Immunosuppressant Agents as Add-On Therapy Failed to Improve the Outcome of Immunoglobulin A Nephropathy with Crescent Score C1.

Background The renoprotective benefits of adding immunosuppressant therapy to corticosteroid (CS) treatment for immunoglobulin A nephropathy (IgAN) patients with less than 25% crescent formation (C1) remains uncertain, warranting further research. Methods A retrospective study was conducted on IgAN patients with crescent C1 lesions confirmed by renal biopsy at Xinqiao Hospital between May 1, 2017, and May 1, 2020. Patients were stratified into either the CS treatment group or the CS combined with an additional immunosuppressant therapy group. Follow-up assessments were conducted within 24 months. Propensity score analysis was used to match patients receiving CS and CS+immunosuppressant drug treatment in a 1:1 ratio. Primary outcomes included changes in estimated glomerular filtration rate (eGFR) and urine albumin-to-creatinine ratio (UACR). Subgroup analyses were performed to evaluate the benefits of different populations. Composite endpoint outcomes comprised a 30% eGFR decrease, end-stage kidney disease (ESKD) necessitating dialysis or transplant, or kidney disease-related mortality. Adverse events were also compared between the two groups. Results: 296 IgAN patients with C1 lesions were included in the analysis. Baseline characteristics indicated that IgAN patients in the CS+immunosuppressant group exhibited poorer renal function and higher UACR levels. Propensity score analysis effectively minimized the influence of baseline clinical characteristics, including age, serum creatinine, initial eGFR, UACR, and 24-hour proteinuria. Both treatment groups demonstrated continuous eGFR improvement and significant UACR reduction during follow-up, especially at 6 months. However, no significant differences in eGFR and UACR reduction rates were observed between the two groups throughout the entire follow-up period, both before and after matching. Subgroup analysis revealed improved eGFR in both treatment groups, notably among patients with an initial eGFR below 90 ml/min/1.73 m2. Conversely, IgAN patients with C1 lesions and a cellular crescent ratio exceeding 50% treated with CS and immunosuppressant therapy experienced a significant improvement in renal function and a decline in urinary protein creatinine ratio. Composite endpoint outcomes did not significantly differ between the two groups, while the incidence of adverse events was comparable. Conclusion Our findings suggest that the addition of immunosuppressant therapy to corticosteroid monotherapy did not confer significant therapeutic advantages in patients with C1 lesions compared to CS monotherapy, although some specific patient populations appeared to derive modest benefits from this combined approach.

Self-Assembling P38 Peptide Inhibitor Nanoparticles Ameliorate the Transition from Acute to Chronic Kidney Disease by Suppressing Ferroptosis.

Accumulating evidence highlights p38 as a crucial factor highly activated during the process of acute kidney injury (AKI), but the application of p38 inhibitor in AKI is quite limited due to the low efficiency and poor kidney-targeting ability. Herein, a novel self-assembling peptide nanoparticle with specific p38-inhibiting activity is constructed, which linked mitogen-activated protein kinase kinase 3b (MKK3b), the functional domain of p38, with the cell-penetrating TAT sequence, ultimately self-assembling into TAT-MKK3b nanoparticles (TMNPs) through tyrosinase oxidation. Subsequent in vitro and in vivo studies demonstrated that TMNPs preferably accumulated in the renal tubular epithelial cells (RTECs) through forming protein coronas by binding to albumin, and strongly improved the reduced renal function of ischemia-reperfusion injury (IRI)-induced AKI and its transition to chronic kidney disease (CKD). Mechanically, TMNPs inhibited ferroptosis via its solute carrier family 7 member 11 (SLC7A11)/glutathione peroxidase 4 (GPX4) axis-inducing capacity and synergistic potent antioxidant property in AKI. The findings indicated that the multifunctional TMNPs exhibited renal targeting, ROS-scavenging, and ferroptosis-mitigating capabilities, which may serve as a promising therapeutic agent for the treatment of AKI and its progression to CKD.

Coordinated optimization of the polymerization and transportation processes to enhance the yield of exopolysaccharide heparosan.

Heparosan as the precursor for heparin biosynthesis has attracted intensive attention while Escherichia coli Nissle 1917 (EcN) has been applied as a chassis for heparosan biosynthesis. Here, after uncovering the pivotal role of KfiB in heparosan biosynthesis, we further demonstrate KfiB is involved in facilitating KpsT to translocate the nascent heparosan polysaccharide chain. As a result, an artificial expression cassette KfiACB was constructed with optimized RBS elements, resulting in 0.77 g/L heparosan in shake flask culture. Moreover, in view of the intracellular accumulation of heparosan, we further investigated the effects of overexpression of the ABC transport system proteins on heparosan biosynthesis. By co-overexpressing KfiACB with KpsTME, the heparosan production in flask cultures was increased to 1.03 g/L with an extracellular concentration of 0.96 g/L. Eventually, the engineered strain EcN/pET-kfiACB3-galU-kfiD-glmM/pCDF-kpsTME produced 12.2 g/L heparosan in 5-L fed-batch cultures while the extracellular heparosan was about 11.2 g/L. The results demonstrate the high-efficiency of the strategy for co-optimizing the polymerization and transportation for heparosan biosynthesis. Moreover, this strategy should be also available for enhancing the production of other polysaccharides.

Minimizing endogenous cryptic plasmids to construct antibiotic-free expression systems for Escherichia coli Nissle 1917.

The probiotic bacterium Escherichia coli Nissle 1917 (EcN) holds significant promise for use in clinical and biological industries. However, the reliance on antibiotics to maintain plasmid-borne genes has overshadowed its benefits. In this study, we addressed this issue by engineering the endogenous cryptic plasmids pMUT1 and pMUT2. The non-essential elements were removed to create more stable derivatives pMUT1NR△ and pMUT2HBC△. Synthetic promoters by integrating binding motifs on sigma factors were further constructed and applied for expression of Bacteroides thetaiotaomicron heparinase III and the biosynthesis of ectoine. Compared to traditional antibiotic-dependent expression systems, our newly constructed antibiotic-free expression systems offer considerable advantages for clinical and synthetic biology applications.

Do residential patterns affect women's labor market performance? An empirical study based on CHFS data.

Based on China Household Finance Survey (CHFS) data from 2019, this paper explores the impact of the residential pattern of coresidence with parents on the labor market performance of women in married families with minor children. The study finds that coresidence with parents significantly increases the possibility of female labor market participation and positively impacts women's employment income. To overcome the potential endogeneity problem of residential patterns, this paper uses the Heckman two-step method and the conditional mixed process estimation method (CMP method) for regression, and the conclusions remain robust. The mechanism analysis shows that coresidence with parents has both grandchild care and elderly care factors, which have a spillover effect and a crowding-out effect on female labor market performance, respectively. Since the spillover effect is more significant than the crowding-out effect, coresidence with parents positively impacts women's labor market performance. The heterogeneity analysis shows that in terms of labor force participation rate, coresidence with parents has a more significant impact on women in families with children aged 0-6, women in families without boys, and women in families with employed husbands. In terms of income, coresidence with parents has a more significant impact on women in families with employed husbands. This study provides a new perspective for promoting female labor market performance and can serve as a reference for future policy formulation.

Two novel gene mutations identified in a child with pulmonary alveolar microlithiasis complicated with bronchitis obliterans: A case report and literature review.

We reported a case of a 7-year-old boy with pulmonary alveolar microlithiasis (PAM) and detected two novel compound heterozygous mutations of solute carrier family 34 member 2 (SLC34A2), EXON:2-6 duplication and c.1218 (EXON:11) C > A (p. Phe406Leu). His symptoms were nonspecific. Chest computed tomography (CCT) showed bronchiectasis, a mosaic feature, and extensive calcifications in both lungs. In addition, bronchoscopy showed bronchitis obliterans which has rarely been reported as a complication in the literature. This case aimed to explore the mechanism of PAM and emphasize the role of gene analysis in diagnosing rare pediatric diseases. Finally, we undertook a review of the current literature containing SLC34A2 gene mutations to update the gene mutation spectrum of PAM.

Fertilizer-induced manganese oxide formation enhances cadmium removal by paddy crusts from irrigation water.

Fertilization is a crucial agrological measure for agricultural production that can significantly impact the removal of Cd from irrigation water by paddy crusts (PC). In this study, laboratory and field experiments were conducted to investigate the impact of fertilization at low, medium, and high concentrations on the accumulation of Cadmium (Cd) in PC and the underlying mechanisms involved. The results showed that only low fertilizer concentration could promote the removal of Cd by PC, which reduced the Cd concentration in irrigation water from 19.52 µg/L to 5.35 µg/L. Conversely, medium and high fertilizer concentrations reduced the accumulation of Cd by PC. After fertilizer addition, the proportion of Fe-Mn oxidizable-Cd in PC reached 55 % (with low concentration of fertilizer treatment). The application of low concentration of fertilizer was found to stimulate the growth of filamentous green algae, leading to a significant increase in the relative abundance of sphingomonadaceae (by 1.39 %) and comamonadaceae (by 1.29 %). The XRD, SEM and correlation analysis show that a large amount of manganese oxide is formed on the surface of PC, which increases the fixation of Cd. These findings provide a new perspective for the remediation of heavy metal contamination in paddy fields.

Multiplex detection of clinical pathogen nucleic acids via a three-way junction structure-based nucleic acid circuit.

Nucleic acid testing technology has made considerable progress in the last few years. However, there are still many challenges in the clinical application of multiple nucleic acid assays, such as how to ensure accurate results, increase speed and decrease cost. Herein, a three-way junction structure has been introduced to specifically translate analytes of loop-mediated isothermal amplification to a catalytic hairpin assembly. For different analyses, a well-optimized nucleic acid circuit can be directly applied to detection, through only one-component replacement, which only not avoids duplicate sequence design but also saves detection cost. Thanks to this design, multiple and logical analysis can be easily realized in a single reaction with ultra-high sensitivity and selectivity. In this paper, Mycoplasma pneumoniae and Streptococcus pneumoniae can be clearly distinguished from the clinical mixed sample with negative control or one analyte in one tube single fluorescence channel. The fair experimental results of actual clinical samples provide a strong support for the possibility of clinical application of this methodology.

Two Stream Active Query Suggestion for Active Learning in Connectomics.

For large-scale vision tasks in biomedical images, the labeled data is often limited to train effective deep models. Active learning is a common solution, where a query suggestion method selects representative unlabeled samples for annotation, and the new labels are used to improve the base model. However, most query suggestion models optimize their learnable parameters only on the limited labeled data and consequently become less effective for the more challenging unlabeled data. To tackle this, we propose a two-stream active query suggestion approach. In addition to the supervised feature extractor, we introduce an unsupervised one optimized on all raw images to capture diverse image features, which can later be improved by fine-tuning on new labels. As a use case, we build an end-to-end active learning framework with our query suggestion method for 3D synapse detection and mitochondria segmentation in connectomics. With the framework, we curate, to our best knowledge, the largest connectomics dataset with dense synapses and mitochondria annotation. On this new dataset, our method outperforms previous state-of-the-art methods by 3.1% for synapse and 3.8% for mitochondria in terms of region-of-interest proposal accuracy. We also apply our method to image classification, where it outperforms previous approaches on CIFAR-10 under the same limited annotation budget. The project page is https://zudi-lin.github.io/projects/#two_stream_active.

How to reprogram human fibroblasts to neurons.

Destruction and death of neurons can lead to neurodegenerative diseases. One possible way to treat neurodegenerative diseases and damage of the nervous system is replacing damaged and dead neurons by cell transplantation. If new neurons can replace the lost neurons, patients may be able to regain the lost functions of memory, motor, and so on. Therefore, acquiring neurons conveniently and efficiently is vital to treat neurological diseases. In recent years, studies on reprogramming human fibroblasts into neurons have emerged one after another, and this paper summarizes all these studies. Scientists find small molecules and transcription factors playing a crucial role in reprogramming and inducing neuron production. At the same time, both the physiological microenvironment in vivo and the physical and chemical factors in vitro play an essential role in the induction of neurons. Therefore, this paper summarized and analyzed these relevant factors. In addition, due to the unique advantages of physical factors in the process of reprogramming human fibroblasts into neurons, such as safe and minimally invasive, it has a more promising application prospect. Therefore, this paper also summarizes some successful physical mechanisms of utilizing fibroblasts to acquire neurons, which will provide new ideas for somatic cell reprogramming.

Enhanced Selective Removal of Cd(II) by an Amino-Functional Water-Retaining Agent Incorporating Nano Hydrous Manganese Oxide.

An amino-functionalized water-retaining agent (PPM40-NH2) and a water-retaining agent lacking functionalization (PPM40) were prepared to investigate their selective Cd(II) removal properties. The affinity for Cd(II) was increased after introducing the amino functional group. The SFCd/Ca of PPM40-NH2 was 3-7 fold higher than that of PPM40 although the CCa was 100-1000 times higher than that of CCd. The chelating effect of -COOH and -NH2 in PPM40-NH2 corresponded well with the selective adsorption of Cd(II), as confirmed by simulations. A seed germination experiment demonstrated that PPM40-NH2 could act as a filter of heavy metals to supply "clean" water for the roots of the pakchoi plant. The leaching experiment indicated that PPM40-NH2 is an efficient in situ fixation agent for the remediation of agricultural soil contaminated with Cd(II) in the presence of high concentrations of Ca(II) salts.

Automatic Regularization of TomoSAR Point Clouds for Buildings Using Neural Networks.

Tomographic SAR (TomoSAR) is a remote sensing technique that extends the conventional two-dimensional (2-D) synthetic aperture radar (SAR) imaging principle to three-dimensional (3-D) imaging. It produces 3-D point clouds with unavoidable noise that seriously deteriorates the quality of 3-D imaging and the reconstruction of buildings over urban areas. However, existing methods for TomoSAR point cloud processing notably rely on data segmentation, which influences the processing efficiency and denoising performance to a large extent. Inspired by regression analysis, in this paper, we propose an automatic method using neural networks to regularize the 3-D building structures from TomoSAR point clouds. By changing the point heights, the surface points of a building are refined. The method has commendable performance on smoothening the building surface, and keeps a precise preservation of the building structure. Due to the regression mechanism, the method works in a high automation level, which avoids data segmentation and complex parameter adjustment. The experimental results demonstrate the effectiveness of our method to denoise and regularize TomoSAR point clouds for urban buildings.

Super-resolution reconstruction for terahertz imaging based on sub-pixel gradient field transform.

This paper presents the gradient-guided image super-resolution reconstruction for terahertz imaging to improve the image quality, taking advantage of super-resolution reconstruction based on adaptive super-pixel gradient field transform. Moreover, spatial entropy-based enhancement and a bilateral filter are introduced to ensure better performance of the reconstruction. Furthermore, we compare the performance of reconstruction operated on terahertz images with frequencies of 0.1 THz, 0.3 THz, 0.5 THz, and 0.7 THz. Experimental results demonstrate that this method successfully improves the image quality and reconstruct high-resolution images from low-resolution images with the peak signal-to-noise ratio and structural similarity index improved. In addition, the signal frequency and intensity are demonstrated to affect the performance of reconstruction.

Active control of terahertz plasmon-induced transparency in the hybrid metamaterial/monolayer MoS2/Si structure.

Active control of terahertz waves is critical to the development of terahertz devices. Two-dimensional materials with excellent optical properties provide more choices for opto-electrical devices due to the advancement in their preparation technology. We proposed a hybrid structure of a metamaterial/monolayer MoS2/Si and investigated its optical properties in the terahertz range. The plasmon-induced transparency (PIT) effect was observed in the transmission spectra, resulting from the near-field coupling of two bright modes. According to the simulated results, this phenomenon confirmed its dependency on the length of the cutwire and the distance between DSSRs. Furthermore, an external optical field supported by a 1064 nm laser could exert a switch effect on the sample. The resonances of the PIT metamaterial disappeared when the optical power was further increased, as the excited carriers in the MoS2/Si substrate blocked the coupling effect. In addition, the experimental results indicated that the PIT metamaterial enhanced the interaction of infrared light with the monolayer MoS2/Si substrate.

Active multifunctional terahertz modulator based on plasmonic metasurface.

An active multifunctional terahertz modulator based on plasmon-induced transparency (PIT) metasurface under the effect of external infrared light was investigated theoretically and experimentally. A distinct transparency window, which resulted from the near-field coupling between two resonators, could be observed in the transmission spectra. Experimental results showed a phenomenon infrared light induced blue shift on the both resonator with increasing optical powers. When the optical power was tuned from 0 mW to 400 mW, the amplitude tunability of transmission at transparency window reached to 34.01%, much larger than that at the two resonance frequencies. Moreover, the phase tunability of the transmission at 0.98 THz reached to 31.35%. Meanwhile, the amplitude variation was limited to 10%. Furthermore, a coupled Lorentz oscillator model was adopted to analyze the near-field interaction of the resonances. Experimental results were in good agreement with the analytical fitting results.

Active optical modulator based on a metasurface in the terahertz region.

The characteristics of the electromagnetically induced transparency (EIT) analog exposed under different illumination powers have been investigated theoretically and experimentally. The EIT analog is composed of a fixed aluminum structure fabricated on the silicon substrate. It was found that the resonance degree of the transparent window displayed a decreasing trend, and a blueshift phenomenon emerged by increasing the powers of the laser. Similarly, the properties of the time delay under different illumination powers have also been researched. The realization of the tuning effect may provide a possible choice for the modulation of the slow light devices.

Reduced Smoothened level rescues Aß-induced memory deficits and neuronal inflammation in animal models of Alzheimer's disease.

Emerging evidence suggests that neuro-inflammation begins early and drives the pathogenesis of Alzheimer's disease (AD), and anti-inflammatory therapies are under clinical development. However, several anti-inflammatory compounds failed to improve memory in clinical trials, indicating that reducing inflammation alone might not be enough. On the other hand, neuro-inflammation is implicated in a number of mental disorders which share the same therapeutic targets. Based on these observations, we screened a batch of genes related with mental disorder and neuro-inflammation in a classical olfactory conditioning in an amyloid beta (Aß) overexpression fly model. A Smoothened (SMO) mutant was identified as a genetic modifier of Aß toxicity in 3-min memory and downregulation of SMO rescued Aß-induced 3-min and 1-h memory deficiency. Also, Aß activated innate inflammatory response in fly by increasing the expression of antimicrobial peptides, which were alleviated by downregulating SMO. Furthermore, pharmaceutical administration of a SMO antagonist LDE rescued Aß-induced upregulation of SMO in astrocytes of mouse hippocampus, improved memory in Morris water maze (MWM), and reduced expression of astrocyte secreting pro-inflammatory factors IL-1ß, TNFα and the microglia marker IBA-1 in an APP/PS1 transgenic mouse model. Our study suggests that SMO is an important conserved modulator of Aß toxicity in both fly and mouse models of AD.

Electrical terahertz modulator based on photo-excited ferroelectric superlattice.

The transmission and dielectric spectra of ferroelectric STO/PT superlattice on Si substrate under simultaneous external optical and electric field were investigated and compared at room temperature. Results found that when with an optical field, the electric field realized an effective modulation on the transmission, which displayed a diode property. In addition, a comprehensive model combined with Debye relaxation and Lorentz model was used to analyze the dielectric spectra, variation of the soft mode with external field was put emphasis on exploring.