Effects of Abaloparatide on Bone Mineral Density in Proximal Femoral Regions Corresponding to Arthroplasty Gruen Zones: A Study of Postmenopausal Women with Osteoporosis.

BACKGROUND: Low hip bone mineral density (BMD) in patients who undergo total hip arthroplasty (THA) increases the risk of periprosthetic fractures, implant instability, and other complications. Recently, emphasis has been placed on bone health optimization: treating low BMD prior to a planned orthopaedic implant procedure in an effort to normalize BMD and reduce the potential risk of future complications. Abaloparatide is a U.S. Food and Drug Administration-approved osteoanabolic agent for men and postmenopausal women with osteoporosis and a candidate drug for bone health optimization that, in addition to benefits at the spine, increases hip BMD and reduces nonvertebral fracture risk. We hypothesized that abaloparatide would improve BMD in proximal femoral regions surrounding a virtual THA stem. METHODS: This post hoc analysis obtained dual x-ray absorptiometry (DXA) hip scans from 500 randomly selected postmenopausal women with osteoporosis from the Phase-3 Abaloparatide Comparator Trial in Vertebral Endpoints (ACTIVE, NCT01343004) study after 0, 6, and 18 months of abaloparatide (250 patients) or placebo (250 patients). Hip DXA scans underwent 3-dimensional (3D) modeling via 3D-Shaper, followed by virtual resection of the proximal femur and simulated placement of a tapered, flat-wedge hip stem that guided delineation of the Gruen zones that were fully (zones 1 and 7) or largely (zones 2 and 6) captured in the scanning region. Integral, cortical, and trabecular volumetric BMD, cortical thickness, and cortical surface BMD (the product of cortical volumetric BMD and cortical thickness) were determined for each zone. RESULTS: Compared with placebo, the abaloparatide group showed greater increases in integral volumetric BMD in all zones at months 6 and 18; cortical surface BMD in zones 1, 6, and 7 at month 6; cortical thickness, cortical volumetric BMD, and cortical surface BMD in all zones at month 18; and trabecular volumetric BMD in zones 1 and 7 at months 6 and 18. CONCLUSIONS: Abaloparatide increases BMD in proximal femoral regions that interact with and support femoral stems, suggesting that abaloparatide may have value for preoperative or potentially perioperative bone health optimization in patients with osteoporosis undergoing THA. LEVEL OF EVIDENCE: Therapeutic Level III. See Instructions for Authors for a complete description of levels of evidence.

Treatment patterns in women with postmenopausal osteoporosis using abaloparatide: a real-world observational study.

Review of medical records from 173 women with osteoporosis who received abaloparatide treatment revealed that 96.0% had at least one visit for osteoporosis management and 55.5% had medication support group access. The most common reasons for discontinuing treatment were financial (31.2%) and tolerability (22.8%). Most patients (64.8%) completed treatment as prescribed. PURPOSE: Abaloparatide is approved for the treatment of women with postmenopausal osteoporosis at high risk for fracture. This study evaluated real-world treatment patterns for patients new to abaloparatide, regardless of osteoporosis treatment history. METHODS: Data for patients with ≥ 1 prescription for abaloparatide were collected retrospectively from six academic and clinical practice settings across the US. RESULTS: A total of 173 patients were enrolled (mean [SD] age, 69.8 [7.4] years). At the time of abaloparatide treatment initiation, 78.6% had received other osteoporosis medications. Mean (SD) time from discontinuation of osteoporosis medications prior to initiation of abaloparatide was 1.7 (3.2) years. Twenty-four months of follow-up data from the initiation date of abaloparatide was collected from 94.0% of patients and 6.0% of patients had 12-24 months of follow-up. During the follow-up period, 96.0% of patients had at least one visit for osteoporosis management and 55.5% had access to a medication support program. The median duration of therapy was 18.6 months and 105/162 (64.8%) completed abaloparatide treatment as prescribed. The most common reasons for treatment discontinuation were financial (31.2%) and tolerability (22.8%). Following completion of a course of treatment with abaloparatide, 82/162 (50.6%) patients transitioned to another osteoporosis medication. The median time between abaloparatide treatment course completion and the initiation of follow-on medication was 21 days. CONCLUSION: Most patients completed treatment with abaloparatide as prescribed, and over half continued with an antiresorptive agent. This favorable conduct may be the result of regular follow-up visits and accessibility to both medication and patient support services.

Assembly of Glycopeptides in Living Cells Resembling Viral Infection for Cargo Delivery.

Self-assembly in living cells represents one versatile strategy for drug delivery; however, it suffers from the limited precision and efficiency. Inspired by viral traits, we here report a cascade targeting-hydrolysis-transformation (THT) assembly of glycosylated peptides in living cells holistically resembling viral infection for efficient cargo delivery and combined tumor therapy. We design a glycosylated peptide via incorporating a ß-galactose-serine residue into bola-amphiphilic sequences. Co-assembling of the glycosylated peptide with two counterparts containing irinotecan (IRI) or ligand TSFAEYWNLLSP (PMI) results in formation of the glycosylated co-assemblies SgVEIP, which target cancer cells via ß-galactose-galectin-1 association and undergo galactosidase-induced morphological transformation. While GSH-reduction causes release of IRI from the co-assemblies, the PMI moieties release p53 and facilitate cell death via binding with protein MDM2. Cellular experiments show membrane targeting, endo-/lysosome-mediated internalization and in situ formation of nanofibers in cytoplasm by SgVEIP. This cascade THT process enables efficient delivery of IRI and PMI into cancer cells secreting Gal-1 and overexpressing ß-galactosidase. In vivo studies illustrate enhanced tumor accumulation and retention of the glycosylated co-assemblies, thereby suppressing tumor growth. Our findings demonstrate an in situ assembly strategy mimicking viral infection, thus providing a new route for drug delivery and cancer therapy in the future.

Lrp13a and Lrp13b serve as vitellogenin receptors in the ovary of zebrafish†.

In oviparous animals, egg yolk is largely derived from vitellogenin, which is taken up from the maternal circulation by the growing oocytes via the vitellogenin receptor. Recently, a novel member of the lipoprotein receptor superfamily termed low-density lipoprotein receptor-related protein 13 was identified and proposed as a candidate of vitellogenin receptor in oviparous animals. However, the roles of low-density lipoprotein receptor-related protein 13 in vitellogenesis are still poorly defined. Here, we investigated the expression, vitellogenin-binding properties, and function of low-density lipoprotein receptor-related protein 13 in zebrafish. Two different lrp13 genes termed lrp13a and lrp13b were found in zebrafish. Reverse transcription polymerase chain reaction and quantitative polymerase chain reaction revealed both lrp13s to be predominantly expressed in zebrafish ovary, and in situ hybridization detected both lrp13s transcripts in the ooplasm of early stage oocytes. Two yeast hybrid studies showed that among eight vitellogenins of zebrafish, Vtg1, 2, and 3 bind to Lrp13a, while Vtg1, 2, and 5 bind to Lrp13b. We created zebrafish lrp13a and lrp13b mutant lines using CRISPR/Cas9. Knockout of lrp13a leads to a male-biased sex ratio and decreased diameter of embryo yolk, while knockout of lrp13b and double knockout of lrp13a and lrp13b leads to the delay of vitellogenesis, followed by follicular atresia. These phenotypes of mutants can be explained by the disruption of vitellogenesis in the absence of Lrp13s. Taken together, our results indicate that both Lrp13a and Lrp13b can serve as vitellogenin receptors in zebrafish among other vitellogenin receptors that are not yet described.

A combination of resistance genes confers high and durable resistance against stripe rust in wheat cultivar Lantian 26.

Lantian 26, a leading elite winter wheat cultivar in Gansu Province since its release in 2010, exhibits high resistance or immunization to stripe rust in adult-plant stage under a high disease pressure in Longnan (southeastern Gansu). Identifying the resistance genes in Lantian 26 could provide a basis for enhanced durability and high levels of resistance in wheat cultivars. Here, a segregating population was developed from a cross between a highly susceptible wheat cv. Mingxian 169 and the highly stripe rust-resistant cv. Lantian 26. The F2 and F2:3 progenies of the cross were inoculated with multiple prevalent virulent races of stripe rust for adult plant-stage resistance evaluation in two different environments. Exon sequence alignment analysis revealed that a stripe rust resistance gene on the 718.4-721.2 Mb region of chromosome 7BL, tentatively named as YrLT26, and a co-segregation STS marker GY17 was developed and validated using the F2:3 population and 103 wheat cultivars. The other two resistance genes, Yr9 and Yr30, were also identified in Lantian 26 using molecular markers. Therefore, the key to high and durable resistance to stripe rust at adult stage is the combination of Yr9, Yr30 and YrLT26 genes in Lantian 26. This could be a considerable strategy for improving the wheat cultivars with effective and durable resistance in the high-pressure region for stripe rust.

Overexpression of OsNAR2.1 by OsNAR2.1 promoter increases drought resistance by increasing the expression of OsPLDα1 in rice.

BACKGROUND: pOsNAR2.1:OsNAR2.1 expression could significantly increase nitrogen uptake efficiency and grain yield of rice. RESULT: This study reported the effects of overexpression of OsNAR2.1 by OsNAR2.1 promoter on physiological and agronomic traits associated with drought tolerance. In comparison to the wild-type (WT), the pOsNAR2.1:OsNAR2.1 transgenic lines exhibited a significant improvement in survival rate when subjected to drought stress and then irrigation. Under limited water supply conditions, compared with WT, the photosynthesis and water use efficiency (WUE) of transgenic lines were increased by 39.2% and 28.8%, respectively. Finally, the transgenic lines had 25.5% and 66.4% higher grain yield than the WT under full watering and limited water supply conditions, respectively. Compared with the WT, the agronomic nitrogen use efficiency (NUE) of transgenic lines increased by 25.5% and 66.4% under full watering and limited water supply conditions, and the N recovery efficiency of transgenic lines increased by 29.3% and 50.2%, respectively. The interaction between OsNAR2.1 protein and OsPLDα1 protein was verified by yeast hybrids. After drought treatment, PLDα activity on the plasma membrane of the transgenic line increased 85.0% compared with WT. CONCLUSION: These results indicated that pOsNAR2.1:OsNAR2.1 expression could improve the drought resistance of rice by increasing nitrogen uptake and regulating the expression of OsPLDα1.

Histone acetyltransferase Sas3 contributes to fungal development, cell wall integrity, and virulence in Aspergillus fumigatus.

Histone acetyltransferase (HAT)-mediated epigenetic modification is essential for diverse cellular processes in eukaryotes. However, the functions of HATs in the human pathogen Aspergillus fumigatus remain poorly understood. In this study, we characterized the functions of MOZ, Ybf2/Sas3, Sas2, and Tip60 (MYST)-family histone acetyltransferase something about silencing (Sas3) in A. fumigatus. Phenotypic analysis revealed that loss of Sas3 results in significant impairments in colony growth, conidiation, and virulence in the Galleria mellonella model. Subcellular localization and Western blot analysis demonstrated that Sas3 localizes to nuclei and is capable of acetylating lysine 9 and 14 of histone H3 in vivo. Importantly, we found that Sas3 is critical for the cell wall integrity (CWI) pathway in A. fumigatus as evidenced by hypersensitivity to cell wall-perturbing agents, altered cell wall thickness, and abnormal phosphorylation levels of CWI protein kinase MpkA. Furthermore, site-directed mutagenesis studies revealed that the conserved glycine residues G641 and G643 and glutamate residue E664 are crucial for the acetylation activity of Sas3. Unexpectedly, only triple mutations of Sas3 (G641A/G643A/E664A) displayed defective phenotypes similar to the Δsas3 mutant, while double or single mutations did not. This result implies that the role of Sas3 may extend beyond histone acetylation. Collectively, our findings demonstrate that MYST-family HAT Sas3 plays an important role in the fungal development, virulence, and cell wall integrity in A. fumigatus. IMPORTANCE: Epigenetic modification governed by HATs is indispensable for various cellular processes in eukaryotes. Nonetheless, the precise functions of HATs in the human pathogen Aspergillus fumigatus remain elusive. In this study, we unveil the roles of MYST-family HAT Sas3 in colony growth, conidiation, virulence, and cell wall stress response in A. fumigatus. Particularly, our findings demonstrate that Sas3 can function through mechanisms unrelated to histone acetylation, as evidenced by site-directed mutagenesis experiments. Overall, this study broadens our understanding of the regulatory mechanism of HATs in fungal pathogens.

A TrkB cleavage fragment in hippocampus promotes Depressive-Like behavior in mice.

Decreased hippocampal tropomyosin receptor kinase B (TrkB) level is implicated in the pathophysiology of stress-induced mood disorder and cognitive decline. However, how TrkB is modified and mediates behavioral responses to chronic stress remains largely unknown. Here the effects and mechanisms of TrkB cleavage by asparagine endopeptidase (AEP) were examined on a preclinical murine model of chronic restraint stress (CRS)-induced depression. CRS activated IL-1ß-C/EBPß-AEP pathway in mice hippocampus, accompanied by elevated TrkB 1-486 fragment generated by AEP. Specifi.c overexpression or suppression of AEP-TrkB axis in hippocampal CaMKIIα-positive cells aggravated or relieved depressive-like behaviors, respectively. Mechanistically, in addition to facilitating AMPARs internalization, TrkB 1-486 interacted with peroxisome proliferator-activated receptor-δ (PPAR-δ) and sequestered it in cytoplasm, repressing PPAR-δ-mediated transactivation and mitochondrial function. Moreover, co-administration of 7,8-dihydroxyflavone and a peptide disrupting the binding of TrkB 1-486 with PPAR-δ attenuated depression-like symptoms not only in CRS animals, but also in Alzheimer's disease and aged mice. These findings reveal a novel role for TrkB cleavage in promoting depressive-like phenotype.

Response rates for lumbar spine, total hip, and femoral neck bone mineral density in men treated with abaloparatide: results from the ATOM study.

Osteoporosis in men is an underappreciated public health issue, accounting for approximately 30% of the societal burden of osteoporosis. Although the prevalence of osteoporosis in men is lower, fracture-related morbidity and mortality rates exceed those of women. Abaloparatide is a synthetic, 34-amino acid peptide with homology to human parathyroid hormone-related protein (PTHrP), which favors bone formation by selective activation of PTH receptor type 1. In the Abaloparatide for the Treatment of Men With Osteoporosis (ATOM; NCT03512262) trial, 228 men with primary or hypogonadism-associated osteoporosis were randomized to receive subcutaneous injections of abaloparatide 80 µg or placebo. Abaloparatide significantly improved LS, TH, and FN BMD when compared with placebo. In this prespecified analysis, the proportion of men with a percent change from baseline of >0%, >3%, and > 6% in BMD at the LS, TH, and FN at 3, 6, and 12 mo and/or a shift in T-score category (based on LS and TH T-scores) at 12 mo was compared between the abaloparatide and placebo groups in ATOM. There were significantly more men with a BMD gain of >3% at all 3 anatomical sites in the abaloparatide than placebo group at month 6 (18/122 [14.8%] vs 1/70 [1.4%], P = .002) and at month 12 (38/119 [31.9%] vs 1/66 [1.5%], P < .0001). At month 3, more men treated with abaloparatide than placebo had a > 3% BMD increase at the LS (82/134 [61.2%] vs 21/68 [30.9%], P < .0001). A greater proportion of men treated with abaloparatide had an improvement in T-score category from osteoporosis to low BMD or normal when compared with placebo. In conclusion, use of abaloparatide compared with placebo for 12 mo resulted in significant and rapid improvements in BMD in men with osteoporosis from the ATOM study.

Construction Strategy and Mechanism of a Novel Wood Preservative with Excellent Antifungal Effects.

Wood is a naturally porous material prone to microbial erosion and degradation in outdoor environments. Therefore, the development of an environmentally friendly wood preservative with excellent antibacterial effects and low toxicity is urgently needed. In this study, nitrogen-doped carbon quantum dots (N-CQDs) with excellent antifungal performance and fluorescent properties were synthesized using a one-step hydrothermal method with chitosan quaternary ammonium salt (HACC) as the raw material. The fluorescence characteristics of N-CQD preservatives can help track their position and distribution in wood. The minimum inhibitory concentration (MIC) of N-CQDs is 1.8 mg/mL, which was nearly 22 times lower than that of HACC (40.0 mg/mL) in the PDA medium. The decay resistance test demonstrated that wood treated with N-CQDs showed a considerably reduced decay degree and its mass loss rate decreased from 46 ± 0.5% to 3.8 ± 0.5%. Biological transmission electron microscopy revealed that N-CQDs effectively destroyed fungal cell structures, thereby hindering the growth of Coriolus versicolor. N-CQDs synthesized using the one-step hydrothermal method can be used as an efficient wood preservative that can effectively improve the utilization and service life of wood.

A New Composite Material with Energy Storage, Electro/Photo-Thermal and Robust Super-Hydrophobic Properties for High-Efficiency Anti-Icing/De-Icing.

All weather, high-efficiency, energy-saving anti-icing/de-icing materials are of great importance for solving the problem of ice accumulation on outdoor equipment surfaces. In this study, a composite material with energy storage, active electro-/photo-thermal de-icing and passive super-hydrophobic anti-icing properties is proposed. Fluorinated epoxy resin and MWCNTs/PTFE particles are used to prepare the top multifunctional anti-icing/de-icing layer, which exhibited super-hydrophobicity with water contact angle greater than 155° and conductivity higher than 69 S m-1 . The super-hydrophobic durability of the top layer is verified through tape peeling and sandpaper abrasion tests. The surface can be heated by applying on voltage or light illumination, showing efficient electro-/photo-thermal and all-day anti-icing/de-icing performance. The oleogel material at the bottom layer is capable to absorb energy during heating process and release it during cooling process by phase transition, which greatly delayed the freezing time and saved energy. The icing test of single ice droplet, electro-/photo-thermal de-icing and defrosting tests also proved the high efficiency and energy saving of the anti-icing/de-icing strategy. This study provided a new way to manufacture multi-functional materials for practical anti-icing/de-icing applications.

Targeted macrophage phagocytosis by Irg1/itaconate axis improves the prognosis of intracerebral hemorrhagic stroke and peritonitis.

BACKGROUND: Macrophages are innate immune cells whose phagocytosis function is critical to the prognosis of stroke and peritonitis. cis-aconitic decarboxylase immune-responsive gene 1 (Irg1) and its metabolic product itaconate inhibit bacterial infection, intracellular viral replication, and inflammation in macrophages. Here we explore whether itaconate regulates phagocytosis. METHODS: Phagocytosis of macrophages was investigated by time-lapse video recording, flow cytometry, and immunofluorescence staining in macrophage/microglia cultures isolated from mouse tissue. Unbiased RNA-sequencing and ChIP-sequencing assays were used to explore the underlying mechanisms. The effects of Irg1/itaconate axis on the prognosis of intracerebral hemorrhagic stroke (ICH) and peritonitis was observed in transgenic (Irg1flox/flox; Cx3cr1creERT/+, cKO) mice or control mice in vivo. FINDINGS: In a mouse model of ICH, depletion of Irg1 in macrophage/microglia decreased its phagocytosis of erythrocytes, thereby exacerbating outcomes (n = 10 animals/group, p < 0.05). Administration of sodium itaconate/4-octyl itaconate (4-OI) promoted macrophage phagocytosis (n = 7 animals/group, p < 0.05). In addition, in a mouse model of peritonitis, Irg1 deficiency in macrophages also inhibited phagocytosis of Staphylococcus aureus (n = 5 animals/group, p < 0.05) and aggravated outcomes (n = 9 animals/group, p < 0.05). Mechanistically, 4-OI alkylated cysteine 155 on the Kelch-like ECH-associated protein 1 (Keap1), consequent in nuclear translocation of nuclear factor erythroid 2-related factor 2 (Nrf2) and transcriptional activation of Cd36 gene. Blocking the function of CD36 completely abolished the phagocytosis-promoting effects of Irg1/itaconate axis in vitro and in vivo. INTERPRETATION: Our findings provide a potential therapeutic target for phagocytosis-deficiency disorders, supporting further development towards clinical application for the benefit of stroke and peritonitis patients. FUNDING: The National Natural Science Foundation of China (32070735, 82371321 to Q. Li, 82271240 to F. Yang) and the Beijing Natural Science Foundation Program and Scientific Research Key Program of Beijing Municipal Commission of Education (KZ202010025033 to Q. Li).

Impact of fiscal decentralization and local government competition on the supply of basic public services: Based on the empirical evidence of prefecture-level cities in China.

Promoting equal access to public services and improving people's well-being is a key link in building a modern national governance system in China. However, under the Chinese-style fiscal decentralization system, local governments face the "dilemma" of economic growth goals and the improvement of people's livelihoods. China's basic public services still have the problems of insufficient supply quantity, unbalanced structure and low efficiency. This paper aims to explore the impact of fiscal decentralization and local government competition on basic public services, and provide a theoretical and practical basis for deepening the reform of China's fiscal and taxation system, perfecting the transfer payment system, and improving the public service provision at the present stage. Under the premise of theoretical hypothesis, based on the panel data of 178 prefecture-level cities in China from 2008 to 2019, which is obtained from the Statistical Yearbook and the Work report of prefecture-level governments, the fixed effect model and threshold model are used for the empirical test. The results show that: first, the increase of fiscal decentralization has a negative impact on supply of basic public services in prefecture-level cities; second, the local government competition aiming at economic growth will intensify the negative impact, and make the relationship between fiscal decentralization and basic public services show nonlinear characteristics; Third, compared with developed areas, the strengthening regulatory effect of local government competition is more obvious in less-developed areas, such as western and northeastern regions, and third-tier, fourth-tier, and fifth-tier cities. Based on these findings, this paper draws the following policy implications: strengthen the reform of the fiscal and taxation system below the provincial level, promote the construction of a direct transfer payment mechanism, adjust the standards and methods of performance appraisal, and use modern information technology to improve the public service demand and interest expression mechanisms.

Real-World Evidence to Support the Registration of a New Osteoporosis Medicinal Product in Europe.

Real-World Evidence (RWE), which has historically been used to support post-approval safety studies, has recently gained acceptance for new drug applications as supportive evidence or as new clinical evidence for medicinal products with orphan designation and/or in disease areas with high unmet need. Here, we present a case study for the use of RWE in the approval of abaloparatide in the European Union (EU) under the tradename Eladynos. In addition to data from the pivotal Phase 3 study, the marketing authorization application (MAA) included clinical data from additional interventional and observational studies, as well as post-marketing data obtained from the United States (US) market since approval of abaloparatide by the Food and Drug Administration (FDA) in 2017. The new interventional studies were not designed to assess fracture efficacy and cardiovascular safety which were topics of concern raised by the Committee for Medicinal Products for Human Use (CHMP) during their review of the initial MAA submitted in 2015. However, these studies taken together with the RWE formed the basis for a new MAA. Prior to the planned resubmission in the EU, national Scientific Advice (SA) was sought on the proposed clinical program, specifically on the relevance of Real-World Data (RWD) derived from an observational study to support and complement the efficacy and safety data already available from prospective randomized clinical trials. This case study demonstrates successful use of RWE to address a previously identified gap raised by the CHMP during the review of an earlier MAA, which led to the approval of Eladynos for the treatment of osteoporosis in the EU.

Tenecteplase Plus Butyphthalide for Stroke Within 4.5-6 Hours of Onset (EXIT-BT): a Phase 2 Study.

To date, the benefit of intravenous thrombolysis is confined to within 4.5 h of onset for acute ischemic stroke (AIS) without advanced neuroimaging selection. The current trial aimed to investigate the safety and efficacy of intravenous tenecteplase (TNK) plus Dl-3-n-Butylphthalide (NBP) in AIS within 4.5 to 6 h of onset. In this randomized, multicenter trial, eligible AIS patients were randomly assigned to receive intravenous TNK (0.25 mg/kg) plus NBP or NBP within 4.5 to 6 h of onset. The primary endpoint was symptomatic intracranial hemorrhage (sICH). Secondary endpoints included excellent functional outcome defined as a modified Rankin Scale score of 0 to 1 at 90 days. 100 patients diagnosed by non-contrast CT (NCCT) were enrolled, including 50 in TNK group and 50 in control group. sICH occurred in 2.0% (1/50) in TNK group and 0.0% (0/49) in control group with no difference (unadjusted P = 0.998). The proportion of excellent functional outcome was 77.6% (38/49) in TNK group and 69.4% (34/49) in control group with non-significance (absolute difference 8.2%, P = 0.36). A significant decrease in NIHSS score at 24 h (P = 0.004) and more early neurological improvement (20.4% vs 4.1%; P = 0.026) was observed in TNK vs control group, but there was no difference in other secondary outcomes. This phase 2 study suggests that intravenous TNK with adjuvant NBP seems safe, feasible and may improve early neurological function in AIS patients within 4.5 to 6 h of symptom onset selected using NCCT.Clinical Trials Registration: This trial was registered with ClinicalTrials.gov (NCT05189509).

Comparison of the cost-effectiveness of sequential treatment with abaloparatide in US men and women at very high risk of fractures.

BACKGROUND: Osteoporotic-related fractures represent an increasing burden to patients, health care systems and society. AIMS: This study estimated cost-effectiveness of sequential treatment with abaloparatide (ABL) followed by alendronate (ALN) compared to relevant alternative strategies in US men and women aged 50 to 80 years at very high fracture risk (bone mineral density T-score ≤ - 2.5 and a recent fracture). METHODS: A lifetime Markov-based microsimulation model was used to estimate healthcare costs and quality-adjusted life years (QALYs). Comparators were sequential treatment with unbranded teriparatide (TPTD)/ALN, generic ALN monotherapy, and no treatment. Analyses were conducted based on initial fracture site (hip, vertebral, or any fracture) and treatment efficacy data (derived from clinical trials or a recent network meta-analysis). RESULTS: From all analyses completed, sequential ABL/ALN demonstrated more QALYs for lower healthcare costs versus unbranded TPTD/ALN. No treatment was dominated (higher costs for less QALYs) versus ALN monotherapy. Sequential ABL/ALN resulted in favorable cost-effectiveness (at US threshold of $150,000/QALY) versus generic ALN monotherapy in men aged ≥ 50 years with any fracture type, women aged ≥ 65 years with any fracture type, and women aged ≥ 55 years having a hip or vertebral fracture. DISCUSSION: Similar cost-effectiveness of sequential ABL/ALN versus unbranded TPTD/ALN, ALN monotherapy, and no treatment was observed in both US men and women at very high fracture risk, with a moderate improvement in cost-effectiveness in men versus women and in patients with a hip or vertebral fracture. CONCLUSIONS: Sequential therapy with ABL/ALN was cost-effective in US men and women at very high risk of fractures.

Heat stress-induced activation of MAPK pathway attenuates Atf1-dependent epigenetic inheritance of heterochromatin in fission yeast.

Eukaryotic cells are constantly exposed to various environmental stimuli. It remains largely unexplored how environmental cues bring about epigenetic fluctuations and affect heterochromatin stability. In the fission yeast Schizosaccharomyces pombe, heterochromatic silencing is quite stable at pericentromeres but unstable at the mating-type (mat) locus under chronic heat stress, although both loci are within the major constitutive heterochromatin regions. Here, we found that the compromised gene silencing at the mat locus at elevated temperature is linked to the phosphorylation status of Atf1, a member of the ATF/CREB superfamily. Constitutive activation of mitogen-activated protein kinase (MAPK) signaling disrupts epigenetic maintenance of heterochromatin at the mat locus even under normal temperature. Mechanistically, phosphorylation of Atf1 impairs its interaction with heterochromatin protein Swi6HP1, resulting in lower site-specific Swi6HP1 enrichment. Expression of non-phosphorylatable Atf1, tethering Swi6HP1 to the mat3M-flanking site or absence of the anti-silencing factor Epe1 can largely or partially rescue heat stress-induced defective heterochromatic maintenance at the mat locus.

IL-10 protects against OPC ferroptosis by regulating lipid reactive oxygen species levels post stroke.

Accumulation of reactive oxygen species (ROS), especially on lipids, induces massive cell death in neurons and oligodendrocyte progenitor cells (OPCs) and causes severe neurologic deficits post stroke. While small compounds, such as deferoxamine, lipostatin-1, and ferrostatin-1, have been shown to be effective in reducing lipid ROS, the mechanisms by which endogenously protective molecules act against lipid ROS accumulation and subsequent cell death are still unclear, especially in OPCs, which are critical for maintaining white matter integrity and improving long-term outcomes after stroke. Here, using mouse primary OPC cultures, we demonstrate that interleukin-10 (IL-10), a cytokine playing roles in reducing neuroinflammation and promoting hematoma clearance, significantly reduced hemorrhage-induced lipid ROS accumulation and subsequent ferroptosis in OPCs. Mechanistically, IL-10 activated the IL-10R/STAT3 signaling pathway and upregulated the DLK1/AMPK/ACC axis. Subsequently, IL-10 reprogrammed lipid metabolism and reduced lipid ROS accumulation. In addition, in an autologous blood injection intracerebral hemorrhagic stroke (ICH) mouse model, deficiency of the endogenous Il-10, specific knocking out Il10r or Dlk1 in OPCs, or administration of ACC inhibitor was associated with increased OPC cell death, demyelination, axonal sprouting, and the cognitive deficits during the chronic phase of ICH and vice versa. These data suggest that IL-10 protects against OPC loss and white matter injury by reducing lipid ROS, supporting further development of potential clinical applications to benefit patients with stroke and related disorders.

Identification of telomere-associated gene signatures to predict prognosis and drug sensitivity in glioma.

OBJECTIVE: Gliomas are a heterogeneous group of brain tumors with distinct biological and clinical properties, leading to significant mortality and morbidity. Emerging evidence shows telomere maintenance has implicated in glioma susceptibility and prognosis. In this study, we comprehensively analyzed gene signatures related to telomere maintenance in glioma and their predictive values for predicting the prognosis and drug sensitivity in glioma. METHODS: We initially identified telomere-related genes differentially expressed between low-grade glioma (LGG) and glioblastoma (GBM) and accordingly developed a risk model by univariate and multivariate Cox analysis to assess the expressions of telomere-related genes across the risk groups. Finally, to assess these genes in immune function the anti-tumor medications often used in the clinical treatment of glioma, we computed immune cell infiltration analysis and drug sensitivity analysis. RESULTS: The consensus clustering analysis identified 20 telomere-related genes which split LGG patients into two distinct subtypes. The patient survival, the expressions of key telomere-related DEGs, and immune cell infiltration significantly differed between Cluster 1 and Cluster 2. The LASSO risk model [riskScore=(0.086)*HOXA7+(0.242)*WEE1+(0.247)*IGF2BP3+(0.052)*DUSP10] showed significant differences regarding the 1-, 3-, 5-year overall survival, immune cell infiltration, and drug sensitivity between high- and low-risk groups. The predictive nomogram constructed to quantify the survival probability of each sample at 1, 3, and 5 years was consistent with the actual patient survival. CONCLUSION: Our comprehensive characterization of telomere-associated gene signatures in glioma reveals their possible roles in the development, tumor microenvironment, and prognosis. The study provides some suggestive relationships between four telomere-related genes (HOXA7, WEE1, IGF2BP3, and DUSP10) and glioma prognosis.

A tau fragment links depressive-like behaviors and cognitive declines in Alzheimer's disease mouse models through attenuating mitochondrial function.

Introduction: Alzheimer's disease (AD) is the most prevalent neurodegenerative disease characterized by extracellular senile plaques including amyloid-ß peptides and intracellular neurofibrillary tangles consisting of abnormal Tau. Depression is one of the most common neuropsychiatric symptoms in AD, and clinical evidence demonstrates that depressive symptoms accelerate the cognitive deficit of AD patients. However, the underlying molecular mechanisms of depressive symptoms present in the process of AD remain unclear. Methods: Depressive-like behaviors and cognitive decline in hTau mice were induced by chronic restraint stress (CRS). Computational prediction and molecular experiments supported that an asparagine endopeptidase (AEP)-derived Tau fragment, Tau N368 interacts with peroxisome proliferator-activated receptor delta (PPAR-δ). Further behavioral studies investigated the role of Tau N368-PPAR-δ interaction in depressive-like behaviors and cognitive declines of AD models exposed to CRS. Results: We found that mitochondrial dysfunction was positively associated with depressive-like behaviors and cognitive deficits in hTau mice. Chronic stress increased Tau N368 and promoted the interaction of Tau N368 with PPAR-δ, repressing PPAR-δ-mediated transactivation in the hippocampus of mice. Then we predicted and identified the binding sites of PPAR-δ. Finally, inhibition of AEP, clearance of Tau N368 and pharmacological activation of PPAR-δ effectively alleviated CRS-induced depressive-like behaviors and cognitive decline in mice. Conclusion: These results demonstrate that Tau N368 in the hippocampus impairs mitochondrial function by suppressing PPAR-δ, facilitating the occurrence of depressive-like behaviors and cognitive decline. Therefore, our findings may provide new mechanistic insight in the pathophysiology of depression-like phenotype in mouse models of Alzheimer's disease.