Role of Histiocyte-Derived frHMGB1 as a Facilitator in Noncanonical Pyroptosis of Monocytes/Macrophages in Lethal Sepsis.

In this study, we investigated the role of the noncanonical pyroptosis pathway in the progression of lethal sepsis. Our findings emphasize the significance of noncanonical pyroptosis in monocytes/macrophages for the survival of septic mice. We observed that inhibiting pyroptosis alone significantly improved the survival rate of septic mice and that the HMGB1 A box effectively suppressed this noncanonical pyroptosis, thereby enhancing the survival of septic mice. Additionally, our cell in vitro experiments unveiled that frHMGB1, originating from lipopolysaccharide-carrying histiocytes, entered macrophages via RAGE, resulting in the direct activation of caspase 11 and the induction of noncanonical pyroptosis. Notably, A box's competitive binding with lipopolysaccharide impeded its entry into the cell cytosol. These findings reveal potential therapeutic strategies for slowing the progression of lethal sepsis by modulating the noncanonical pyroptosis pathway.

Clinical and genetic characteristics in a Chinese cohort of complex spastic paraplegia type 4.

Spastic paraplegia type 4 (SPG4), caused by SPAST mutations, is the most predominant subtype of hereditary spastic paraplegia. Most documented SPG4 patients present as pure form, with the complex form rarely reported. We described the clinical and genetic features of 20 patients with complex phenotypes of SPG4 and further explored the genotype-phenotype correlations. We collected detailed clinical data of all SPG4 patients and assessed their phenotypes. SPAST gene mutations were identified by Multiplex ligation-dependent probe amplification in combination with whole exome sequencing. We further performed statistical analysis in genotype and phenotype among patients with various manifestations and different variants. Out of 90 SPG4 patients, 20 patients (male:female = 16:4) with additional neurologic deficits, namely complex form, were included in our study. The bimodal distribution of age of onset at 0-10 and 21-40 years old is concluded. On cranial MRI, obvious white matter lesions can be observed in five patients. We identified 9 novel and 8 reported SPAST mutations, of which 11 mutations were located in AAA (ATPase associated with various cellular activities) domain. The AAA cassette of spastin is the hottest mutated region among complex SPG4. All patients with cognitive impairment (CI) are males (n = 9/9). Additionally, 80% patients with ataxia are due to frameshift mutations (n = 4/5). Overall, our study summarized and analyzed the genetic and phenotypic characteristics of complex SPG4, making up over 1/5 of in-house SPG4 cohort, among which CI and ataxia are the most common features. Further studies are expected to explore the underlying mechanisms.

Clinical and Genetic Spectrum in a Large Cohort of Hereditary Spastic Paraplegia.

BACKGROUND: Next-generation sequencing-based molecular assessment has benefited the diagnosis of hereditary spastic paraplegia (HSP) subtypes. However, the clinical and genetic spectrum of HSP due to large fragment deletions/duplications has yet to be fully defined. OBJECTIVE: We aim to better characterize the clinical phenotypes and genetic features of HSP and to provide new thoughts on diagnosis. METHODS: Whole-exome sequencing (WES) was performed in patients with clinically suspected HSP, followed by multiple ligation-dependent probe amplification (MLPA) sequentially carried out for those with negative findings in known causative genes. Genotype-phenotype correlation analyses were conducted under specific genotypes. RESULTS: We made a genetic diagnosis in 60% (162/270) of patients, of whom 48.9% (132/270) had 24 various subtypes due to point mutations (SPG4/SPG11/SPG35/SPG7/SPG10/SPG5/SPG3A/SPG2/SPG76/SPG30/SPG6/SPG9A/SPG12/SPG15/SPG17/SPG18/SPG26/SPG49/SPG55/SPG56/SPG57/SPG62/SPG78/SPG80). Thirty patients were found to have causative rearrangements by MLPA (11.1%), among which SPG4 was the most prevalent (73.3%), followed by SPG3A (16.7%), SPG6 (3.3%), SPG7 (3.3%), and SPG11 (3.3%). Clinical analysis showed that some symptoms were often related to specific subtypes, and rearrangement-related SPG3A patients seemingly had later onset. We observed a presumptive anticipation among SPG4 and SPG3A families due to rearrangement. CONCLUSIONS: Based on the largest known Asian HSP cohort, including the largest subgroup of rearrangement-related pedigrees, we gain a comprehensive understanding of the clinical and genetic spectrum of HSP. We propose a diagnostic flowchart to sequentially detect the causative genes in practice. Large fragment mutations account for a considerable proportion of HSP, and thus, MLPA screening acts as a beneficial supplement to routine WES. © 2024 International Parkinson and Movement Disorder Society.

The Phenotypic and Genotypic Spectrum of CSF1R-Related Disorder in China.

BACKGROUND: Colony-stimulating factor 1 receptor (CSF1R)-related disorder (CRD) is a rare autosomal dominant disease. The clinical and genetic characteristics of Chinese patients have not been elucidated. OBJECTIVE: The objective of the study is to clarify the core features and influence factors of CRD patients in China. METHODS: Clinical and genetic-related data of CRD patients in China were collected. Mini-Mental State Examination (MMSE), Montreal Cognitive Assessment (MoCA), and Sundal MRI Severity Score were evaluated. Whole exome sequencing was used to analyze the CSF1R mutation status. Patients were compared between different sexes, mutation types, or mutation locations. RESULTS: A total of 103 patients were included, with a male-to-female ratio of 1:1.51. The average age of onset was (40.75 ± 8.58). Cognitive impairment (85.1%, 86/101) and parkinsonism (76.2%, 77/101) were the main clinical symptoms. The most common imaging feature was bilateral asymmetric white matter changes (100.0%). A total of 66 CSF1R gene mutants (22 novel mutations) were found, and 15 of 92 probands carried c.2381 T > C/p.I794T (16.30%). The MMSE and MoCA scores (17.0 [9.0], 11.90 ± 7.16) of female patients were significantly lower than those of male patients (23.0 [10.0], 16.36 ± 7.89), and the white matter severity score (20.19 ± 8.47) of female patients was significantly higher than that of male patients (16.00 ± 7.62). There is no statistical difference in age of onset between male and female patients. CONCLUSIONS: The core manifestations of Chinese CRD patients are progressive cognitive decline, parkinsonism, and bilateral asymmetric white matter changes. Compared to men, women have more severe cognitive impairment and imaging changes. c.2381 T > C/p.I794T is a hotspot mutation in Chinese patients. © 2024 International Parkinson and Movement Disorder Society.

Spastic paraplegia type 76 due to novel CAPN1 mutations: three case reports with literature review.

Spastic paraplegia type 76 (SPG76) is a subtype of hereditary spastic paraplegia (HSP) caused by calpain-1 (CAPN1) mutations. Our study described the phenotypic and genetic characteristics of three families with spastic ataxia due to various CAPN1 mutations and further explored the pathogenesis of the two novel mutations. The three patients were 48, 39, and 48 years old, respectively. Patients 1 and 3 were from consanguineous families, while patient 2 was sporadic. Physical examination showed hypertonia, hyperreflexia, and Babinski signs in the lower limbs. Patients 2 and 3 additionally had dysarthria and depression. CAPN1 mutations were identified by whole-exome sequencing, followed by Sanger sequencing and co-segregation analysis within the family. Functional examination of the newly identified mutations was further explored. Two homozygous mutations were detected in patient 1 (c.213dupG, p.D72Gfs*95) and patient 3 (c.1729+1G>A) with HSP, respectively. Patient 2 had compound heterozygous mutations c.853C>T (p.R285X) and c.1324G>A (p.G442S). Western blotting revealed the p.D72Gfs*95 with a smaller molecular weight than WT and p.G442S. In vitro, the wild-type calpain-1 is mostly located in the cytoplasm and colocalized with tubulin by immunostaining. However, p.D72Gfs*95 and p.G442S abnormally formed intracellular aggregation, with little colocalization with tubulin. In this study, we identified three cases with SPG76, due to four various CAPN1 mutations, presenting lower limb spasticity and ataxia, with or without bulbar involvement and emotional disorder. Among these, c.213dupG and c.1324G>A are first identified in this paper. The genotype-phenotype correlation of the SPG76 cases reported worldwide was further summarized.

Dual-polarization interferometric fiber optic gyroscope based on a four-port circulator.

The dual-polarization interferometric fiber optic gyroscope (IFOG) has been studied for many years and achieved remarkable performance. In this study, we propose a novel dual-polarization IFOG configuration based on a four-port circulator, in which the polarization coupling errors and the excess relative intensity noise are well handled meanwhile. Experimental measurements of the short-term sensitivity and long-term drift using a fiber coil with a length of 2 km and a diameter of 14 cm show that the angle random walk of 5.0×10-5∘/h and bias instability of 9.0 × 10-5 °/h are achieved. Moreover, the root power spectrum density of 20n r a d/s/H z is almost flat from 0.001 Hz to 30 Hz. We believe this dual-polarization IFOG is a preferred candidate for the reference-grade performance IFOG.

Compensation of scale factor nonlinear error introduced by harmonic distortion for open-loop fiber optic gyroscopes.

The scale factor (SF) of a gyroscope is the ratio of the detection output rotational rate and the input, and is expected to be a constant. However, for open-loop interferometric fiber optic gyroscopes (IFOGs) with sinusoidal modulation, harmonic amplitudes are inevitably affected by detection defects, such as nonuniform frequency response of the photodetector or unequal gain of amplification circuits. As a result, harmonic distortion leads to SF nonlinearity, which seriously hinders the accuracy of high-precision gyroscopes. In this Letter, the theoretical form of the SF error introduced by harmonic distortion of open-loop gyroscopes is analyzed, and an effective and simple compensation method is proposed. Instead of traversing the whole dynamic range, the proposed method simplifies the calibration pretest, where only a section of the dynamic range needs to be tested. Experimental results on an open-loop IFOG prototype show that, with our proposed method, the SF nonlinear error is suppressed to 2.5 ppm within the range -300 to +300∘/s, which is 33 times less than that before compensation.

Angular accelerometer based on a dual-polarization fiber-optic Sagnac interferometer.

High-performance angular accelerometers are essential for precise dynamics control of aircraft, satellites, etc. Here, we propose, for the first time to the best of our knowledge, an angular accelerometer based on a dual-polarization fiber-optic Sagnac interferometer, which exhibits relatively high sensitivity and a broad bandwidth. The experimental results show that the angular accelerometer achieves a flat frequency response in the bandwidth range of 0.01-100 Hz. The sensitivity reaches 6.6 × 10-8 rad/s2/Hz. In addition, the proposed fiber-optic angular accelerometer does not rely on any mechanical structure and has strong environmental adaptability. This research provides a feasible solution for the design and implementation of new high-performance angular accelerometers, which contributes to their development in the fields of inertial navigation and rotational seismology.

Interferometric fiber-optic gyroscope based on mode-division multiplexing.

The interferometric fiber-optic gyroscope (IFOG) is widely used in the fields of inertial navigation and rotational seismology. A direct way to improve the sensitivity of the IFOG is to increase the length of the sensing fiber, but this increases the cost and size of the gyroscope. Here, we propose an IFOG based on mode-division multiplexing (MDM), which exhibits relatively high performance. The experimental results show that, the proposed IFOG is improved to twice as much in terms of sensitivity, angle random walk, and bias instability with the use of MDM. This research provides a novel, to the best of our knowledge, solution for the design and implementation of low-cost, high-sensitivity IFOGs, which could contribute to their application in a wider range of fields.

The marksman: Bioactivated nematicides selectively kill plant-parasitic nematodes.

Plant-parasitic nematodes destroy crops and have a major impact on the food supply, but using chemicals to control them poses a risk to other animals and people. Selectivins kill nematodes but have little effect on other organisms.

TMEM151A Variants Cause Paroxysmal Kinesigenic Dyskinesia: A Large-Sample Study.

BACKGROUND: Paroxysmal kinesigenic dyskinesia (PKD) is the most common type of paroxysmal dyskinesias. Only one-third of PKD patients are attributed to proline-rich transmembrane protein 2 (PRRT2) mutations. OBJECTIVE: We aimed to explore the potential causative gene for PKD. METHODS: A cohort of 196 PRRT2-negative PKD probands were enrolled for whole-exome sequencing (WES). Gene Ranking, Identification and Prediction Tool, a method of case-control analysis, was applied to identify the candidate genes. Another 325 PRRT2-negative PKD probands were subsequently screened with Sanger sequencing. RESULTS: Transmembrane Protein 151 (TMEM151A) variants were mainly clustered in PKD patients compared with the control groups. 24 heterozygous variants were detected in 25 of 521 probands (frequency = 4.80%), including 18 missense and 6 nonsense mutations. In 29 patients with TMEM151A variants, the ratio of male to female was 2.63:1 and the mean age of onset was 12.93 ± 3.15 years. Compared with PRRT2 mutation carriers, TMEM151A-related PKD were more common in sporadic PKD patients with pure phenotype. There was no significant difference in types of attack and treatment outcome between TMEM151A-positive and PRRT2-positive groups. CONCLUSIONS: We consolidated mutations in TMEM151A causing PKD with the aid of case-control analysis of a large-scale WES data, which broadens the genotypic spectrum of PKD. TMEM151A-related PKD were more common in sporadic cases and tended to present as pure phenotype with a late onset. Extensive functional studies are needed to enhance our understanding of the pathogenesis of TMEM151A-related PKD. © 2021 International Parkinson and Movement Disorder Society.

Novel IBA57 mutations in two chinese patients and literature review of multiple mitochondrial dysfunction syndrome.

Multiple mitochondrial dysfunction syndrome (MMDS) refers to a class of mitochondrial diseases caused by nuclear gene mutations, which usually begins in early infancy and is classically characterized by markedly impaired neurological development, generalized muscle weakness, lactic acidosis, and hyperglycinemia, cavitating leukoencephalopathy, respiratory failure, as well as early fatality resulted from dysfunction of energy metabolism in multiple systems. So far, six types of MMDS have been identified based on different genotypes, which are caused by mutations in NFU1, BOLA3, IBA57, ISCA2, ISCA1 and PMPCB, respectively. IBA57 encodes a protein involved in the mitochondrial Fe/S cluster assembly process, which plays a vital role in the activity of multiple mitochondrial enzymes. Herein, detailed clinical investigation of 2 Chinese patients from two unrelated families were described, both of them showed mildly delay in developmental milestone before disease onset, the initial symptoms were all presented with acute motor and mental retrogression, and brain MRI showed diffused leukoencephalopathy with cavities, dysplasia of corpus callosum and cerebral atrophy. Exome sequencing revealed three IBA57 variants, one shared variant (c.286T>C) has been previously reported, the remaining two (c.189delC and c.580 A>G) are novel. To enhance the understanding of this rare disease, we further made a literature review about the current progress in clinical, genetic and treatment of the disorder. Due to the rapid progress of MMDS, early awareness is crucial to prompt and proper administration, as well as genetic counseling.

Inter-User Distance Estimation Based on a New Type of Fingerprint in Massive MIMO System for COVID-19 Contact Detection.

In this paper, we address the challenging task of estimating the distance between different users in a Millimeter Wave (mmWave) massive Multiple-Input Multiple-Output (mMIMO) system. The conventional Time of Arrival (ToA) and Angle of Arrival (AoA) based methods need users under the Line-of-Sight (LoS) scenario. Under the Non-LoS (NLoS) scenario, the fingerprint-based method can extract the fingerprint that includes the location information of users from the channel state information (CSI). However, high accuracy CSI estimation involves a huge overhead and high computational complexity. Thus, we design a new type of fingerprint generated by beam sweeping. In other words, we do not have to know the CSI to generate fingerprint. In general, each user can record the Received Signal Strength Indicator (RSSI) of the received beams by performing beam sweeping. Such measured RSSI values, formatted in a matrix, could be seen as beam energy image containing the angle and location information. However, we do not use the beam energy image as the fingerprint directly. Instead, we use the difference between two beam energy images as the fingerprint to train a Deep Neural Network (DNN) that learns the relationship between the fingerprints and the distance between these two users. Because the proposed fingerprint is rich in terms of the users' location information, the DNN can easily learn the relationship between the difference between two beam energy images and the distance between those two users. We term it as the DNN-based inter-user distance (IUD) estimation method. Nonetheless, we investigate the possibility of using a super-resolution network to reduce the involved beam sweeping overhead. Using super-resolution to increase the resolution of low-resolution beam energy images obtained by the wide beam sweeping for IUD estimation can facilitate considerate improvement in accuracy performance. We evaluate the proposed DNN-based IUD estimation method by using original images of resolution 4 × 4, 8 × 8, and 16 × 16. Simulation results show that our method can achieve an average distance estimation error equal to 0.13 m for a coverage area of 60 × 30 m2. Moreover, our method outperforms the state-of-the-art IUD estimation methods that rely on users' location information.

The Development of a New IFOG-Based 3C Rotational Seismometer.

For many years, seismological research mainly focuses on translational ground motions due to the lack of appropriate sensors. However, because of the development of devices based on Sagnac effect, measuring rotational waves directly comes available. In this work, a portable three-component broadband rotational seismometer named RotSensor3C based on open loop interferometric fiber optic gyroscope (IFOG) is designed and demonstrated. Laboratory tests and results are illustrated in detail. The self-noise ranging from 0.005 Hz to 125 Hz is about 1.2×10-7rads-1/Hz, and with the harmonics compensation the scale factor variation over ±250∘/s is lower than 10 ppm (parts per million). The misalignment matrix method is adopted to revise the output rotation rate. In a special near field experiment using the explosive source, the back-azimuths and phase velocity are estimated by the recorded acceleration and rotation rate. All the results prove the practicability of this new rotational sensor.

PGE2 ameliorated viral myocarditis development and promoted IL-10-producing regulatory B cell expansion via MAPKs/AKT-AP1 axis or AhR signaling.

B10 cells, a specific subset of regulatory B cells, are capable of regulating immune response and restricting inflammation and autoimmune disease progression by producing IL-10. B10 cells frequently change significantly during inflammation and autoimmunity. However, how B10 cell populations change in viral myocarditis (VMC) remains unclear. Therefore, this work was conducted to clarify the changes in B10 cells and their potential mechanisms. Our results showed that the B10 cell frequency significantly changed in the VMC model. Changes in prostaglandin E2 (PGE2) levels in VMC model hearts were consistent with B10 expansion. PGE2 induced B10 cell expansion via the MAPKs/AKT-AP1 axis or AhR signaling. Additionally, PGE2-pretreated B10 cells inhibited naïve CD4+ T cell differentiation into Th17 cells. In vivo, PGE2 treatment or adoptive B10 cell transfer significantly restricted VMC development. Our results provide sufficient evidence that PGE2-induced B10 cell expansion may become a promising therapeutic approach for VMC and acute inflammatory injury.

Sensitivity enhancement through RIN suppression in dual-polarization fiber optic gyroscopes for rotational seismology.

Portable sensors with a sufficiently high sensitivity in detecting small rotational motions have attracted significant attention in the field of rotational seismology. In this study, we propose and demonstrate a dual-polarization fiber optic gyroscope (IFOG) with a portable-sized fiber coil. Excess relative intensity noise (RIN) is effectively compensated for owing to the opposite parities and strong correlation of the two orthogonal polarized light, whereas other noises including coherent phase noise and thermal phase noise have also been handled well. In a test on detecting the rotation rate of the Earth, an enhanced sensitivity of 20nrad/s/Hz over a frequency range of 0.01 Hz to 30 Hz was demonstrated using the proposed design with an enclosed area of only 68 m2.

HMGB1 A box protects neurons by potently inhibiting both microglia and T cell-mediated inflammation in a mouse Parkinson's disease model.

In the subacute Parkinson's disease (PD) mice model of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP), injection of HMGB1 competitive inhibitor protein HMGB1 A box and the ethyl pyruvate (EP) that inhibit the release of HMGB1 from cells restored the number of dopaminergic neurons and TH+ fibers in the SN and striatum. Our data show that A box up-regulated CD200-CD200R signal of microglia inhibited the activation of microglia mediated by HMGB1, and the production of TNF-α, IL-1ß and IL-6 in vivo and in vitro mixed culture system. Microglia overexpressing CD200R produced less inflammatory chemokines and reduced the loss of TH+ neurons. In addition, HMGB1 A box decreased the level of CCL5 and significantly inhibited the infiltration of almost all T cells including Th17 and the proportion of Th17 in CD4+ T cells. In vitro MPP+ induced model and HMGB1-stimulated mesencephalic cell system activated microglia induced the differentiation of naïve T cells to Th17, and A box significantly inhibited this process. To sum up, our results show that HMGB1 A box targeting HMGB1, which effectively reduces the activation of microglia in MPTP PD model by restoring CD200-CD200R signal inhibit microglia mediated neuroinflammation and the differentiation of T cells to Th17.

Thermal phase noise in giant interferometric fiber optic gyroscopes.

The thermal phase noise in giant interferometric fiber optic gyroscopes (fiber length L > 10 km) and its impact on the detection sensitivity are theoretically derived and experimentally verified. It is confirmed that thermal phase noise cannot be overlooked for the giant IFOGs. Utilizing high order eigen frequency modulation can effectively suppress the walk-off component of thermal phase noise, but the residual part contributes to high-frequency range thus limits the detection bandwidth of giant IFOGs. The self-noise is experimentally demonstrated as 3.5 nrad/s/Hz at low frequencies and 5.2 nrad/s/Hz at 100 Hz in the IFOG with a 30-km single mode fiber coil. Discussions about the fiber characteristics on thermal phase noise are presented, which paves the way to the design of giant IFOGs.

Downregulated Rac1 promotes apoptosis and inhibits the clearance of apoptotic cells in airway epithelial cells, which may be associated with airway hyper-responsiveness in asthma.

The accumulation of airway apoptotic cells may be an important factor causing airway hyper-responsiveness (AHR). Whether the apoptotic cells can be promptly removed is related to the occurrence and course of asthma. In recent years, studies have shown that Rac1 is involved in many cellular biological activities including the formation and elimination of apoptotic cells. In this study, based on the analysis of airway local cells and related factors in asthmatic mice, we evaluated the expression of Rac1 in airway epithelial cells or phagocytes and analysed its relationship with the incidence of apoptosis or scavenging of apoptotic cells. Our data showed that the expression level of Rac1 in asthmatic mice decreased significantly, while the expression of IL-33 increased obviously. The airway epithelial cell line was stimulated by curcumin at 50 µmol/L for 24-48 hours; more than 50% of the cells were apoptotic, and of which, about 20% were late apoptosis. Rac1 inhibitor (NSC23766) can enhance the apoptosis effect. In addition, the ability of phagocytosis and migration in the epithelial cells or macrophages was increased following the application of Rac1 inhibitors or specific siRNA in a dose-dependent manner, and the expression level of IL-33 was simultaneously increased after blocking Rac1. It is suggested that the down regulation of Rac1 in asthma may contribute to the apoptosis of airway epithelial cells and affect the clearance of apoptotic cells, which will lead to the aggregation of the apoptotic cells in the respiratory tract and participate in AHR.

Prognostic impact of tumor-associated macrophage infiltration in esophageal cancer: a meta-analysis.

Aim: To provide clarity surrounding the association between tumor-associated macrophages (TAMs) and esophageal cancer prognosis. Materials & methods: Several databases were searched. The meta-analysis was conducted by using software Stata 12.0 and Revman. Results: Sixteen studies were included in this analysis (2292 samples). CD68+ TAM density was not associated with overall survival (OS; hazard ratio [HR]: 0.88, 95% CI: 0.67-1.15; p = 0.33) and disease-free survival (HR: 1.25, 95% CI: 0.66-2.35; p = 0.49). M2-like TAMs were associated with poor overall survival (HR: 1.47, 95% CI: 1.10-1.98; p = 0.01), Tumor, Node, Metastasis staging and vessel metastasis. Conclusion: CD68+ TAM density is not associated with esophageal cancer progression, while CD163+ M2-like TAMs is a potential risk factor.