pH sensing controls tissue inflammation by modulating cellular metabolism and endo-lysosomal function of immune cells.

Extracellular acidification occurs in inflamed tissue and the tumor microenvironment; however, a systematic study on how pH sensing contributes to tissue homeostasis is lacking. In the present study, we examine cell type-specific roles of the pH sensor G protein-coupled receptor 65 (GPR65) and its inflammatory disease-associated Ile231Leu-coding variant in inflammation control. GPR65 Ile231Leu knock-in mice are highly susceptible to both bacterial infection-induced and T cell-driven colitis. Mechanistically, GPR65 Ile231Leu elicits a cytokine imbalance through impaired helper type 17 T cell (TH17 cell) and TH22 cell differentiation and interleukin (IL)-22 production in association with altered cellular metabolism controlled through the cAMP-CREB-DGAT1 axis. In dendritic cells, GPR65 Ile231Leu elevates IL-12 and IL-23 release at acidic pH and alters endo-lysosomal fusion and degradation capacity, resulting in enhanced antigen presentation. The present study highlights GPR65 Ile231Leu as a multistep risk factor in intestinal inflammation and illuminates a mechanism by which pH sensing controls inflammatory circuits and tissue homeostasis.

Transcranial volumetric imaging using a conformal ultrasound patch.

Accurate and continuous monitoring of cerebral blood flow is valuable for clinical neurocritical care and fundamental neurovascular research. Transcranial Doppler (TCD) ultrasonography is a widely used non-invasive method for evaluating cerebral blood flow1, but the conventional rigid design severely limits the measurement accuracy of the complex three-dimensional (3D) vascular networks and the practicality for prolonged recording2. Here we report a conformal ultrasound patch for hands-free volumetric imaging and continuous monitoring of cerebral blood flow. The 2 MHz ultrasound waves reduce the attenuation and phase aberration caused by the skull, and the copper mesh shielding layer provides conformal contact to the skin while improving the signal-to-noise ratio by 5 dB. Ultrafast ultrasound imaging based on diverging waves can accurately render the circle of Willis in 3D and minimize human errors during examinations. Focused ultrasound waves allow the recording of blood flow spectra at selected locations continuously. The high accuracy of the conformal ultrasound patch was confirmed in comparison with a conventional TCD probe on 36 participants, showing a mean difference and standard deviation of difference as -1.51 ± 4.34 cm s-1, -0.84 ± 3.06 cm s-1 and -0.50 ± 2.55 cm s-1 for peak systolic velocity, mean flow velocity, and end diastolic velocity, respectively. The measurement success rate was 70.6%, compared with 75.3% for a conventional TCD probe. Furthermore, we demonstrate continuous blood flow spectra during different interventions and identify cascades of intracranial B waves during drowsiness within 4 h of recording.

A wearable cardiac ultrasound imager.

Continuous imaging of cardiac functions is highly desirable for the assessment of long-term cardiovascular health, detection of acute cardiac dysfunction and clinical management of critically ill or surgical patients1-4. However, conventional non-invasive approaches to image the cardiac function cannot provide continuous measurements owing to device bulkiness5-11, and existing wearable cardiac devices can only capture signals on the skin12-16. Here we report a wearable ultrasonic device for continuous, real-time and direct cardiac function assessment. We introduce innovations in device design and material fabrication that improve the mechanical coupling between the device and human skin, allowing the left ventricle to be examined from different views during motion. We also develop a deep learning model that automatically extracts the left ventricular volume from the continuous image recording, yielding waveforms of key cardiac performance indices such as stroke volume, cardiac output and ejection fraction. This technology enables dynamic wearable monitoring of cardiac performance with substantially improved accuracy in various environments.

Akkermansia muciniphila phospholipid induces homeostatic immune responses.

Multiple studies have established associations between human gut bacteria and host physiology, but determining the molecular mechanisms underlying these associations has been challenging1-3. Akkermansia muciniphila has been robustly associated with positive systemic effects on host metabolism, favourable outcomes to checkpoint blockade in cancer immunotherapy and homeostatic immunity4-7. Here we report the identification of a lipid from A. muciniphila's cell membrane that recapitulates the immunomodulatory activity of A. muciniphila in cell-based assays8. The isolated immunogen, a diacyl phosphatidylethanolamine with two branched chains (a15:0-i15:0 PE), was characterized through both spectroscopic analysis and chemical synthesis. The immunogenic activity of a15:0-i15:0 PE has a highly restricted structure-activity relationship, and its immune signalling requires an unexpected toll-like receptor TLR2-TLR1 heterodimer9,10. Certain features of the phospholipid's activity are worth noting: it is significantly less potent than known natural and synthetic TLR2 agonists; it preferentially induces some inflammatory cytokines but not others; and, at low doses (1% of EC50) it resets activation thresholds and responses for immune signalling. Identifying both the molecule and an equipotent synthetic analogue, its non-canonical TLR2-TLR1 signalling pathway, its immunomodulatory selectivity and its low-dose immunoregulatory effects provide a molecular mechanism for a model of A. muciniphila's ability to set immunological tone and its varied roles in health and disease.

Fast inflows as the adjacent fuel of supermassive black hole accretion disks in quasars.

Quasars, which are exceptionally bright objects at the centres (or nuclei) of galaxies, are thought to be produced through the accretion of gas into disks surrounding supermassive black holes1-3. There is observational evidence at galactic and circumnuclear scales4 that gas flows inwards towards accretion disks around black holes, and such an inflow has been measured at the scale of the dusty torus that surrounds the central accretion disk5. At even smaller scales, inflows close to an accretion disk have been suggested to explain the results of recent modelling of the response of gaseous broad emission lines to continuum variations6,7. However, unambiguous observations of inflows that actually reach accretion disks have been elusive. Here we report the detection of redshifted broad absorption lines of hydrogen and helium atoms in a sample of quasars. The lines show broad ranges of Doppler velocities that extend continuously from zero to redshifts as high as about 5,000 kilometres per second. We interpret this as the inward motion of gases at velocities comparable to freefall speeds close to the black hole, constraining the fastest infalling gas to within 10,000 gravitational radii of the black hole (the gravitational radius being the gravitational constant multiplied by the object mass, divided by the speed of light squared). Extensive photoionization modelling yields a characteristic radial distance of the inflow of approximately 1,000 gravitational radii, possibly overlapping with the outer accretion disk.

Mechanical force determines chimeric antigen receptor microclustering and signaling.

Chimeric antigen receptor (CAR) T cells are activated to trigger the lytic machinery after antigen engagement, and this has been successfully applied clinically as therapy. The mechanism by which antigen binding leads to the initiation of CAR signaling remains poorly understood. Here, we used a set of short double-stranded DNA (dsDNA) tethers with mechanical forces ranging from ∼12 to ∼51 pN to manipulate the mechanical force of antigen tether and decouple the microclustering and signaling events. Our results revealed that antigen-binding-induced CAR microclustering and signaling are mechanical force dependent. Additionally, the mechanical force delivered to the antigen tether by the CAR for microclustering is generated by autonomous cell contractility. Mechanistically, the mechanical-force-induced strong adhesion and CAR diffusion confinement led to CAR microclustering. Moreover, cytotoxicity may have a lower mechanical force threshold than cytokine generation. Collectively, these results support a model of mechanical-force-induced CAR microclustering for signaling.

eIF2α incites photoreceptor cell and retina damage by all-trans-retinal.

Dry age-related macular degeneration (AMD) and recessive Stargardt's disease (STGD1) lead to irreversible blindness in humans. The accumulation of all-trans-retinal (atRAL) induced by chaos in visual cycle is closely associated with retinal atrophy in dry AMD and STGD1 but its critical downstream signaling molecules remain ambiguous. Here, we reported that activation of eukaryotic translation initiation factor 2α (eIF2α) by atRAL promoted retinal degeneration and photoreceptor loss through activating c-Jun N-terminal kinase (JNK) signaling-dependent apoptosis and gasdermin E (GSDME)-mediated pyroptosis. We determined that eIF2α activation by atRAL in photoreceptor cells resulted from endoplasmic reticulum homeostasis disruption caused at least in part by reactive oxygen species production, and it activated JNK signaling independent of and dependent on activating transcription factor 4 and the activating transcription factor 4/transcription factor C/EBP homologous protein (CHOP) axis. CHOP overexpression induced apoptosis of atRAL-loaded photoreceptor cells through activating JNK signaling rather than inhibiting the expression of antiapoptotic gene Bcl2. JNK activation by eIF2α facilitated photoreceptor cell apoptosis caused by atRAL via caspase-3 activation and DNA damage. Additionally, we demonstrated that eIF2α was activated in neural retina of light-exposed Abca4-/-Rdh8-/- mice, a model that shows severe defects in atRAL clearance and displays primary features of human dry AMD and STGD1. Of note, inhibition of eIF2α activation by salubrinal effectively ameliorated retinal degeneration and photoreceptor apoptosis in Abca4-/-Rdh8-/- mice upon light exposure. The results of this study suggest that eIF2α is an important target to develop drug therapies for the treatment of dry AMD and STGD1.

Identification and validation of anti-protein arginine methyltransferase 5 (PRMT5) antibody as a novel biomarker for systemic sclerosis (SSc).

OBJECTIVES: In the complex panorama of autoimmune diseases, the characterisation of pivotal contributing autoantibodies that are involved in disease progression remains challenging. This study aimed to employ a global antibody profiling strategy to identify novel antibodies and investigate their association with systemic sclerosis (SSc). METHODS: We implemented this strategy by conducting immunoprecipitation (IP) following on-bead digestion with the sera of patients with SSc or healthy donors, using antigen pools derived from cell lysates. The enriched antigen-antibody complex was proceeded with mass spectrometry (MS)-based quantitative proteomics and over-represented by bioinformatics analysis. The candidate antibodies were then orthogonally validated in two independent groups of patients with SSc. Mice were immunised with the target antigen, which was subsequently evaluated by histological examination and RNA sequencing. RESULTS: The IP-MS analysis, followed by validation in patients with SSc, revealed a significant elevation in anti-PRMT5 antibodies among patients with SSc. These antibodies exhibited robust diagnostic accuracy in distinguishing SSc from healthy controls and other autoimmune conditions, including systemic lupus erythematosus and Sjögren's syndrome, with an area under the curve ranging from 0.900 to 0.988. The elevation of anti-PRMT5 antibodies was verified in a subsequent independent group with SSc using an additional method, microarray. Notably, 31.11% of patients with SSc exhibited seropositivity for anti-PRMT5 antibodies. Furthermore, the titres of anti-PRMT5 antibodies demonstrated a correlation with the progression or regression trajectory in SSc. PRMT5 immunisation displayed significant inflammation and fibrosis in both the skin and lungs of mice. This was concomitant with the upregulation of multiple proinflammatory and profibrotic pathways, thereby underscoring a potentially pivotal role of anti-PRMT5 antibodies in SSc. CONCLUSIONS: This study has identified anti-PRMT5 antibodies as a novel biomarker for SSc.

Optimizing the aldosterone-to-renin ratio cut-off for screening primary aldosteronism based on cardiovascular risk: a collaborative study.

OBJECTIVES: Aldosterone-to-renin ratio (ARR) based screening is the first step in the diagnosis of primary aldosteronism (PA). However, the guideline-recommended ARR cutoff covers a wide range, from the equivalent of 1.3 to 4.9 ng·dl-1/mIU∙l-1. We aimed to optimize the ARR cutoff for PA screening based on the risk of cardiovascular diseases (CVD). METHODS: Longitudinally, we included hypertensive participants from the Framingham Offspring Study (FOS) who attended the sixth examination cycle and followed up until 2014. At baseline (1995-1998), we used circulating concentrations of aldosterone and renin to calculate ARR (unit: ng·dl-1/mIU∙l-1) among 1,433 subjects who were free of CVD. We used spline regression to calculate the ARR threshold based on the incident CVD. We used cross-sectional data from the Chongqing Primary Aldosteronism Study (CONPASS) to explore whether the ARR cutoff selected from FOS is applicable to PA screening. RESULTS: In FOS, CVD risk increased with an increasing ARR until a peak of ARR 1.0, followed by a plateau in CVD risk (hazard ratio 1.49, 95%CI 1.19-1.86). In CONPASS, when compared to essential hypertension with ARR < 1.0, PA with ARR ≥ 1.0 carried a higher CVD risk (odds ratio 2.24, 95%CI 1.41-3.55), while essential hypertension with ARR ≥ 1.0 had an unchanged CVD risk (1.02, 0.62-1.68). Setting ARR cutoff at 2.4 ~ 4.9, 10% ~30% of PA subjects would be unrecognized although they carried a 2.45 ~ 2.58-fold higher CVD risk than essential hypertension. CONCLUSIONS: The CVD risk-based optimal ARR cutoff is 1.0 ng·dl-1/mIU∙l-1 for PA screening. The current guideline-recommended ARR cutoff may miss patients with PA and high CVD risk. CLINICAL TRIAL REGISTRATION: ClinicalTrials.gov (NCT03224312).

HostNet: improved sequence representation in deep neural networks for virus-host prediction.

BACKGROUND: The escalation of viruses over the past decade has highlighted the need to determine their respective hosts, particularly for emerging ones that pose a potential menace to the welfare of both human and animal life. Yet, the traditional means of ascertaining the host range of viruses, which involves field surveillance and laboratory experiments, is a laborious and demanding undertaking. A computational tool with the capability to reliably predict host ranges for novel viruses can provide timely responses in the prevention and control of emerging infectious diseases. The intricate nature of viral-host prediction involves issues such as data imbalance and deficiency. Therefore, developing highly accurate computational tools capable of predicting virus-host associations is a challenging and pressing demand. RESULTS: To overcome the challenges of virus-host prediction, we present HostNet, a deep learning framework that utilizes a Transformer-CNN-BiGRU architecture and two enhanced sequence representation modules. The first module, k-mer to vector, pre-trains a background vector representation of k-mers from a broad range of virus sequences to address the issue of data deficiency. The second module, an adaptive sliding window, truncates virus sequences of various lengths to create a uniform number of informative and distinct samples for each sequence to address the issue of data imbalance. We assess HostNet's performance on a benchmark dataset of "Rabies lyssavirus" and an in-house dataset of "Flavivirus". Our results show that HostNet surpasses the state-of-the-art deep learning-based method in host-prediction accuracies and F1 score. The enhanced sequence representation modules, significantly improve HostNet's training generalization, performance in challenging classes, and stability. CONCLUSION: HostNet is a promising framework for predicting virus hosts from genomic sequences, addressing challenges posed by sparse and varying-length virus sequence data. Our results demonstrate its potential as a valuable tool for virus-host prediction in various biological contexts. Virus-host prediction based on genomic sequences using deep neural networks is a promising approach to identifying their potential hosts accurately and efficiently, with significant impacts on public health, disease prevention, and vaccine development.

Inhibition of squalene epoxidase linking with PI3K/AKT signaling pathway suppresses endometrial cancer.

Endometrial cancer (EC) is a common malignant tumor that lacks any therapeutic target and, in many cases, recurrence is the leading ca use of morbidity and mortality in women. Widely known EC has a strongly positive correlation with abnormal lipid metabolism. Squalene epoxidase (SQLE), a crucial enzyme in the cholesterol synthesis pathway regulating lipid metabolic processes has been found to be associated with various cancers in recent years. Here, we focused on studying the role of SQLE in EC. Our study revealed that SQLE expression level was upregulated significantly in EC tissues. In vitro experiments showed that SQLE overexpression significantly promoted the proliferation, and inhibited cell apoptosis of EC cells, whereas SQLE knockdown or use of terbinafine showed the opposite results. Furthermore, we found out that the promotional effect of SQLE on the proliferation of EC cells might be achieved by activating the PI3K/AKT pathway. In vivo, studies confirmed that the knockdown of SQLE or terbinafine can observably inhibit tumor growth in nude mice. These results indicate that SQLE may promote the progression of EC by activating the PI3K/AKT pathway. Moreover, SQLE is a potential target for EC treatment and its inhibitor, terbinafine, has the potential to become a targeted drug for EC treatment.

Performance assessment of the Bruker Biotyper MALDI-TOF MS for the identification of difficult-to-identify viridans group streptococci.

Differentiating Streptococcus pneumoniae among nonpneumococcal viridans group streptococci (VGS) is challenging in conventional laboratories. Therefore, we aimed to evaluate the performance of the latest Bruker Biotyper matrix-assisted laser desorption ionization-time of flight mass spectrometry (MALDI-TOF MS) system in identifying VGS by comparing the results to those of the specific gene sequencing approach. Clinical isolates were initially identified using the BD Phoenix system to identify Streptococcus species. The optochin test was used to distinguish nonpneumococcal VGS from S. pneumoniae. The species of individual reference strains and clinical isolates were determined by comparing the sequences of the 16S rDNA, gyrB, sodA, groESL, or coaE genes with those in the GenBank sequence databases. We evaluated the performance of the Bruker Biotyper MALDI-TOF MS in VGS identification using two different machines with three databases. We collected a total of 103 nonpneumococcal VGS and 29 S. pneumoniae blood isolates at a medical center in northern Taiwan. Among these isolates, only seven could not be identified at the species level by the specific gene sequencing approach. We found that none of the nonpneumococcal VGS isolates were misidentified as pneumococci by the latest Biotyper system, and vice versa. However, certain strains, especially those in the mitis and bovis groups, could still not be correctly identified. The latest Bruker Biotyper 4.1 (DB_10833) showed significant improvement in identifying VGS strains. However, a specific gene sequencing test is still needed to precisely differentiate the species of strains in the mitis and bovis groups.

Human Herpesvirus 6A U4 Inhibits Proteasomal Degradation of the Amyloid Precursor Protein.

Human herpesvirus 6 (HHV-6) belongs to the betaherpesvirus subfamily and is divided into two distinct species, HHV-6A and HHV-6B. HHV-6 can infect nerve cells and is associated with a variety of nervous system diseases. Recently, the association of HHV-6A infection with Alzheimer's disease (AD) has been suggested. The main pathological phenomena of AD are the accumulation of ß-amyloid (Aß), neurofibrillary tangles, and neuroinflammation; however, the specific molecular mechanism of pathogenesis of AD is not completely clear. In this study, we focused on the effect of HHV-6A U4 gene function on Aß expression. Coexpression of HHV-6A U4 with amyloid precursor protein (APP) resulted in inhibition of ubiquitin-mediated proteasomal degradation of APP. Consequently, accumulation of ß-amyloid peptide (Aß), insoluble neurofibrillary tangles, and loss of neural cells may occur. Immunoprecipitation coupled with mass spectrometry (IP-MS) showed that HHV-6A U4 protein interacts with E3 ubiquitin ligase composed of DDB1 and cullin 4B, which is also responsible for APP degradation. We hypothesize that HHV-6A U4 protein competes with APP for binding to E3 ubiquitin ligase, resulting in the inhibition of APP ubiquitin modification and clearance. Finally, this leads to an increase in APP expression and Aß deposition, which are the hallmarks of AD. These findings provide novel evidence for the etiological hypothesis of AD, which can contribute to the further analysis of the role of HHV-6A in AD. IMPORTANCE The association of HHV-6A infection with Alzheimer's disease has attracted increasing attention, although its role and molecular mechanism remain to be established. Our results here indicate that HHV-6A U4 inhibits amyloid precursor protein (APP) degradation. U4 protein interacts with CRLs (cullin-RING E3 ubiquitin-protein ligases), which is also responsible for APP degradation. We propose a model in which U4 competitively binds to CRLs with APP, resulting in APP accumulation and Aß generation. Our findings provide new insights into the etiological hypothesis of HHV-6A in AD that can help further analyses.

Associations between Serial Intravitreal Injections and Dry Eye.

PURPOSE: To investigate the effects of serial intravitreal injections (IVIs) on the ocular surface and meibomian glands (MGs) in patients treated with anti-vascular endothelial growth factor (anti-VEGF) for neovascular age-related macular degeneration (nAMD). DESIGN: Retrospective, controlled, observational study. PARTICIPANTS: Patients with nAMD receiving unilateral IVIs with anti-VEGF agents. The fellow eye was used as control. METHODS: Tear film and ocular surface examinations were performed on a single occasion at a minimum of 4 weeks after IVI. A pre-IVI asepsis protocol with povidone-iodine (PVP-I) was applied. MAIN OUTCOME MEASURES: Upper and lower MG loss, tear meniscus height (TMH), bulbar redness (BR) score, noninvasive tear break-up time (NIBUT), tear film osmolarity (TOsm), Schirmer test, corneal staining, fluorescein tear film break-up time (TBUT), meibomian gland expressibility (ME), and meibum quality. RESULTS: Ninety patients with a mean age of 77.5 years (standard deviation [SD], 8.4; range 54-95) were included. The median number of IVIs in treated eyes was 19.5 (range, 2-132). Mean MG loss in the upper eyelid was 19.1% (SD, 11.3) in treated eyes and 25.5% (SD, 14.6) in untreated fellow eyes (P = 0.001). For the lower eyelid, median MG loss was 17.4% (interquartile range [IQR], 9.4-29.9) in treated eyes and 24.5% (IQR, 14.2-35.2) in fellow eyes (P < 0.001). Mean BR was 1.32 (SD, 0.46) in treated eyes versus 1.44 (SD, 0.45) in fellow eyes (P = 0.017). Median TMH was 0.36 mm (IQR, 0.28-0.52) in treated eyes and 0.32 mm (IQR, 0.24-0.49) in fellow eyes (P = 0.02). There were no differences between treated and fellow eyes regarding NIBUT, TOsm, Schirmer test, corneal staining, fluorescein TBUT, ME, or meibum quality. CONCLUSIONS: Repeated IVIs with anti-VEGF with preoperative PVP-I application was associated with reduced MG loss, increased tear volume, and reduced signs of inflammation compared with fellow nontreated eyes in patients with nAMD. This regimen may thus have a beneficial effect on the ocular surface. FINANCIAL DISCLOSURE(S): Proprietary or commercial disclosure may be found after the references.

Primary aldosteronism and lower-extremity arterial disease: a two-sample Mendelian randomization study.

BACKGROUND AND AIMS: Primary aldosteronism (PA) is an adrenal disorder of autonomous aldosterone secretion which promotes arterial injury. We aimed to explore whether PA is causally associated with lower-extremity arterial disease (LEAD). METHODS: We included 39,713 patients with diabetes and 419,312 participants without diabetes from UK Biobank. We derived a polygenic risk score (PRS) for PA based on previous genome-wide association studies (GWAS). Outcomes included LEAD and LEAD related gangrene or amputation. We conducted a two-sample Mendelian randomization analysis for PA and outcomes to explore their potential causal relationship. RESULTS: In whole population, individuals with a higher PA PRS had an increased risk of LEAD. Among patients with diabetes, compared to the subjects in the first tertile of PA PRS, subjects in the third tertile showed a 1.24-fold higher risk of LEAD (OR 1.24, 95% CI 1.03-1.49) and a 2.09-fold higher risk of gangrene (OR 2.09, 95% CI 1.27-3.44), and 1.72-fold higher risk of amputation (OR 1.72, 95% CI 1.10-2.67). Among subjects without diabetes, there was no significant association between PA PRS and LEAD, gangrene or amputation. Two-sample Mendelian randomization analysis indicated that genetically predictors of PA was significantly associated with higher risks of LEAD and gangrene (inverse variance weighted OR 1.20 [95% CI 1.08-1.34]) for LEAD, 1.48 [95% CI 1.28-1.70] for gangrene), with no evidence of significant heterogeneity or directional pleiotropy. CONCLUSIONS: Primary aldosteronism is genetically and causally associated with higher risks of LEAD and gangrene, especially among patients with diabetes. Targeting on the autonomous aldosterone secretion may prevent LEAD progression.

Characterization of neuroinflammation pattern in anti-LGI1 encephalitis based on TSPO PET and symptom clustering analysis.

PURPOSE: TSPO PET with radioligand [18F]DPA-714 is an emerging molecular imaging technique that reflects cerebral inflammation and microglial activation, and it has been recently used in central nervous system diseases. In this study, we aimed to investigate the neuroinflammation pattern of anti-leucine-rich glioma-inactivated 1 (LGI1) protein autoimmune encephalitis (AIE) and to evaluate its possible correlation with clinical phenotypes. METHODS: Twenty patients with anti-LGI1 encephalitis from the autoimmune encephalitis cohort in Huashan Hospital and ten with other AIE and non-inflammatory diseases that underwent TSPO PET imaging were included in the current study. Increased regional [18F]DPA-714 retention in anti-LGI1 encephalitis was detected on a voxel basis using statistic parametric mapping analysis. Multiple correspondence analysis and hierarchical clustering were conducted for discriminate subgroups in anti-LGI1 encephalitis. Standardized uptake value ratios normalized to the cerebellum (SUVRc) were calculated for semiquantitative analysis of TSPO PET features between different LGI1-AIE subgroups. RESULTS: Increased regional retention of [18F]DPA-714 was identified in the bilateral hippocampus, caudate nucleus, and frontal cortex in LGI1-AIE patients. Two subgroups of LGI1-AIE patients were distinguished based on the top seven common symptoms. Patients in cluster 1 had a high frequency of facio-brachial dystonic seizures than those in cluster 2 (p = 0.004), whereas patients in cluster 2 had a higher frequency of general tonic-clonic (GTC) seizures than those in cluster 1 (p < 0.001). Supplementary motor area and superior frontal gyrus showed higher [18F]DPA-714 retention in cluster 2 patients compared with those in cluster 1 (p = 0.024; p = 0.04, respectively). CONCLUSIONS: Anti-LGI1 encephalitis had a distinctive molecular imaging pattern presented by TSPO PET scan. LGI1-AIE patients with higher retention of [18F]DPA-714 in the frontal cortex were more prone to present with GTC seizures. Further studies are required for verifying its value in clinical application.

Immunotherapies for the Effective Treatment of Primary Autoimmune Cerebellar Ataxia: a Case Series.

Primary autoimmune cerebellar ataxia (PACA) is an idiopathic sporadic cerebellar ataxia that is thought to be immune-mediated but lacks biomarkers or a known cause. Here, we report two cases of immune-mediated cerebellar ataxia that responded favorably to immunotherapy, in which tissue-based indirect immunofluorescence test for serum or cerebrospinal fluid (CSF) samples yielded positive results. Case 1 was a 78-year-old man who presented with subacute progressive gait ataxia with truncal instability and dysarthria in response to steroids. Case 2 was a 62-year-old man who presented with relapses and remissions of acute progressive cerebellar ataxia occurring 1-2 times per year. Despite a favorable response to steroid treatment, he relapsed repeatedly in the absence of long-term immunosuppression. In the case of "idiopathic" cerebellar ataxia, immune-mediated causes should be investigated, and immunotherapy may have therapeutic effects.

Active Targeted Janus Theranostic Nanoplatforms Enable Chemo-Photothermal Therapy to Inhibit the Growth of Breast Cancer.

Nanoscale structures have been developed to serve various functions in cancer therapy, encompassing areas such as diagnosis, biomedical visualization, tissue regeneration, and drug delivery. Based on biocompatible chitosan oligosaccharides (COS) and gold nanorods (GNRs), we designed the drug delivery systems (GNR@polyacrylic acid-Mn@COS Janus nanoparticles (JNPs)), which achieved paclitaxel (PTX) loaded on the side of GNRs, and the PAA-Mn domain served as magnetic resonance imaging contrast agents. This system was found to be effectively delivered to tumor sites through the enhanced permeability and retention (EPR) effect and the active target of the COS. The uniform JNPs selectively targeted cancer cells instead of normal cells through interacting with the COS on the surface of tumor cells, and the pH/NIR-responsive drug release behavior further enhanced their therapeutic effects. The in vivo effects of JNPs against tumors were evaluated using subcutaneous and orthotopic lung metastasis models, yielding promising outcomes for both tumor diagnosis and cancer treatment. In conclusion, the obtained JNPs hold great promise as a theranostic nanoplatform with synergistic chemotherapeutic and photothermal effects.

PD-L1 Blockade Peptide-Modified Polymeric Nanoparticles for Oxygen-Independent-Based Hypoxic Tumor Photo/Thermodynamic Immunotherapy.

Distant metastasis of malignant tumors is considered to be the main culprit for the failure of current antitumor treatments. Conventional single treatments often exhibit limited efficacy in inhibiting tumor metastasis. Therefore, there is a growing interest in developing collaborative antitumor strategies based on photothermal therapy (PTT) and free-radical-generated photodynamic therapy (PDT), especially utilizing oxygen-independent nanoplatforms, to address this challenge. Such antitumor strategies can enhance the therapeutic outcomes by ensuring the cytotoxicity of free radicals even in the hypoxic tumor microenvironment, thereby improving the effective suppression of primary tumors. Additionally, these approaches can stimulate the production of tumor-associated antigens and amplify the immunogenic cell death (ICD) effects, potentially feasible for enhancing the therapeutic outcomes of immunotherapy. Herein, we fabricated a functional nanosystem that co-loads IR780 and 2,2'-azobis[2-(2-imidazolin-2-yl)propane]-dihydrochloride (AIPH) to realize PTT-triggered thermodynamic combination therapy via the oxygen-independent pathway for the elimination of primary tumors. Furthermore, the nanocomposites were surface-decorated with a predesigned complex peptide (PLGVRGC-anti-PD-L1 peptide, MMP-sensitive), which facilitated the immunotherapy targeting distant tumors. Through the specific recognition of matrix metalloproteinase (MMP), the sensitive segment on the obtained aNC@IR780A was cleaved. As a result, the freed anti-PD-L1 peptide effectively blocked immune checkpoints, leading to the infiltration and activation of T cells (CTLs). This nanosystem was proven to be effective at inhibiting both primary tumors and distant tumors, providing a promising combination strategy for tumor PTT/TDT/immunotherapy.

Calcium Orthophosphate in Liposomes for Co-Delivery of Doxorubicin Hydrochloride/Paclitaxel in Breast Cancer.

Nanoparticles (NPs) show great advantages in cancer treatment by enabling controlled and targeted delivery of payloads to tumor sites through the enhanced permeability and retention (EPR) effect. In this study, highly effective pH-responsive and biodegradable calcium orthophosphate@liposomes (CaP@Lip) NPs with a diameter of 110 ± 20 nm were designed and fabricated. CaP@Lip NPs loaded with hydrophobic paclitaxel and hydrophilic doxorubicin hydrochloride achieved excellent drug loading efficiencies of 70 and 90%, respectively. Under physiological conditions, the obtained NPs are negatively charged. However, they switched to positively charged when exposed to weak acidic environments by which internalization can be promoted. Furthermore, the CaP@Lip NPs exhibit an obvious structural collapse under acid conditions (pH 5.5), which confirms their excellent biodegradability. The "proton expansion" effect in endosomes and the pH-responsiveness of the NPs facilitate the release of encapsulated drugs from individual channels. The effectiveness and safety of the drug delivery systems were demonstrated through in vitro and in vivo experiments, with a 76% inhibition of tumor growth. These findings highlight the high targeting ability of the drug-loaded NPs to tumor sites through the EPR effect, effectively suppressing tumor growth and metastasis. By combining CaP NPs and liposomes, this study not only resolves the toxicity of CaP but also enhances the stability of liposomes. The CaP@Lip NPs developed in this study have significant implications for biomedical applications and inspire the development of intelligent and smart drug nanocarriers and release systems for clinical use.