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Abstract Objective The accessibility issue of orphan drugs in China is prominent. Based on real-world data from a tier-one city in Northeast China, this study aims to analyze the current usage and affordability of orphan drugs for rare diseases. Methods The data was sourced from the health insurance claims data of a certain city from 2018 to 2021, including a total of 16 orphan drugs. The utilization of orphan drugs is assessed using four indicators: frequency of medical insurance claims, medication cost, defined daily doses (DDDs), and defined daily drug cost (DDDc). Affordability is measured using the concept of catastrophic health expenditure (CHE). Results Between January 2018 and December 2021, there were a total of 2,851 medical insurance claims in the city, with a total medication costs of $3.08 million. Overall, during the study, there was a year-on-year increase in the utilization frequency of individual rare disease drugs in the city, with DDDs rising from 140.22 in 2018 to 3983.63 in 2021. Additionally, the annual medication costs of individual drugs showed a consistent upward trend, increasing from $10,953.53 in 2018 to $120,491.36 in 2021. However, the DDDc of individual drugs decreased from $398.12 in 2018 to $96.65 in 2021.The number of sales and the amount of sales for orphan drugs in community pharmacies have significantly increased. Prior to medical insurance coverage, out of the 16 orphan drugs, 9 drugs had annual treatment costs exceeding CHE for urban residents, and 15 drugs had annual treatment costs exceeding CHE for rural residents. After medical insurance coverage, there were no drugs with out-of-pocket costs exceeding CHE for urban residents, while 8 drugs had out-of-pocket costs exceeding CHE for rural residents. Furthermore, both before and after medical insurance coverage, the four treatment drugs for idiopathic pulmonary arterial hypertension were more affordable compared to the four treatment drugs for multiple sclerosis. Conclusion The usage frequency of orphan drugs in a certain city increased gradually, but the disease burden remained heavy. More policy support should be provided to the priority rare disease populations, and the rare disease medical security and diagnosis and treatment systems should be improved.

The rapid advancement of wearable devices and flexible electronics has spurred an increasing need for high-performance, thin, lightweight, and flexible energy storage devices. In particular, thin and lightweight zinc-ion batteries require battery materials that possess exceptional flexibility and mechanical stability to accommodate complex deformations often encountered in flexible device applications. Moreover, the development of compact and thin battery structures is essential to minimize the overall size and weight while maintaining excellent electrochemical performance, including high energy density, long cycle life, and stable charge/discharge characteristics, to ensure their versatility across various applications. Researchers have made significant strides in enhancing the battery’s performance by optimizing crucial components such as electrode materials, electrolytes, separators, and battery structure. This review provides a comprehensive analysis of the design principles essential for achieving thinness in zinc-ion batteries, along with a summary of the preparation methods and potential applications of these batteries. Moreover, it delves into the challenges associated with achieving thinness in zinc-ion batteries and proposes effective countermeasures to address these hurdles. This review concludes by offering insights into future developments in this field, underscoring the continual advancements and innovations that can be expected.

We have generated an iPSCs line (IPS-AML2-C3, SYSUSHi002-A) from AML cells of a 71-year-old male Acute Myeloid Leukaemia patient with TP53 gene mutation (TP53: c.824G > A, p.Cys275Tyr) using episomal plasmids encoding the factors OCT4, SOX2, KLF4, L-MYC and human miR-302. The IPS-AML2-C3 (SYSUSHi002-A) iPSC line displayed typical embryonic stem cell-like morphology, carried the TP53 gene mutation, expressed several pluripotent stem cell makers, retained normal karyotype (46, XY), and was capable of forming three germ layer cells in vitro.

Abstract Traditional Chinese medicine (TCM) is an experienced‐based discipline and plays an important role in the current medical system. Digitalizing key features is the best way to con‐duct an in‐depth analysis of TCM. However, due to its complex generation mechanism, the crucial pulse‐taking procedure is hard to be digitalized and analyzed. This article fabricated a flexible piezoelectric sensor to gather data for the pulse‐taking procedure. The sensitivity of the proposed flexible sensor reached 0.34 V/kPa, so we adopted peripheral circuits to make its output signals stay in a reasonable range (± 0.5 V) for convenient data collection. We used the sensor to recognize whether a woman is pregnant since it has solid golden standards. The pulse signal was fused via mapping the signal spectrogram into a 3‐dimension tensor. The fused matrix was then processed by GoogleNet and reached a 90.48% correction rate. This result shows that the pulse condition has statistical differences, which solidified the objectivity of pulse diagnosis and escalated the TCM's digitalization level.

Abstract Transition metal fluorides (TMFs) cathode materials have shown extraordinary promises for electrochemical energy storage, but the understanding of their electrochemical reaction mechanisms is still a matter of debate due to the complicated and continuous changing in the battery internal environment. Here, we design a novel iron fluoride (FeF2) aggregate assembled with cylindrical nanoparticles as cathode material to build FeF2 lithium‐ion batteries (LIBs) and employ advanced in situ magnetometry to detect their intrinsic electronic structure during cycling in real time. The results show that FeF2 cannot be involved in complete conversion reactions when the FeF2 LIBs operate between the conventional voltage range of 1.0–4.0 V, and that the corresponding conversion ratio of FeF2 can be further estimated. Importantly, we first demonstrate that the spin‐polarized surface capacitance exists in the FeF2 cathode by monitoring the magnetic responses over various voltage ranges. The research presents an original and insightful method to examine the conversion mechanism of TMFs and significantly provides an important reference for the future artificial design of energy systems based on spin‐polarized surface capacitance.

Obesity has become one of the major public health problems in both the developing and developed countries. Recent studies have suggested that the purinergic signalling is involved in obesity-associated end-organ damage through purine P1 and P2 receptors. In the search for new components for the treatments of obesity, we and other researchers have found much evidence that natural plant extracts may be promising novel therapeutic approaches by modulating purinergic signalling. In this review, we summarize a critical role of purinergic signalling in modulating obesity-associated end-organ damage, such as overhigh appetite, myocardial ischemia, inflammation, atherosclerosis, non-alcoholic fatty liver disease (NAFLD), hepatic steatosis and renal inflammation. Moreover, we focus on the potential roles of several natural plant extracts, including quercetin, resveratrol/trans-resveratrol, caffeine, evodiamine and puerarin, in alleviating obesity-associated end-organ damage via purinergic signalling. We hope that the current knowledge of the potential roles of natural plant extracts in regulating purinergic signalling would provide new ideas for the treatment of obesity and obesity-associated end-organ damage.

Abstract Design of supportive atomic sites with a controllably adjusted coordinating environment is essential to advancing the reduction of CO2 to value‐added fuels and chemicals and to achieving carbon neutralization. Herein, atomic Ni (Zn) sites that are uniquely coordinated with ternary Zn (Ni)/N/O ligands were successfully decorated on formamide‐derived porous carbon nanomaterials, possibly forming an atomic structure of Ni(N2O1)‐Zn(N2O1), as studied by combining X‐ray photoelectron spectroscopy and X‐ray absorption spectroscopy. With the mediation of additional O coordination, the Ni–Zn dual site induces significantly decreased desorption of molecular CO. The NiZn‐NC decorated with rich Ni(N2O1)‐Zn(N2O1) sites remarkably gained >97% CO Faraday efficiency over a wide potential range of ‒0.8 to ‒1.1 V (relative to reversible hydrogen electrode). Density functional theory computations suggest that the N/O dual coordination effectively modulates the electronic structure of the Ni–Zn duplex and optimizes the adsorption and conversion properties of CO2 and subsequent intermediates. Different from the conventional pathway of using Ni as the active site in the Ni–Zn duplex, it is found that the Ni‐neighboring Zn sites in the Ni(N2O1)‐Zn(N2O1) coordination showed much lower energy barriers of the CO2 protonation step and the subsequent dehydroxylation step.

Abstract The fabrication of flexible catalytic films with isolated single/dual‐atomic sites and their integration in wearable electronics is challenging. Herein, an efficient method to prepare atomically dispersed binary Ni/Co‐decorated flexible carbon nanofiber (NiCo‐CNF) film using formamide‐derived cyano‐specific NiCo‐NC as nanofillers was developed. The optimized Ni1Co1‐CNF catalytic film, having large‐area, high density of adjacent Ni‐N4 and Co‐N4 active sites, and good mechanical properties under repeated bending and release conditions, possessed high catalytic activity towards oxygen reduction reaction (ORR) and oxygen evolution reaction (OER). The ORR/OER potential difference (ΔE10) for Ni1Co1‐CNF at 10.0 mA cm−2 was highly comparable with the Pt/C+RuO2 mixture. In addition, flexible Ni1Co1‐CNF‐assembled Zn‐air battery displayed very good mechanical robustness and cycling stability. Our work may inspire the fabrication of other atomic metal‐decorated films for membrane electrocatalysis.

Given the advancements in modern living standards and technological development, conventional smart devices have proven inadequate in meeting the demands for a high-quality lifestyle. Therefore, a revolution is necessary to overcome this impasse and facilitate the emergence of flexible electronics. Specifically, there is a growing focus on health detection, necessitating advanced flexible preparation technology for biosensor-based smart wearable devices. Nowadays, numerous flexible products are available on the market, such as electronic devices with flexible connections, bendable LED light arrays, and flexible radio frequency electronic tags for storing information. The manufacturing process of these devices is relatively straightforward, and their integration is uncomplicated. However, their functionality remains limited. Further research is necessary for the development of more intricate applications, such as intelligent wearables and energy storage systems. Taking smart wear as an example, it is worth noting that the current mainstream products on the market primarily consist of bracelet-type health testing equipment. They exhibit limited flexibility and can only be worn on the wrist for measurement purposes, which greatly limits their application diversity. Flexible energy storage and flexible display also face the same problem, so there is still a lot of room for development in the field of flexible electronics manufacturing. In this review, we provide a brief overview of the developmental history of flexible devices, systematically summarizing representative preparation methods and typical applications, identifying challenges, proposing solutions, and offering prospects for future development.

Adenosine monophosphosphate-activated protein kinase (AMPK) and its activator metformin were found to be involved in the regulation of fibroblast activation and pulmonary fibrosis. However, the regulatory mechanism has been undetermined. Recently, AMPK has been reported to exert its effect through inhibiting bone morphogenetic protein (BMP) pathway. In this study, human fetal lung fibroblast (HFL-1) cells were treated with metformin or specific AMPKα1 mutants, including constitutively activated mutant (AMPK-CA) and dominant negative mutant (AMPK-DN), combined with BMP9, and then the absorbance of these cells was measured by cell counting kit (CCK)-8 assay. The colony number of HFL-1 cells stimulated by metformin with or without BMP9 was examined by colony formation assay. The protein expressions of differentiated markers (α-smooth muscle actin, collagen I and collagen III) and the key molecules of BMP9 signaling, including activin receptor-like kinase (ALK) one and phosphorylated small mother against decapentaplegic (p-Smad)1/5, were also evaluated by western blot. Data revealed that BMP9 induced the proliferation and differentiation of HFL-1 cells which was suppressed by metformin or AMPK-CA. Meanwhile, the effect of metformin on BMP9-induced activation was counteracted by AMPK-DN. In addition, we found that the expressions of ALK1 and p-Smad1/5 induced by BMP9 were attenuated by metformin and AMPK-CA, whereas the inhibitory responses of metformin to the increased ALK1 and p-Smad1/5 were reduced by AMPK-DN. Accordingly, these results suggested that metformin mitigated BMP9-induced proliferation and differentiation of HFL-1 cells, which was achieved partly through the activation of AMPK and inhibition of ALK1/Smad1/5 signaling.

Wearable sensors open unprecedented opportunities for long-term health monitoring and human–machine interaction. Electrospinning is considered to be an ideal technology to produce functional structures for wearable sensors because of its unique merits to endow devices with highly designable functional microstructures, outstanding breathability, biocompatibility, and comfort, as well as its low cost, simple process flow, and high productivity. Recent advances in wearable sensors with one-, two-, or three-dimensional (1D, 2D, or 3D) electrospun microstructures have promoted various applications in healthcare, action monitoring, and physiological information recognition. Particularly, the development of various novel electrospun microstructures different from conventional micro/nanofibrous structures further enhances the electrical, mechanical, thermal, and optical performances of wearable sensors and provides them with multiple detection functions and superior practicality. In this review, we discuss (i) the principle and typical apparatus of electrospinning, (ii) 1D, 2D, and 3D electrospun microstructures for wearable sensing and their construction strategies and physical properties, (iii) applications of microstructured electrospun wearable devices in sensing pressure, temperature, humidity, gas, biochemical molecules, and light, and (iv) challenges of future electrospun wearable sensors for physiological signal recognition, behavior monitoring, personal protection, and health diagnosis.

Abstract Herein, a hierarchically porous N, S‐co‐doped carbon material (named as NS‐C) has been efficiently fabricated from halogenated polymer to meet the targets of the low‐cost anode and cathode materials for Li‐based batteries. Thanks to its large N (∼5.4 at.%) and S (∼1.1 at.%) contents, large specific surface area (∼1510 m2 g–1), and beneficial pore hierarchy, the NS‐C exhibits superior bifunctional performance as anode material and S host for Li‐S cathode. The NS‐C/sulfur composite (named as S@NS‐C) delivers a large capacity of 1125 mAh g–1 at 0.1 C and maintains a capacity of 401 mAh g–1 at 5 C. A continuous long‐term use for 200 cycles at 2 C achieves large capacity retention of 80.5%. Furthermore, the NS‐C can also serve as anode material for stable Li‐ion storage with large capacity, showing very limited capacity fading for over 1000 cycles at both 0.1 and 1.0 A g–1. Moreover, considering the huge amount of halogenated polymer plastic wastes buried, burned, or discarded in the environments, our developed route of simple conversion of halogenated polymers into functional carbon materials for Li‐ion battery anode and S host for Li‐S battery cathode is advantageous for both environmental protection and Li‐based battery industry.

Flexible zinc batteries have great potential in wearable electronic devices due to their high safety, low cost, and environmental friendliness. In the past few years, a great deal of work on flexible zinc batteries has been reported, with exciting results. Therefore, many solutions have been proposed in electrode design and electrolyte preparation to ensure the desired flexibility without sacrificing the capacity. This paper reviews the recent progress of flexible zinc batteries. We discuss the differences between various anode materials, cathode materials, and electrolytes, introduce the differences of electrode preparation methods of active materials on flexible substrates and their influence on the performance of the battery. Finally, the challenges and future research trends of flexible zinc batteries in capacity and mechanical properties are pointed out.

ABSTRACT Chlamydia trachomatis is an obligate intracellular bacterium whose unique developmental cycle consists of an infectious elementary body and a replicative reticulate body. Progression of this developmental cycle requires temporal control of the transcriptome. In addition to the three chlamydial sigma factors (σ66, σ28, and σ54) that recognize promoter sequences of genes, chlamydial transcription factors are expected to play crucial roles in transcriptional regulation. Here, we investigate the function of GrgA, a Chlamydia-specific transcription factor, in C. trachomatis transcriptomic expression. We show that 10 to 30 min of GrgA overexpression induces 13 genes, which likely comprise the direct regulon of GrgA. Significantly, σ66-dependent genes that code for two important transcription repressors are components of the direct regulon. One of these repressors is Euo, which prevents the expression of late genes during early phases. The other is HrcA, which regulates molecular chaperone expression and controls stress response. The direct regulon also includes a σ28-dependent gene that codes for the putative virulence factor PmpI. Furthermore, overexpression of GrgA leads to decreased expression of almost all tRNAs. Transcriptomic studies suggest that GrgA, Euo, and HrcA have distinct but overlapping indirect regulons. These findings, together with temporal expression patterns of grgA, euo, and hrcA, indicate that a transcriptional regulatory network of these three transcription factors plays critical roles in C. trachomatis growth and development. IMPORTANCE Chlamydia trachomatis is the most prevalent sexually transmitted bacterial pathogen worldwide and is a leading cause of preventable blindness in underdeveloped areas as well as some developed countries. Chlamydia carries genes that encode a limited number of known transcription factors. While Euo is thought to be critical for early chlamydial development, the functions of GrgA and HrcA in the developmental cycle are unclear. Activation of euo and hrcA immediately following GrgA overexpression indicates that GrgA functions as a master transcriptional regulator. In addition, by broadly inhibiting tRNA expression, GrgA serves as a key regulator of chlamydial protein synthesis. Furthermore, by upregulating pmpI, GrgA may act as an upstream virulence determinant. Finally, genes coregulated by GrgA, Euo, and HrcA likely play critical roles in chlamydial growth and developmental control.

Chlamydia trachomatisChlamydia

Purpose: To compare health-related quality of life (HRQOL) of high-dose-rate brachytherapy (HDRB) versus low dose-rate brachytherapy (LDRB) for localized prostate cancer in a multi-institutional phase 2 randomized trial. Methods and Materials: Men with favorable-risk prostate cancer were randomized between monotherapy brachytherapy with either Iodine-125 LDRB to 144 Gy or single-fraction Iridium-192 HDRB to 19 Gy. HRQOL and urinary toxicity were recorded at baseline and at 1, 3, 6, and 12 months using the Expanded Prostate Cancer Index Composite (EPIC)-26 scoring and the International Prostate Symptom Score (IPSS). Independent samples t test and mixed effects modeling were performed for continuous variables. Time to IPSS resolution, defined as return to its baseline score ±5 points, was calculated using Kaplan-Meier estimator curves with the log-rank test. A multiple-comparison adjusted P value of ≤.05 was considered significant. Results: LDRB and HDRB were performed in 15 and 16 patients, respectively, for a total of 31 patients. At 3 months, patients treated with LDRB had a higher IPSS score (mean, 15.5 vs 6.0, respectively; P = .003) and lower EPIC urinary irritative score (mean, 69.2 vs 85.3, respectively; P = .037) compared with those who received HDRB. On repeated measures at 1, 3, 6, and 12 months, the IPSS (P = .003) and EPIC urinary irritative scores (P = .019) were significantly better in the HDR arm, translating into a lower urinary toxicity profile. There were no significant differences in the EPIC urinary incontinence, sexual, or bowel habit scores between the 2 groups at any measured time point. Time to IPSS resolution was significantly shorter in the HDRB group (mean, 2.0 months) compared with the LDRB group (mean, 6.0 months; P = .028). Conclusions: HDRB monotherapy is a promising modality associated with a lower urinary toxicity profile and higher HRQOL in the first 12 months compared with LDRB.

Pre-cooling in a re-condenser is one of the key tasks for the smooth operation in a liquefied natural gas receiving station. It should be conducted economically and efficiently to ensure operation safety so that the re-condenser material damage caused by the thermal stress can be avoided. In this paper, a pre-cooling temperature model based on the computational fluid dynamics technology has been established to complete the large-grid calculation in the re-condenser. Combined with the component transport equation and volume of fluid multi-phase flow model, a theoretical system has been built which can be applied to both the gas phase pre-cooling model and the liquid phase pre-cooling model. The fast and stable calculation of the multi-component multiphase and large-scale has been realized through controlling the grid optimization, dynamic relaxation factor, and phase change model selection. To realize the coupling between the temperature model and the stress model and analyze the thermal stress caused by the temperature change in the pre-cooling real time, a pre-cooling stress model has been constructed and a temperature difference algorithm has been proposed. After analyzing the overall and local model of the re-condenser, the thermal deformation and thermal stress during the pre-cooling of the re-condenser can be comprehensively analyzed, and the detailed analysis of the stress and fatigue life at the peak stress region (e.g., the nozzle) can be achieved. The prediction accuracy of the pre-cooling temperature–stress model has been verified by the on-site measured data. They have great popularizing and applying values. The two models can provide scientific support in pre-cooling scheme design, optimization, pre-cooling flow, and structural safety, and when applied to engineering, they can lead to significant economic and safety benefits.

Lactate and isoprene are two common monomers for the industrial production of polyesters and synthetic rubbers. The present study tested the co-production of D-lactate and isoprene by engineered Escherichia coli in microaerobic conditions. The deletion of alcohol dehydrogenase (adhE) and acetate kinase (ackA) genes, along with the supplementation with betaine, improved the co-production of lactate and isoprene from the substrates of glucose and mevalonate. In fed-batch studies, microaerobic fermentation significantly improved the isoprene concentration in fermentation outlet gas (average 0.021 g/L), compared with fermentation under aerobic conditions (average 0.0009 g/L). The final production of D-lactate and isoprene can reach 44.0 g/L and 3.2 g/L, respectively, through fed-batch microaerobic fermentation. Our study demonstrated a dual-phase production strategy in the co-production of isoprene (gas phase) and lactate (liquid phase). The increased concentration of gas-phase isoprene could benefit the downstream process and decrease the production cost to collect and purify the bio-isoprene from the fermentation outlet gas. The proposed microaerobic process can potentially be applied in the production of other volatile bioproducts to benefit the downstream purification process.

Abstract Background Whole-cell tumor vaccines have shown much promise; however, only limited success has been achieved for the goal of eliciting robust tumor-specific T-cell responses. Methods Hepatocellular carcinoma (HCC) cells, H22 and Hepa1–6, were modified by blocking the STAT3 signaling pathway with a STAT3 decoy oligodeoxynucleotide, and the immunogenicity and possibility of using these cell lysates as a vaccine were evaluated. Results STAT3-blocked whole HCC cell lysates inhibited tumor growth and tumorigenesis, and prolonged the survival of tumor-bearing mice. In addition, STAT3-blocked whole HCC cell lysates stimulated the activation of T cells and natural killer (NK) cells, and enhanced the infiltration of cytotoxic CD8+ T cells in the tumor tissues. In addition, the maturation of dendritic cells (DCs) was enhanced, which promoted the generation of immunological memory against HCC. Furthermore, secondary immune responses could be primed as soon as these immunized mice were challenged with HCC cells, accompanied by T cell and NK cell activation and infiltration. Additionally, immunization with this vaccine decreased the generation of Tregs and the production of TGF-β and IL-10. Importantly, STAT3-blocked whole HCC cell lysates prevented HCC-mediated exhaustion of T cells and NK cells, showing low expression of checkpoint molecules such as PD-1 and TIGIT on T cells and NK cells in the immunized mice. Conclusions The newly generated STAT3-blocked whole-cell HCC vaccine has potential for cancer cell vaccination.

Resistance to tamoxifen (Tam), a widely used antagonist of the estrogen receptor (ER), is a common obstacle to successful breast cancer treatment. While adjuvant therapy with Tam has been shown to significantly decrease the rate of disease recurrence and mortality, recurrent disease occurs in one third of patients treated with Tam within 5 years of therapy. A better understanding of gene expression alterations associated with Tam resistance will facilitate circumventing this problem. Using a next generation sequencing approach and a new bioinformatics model, we compared the transcriptomes of Tam-sensitive and Tam-resistant breast cancer cells for identification of genes involved in the development of Tam resistance. We identified differential expression of 1215 mRNA and 513 small RNA transcripts clustered into ERα functions, cell cycle regulation, transcription/translation, and mitochondrial dysfunction. The extent of alterations found at multiple levels of gene regulation highlights the ability of the Tam-resistant cells to modulate global gene expression. Alterations of small nucleolar RNA, oxidative phosphorylation, and proliferation processes in Tam-resistant cells present areas for diagnostic and therapeutic tool development for combating resistance to this anti-estrogen agent.