The demise of the giant ape Gigantopithecus blacki.

The largest ever primate and one of the largest of the southeast Asian megafauna, Gigantopithecus blacki1, persisted in China from about 2.0 million years until the late middle Pleistocene when it became extinct2-4. Its demise is enigmatic considering that it was one of the few Asian great apes to go extinct in the last 2.6 million years, whereas others, including orangutan, survived until the present5. The cause of the disappearance of G. blacki remains unresolved but could shed light on primate resilience and the fate of megafauna in this region6. Here we applied three multidisciplinary analyses-timing, past environments and behaviour-to 22 caves in southern China. We used 157 radiometric ages from six dating techniques to establish a timeline for the demise of G. blacki. We show that from 2.3 million years ago the environment was a mosaic of forests and grasses, providing ideal conditions for thriving G. blacki populations. However, just before and during the extinction window between 295,000 and 215,000 years ago there was enhanced environmental variability from increased seasonality, which caused changes in plant communities and an increase in open forest environments. Although its close relative Pongo weidenreichi managed to adapt its dietary preferences and behaviour to this variability, G. blacki showed signs of chronic stress and dwindling populations. Ultimately its struggle to adapt led to the extinction of the greatest primate to ever inhabit the Earth.

A mitochondrial RNA processing protein mediates plant immunity to a broad spectrum of pathogens by modulating the mitochondrial oxidative burst.

Mitochondrial function depends on the RNA processing of mitochondrial gene transcripts by nucleus-encoded proteins. This posttranscriptional processing involves the large group of nuclear-encoded pentatricopeptide repeat (PPR) proteins. Mitochondrial processes represent a crucial part in animal immunity, but whether mitochondria play similar roles in plants remains unclear. Here, we report the identification of RESISTANCE TO PHYTOPHTHORA PARASITICA 7 (AtRTP7), a P-type PPR protein, in Arabidopsis thaliana and its conserved function in immunity to diverse pathogens across distantly related plant species. RTP7 affects the levels of mitochondrial reactive oxygen species (mROS) by participating in RNA splicing of nad7, which encodes a critical subunit of the mitochondrial respiratory chain Complex I, the largest of the four major components of the mitochondrial oxidative phosphorylation system. The enhanced resistance of rtp7 plants to Phytophthora parasitica is dependent on an elevated mROS burst, but might be independent from the ROS burst associated with plasma membrane-localized NADPH oxidases. Our study reveals the immune function of RTP7 and the defective processing of Complex I subunits in rtp7 plants resulted in enhanced resistance to both biotrophic and necrotrophic pathogens without affecting overall plant development.

Predictive value of cytokines combined with human neutrophil lipocalinin acute ischemic stroke-associated pneumonia.

OBJECTIVE: To explore the predictive value of interleukin-6 (IL-6) combined with human neutrophil lipocalin (HNL) of stroke-associated pneumonia (SAP) in patients who were diagnosed with acute ischemic stroke (AIS). METHODS: 108patients were divided into two groups: pneumonia group (52 cases) and non-pneumonia group (56 cases), according to whether the patients developed SAP within 7 days of admission. General information was compared between the two groups, like age, gender, history of hypertension, diabetes mellitus, cardiovascular disease, dysphagia, smoking and alcoholhistory. Clinical data were recorded and compared, including lipid profile, interleukin-6 (IL-6), homocysteine (Hcy), National Institutes of Health Stroke Scale (NIHSS) score, and HNL. Multivariate Logistic regression analysis was used to screen the risk factors of AIS-AP, and the predictive value of IL-6 and HNL alone and in combination was evaluated by receiver operating characteristic curve (ROC curve). RESULTS: Logistic regression analysis showed that dysphagia (OR,0.018; 95% CI, 0.001 ~ 0.427; P = 0.013), increased NIHSS scores(OR,0.012; 95% CI, 0.000 ~ 0.434; P = 0.016), and high levels of IL-6 (OR,0.014; 95% CI, 0.000 ~ 0.695; P = 0.032)and HNL (OR,0.006; 95% CI, 0.000 ~ 0.280; P = 0.009) were independent risk factors for SAP with significant difference (all P < 0.05). According to the ROC curve analysis of IL-6, the area under the curve (AUC) was 0.881 (95% CI: 0.820 ~ 0.942), and the optimal cutoff value was 6.89 pg/mL with the sensitivity of 73.1% and specificity of 85.7%. As for the ROC curve analysis of HNL, the AUC was 0.896 (95% CI: 0.839 ~ 0.954), and the best cutoff value was 99.66ng/mL with the sensitivity of 76.9% and specificity of 89.3%. The AUC of the combination of IL-6 and HNL increased to 0.952 (95% CI: 0.914 ~ 0.989), and the sensitivity and specificity increased to 80.8% and 92.9%, respectively. CONCLUSION: In this research, the levels of IL-6 ≥ 6.89 pg/mL and HNL ≥ 99.66ng/mL were considered as risk factors for AIS patients complicated with SAP. The combined detection had higher predictive value for patients with SAP, which may help to identify who were in highrisk.

VCAM-1+ macrophages guide the homing of HSPCs to a vascular niche.

Haematopoietic stem and progenitor cells (HSPCs) give rise to all blood lineages that support the entire lifespan of vertebrates1. After HSPCs emerge from endothelial cells within the developing dorsal aorta, homing allows the nascent cells to anchor in their niches for further expansion and differentiation2-5. Unique niche microenvironments, composed of various blood vessels as units of microcirculation and other niche components such as stromal cells, regulate this process6-9. However, the detailed architecture of the microenvironment and the mechanism for the regulation of HSPC homing remain unclear. Here, using advanced live imaging and a cell-labelling system, we perform high-resolution analyses of the HSPC homing in caudal haematopoietic tissue of zebrafish (equivalent to the fetal liver in mammals), and reveal the role of the vascular architecture in the regulation of HSPC retention. We identify a VCAM-1+ macrophage-like niche cell population that patrols the inner surface of the venous plexus, interacts with HSPCs in an ITGA4-dependent manner, and directs HSPC retention. These cells, named 'usher cells', together with caudal venous capillaries and plexus, define retention hotspots within the homing microenvironment. Thus, the study provides insights into the mechanism of HSPC homing and reveals the essential role of a VCAM-1+ macrophage population with patrolling behaviour in HSPC retention.

Canine sexual dimorphism in Ardipithecus ramidus was nearly human-like.

Body and canine size dimorphism in fossils inform sociobehavioral hypotheses on human evolution and have been of interest since Darwin's famous reflections on the subject. Here, we assemble a large dataset of fossil canines of the human clade, including all available Ardipithecus ramidus fossils recovered from the Middle Awash and Gona research areas in Ethiopia, and systematically examine canine dimorphism through evolutionary time. In particular, we apply a Bayesian probabilistic method that reduces bias when estimating weak and moderate levels of dimorphism. Our results show that Ar. ramidus canine dimorphism was significantly weaker than in the bonobo, the least dimorphic and behaviorally least aggressive among extant great apes. Average male-to-female size ratios of the canine in Ar. ramidus are estimated as 1.06 and 1.13 in the upper and lower canines, respectively, within modern human population ranges of variation. The slightly greater magnitude of canine size dimorphism in the lower than in the upper canines of Ar. ramidus appears to be shared with early Australopithecus, suggesting that male canine reduction was initially more advanced in the behaviorally important upper canine. The available fossil evidence suggests a drastic size reduction of the male canine prior to Ar. ramidus and the earliest known members of the human clade, with little change in canine dimorphism levels thereafter. This evolutionary pattern indicates a profound behavioral shift associated with comparatively weak levels of male aggression early in human evolution, a pattern that was subsequently shared by Australopithecus and Homo.

Quality markers of Polygala fallax Hemsl decoction based on qualitative and quantitative analysis combined with network pharmacology and chemometric analysis.

INTRODUCTION: Polygala fallax Hemsl (PFH) is a widely used herbal medicine in Guangxi, China. At present, research on PFH mainly focuses on extraction technology and cultivation, lacking quality control standards for systematic evaluation. OBJECTIVES: The study aimed to assess the quality of PFH from different sources and to predict markers that would help assess quality. METHODS: Fingerprinting of 15 batches of PFH samples was performed by ultra-high performance liquid chromatography (UPLC) and similarity was assessed using hierarchical cluster analysis (HCA), principal component analysis (PCA), and orthogonal partial least squares discrimination (OPLS-DA). Differential components were screened by mathematical analysis, and a "component-target-pathway" network map was constructed in combination with network pharmacology, quality markers (Q-markers) of PFH were predicted, and quantitative analysis was performed. RESULTS: Fifteen batches were fingerprinted for PFH, with 11 common peaks, and peak 5 was identified as 4-hydroxybenzoic acid, which was generally consistent with the results of HCA, PCA, and OPLS-DA. Network pharmacology screened 18 potential compounds, 45 core targets, and 20 key pathways, integrating fingerprinting, pattern recognition, and network pharmacology methods. One of the potential Q-markers that can identify the principle of testability, efficacy, and specificity is 4-hydroxybenzoic acid, whose content ranges from 0.0188 to 1.4517 mg/g. CONCLUSION: The potential Q-markers of PFH were predicted by integrating fingerprinting, pattern recognition, and network pharmacological analysis, which provided a scientific basis for the overall control and evaluation of the quality of PFH and a theoretical reference for the study of the quality standard of multi-base traditional Chinese medicine.

Advanced Dielectric Resonator Antenna Technology for 5G and 6G Applications.

We review dielectric resonator antenna (DRA) designs. This review examines recent advancements across several categories, specifically focusing on their applicability in array configurations for millimeter-wave (mmW) bands, particularly in the context of 5G and beyond 5G applications. Notably, the off-chip DRA designs, including in-substrate and compact DRAs, have gained prominence in recent years. This surge in popularity can be attributed to the rapid development of cost-effective multilayer laminate manufacturing techniques, such as printed circuit boards (PCBs) and low-temperature co-fired ceramic (LTCC). Furthermore, there is a growing demand for DRAs with beam-steering, dual-band functions, and on-chip alignment availability, as they offer versatile alternatives to traditional lossy printed antennas. DRAs exhibit distinct advantages of lower conductive losses and greater flexibility in shapes and materials. We discuss and compare the performances of different DRA designs, considering their material usage, manufacturing feasibility, overall performance, and applications. By exploring the pros and cons of these diverse DRA designs, this review provides valuable insights for researchers in the field.

Selective 1,2-Hydroarylation(Alkenylation) of gem-Difluoroalkenes to Access (-CF2 H) Motifs.

An emerging class of C-C coupling transformations that furnish drug-like building blocks involves catalytic hydrocarbonation of alkenes. However, despite notable advances in the field, hydrocarbon addition to gem-difluoroalkenes without additional electronic activation remains largely unsuccessful. This owes partly to poor reactivity and the propensity of difluoroalkenes to undergo defluorinative side reactions. Here, we report a nickel catalytic system that promotes efficient 1,2-selective hydroarylation and hydroalkenylation, suppressing defluorination and providing straightforward access to a diverse assortment of prized organofluorides bearing difluoromethyl-substituted carbon centers. In contrast to radical-based pathways and reactions triggered by hydrometallation via a nickel-hydride complex, our experimental and computational studies support a mechanism in which a catalytically active nickel-bromide species promotes selective carbonickelation with difluoroalkenes followed by alkoxide exchange and hydride transfer, effectively overcoming the difluoroalkene's intrinsic electronic bias.

Performance of Orbicella faveolata larval cohorts does not align with previously observed thermal tolerance of adult source populations.

Orbicella faveolata, commonly known as the mountainous star coral, is a dominant reef-building species in the Caribbean, but populations have suffered sharp declines since the 1980s due to repeated bleaching and disease-driven mortality. Prior research has shown that inshore adult O. faveolata populations in the Florida Keys are able to maintain high coral cover and recover from bleaching faster than their offshore counterparts. However, whether this origin-specific variation in thermal resistance is heritable remains unclear. To address this knowledge gap, we produced purebred and hybrid larval crosses from O. faveolata gametes collected at two distinct reefs in the Upper Florida Keys, a nearshore site (Cheeca Rocks, CR) and an offshore site (Horseshoe Reef, HR), in two different years (2019, 2021). We then subjected these aposymbiotic larvae to severe (36°C) and moderate (32°C) heat challenges to quantify their thermal tolerance. Contrary to our expectation based on patterns of adult thermal tolerance, HR purebred larvae survived better and exhibited gene expression profiles that were less driven by stress response under elevated temperature compared to purebred CR and hybrid larvae. One potential explanation could be the compromised reproductive output of CR adult colonies due to repeated summer bleaching events in 2018 and 2019, as gametes originating from CR in 2019 contained less storage lipids than those from HR. These findings provide an important counter-example to the current selective breeding paradigm, that more tolerant parents will yield more tolerant offspring, and highlight the importance of adopting a holistic approach when evaluating larval quality for conservation and restoration purposes.

Exosome-transmitted circCABIN1 promotes temozolomide resistance in glioblastoma via sustaining ErbB downstream signaling.

Although temozolomide (TMZ) provides significant clinical benefit for glioblastoma (GBM), responses are limited by the emergence of acquired resistance. Here, we demonstrate that exosomal circCABIN1 secreted from TMZ-resistant cells was packaged into exosomes and then disseminated TMZ resistance of receipt cells. CircCABIN1 could be cyclized by eukaryotic translation initiation factor 4A3 (EIF4A3) and is highly expressed in GBM tissues and glioma stem cells (GSCs). CircCABIN1 is required for the self-renewal maintenance of GSCs to initiate acquired resistance. Mechanistically, circCABIN1 regulated the expression of olfactomedin-like 3 (OLFML3) by sponging miR-637. Moreover, upregulation of OLFML3 activating the ErbB signaling pathway and ultimately contributing to stemness reprogramming and TMZ resistance. Treatment of GBM orthotopic mice xenografts with engineered exosomes targeting circCABIN1 and OLFML3 provided prominent targetability and had significantly improved antitumor activity of TMZ. In summary, our work proposed a novel mechanism for drug resistance transmission in GBM and provided evidence that engineered exosomes are a promising clinical tool for cancer prevention and therapy.

Integrating model explanations and hybrid priors into deep stacked networks for the "safe zone" prediction of acetabular cup.

BACKGROUND: Existing state-of-the-art "safe zone" prediction methods are statistics-based methods, image-matching techniques, and machine learning methods. Yet, those methods bring a tension between accuracy and interpretability. PURPOSE: To explore the model explanations and estimator consensus for "safe zone" prediction. MATERIAL AND METHODS: We collected the pelvic datasets from Orthopaedic Hospital, and a novel acetabular cup detection method is proposed for automatic ROI segmentation. Hybrid priors comprising both specific priors from data and general priors from experts are constructed. Specifically, specific priors are constructed based on the fine-tuned ResNet-101 convolutional neural networks (CNN) model, and general priors are constructed based on expert knowledge. Our method considers the model explanations and dynamic consensus through appending a SHapley Additive exPlanations (SHAP) module and a dynamic estimator stacking. RESULTS: The proposed method achieves an accuracy of 99.40% and an area under the curve of 0.9998. Experimental results show that our model achieves superior results to the state-of-the-art conventional ensemble classifiers and deep CNN models. CONCLUSION: This new screening model provides a new option for the "safe zone" prediction of acetabular cup.

Enhanced Adsorption of Hexavalent Chromium from Aqueous Solutions by Iron- manganese Modified Cedarwood Biochar: Synthesis, Performance, Mechanism, and Variables.

Three modified biochar (Cunninghamia lanceolata) with iron and manganese elementals (FMBCs) were successfully prepared and used to remove hexavalent chromium (Cr(VI)) from aqueous solutions. The biochar before and after decoration were characterized by advanced instruments. The adsorption capacities of modified biochar in different Cr(VI) (20 mg·L- 1, 1 mg·L- 1) solutions were 4868.28 mg·kg- 1 and 300 mg·kg- 1. The Cr(VI) removal was highest at pH 2. The possible adsorption was considered to be ion exchange adsorption, chemisorption, and electrostatic attraction. Meanwhile, interfering ions are conducive to increasing the adsorption content. FMBCs prepared at different temperatures showed different characteristics, single-use and cycle-use performance, and high and low concentration removal superiority. The result indicated that FMBCs had a promising potential as an adsorbent to remove toxic and harmful Cr(VI) from aqueous solutions.

The earliest hylobatid from the Late Miocene of China.

Yuanmoupithecus xiaoyuan, a small catarrhine from the Late Miocene of Yunnan in southern China, was initially suggested to be related to Miocene proconsuloids or dendropithecoids from East Africa, but subsequent reports indicated that it might be more closely related to hylobatids. Here, detailed comparisons of the material, including seven newly discovered teeth and a partial lower face of a juvenile individual, provide crucial evidence to help establish its phylogenetic relationships. Yuanmoupithecus exhibits a suite of synapomorphies that support a close phylogenetic relationship with extant hylobatids. Furthermore, based on the retention of several primitive features of the dentition, Yuanmoupithecus can be shown to be the sister taxon of crown hylobatids. The contention that Kapi ramnagarensis from the Middle Miocene of India might represent an earlier species of hylobatid is not supported here. Instead, Kapi is inferred to be a specialized pliopithecoid more closely related to Krishnapithecus krishnaii from the Late Miocene of India. Currently then, Yuanmoupithecus represents the earliest known definitively identified hylobatid and the only member of the clade predating the Pleistocene. It extends the fossil record of hylobatids back to 7-8 Ma and fills a critical gap in the evolutionary history of hominoids that has up until now remained elusive. Even so, molecular estimates of a divergence date of hylobatids from other hominoids at about 17-22 Ma signifies that there is still a substantial gap in the fossil record of more than 10 million years that needs to be filled in order to document the biogeographic origins and early evolution of hylobatids.

Microfluidic post method for 3-dimensional modeling of platelet-leukocyte interactions.

Microvascular thrombosis and inflammation (thromboinflammation) are major causes of morbidity and mortality in critically ill patients with limited therapeutic options. Platelets are central to thromboinflammation, and microvascular platelet thrombi are highly effective at recruiting and activating leukocytes at sites of endothelial injury. Whilst parallel-plate flow chambers, microslides and straight microchannel assays have been widely used to recapitulate leukocyte adhesive behavior on 2-dimensional (2D) surfaces, none of these methods achieve high fidelity 3-dimensional (3D) geometries emulating microvascular platelet thrombi. As a result, the role of hydrodynamic factors in regulating leukocyte interactions with platelet thrombi remains ill-defined. Here, we report a microfluidic post model that allows visualization and analysis of neutrophil-platelet interactions in a 3D flow field. We have utilized the unique mechanosensitive features of platelets to enable selective micropatterning of the 3D posts with human or mouse platelets. By modulating the activation status of platelets, our method enables precise control of platelet surface reactivity and neutrophil recruitment. In addition, our microfluidic post assay accurately recapitulated the rolling versus stationary adhesion behavior of single neutrophils and demonstrated the efficacy of the P-selectin and Mac-1 blocking antibodies to reduce neutrophil recruitment and stationary adhesion, respectively. Moreover, the geometry of posts had a major influence on the efficiency of neutrophil recruitment and adhesion stability. This new post method highlights the importance of platelet 3D geometries in facilitating efficient, localized neutrophil recruitment. These findings have potentially important implications for the potent proinflammatory function of microvascular platelet thrombi.

Dynamic topology of double-stranded telomeric DNA studied by single-molecule manipulation in vitro.

The dynamic topological structure of telomeric DNA is closely related to its biological function; however, no such structural information on full-length telomeric DNA has been reported due to difficulties synthesizing long double-stranded telomeric DNA. Herein, we developed an EM-PCR and TA cloning-based approach to synthesize long-chain double-stranded tandem repeats of telomeric DNA. Using mechanical manipulation assays based on single-molecule atomic force microscopy, we found that mechanical force can trigger the melting of double-stranded telomeric DNA and the formation of higher-order structures (G-quadruplexes or i-motifs). Our results show that only when both the G-strand and C-strand of double-stranded telomeric DNA form higher-order structures (G-quadruplexes or i-motifs) at the same time (e.g. in the presence of 100 mM KCl under pH 4.7), that the higher-order structure(s) can remain after the external force is removed. The presence of monovalent K+, single-wall carbon nanotubes (SWCNTs), acidic conditions, or short G-rich fragments (∼30 nt) can shift the transition from dsDNA to higher-order structures. Our results provide a new way to regulate the topology of telomeric DNA.

Fracture line distribution in femoral head fractures: a complement to Pipkin, Brumback, and AO/OTA classifications.

PURPOSE: This study aimed to explore the fracture line distribution and validate fracture classifications of Femoral head fractures (FHFs). MATERIALS AND METHODS: A total of 209 FHFs were reviewed retrospectively. Subjects were classified by associated injuries and commonly used fracture classifications (Pipkin, Brumback, and AO/OTA), and the universality degree of classifications was evaluated. The fracture line directions were determined in the coronal and axial CT planes. 3D mapping analysis of fracture lines was performed separately by each group. 3D maps were employed to analyze the discrimination degree of inter-subtype classifications and create a new classification. The subjects were subsequently reclassified. Correlations between classifications were analyzed to determine the matching degree of the three classifications. RESULTS: The universality degrees were 98.6% (pipkin), 44.5% (Brumback), and 94.3% (AO/OTA). The cases of (100%) Brumback and (98.5%) AO/OTA can be classified by Pipkin. The mean angles of fracture lines to the coronal and axial axis of primary compressive trabeculae were 20.25° and 54.56°. The discrimination degrees of inter-subtype of classifications were 0 (Pipkin), 60% (Brumback), and 33% (AO/OTA). A new classification with three regions and five types was created on 3D maps. Pipkin and AO/OTA matched one region, while Brumback matched two regions. CONCLUSIONS: There were three distributed fracture regions in FHFs that mismatched Pipkin, Brumback, and AO/OTA classifications. The new classification, based on morphometric features of FHFs, could compensate for the shortcomings of commonly used classifications, improving their applicability in treating FHFs.

Nanomaterials Used in Fluorescence Polarization Based Biosensors.

Fluorescence polarization (FP) has been applied in detecting chemicals and biomolecules for early-stage diagnosis, food safety analyses, and environmental monitoring. Compared to organic dyes, inorganic nanomaterials such as quantum dots have special fluorescence properties that can enhance the photostability of FP-based biosensing. In addition, nanomaterials, such as metallic nanoparticles, can be used as signal amplifiers to increase fluorescence polarization. In this review paper, different types of nanomaterials used in in FP-based biosensors have been reviewed. The role of each type of nanomaterial, acting as a fluorescent element and/or the signal amplifier, has been discussed. In addition, the advantages of FP-based biosensing systems have been discussed and compared with other fluorescence-based techniques. The integration of nanomaterials and FP techniques allows biosensors to quickly detect analytes in a sensitive and cost-effective manner and positively impact a variety of different fields including early-stage diagnoses.

Evolutionary trend in dental size in fossil orangutans from the Pleistocene of Chongzuo, Guangxi, southern China.

More than 800 isolated teeth of fossil Pongo have been recovered from cave sites in the vicinity of Chongzuo in Guangxi, southern China, ranging from the Early to Late Pleistocene (2.0-0.1 Ma). These collections provide a unique regional window into the evolutionary history of orangutans over a two-million-year period at the northernmost extent of their former geographic range. Here we investigate the nature and timing of the evolutionary change in the dental size of fossil orangutans from Chongzuo. Fossil tooth size (mesiodistal length∗buccolingual breadth) was compared against an extant Pongo pygmaeus standard (n = 106 individuals). During the course of the Pleistocene, orangutans from southern China exhibited a progressive reduction in overall dental size. Early Pleistocene Pongo has cheek teeth with occlusal areas that are 38.1% larger than those of extant P. pygmaeus. Those from the Middle and Late Pleistocene are 25.2% and 18.9% larger, respectively. Previously, the size difference in dentition between the Early to Middle Pleistocene and Middle to Late Pleistocene samples was used to differentiate time-successive species of Pongo, namely Pongo weidenreichi and Pongo devosi. However, with access to larger samples and better representation of populations through time, the evidence in support of this taxonomic arrangement requires reconsideration. Diminution of the teeth now appears to be a gradual evolutionary transformation rather than a punctuated event. Moreover, the morphological features that distinguish the Chongzuo fossil orangutans from extant Pongo spp. remain uniform throughout the Pleistocene. Retaining P. weidenreichi and P. devosi as anagenetic species remains an option, but, given the current evidence, we consider it preferable to assign all of the fossil orangutans from Chongzuo to P. weidenreichi. Beyond resolving questions of alpha taxonomy, the study of fossil orangutan dental size provides a basis for estimating body mass, which has implications for interpreting the paleobiology of Pleistocene Pongo in southern China.

A long-acting isomer of Ac-SDKP attenuates pulmonary fibrosis through SRPK1-mediated PI3K/AKT and Smad2 pathway inhibition.

Idiopathic pulmonary fibrosis (IPF) is a progressive, life-threatening lung disease with a poor prognosis. N-acetyl-seryl-aspartyl-lysyl-proline (Ac-SDKP) is a critical negative regulator of fibrosis development. However, it's extremely short half-life greatly limits its applications. Previously, we reported an Ac-SDKP analog peptide in which Asp and Lys residues were replaced with D-amino acids (Ac-SDD KD P). Ac-SDD KD P exhibits better resistance to angiotensin-1-converting enzyme (ACE)-mediated degradation and a longer half-life than Ac-SDKP in rat and human sera. The objective of this study was to explore the potential application of Ac-SDD KD P for the treatment of IPF and to clarify the underlying mechanisms. We found that Ac-SDD KD P exerted similar antifibrotic effects as Ac-SDKP on human fetal lung fibroblast-1 (HFL-1) proliferation, α-smooth muscle actin (α-SMA), collagen I and collagen III expression, and Smad-2 phosphorylation in vitro. In vivo, Ac-SDD KD P exhibited significantly greater protective effects against bleomycin-induced pulmonary fibrosis than Ac-SDKP in mice. α-SMA, CD45, collagen I and collagen III expression, and Smad-2 phosphorylation were significantly decreased in the lungs of Ac-SDD KD P-treated but not Ac-SDKP-treated mice. Furthermore, a pull-down experiment was used to screen for molecules that interact with Ac-SDKP. Co-immunoprecipitation (Co-IP) and computer-based molecular docking experiments demonstrated an interaction between Ac-SDKP or Ac-SDD KD P (Ac-SDKP/Ac-SDD KD P) and serine/arginine-rich protein-specific kinase 1 (SRPK1) that caused inhibition SRPK1-mediated phosphatidylinositol-3 kinase/ serine/threonine kinase (PIK3/AKT) signaling pathway activation and Smad2 phosphorylation and thereby attenuated lung fibrosis. Our data suggest that long-acting Ac-SDD KD P may potentially be an effective drug for the treatment of pulmonary fibrosis. The interacting molecule and antifibrotic mechanism of Ac-SDKP/Ac-SDD KD P were also identified, providing an experimental and theoretical foundation for the clinical application of the drug.

A new genus of pliopithecoid from the late Early Miocene of China and its implications for understanding the paleozoogeography of the Pliopithecoidea.

A diversity of pliopithecoids is known from Miocene localities in Europe, but until recently, this group was relatively poorly represented in China. However, new discoveries have shown that Chinese pliopithecoids were taxonomically diverse and geographically widespread. The earliest pliopithecoids in China (and Eurasia) are Dionysopithecus and Platodontopithecus from the Early Miocene of Sihong, Jiangsu (∼19-18 Ma). During the Middle Miocene (∼15-12 Ma), several species of pliopithecoids are recorded at localities in Gansu Province (Laogou), Inner Mongolia (Damiao), Xinjiang Uygur Autonomous Region (Tieersihabahe), and Ningxia Hui Autonomous Region (Tongxin). Finally, a late-surviving anapithecine crouzeliid, Laccopithecus robustus, is known from the Late Miocene (∼7 Ma) of Shihuiba in Yunnan, which postdates the extinction of pliopithecoids in Europe (during MN 10). Paleontological investigations at a late Early Miocene locality near Fanchang in Anhui Province have yielded a large sample of isolated teeth (more than one hundred) of a previously unknown species of pliopithecoid. The associated micromammals indicate an age contemporaneous with the Shanwang Formation in Shandong Province (MN 3-4, ∼18-17 Ma). All of the permanent teeth are represented except for I2. With its unique suite of dental features, the Fanchang pliopithecoid can be attributed to a new species and genus. Shared derived features of the lower molars confirm that the Fanchang pliopithecoid has its closest affinities with European crouzeliids, but a number of primitive traits indicate that it is a stem member of the clade. The evidence points to China as an important center for the early diversification of pliopithecoids. Contrary to previous zoogeographic scenarios, the occurrence of an early crouzeliid in China implies that the Pliopithecidae and Crouzeliidae may have diverged from a stem pliopithecoid in Asia during the Early Miocene before their arrival in Europe.