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Abnormal proliferation of aggressive fibroblast-like synoviocytes (FLS) and perpetuate synovial inflammation can inevitably accelerate the progression of rheumatoid arthritis (RA). Herein, a strategy of simultaneously promoting FLS apoptosis and inhibiting inflammation as mediated by macrophages is proposed to restore synovial homeostasis for effective RA therapy. A hyaluronic acid-based dissolvable microneedle (MN) is fabricated for transdermal delivery of dual human serum albumin (HSA)-contained biomimetic nanocomplexes to regulate RA FLS and macrophages. Upon skin insertion, dual nanocomplexes are released rapidly from the MN and accumulate in RA joint microenvironment through both passive and active targeting as mediated by HSA. Thioketal-crosslinked fluorinated polyethyleneimine 1.8 K (TKPF) was constructed to bind the plasmid encoding pro-apoptotic gene PUMA with HSA coating layer (TKPF/pPUMA@HSA, TPH). TPH nanocomplexes can upregulate PUMA through RA FLS transfection to trigger efficient apoptosis. Also, HSA nanocomplexes encapsulating the classic anti-inflammatory natural product celastrol (Cel@HSA, CH) can inhibit inflammation of macrophages through blocking NF-κB pathway activation. TPH/CH MN can deplete RA FLS and inhibit M1 macrophage activation, suppress synovial hyperplasia as well as reduce bone and cartilage erosion in a collagen-induced arthritis (CIA) mouse model, demonstrating a promising strategy for efficient RA treatment.

Abstract Elastocaloric cooling has emerged as an eco-friendly technology capable of eliminating greenhouse-gas refrigerants. However, its development is limited by the large driving force and low efficiency in uniaxial loading modes. Here, we present a low-force and energy-efficient elastocaloric air cooling approach based on coil-bending of NiTi ribbons/wires. Our air cooler achieves continuous cold outlet air with a temperature drop of 10.6 K and a specific cooling power of 2.5 W g−1 at a low specific driving force of 26 N g−1. Notably, the cooler shows a system coefficient of performance of 3.7 (ratio of cooling power to rotational mechanical power). These values are realized by the large specific heat transfer area (12.6 cm2 g−1) and the constant cold zone of NiTi wires. Our coil-bending system exhibits a competitive performance among caloric air coolers.

Normalizing inflamed soils including reactive oxygen species (ROS), nitric oxide (NO), cell-free DNA, and regulating inflammation-related seeds such as macrophages, neutrophils, fibroblasts, represent a promising strategy to maintain synovial tissue homeostasis for rheumatoid arthritis (RA) treatment. Herein, ROS scavenging amphiphilic block copolymer PEGylated bilirubin and NO-scavenging PEGylated o-phenylenediamine were fabricated to self-assemble into a dually responsive nanoparticle loaded with JAK inhibitor notopterol (Not@BR/oPDA-PEG, NBOP NPs). The simultaneous ROS and NO depletion combined with JAK-STAT pathway inhibition could not only promote M2 polarization to reduce further ROS and NO generation, but also decrease cytokines and chemokines to prevent immune cell recruitment. Specifically, NBOP NPs responded to high level ROS and NO, and disintegrated to release notopterol in inflamed joints as the hydrophobic heads BR and oPDA were transformed into hydrophilic ones. The released notopterol could inhibit the JAK-STAT pathway of inflammatory cells to reduce the secretion of pro-inflammatory cytokines and chemokines. This strategy represented an effective way to regulate RA soils and seeds through breaking the positive feedback loop of inflammation aggravation, achieving an excellent anti-RA efficacy in a collagen-induced arthritis rat model. Taken together, our work offered a reference to adjust RA soils and seeds for enhanced RA treatment.

Objectives: To investigate gadolinium deposition in the liver and brain in a rat model with liver fibrosis (LF) after intravenous administration of gadoxetate disodium (GD) and the histological effects of gadolinium deposition in the liver and brain. Methods: Adult male Sprague–Dawley rats were randomly assigned to one of the three groups: 1) LF group received intraperitoneal injection of carbon tetrachloride (CCl4) for 9 weeks alone; 2) LF&GD group received CCl4 and intravenous administration of GD (for 5 consecutive days); 3) GD group received olive oil and GD. Seven days after the final injection of GD, the deep cerebellar nuclei (DCN) and liver were excised to determine gadolinium concentrations via inductively coupled plasma mass spectrometry, and histologic staining was performed. Bonferroni's post-hoc test and Wilcoxon rank sum test were used to compare the differences between the three groups. Results: The concentrations of retained gadolinium in the liver in the LF&GD group (2.18 ± 0.44 μg/g) were significantly greater compared to the LF group (0.02 ± 0.01 μg/g, P

This paper briefly describes the theoretical basis of the DRY-1B capacitive component drilling strain gauge (drilling strain gauge). It discusses critical technologies such as micro-displacement sensing, noise reduction, temperature control, performance testing, and calibration. The strain gauge achieved high resolution (≥5×10−11ε), wideband (10–100 Hz optional), extensive dynamic range (≥1×10−3ε), 24-bit AD recording, low power consumption (< 3W), and other technical indicators. Its performance is better than the United States PBO and Japan borehole strain gauge of the same period, and it is an international leading long-term observation instrument for crustal movement, which can basically meet the observation requirements of creep movement with slow accumulation of long-term strain and seismic and volcanic activity with a rapid change of short-term strain. Since 2008, through the application of more than 20 geostress stations, the borehole strain gauge has recorded a large amount of strain information, such as crustal deformation, fault activity, co-seismic strain wave, strain step, and ore pressure activity. Based on the results of the self-consistency test of strain monitoring data of the geostress station in the Beichangshan Mountain and the analysis of seismic mapping capacity of the Turkey earthquake, it is found that the strain curves of the 1#+3# and 2#+4# capacitance sensors at the Beichangshan Mountain stress station are generally stable, and the correlation coefficient R2 is 0.95. The annual variation rate of the differential strain of 1#–3# and 2#–4# elements is 10−8 magnitude, which reflects that the shear stress is dominant in the Long Island area and the stress environment of seismic activity is relatively high. The strain gauge was used to observe the apparent co-seismic strain response of Turkey’s M 7.8 and M 7.5 earthquakes on February 6, 2023. In particular, it obtained the M 7.8 main seismic surface wave period of 50–60 s, presenting an out-facing wave anomaly. Theoretically, the strain wave generated by the M 0.74 earthquakes within 100 km can be distinguished, and the application demonstration effect has been achieved. The borehole strain gauge has good popularization value and application prospects in geodynamics research and internal dynamic geological disaster monitoring.

The article reviews the development of the volumetric borehole strain gauge. In response to the current problems of insufficient stability and bandwidth and low calibration accuracy of the volumetric strain gauge, a TY-2B-type small volumetric borehole strain gauge was developed with innovative improvements in the hydraulic sensor, control circuit, and calibration method. The improved hydraulic sensor improves the accuracy and reduces the instrument’s volume; the improved control circuit increases the sampling rate, bandwidth, and the instrument’s stability; the innovative piezoelectric ceramic calibration technology raises the reliability of the monitoring data. The test results show that the improved TY-2B volumetric strain gauge has a low power consumption of less than 3 W, good long-term stability, high sensitivity with a resolution of 10-11 ε, and suitable high-frequency and low-frequency. It has a sampling rate of 100 Hz and can acquire complete seismic strain waveforms with precise and stable solid tide waveforms. It is small and light, with a reduced outer diameter of Φ89 mm for Φ100 mm drilling, a length of 1300 mm, and a weight of 45 kg for easy transport and installation. After 15 years of laboratory and field station testing, it obtained good monitoring data and demonstrated its highly sensitive seismic reflection capability. The observed response of the volumetric strain station in the northern section of Longmen Mountain to the 2010 Yushu earthquake and the 2023 Turkey earthquake shows that the TY-series high-precision volumetric strain gauge is not only a static strain gauge but also a broad-frequency strain seismograph with dynamic-static calibration capability. It has a unique advantage over pendulum seismometers in that it can observe both the long-term slow deformation and accumulation of deformation in the earth’s crust and the transient subtle features of crustal rupture and deformation. The long-term trends of the monitoring curves obtained from the Qingchuan–Hanzhong volumetric strain stations since the Wenchuan earthquake and the Guangzhou station since 2021 are consistent with the regional geological characteristics reflected by the seismic and tectonic geological data, indicating that the TY-2B volumetric strain gauge can meet the needs of geological scientific research and geological hazard observation.

In order to obtain the in-situ stress field characteristics and analyze tectonic stability in the Motuo key area of the eastern Himalayan syntaxis, the in-situ stress measurement of one in-situ stress hole and 11 test sections of the Xirang section of the Motuo fault zone were carried out by the hydraulic fracturing method. The results show that the maximum and minimum horizontal principal stress values (SH, Sh) in the test section of 61.43−121.34 m are 3.05−14.50 MPa and 2.16−9.87 MPa, respectively, and the vertical principal stress values (Sv) are 1.63−3.31 MPa, namely, SH>Sh>Sv. The in-situ stress field at the measuring point is dominated by horizontal compression, and all of them belong to the in-situ stress state of reverse fault. The principal stress values gradually increase with the increase of depth, and the dominant direction of the maximum principal stress is NEE. In the whole range of in-situ stress depth, the lateral pressure coefficients (Kav) are 1.39−4.38, the maximum horizontal stress coefficients (KHv) are greater than 1, and the ratio increases with the increase of depth. The regional stress field of this key area is dominated by horizontal stress and it is highly directional. The horizontal stress coefficients (KHh) of all test sections are 1.23−1.66, which are similar to the calculation results of in-situ stress characteristic parameters in Linzhi−Tongmai section. The horizontal tectonic stress of the shallow level at 98 m is relatively small, and the stress accumulation level is low. The friction coefficient required to maintain fault stability is smaller than the critical friction coefficient of actual fault, and the tectonic environment is relatively stable. When the depth exceeds 98 m, the friction coefficient required to maintain fault stability is close to the critical friction coefficient value of the actual fault due to the dominant role of horizontal tectonic stress, and there is a small risk of fault instability slip. The superposition of the Coulomb stress change in the sinistral strike-slip direction and the thrust direction caused by the strong regional earthquakes on the fault plane of the Motuo fault zone in the study area are all negative numbers, which inhibits fault slip and does not increase the risk of fault activity in the study area.

Abstract Haemoglobin E (HbE) β-thalassaemia causes approximately 50% of all severe thalassaemia worldwide; equating to around 30,000 births per year. HbE β-thalassaemia is due to a point mutation in codon 26 of the human HBB gene on one allele (GAG; glutamatic acid → AAG; lysine, E26K), and any mutation causing severe β-thalassaemia on the other. When inherited together in compound heterozygosity these mutations can cause a severe thalassaemic phenotype. However, if only one allele is mutated individuals are carriers for the respective mutation and have an asymptomatic phenotype (β-thalassaemia trait). Here we describe a base editing strategy which corrects the HbE mutation either to wildtype (WT) or a normal variant haemoglobin (E26G) known as Hb Aubenas and thereby recreates the asymptomatic trait phenotype. We have achieved editing efficiencies in excess of 90% in primary human CD34 + cells. We demonstrate editing of long-term repopulating haematopoietic stem cells (LT-HSCs) using serial xenotransplantation in NSG mice. We have profiled the off-target effects using a combination of circularization for in vitro reporting of cleavage effects by sequencing (CIRCLE-seq) and deep targeted capture and have developed machine-learning based methods to predict functional effects of candidate off-target mutations.

With the implementation of the Law on Doctors of the People's Republic of China on March 1, 2022, off-label use of drugs has been included into the legislation for the first time. The Law on Doctors of the People's Republic of China stipulates: 'In the absence of effective or better treatment approaches and other special circumstances, after obtaining the informed consent of the patient/guardian/entrusted agent, the clinician can undertake a usage not specified in the drug instruction if supported with evidence. Medical institutions are suggested to establish a management system to review the suitability of prescriptions and medications and strictly standardize the medication behavior of clinicians'. In view of this, Peking Union Medical College Hospital has established the management system for off-label drug use based on evidence-based methods, with the aim to strengthen its management and rational use in our hospital. The measures for off-label drug use have been formulated to safeguard the doctors' legitimate rights, as well as to strictly standardize practicing behavior. Contingency plans have been established for risk prevention and control to protect the patients' rights and escort the off-label use of drugs. Hierarchical management based on the patients' needs and the types of evidence sources for off-label medication use have been adopted to improve its feasibility.

As an emerging cancer therapeutic target, non-apoptotic cell death such as ferroptosis, necroptosis and pyroptosis, etc., has revealed significant potential in cancer treatment for bypassing apoptosis to enhance the undermined therapeutic efficacy triggered by apoptosis resistance. A variety of anticancer drugs, synthesized compounds and natural products have been proven recently to induce non-apoptotic cell death and exhibit excellent anti-tumor effects. Moreover, the convergence of nanotechnology with functional materials and biomedicine science has provided tremendous opportunities to construct non-apoptotic cell death-based nanomedicine for innovative cancer therapy. Nanocarriers are not only employed in targeted delivery of non-apoptotic inducers, but also used as therapeutic components to induce non-apoptotic cell death to achieve efficient tumor treatment. This review first introduces the main characteristics, the mechanism and various pharmacological modulators of different non-apoptotic cell death forms, including ferroptosis, necroptosis, pyroptosis, autophagy, paraptosis, lysosomal-dependent cell death, and oncosis. Second, we comprehensively review the latest progresses of nanomedicine that induces various forms of non-apoptotic cell death and focus on the nanomedicine targeting different pathways and components. Furthermore, the combination therapies of non-apoptotic cell death with photothermal therapy, photodynamic therapy, immunotherapy and other modalities are summarized. Finally, the challenges and future perspectives in this regard are also discussed.

Abstract Hair conditions, such as hair loss and graying, are prevalent human conditions. But they are often poorly controlled due to our insufficient understanding of human scalp hair follicle (hsHF) in health and disease. Here we describe a comprehensive single-cell RNA-seq (scRNA-seq) analysis on highly purified black and early-stage graying hsHFs. Based on these, a concise single-cell atlas for hsHF and its early graying changes is generated and verified using samples from multiple independent individuals. These data reveal the lineage trajectory of hsHF in unprecedented detail and uncover its multiple unexpected features not found in mouse HFs, including the presence of an innerbulge like compartment in the growing phase, lack of a discrete companion layer, and enrichment of EMT features in HF stem cells (HFSCs). Moreover, we demonstrate that besides melanocyte depletion, early-stage human hair graying is also associated with specific depletion of matrix hair progenitors but not HFSCs. The hair progenitors’ depletion is accompanied by their P53 pathway activation whose pharmaceutical blockade can ameliorate hair graying in mice, enlightening a promising therapeutic avenue for this prevalent hair condition.

Chromosome conformation capture (3 C) techniques have captured largescale 3D genome architecture. Here the authors present their “Tiled-MCC” approach for generation of 3 C data across megabase-scale loci at very high (up to 20 bp) resolution, which allowed them to observe nano-scale chromatin structures and investigate how these structures depend on cohesin and CTCF.

Gastric cancer is a tumor type characterized by lymph node metastasis and the invasion of local tissues. There is thus a critical need to clarify the molecular mechanisms governing gastric cancer onset and progression to guide the treatment of this disease. Long non-coding RNAs and mRNA expression profiles associated with early and local advanced gastric cancer were examined through microarray analyses, with GO and KEGG analyses being employed as a means of exploring the functional roles of those long non-coding RNAs and mRNAs that were differentially expressed in gastric cancer. In total, 1005 and 1831 lncRNAs and mRNAs, respectively, were found to be differentially expressed between early and local advanced gastric cancer. GO and KEGG analyses revealed several pathways and processes that were dysregulated, including the RNA transport, ECM-receptor interaction, and mRNA splicing pathways. In co-expression networks, E2F1, E2F4, and STAT2 were identified as key transcriptional regulators of these processes. Moreover, thrombospondin-2 was confirmed as being expressed at high levels in more advanced gastric cancer by both the GEO and TCGA databases. RNA-sequencing analyses of SGC-790 cells transfected to express thrombospondin-2 further revealed this gene to enhance NF-kB and TNF pathway signaling activity. These results offer insight into gastric cancer-related regulatory networks and suggest thrombospondin-2 to be an important oncogene that drives the progression of this deadly cancer type.

Abstract A two‐step process, including the premetallization of the SiC ceramic by Ag‐26.7Cu‐4Ti+B4C and the followed brazing with the Al‐based filler alloy, was developed to join 2219 aluminum alloy and the metallized SiC. The influence of metallization temperature and the B4C addition on the microstructure and mechanical properties of the joint was analyzed. The reaction products of Ti and B4C were detected in the brazing seam, such as Ti2B, TiC and graphite. With increasing of metallization temperature and B4C addition content, the shear strength of joint first increased and then decreased. The joint shear strength reached 14.0 MPa when SiC metallized with Ag‐26.7Cu‐4Ti+1%B4C at 930°C for 10 min, which showed that appropriate addition of B4C in Ag‐26.7Cu‐4Ti metallization layer could regulate the coefficient of thermal expansion difference between 2219 aluminum alloy and SiC to relieve the residual stress and improve the shear strength of their brazed joint.

In this article, the elastocaloric effect of a commercial superelastic NiTi shape memory alloy (SMA) tube (with an outer diameter of 5 mm and wall thickness of 1 mm) to be applied in a compressive cooler was measured and analyzed. The elastocaloric effect of the tube was measured vs the applied strain and strain rate. The largest temperature changes of 21 K during loading and 16 K during unloading were measured at an applied strain of 3.30% and strain rate of 0.33 s−1. In the fatigue testing of the sample, only 0.20% of the residual strain accumulated after a runout of 1 × 106 sinusoidal force-controlled loading–unloading cycles at a maximum compressive stress of 1100 MPa and frequency of 20 Hz. Numerical results of the cooling characteristics of a compressive device using a single NiTi tube with the above-mentioned cross section and an aspect ratio of 60:1 as the refrigerant showed that the device could produce a total cooling power of up to 20 W and a coefficient of performance of up to 6.5. The results of this article demonstrate that superelastic NiTi SMA tubes of suitable wall thickness and aspect ratios are good candidates to be applied in a compressive elastocaloric cooler.

Globin loci harbor genes that are expressed embryonically and silenced postnatally. Here the authors show that zeta-globin silencing depends upon selective hypoacetylation of its TAD subdomain, which blocks its interaction with the alpha-globin super-enhancer, and zeta-globin can be reactivated by acetylation.

Cationic polymer polyethylenimine (PEI) plays a crucial role in gene delivery. However, high molecular weight PEI leads to higher efficient transfection efficacy and higher cytotoxicity while low molecular weight PEI exhibits lower transfection performance with lower toxicity. Therefore, effective chemical modification of PEI is required to enhance transfection activity and improve biocompatibility. Here, reactive oxygen species (ROS) responsive PEI-based fluorinated polymers (TKPF) with three degrees of fluorination (TKPF12.5%, TKPF25% and TKPF50%) were designed and synthesized by crosslinking low molecular weight PEI (PEI 1.8K) with a thioketal (TK) linker and then modifying heptafluorobutyric anhydride onto their surface. Such gene vectors exhibited the following features: (1) fluorination reduced the positive charge density and endowed hydrophobic and lipophobic characteristics to resist serum interactions; (2) The fluorophilic effect mediated efficient cellular uptake and endosomal escape; (3) ROS-responsive TK linker allowed the polyplex disassembly to decrease the cytotoxicity of the polycations and improve the release of payloads at specific sites. TKPFs attained superior transfection efficiency in multiple cell lines (293TN cells and B16F10 cells) in vitro and showed excellent biocompatibility. Notably, TKPFs also exhibited great serum resistance in gene delivery and TKPF50% transfected nearly 80% cells in the presence of 70% FBS. These results demonstrates that the fluorination and ROS responsiveness combined polycations are excellent gene-delivery vectors with serum-resistant capacity for further application.

The role of BRD4 and Mediator in regulating enhancer-promoter interactions is poorly understood. Here the authors find that treatment with BET inhibitors or pharmacological degradation of BRD4 disrupts transcription while having very little effect on enhancer-promoter interactions.

Summary: Human hematopoiesis is a dynamic process that starts in utero 18–21 days post-conception. Understanding the site- and stage-specific variation in hematopoiesis is important if we are to understand the origin of hematological disorders, many of which occur at specific points in the human lifespan. To unravel how the hematopoietic stem/progenitor cell (HSPC) compartment changes during human ontogeny and the underlying gene regulatory mechanisms, we compare 57,489 HSPCs from 5 different tissues spanning 4 developmental stages through the human lifetime. Single-cell transcriptomic analysis identifies significant site- and developmental stage-specific transitions in cellular architecture and gene regulatory networks. Hematopoietic stem cells show progression from cycling to quiescence and increased inflammatory signaling during ontogeny. We demonstrate the utility of this dataset for understanding aberrant hematopoiesis through comparison to two cancers that present at distinct time points in postnatal life—juvenile myelomonocytic leukemia, a childhood cancer, and myelofibrosis, which classically presents in older adults.

Abstract Background Human bone marrow-derived mesenchymal stem/stromal cells (hBM MSCs) have multiple functions, critical for skeletal formation and function. Their functional heterogeneity, however, represents a major challenge for their isolation and in developing potency and release assays to predict their functionality prior to transplantation. Additionally, potency, biomarker profiles and defining mechanisms of action in a particular clinical setting are increasing requirements of Regulatory Agencies for release of hBM MSCs as Advanced Therapy Medicinal Products for cellular therapies. Since the healing of bone fractures depends on the coupling of new blood vessel formation with osteogenesis, we hypothesised that a correlation between the osteogenic and vascular supportive potential of individual hBM MSC-derived CFU-F (colony forming unit-fibroblastoid) clones might exist. Methods We tested this by assessing the lineage (i.e. adipogenic (A), osteogenic (O) and/or chondrogenic (C)) potential of individual hBM MSC-derived CFU-F clones and determining if their osteogenic (O) potential correlated with their vascular supportive profile in vitro using lineage differentiation assays, endothelial-hBM MSC vascular co-culture assays and transcriptomic (RNAseq) analyses. Results Our results demonstrate that the majority of CFU-F (95%) possessed tri-lineage, bi-lineage or uni-lineage osteogenic capacity, with 64% of the CFU-F exhibiting tri-lineage AOC potential. We found a correlation between the osteogenic and vascular tubule supportive activity of CFU-F clones, with the strength of this association being donor dependent. RNAseq of individual clones defined gene fingerprints relevant to this correlation. Conclusions This study identified a donor-dependent correlation between osteogenic and vascular supportive potential of hBM MSCs and important gene signatures that support these functions that are relevant to their bone regenerative properties.

Humanized immune system (HIS) mouse models are useful tools for the in vivo investigation of human hematopoiesis. However, the majority of HIS models currently in use are biased towards lymphocyte development and fail to support long-term multilineage leucocytes and erythrocytes. Those that achieve successful multilineage reconstitution often require preconditioning steps which are expensive, cause animal morbidity, are technically demanding, and poorly reproducible. In this study, we address this challenge by using HSPC-NBSGW mice, in which NOD,B6.SCID IL-2rγ-/-KitW41/W41 (NBSGW) mice are engrafted with human CD133+ hematopoietic stem and progenitor cells (HSPCs) without the need for preconditioning by sublethal irradiation. These HSPCs are enriched in long-term hematopoietic stem cells (LT-HSCs), while NBSGW mice are permissive to human hematopoietic stem cell (HSC) engraftment, thus reducing the cell number required for successful HIS development. B cells reconstitute with the greatest efficiency, including mature B cells capable of class-switching following allogeneic stimulation and, within lymphoid organs and peripheral blood, T cells at a spectrum of stages of maturation. In the thymus, human thymocytes are identified at all major stages of development. Phenotypically distinct subsets of myeloid cells, including dendritic cells and mature monocytes, engraft to a variable degree in the bone marrow and spleen, and circulate in peripheral blood. Finally, we observe human erythrocytes which persist in the periphery at high levels following macrophage clearance. The HSPC-NBSGW model therefore provides a useful platform for the study of human hematological and immunological processes and pathologies.

The past five decades have seen significant progress in our understanding of human hematopoiesis. This has in part been due to the unprecedented development of advanced technologies, which have allowed the identification and characterization of rare subsets of human hematopoietic stem and progenitor cells and their lineage trajectories from embryonic through to adult life. Additionally, surrogate in vitro and in vivo models, although not fully recapitulating human hematopoiesis, have spurred on these scientific advances. These approaches have heightened our knowledge of hematological disorders and diseases and have led to their improved diagnosis and therapies. Here, we review human hematopoiesis at each end of the age spectrum, during embryonic and fetal development and on aging, providing exemplars of recent progress in deciphering the increasingly complex cellular and molecular hematopoietic landscapes in health and disease. This review concludes by highlighting links between chronic inflammation and metabolic and epigenetic changes associated with aging and in the development of clonal hematopoiesis.

Background: Epilepsy is a chronic, complex, unprovoked, and recurrent disorder of the nervous system that affected several people worldwide. Phyllanthus amarus (PA) has been documented to have neuroprotective potential. Aim: To evaluate the potential of standardized extract of PA and its possible mechanism of action against the Pentylenetetrazol (PTZ)-induced convulsion and kindling associated post-ictal depression in experimental mice. Materials and Methods: Phyllathin was isolated from methanolic extract of PA and well-characterized using HPTLC, ESI-MS/MS, and LC/MS. Phyllathin containing a standardized extract of PA (50, 100, and 200 mg/kg) was administered in convulsed and kindled mice, followed by an assessment of various parameters. Results: The spectral analysis confirmed the molecular formula and weight of phyllanthin as C 24 H 34 O 6 and 418.2342 Da. PA (100 and 200 mg/kg) significantly ameliorated PTZ-induced ( p < 0.05) duration, onset of tonic-clonic convulsion, and mortality in mice. It also significantly attenuated ( p < 0.05) PTZ-induced kindling in mice. Alteration in brain GABA, dopamine, and glutamate, Na + K + ATPase, Ca +2 -ATPase activities, and oxido-nitrosative stress in kindled mice was significantly restored ( p < 0.05) by PA treatment. It also significantly ( p < 0.05) down-regulated brain mRNA expressions of NF-κB, TNF-α, IL-1β, COX-2, and TLR-4. Histological aberrations induced by PTZ in the brain of a kindled rat was significantly ( p < 0.05) ameliorated by PA. Conclusion: Phyllanthin containing a standardized extract of PA exerts its antiepileptic potential via balancing excitatory (glutamate) and inhibitory (GABA) brain monoamines, voltage-gated ion channels (Na + K + /Ca +2 -ATPase) and inhibition of NF-κB/TLR-4 pathway to ameliorate neuroinflammation (TNF-α, IL-1β, and COX-2) in experimental mice.

Previously, we have demonstrated a viable approach based on microstructural and topological modulation of periodically arranged elements to program wave scattering in ferromagnetic glass-coated microwire metacomposites. In order to fully exploit the intrinsic structure of the composite, here, we implement the concept of composites plainification by an in-built vertical interface on randomly dispersed short-cut microwires allowing the adjustment of electromagnetic properties to a larger extent. Such interface was modified through arranging wires with different internal structures in two separated regions and by alternating these regions through wire concentration variations associated with polarization differences across the interface. When the wire concentration was equal in both regions, two well-defined transmission windows with varied amplitude and bandwidth were generated. Wire concentration fluctuations resulted in strong scattering changes ranging from broad passbands to pronounced stopbands, demonstrating the intimate relationship between wire content and space charge variations at the interface. This provides a new method to rationally exploit interfacial effects and microstructural features of microwire metacomposites. Moreover, the advantages of enabling tunable scattering spectra by merely 0.053 vol.% of fillers and simple structure make the proposed plainification strategy instrumental to designing filters with broadband frequency selectivity.