fact, strategies for developing DKK1 inhibitors have produced encouraging clinical results in different pathological models, and many publications provide detailed information about these inhibitors, which include small molecules, antibodies, and nucleic acids, and may function at the protein or mRNA level. However, no systematic review has yet provided an overview of the various aspects of their development and prospects. Therefore, we review the DKK1 inhibitors currently available or under study and provide an outlook on future studies involving DKK1 and drug discovery.

Intense 2.1-4.2 µm broadband emission of Co/Er:PbF2 mid-infrared laser crystal.

A novel mid-infrared (MIR) laser crystal Co/Er:PbF2 was successfully grown. The use of Er3+ ion co-doping to sensitize a Co2+ ion and enhance the 2.1-4.2 µm broadband MIR emission of the Co2+ ion in a PbF2 crystal was studied for the first time, to the best of our knowledge. The Er3+ ion was demonstrated to be an effective sensitizer of the Co2+ ion, making the Co/Er:PbF2 crystal propitious to be pumped by commercialized laser diodes. Furthermore, with Er3+ ion co-doping, the local symmetry of Co2+ and Er3+ ions was seriously distorted, thereby enhancing the 2.1-4.2 µm MIR emissions. This study provides a path for designing MIR laser materials with optimal performance.

Yb:GdScO3 crystal for efficient ultrashort pulse lasers.

We present, to the best of our knowledge, the first demonstration of thermal, optical, and laser properties of Yb:GdScO3 for potentially efficient ultrashort pulse lasers. The stimulated emission cross section at 1025 nm (E//c) is 0.46×10-20cm2 with the emission band width of 85 nm, even broader than the well-known Yb:CaGdAlO4. It has quite a high thermal conductivity of 5.54W/(m⋅K) at 50°C, comparable with Yb:YAG. In the continuous-wave regime, the maximum output power of 13.45 W at 1063.9 nm was generated with the optical-to-optical efficiency of 63.3%. These results suggest that the Yb:GdScO3 crystal is a promising candidate for ultrashort pulse lasers.

Dickkopf-1: A Promising Target for Cancer Immunotherapy.

Clinical studies in a range of cancers have detected elevated levels of the Wnt antagonist Dickkopf-1 (DKK1) in the serum or tumors of patients, and this was frequently associated with a poor prognosis. Our analysis of DKK1 gene profile using data from TCGA also proves the high expression of DKK1 in 14 types of cancers. Numerous preclinical studies have demonstrated the cancer-promoting effects of DKK1 in both in vitro cell models and in vivo animal models. Furthermore, DKK1 showed the ability to modulate immune cell activities as well as the immunosuppressive cancer microenvironment. Expression level of DKK1 is positively correlated with infiltrating levels of myeloid-derived suppressor cells (MDSCs) in 20 types of cancers, while negatively associated with CD8+ T cells in 4 of these 20 cancer types. Emerging experimental evidence indicates that DKK1 has been involved in T cell differentiation and induction of cancer evasion of immune surveillance by accumulating MDSCs. Consequently, DKK1 has become a promising target for cancer immunotherapy, and the mechanisms of DKK1 affecting cancers and immune cells have received great attention. This review introduces the rapidly growing body of literature revealing the cancer-promoting and immune regulatory activities of DKK1. In addition, this review also predicts that by understanding the interaction between different domains of DKK1 through computational modeling and functional studies, the underlying functional mechanism of DKK1 could be further elucidated, thus facilitating the development of anti-DKK1 drugs with more promising efficacy in cancer immunotherapy.

Cadmium induces apoptosis of pig lymph nodes by regulating the PI3K/AKT/HIF-1α pathway.

OBJECTIVE: This study was aimed to explore the possible mechanism of environmental metal cadmium (Cd) inducing apoptosis of pig lymph nodes. METHOD: 10 healthy 6-week-old weaned piglets were randomly divided into two groups (n = 5 pigs/group). The control group was fed with a basic diet, and the test group was fed with a basic diet of 20 mg/kg CdCl2. RESULTS: The Cd deposition in mesenteric lymph nodes (MLN), inguinal lymph nodes (ILN) and submaxillary lymph nodes (SLN) after Cd exposure was 2.37 folds, 1.4 folds and 1.8 folds of the control group, respectively. And the rate of MLN and ILN apoptotic cells in the Cd group was 4.11 folds and 9.18 folds of the control group, respectively. The mRNA levels of SOD1, SOD2, CAT, GPX1 and GSH in the Cd group were reduced. Similarly, the two-phase detoxification enzymes had a significant downward trend. Cd exposure decreased the activities of GSH, GSH-Px, SOD, CAT, and increased H2O2 and MDA levels. The mRNA and protein levels of Drp1 and Mff in the Cd group were higher than the corresponding control group, and the mRNA and protein levels of Mfn1 and Mfn2 were lower than those in the control group. In addition, the mRNA and protein levels of pro-apoptotic genes in the Cd group were lower than those in the control group. Cd can significantly reduce the expression of PI3K, AKT and HIF-1α in the three lymph nodes. In summary, Cd induces oxidative stress and regulates the PI3K/AKT/HIF-1α signal transduction pathway to cause mitochondrial dynamics disorder, which leads to the apoptosis of pig lymph nodes, suggesting that Cd-induced mitochondrial pathway apoptosis is related to Cd pig lymph nodes play an important role in the toxicity mechanism.

Antagonistic effect of VDR/CREB1 pathway on cadmium-induced apoptosis in porcine spleen.

Cadmium (Cd) is a toxic trace element that can enter the environment with industrial waste and accumulate in the body but the health effects of Cd on ternary pigs are still lacking in research. In order to explore the effect of Cd on the apoptosis of pig spleen and its mechanism, this study chose ternary pig as the research object to detect relevant indicators in pig spleen under Cd exposure. The results of this study showed that Cd exposure can induce apoptosis by promoting the absorption of various toxic trace elements in the spleen and inducing oxidative stress. We also found that the mechanism of Cd-induced apoptosis is closely related to the VDR/CREB1 pathway. On the one hand, Cd exposure can activate VDR, and indirectly regulate the CYP family, affecting the normal function of the spleen. On the other hand, VDR and its downstream genes antagonize the toxicity of Cd by maintaining the stability of the mitochondrial-related endoplasmic reticulum membrane structure. Our research will help researchers to further understand the physiological toxicity of Cd.

Connective Tissue Growth Factor: From Molecular Understandings to Drug Discovery.

Connective tissue growth factor (CTGF) is a key signaling and regulatory molecule involved in different biological processes, such as cell proliferation, angiogenesis, and wound healing, as well as multiple pathologies, such as tumor development and tissue fibrosis. Although the underlying mechanisms of CTGF remain incompletely understood, a commonly accepted theory is that the interactions between different protein domains in CTGF and other various regulatory proteins and ligands contribute to its variety of functions. Here, we highlight the structure of each domain of CTGF and its biology functions in physiological conditions. We further summarized main diseases that are deeply influenced by CTGF domains and the potential targets of these diseases. Finally, we address the advantages and disadvantages of current drugs targeting CTGF and provide the perspective for the drug discovery of the next generation of CTGF inhibitors based on aptamers.

Selenium deficiency causes immune damage by activating the DUSP1/NF-κB pathway and endoplasmic reticulum stress in chicken spleen.

Selenium (Se) is an essential trace element and its deficiency can lead to immune dysfunction. Many studies have investigated the immune damage caused by Se deficiency in chickens, but its mechanism still needs to be explored. In this study, we fed 1-day-old Hyline male chickens with Se deficient diets (the Se content was 0.008 mg kg-1 of diet) and a basal diet (the Se content was 0.15 mg kg-1 of diet). The spleen was collected at the sixth week and used for subsequent experiments. The pathological analysis showed that Se deficiency leads to the destruction of the normal nuclear structure of the spleen cell, and we can observe obvious chromatin condensation and nuclear debris. We constructed a transcriptome database and analyzed the abundance of various genes in the spleen by transcriptome sequence. The analysis of differentially expressed genes (DEGS) showed significant changes in 337 genes, including 210 up-regulations and 127 down-regulations after feeding Se deficient diets. Se deficiency can significantly change oxidative stress and inflammatory response genes in chicken spleen. This study confirmed that Se deficiency increased the IL-2 levels, whereas it down-regulated IL-17, IFN-γ and Foxp3, which indicates that the immune dysfunction of the spleen and Th1/Th2 is imbalanced. We also found that Se deficiency down-regulated some related genes for endoplasmic reticulum Ca2+ transport, leading to endoplasmic reticulum stress (ERS). Moreover, we determined that Se deficiency triggered the low expression of DUSP1/NF-κB. In summary, our results indicate that Se deficiency can inhibit the spleen immune function of chickens by regulating the DUSP1/NF-κB pathway and ERS, leading to spleen damage in chickens. Based on transcriptomics research, our results will help further study the harmful effects of Se deficiency.

Cathepsin K: The Action in and Beyond Bone.

Cathepsin K (CatK) is one of the most potent proteases in lysosomal cysteine proteases family, of which main function is to mediate bone resorption. Currently, CatK is among the most attractive targets for anti-osteoporosis drug development. Although many pharmaceutical companies are working on the development of selective inhibitors for CatK, there is no FDA approved drug till now. Odanacatib (ODN) developed by Merck & Co. is the only CatK inhibitor candidate which demonstrated high therapeutic efficacy in patients with postmenopausal osteoporosis in Phase III clinical trials. Unfortunately, the development of ODN was finally terminated due to the cardio-cerebrovascular adverse effects. Therefore, it arouses concerns on the undesirable CatK inhibition in non-bone sites. It is known that CatK has far-reaching actions throughout various organs besides bone. Many studies have also demonstrated the involvement of CatK in various diseases beyond the musculoskeletal system. This review not only summarized the functional roles of CatK in bone and beyond bone, but also discussed the potential relevance of the CatK action beyond bone to the adverse effects of inhibiting CatK in non-bone sites.