Magnetic resonance imaging features of progressive familial intrahepatic cholestasis type 3.

PURPOSE: Progressive familial intrahepatic cholestasis type 3 (PFIC-3) is a rare autosomal recessive cholestatic liver disorder. This study aimed to present the clinical and magnetic resonance imaging (MRI) features of three patients with PFIC­3. METHODS: The study included three patients with cholestasis and pathogenic variants in the ABCB4 gene identified by next-generation sequencing of a targeted-gene panel or by whole-exome sequencing. The clinical, laboratory, histological, molecular, and MRI features of the patients were collected. RESULTS: Three patients (one male and two females) were enrolled. The age when clinical signs and symptoms were first noted was 21, 14, and 39 years, respectively, and the signs and symptoms included pruritus and splenomegaly (in all three patients). Parenchymatous lace-like fibrosis was associated with periportal hyperintensity and periportal halo sign in three patients. Segmental atrophy was observed in two patients, diffuse atrophy was observed in one patient, and liver surface irregularity caused by regenerating nodules was observed in three patients. Magnetic resonance cholangiopancreatography (MRCP) images showed irregular bile duct changes in three patients, focal hilar bile duct stenosis, and local intrahepatic bile duct dilatation. CONCLUSIONS: Imaging studies using MRI and MRCP can support the clinical and laboratory results in cases of PFIC­3 and can also be used as a noninvasive diagnostic option.

Ionic-physical-chemical triple cross-linked all-biomass-based aerogel for thermal insulation applications.

Aerogels, as a unique porous material, are expected to be used as insulation materials to solve the global environmental and energy crisis. Using chitosan, citric acid, pectin and phytic acid as raw materials, an all-biomass-based aerogel with high modulus was prepared by the triple strategy of ionic, physical and chemical cross-linking through directional freezing technique. Based on this three-dimensional network, the aerogel exhibited excellent compressive modulus (24.89 ± 1.76 MPa) over a wide temperature range and thermal insulation properties. In the presence of chitosan, citric acid and phytic acid, the aerogel obtained excellent fire safety (LOI value up to 31.2%) and antibacterial properties (antibacterial activity against Staphylococcus aureus and Escherichia coli reached 81.98% and 67.43%). In addition, the modified aerogel exhibited excellent hydrophobicity (hydrophobic angle of 146°) and oil-water separation properties. More importantly, the aerogel exhibited a biodegradation rate of up to 40.31% for 35 days due to its all-biomass nature. This work provides a green and sustainable strategy for the production of highly environmentally friendly thermal insulation materials with high strength, flame retardant, antibacterial and hydrophobic properties.

First Detection of Atractylodes Mild Mottle Virus in Atractylodes lancea (Thunb.) DC. in Hubei Province of China.

The cultivated aromatic medicinal herb Atractylodes lancea (Thunb.) DC. is widely used in the pharmaceuticals, nutraceuticals, and cosmetics industries (Na-Bangchang et al. 2014; Zhan et al. 2023). Huanggang in Hubei Province is a major production area for A. lancea (Huang et al. 2022; Wang et al. 2023). In April 2023, more than two-thirds of the surveyed plant leaves in this region exhibited virus-like symptoms, such as curling and mosaic patterns. To identify the underlying cause, 80 symptomatic plant leaf samples were collected from four fields (20 leaves per field) in this region and pooled for virome analysis. Total RNA, including ribosomal RNA, was extracted from the pooled samples using the Plant RNA Extraction Mini Kit (Onrew Biotech, Guangdong, China), for sequencing library construction. The Illumina NovaSeq 6000 platform was used to sequence the library and generate 150 bp paired-end reads. After processing the raw data with Trimmomatic software, a total of 44,354,650 high-quality clean reads were obtained. The clean reads were aligned against ribosomal RNA using BWA software (v0.7.17) to avoid interference and eliminate corresponding sequences. After removing potential contamination, contig assembly of the clean reads was performed using Megahit software (v1.2.9). The resulting contigs were compared with the virus NT database using the BLASTn program. Sequence pairwise comparison revealed 8 contigs (574 nt to 2243 nt) with identities ranging from 81.88% to 90.77% with Atractylodes mild mottle virus (AMMV, NC_027924.1, Lim et al., 2015). Additionally, contigs mapped to Carlavirus, Pelarspovirus, and other plant viruses in our virome dataset had low coverage and pairwise identity (less than 70%), which need to be further investigated. The presence of AMMV was confirmed by aligning the clean reads to the reference sequence (NC_027924.1) using BWA and SAMtools software, resulting in a consensus sequence (8024 nt) with gaps. DNA extraction from the pooled samples was performed using the Rapid Universal Genomic DNA Extraction Kit (Simgen, Zhejiang, China). Two pairs of specific primers, 3399F (5'-AAAGAAGAACCTCCTGATACGG-3')/5924R (5'-TGAACCTGATTCTCTTGGC-3') and 1830F (5'- CTCAGGAAATCCCAATGC -3')/3640R(5'-TTTCCCAATGTTCTTCGGG-3'), were designed to amplify the complete gene sequences of polymerase and coat protein (CP), based on the consensus sequence. The PCR products with the lengths of 2521 bp and 1814 bp were cloned into the pMD18-T vector (Takara Biotech, Dalian, China) for sequencing. The BLASTn analysis showed that the polymerase and CP gene sequences shared an identity of 94.51% (1929/2041 nt) and 88.41% (1419/1605 nt) with the AMMV isolate (NC_027924.1), respectively. The sequences have been deposited in GenBank under the accession numbers OR544810 and OR544811. We collected leaves from 32 A. lancea plants (16 symptomatic and 16 asymptomatic) in the fields. RT-PCR was conducted using CPF (5'-CTGCGAATATGAAAGTGC-3') and CPR (5'-GGTGAGCTTGTCTGTTAGG-3') primers, which were designed targeting a 527bp fragment of the CP gene (OR544811). Amplicons of the expected size (527bp) were detected in 24 plants (11 symptomatic and 13 asymptomatic), three of which were sequenced by Sanger sequencing, showing a 100% match to OR544811. These findings indicate that AMMV is prevalent in the major production area of A. lancea. Further research is needed to better characterize the potential risks of AMMV to A. lancea cultivation in China as well as other countries.

Dictamnine Ameliorates DNFB-Induced Atopic Dermatitis Like Skin Lesions in Mice by Inhibiting M1 Macrophage Polarization and Promoting Autophagy.

Autophagy and M1 macrophage polarization play important roles in the regulation of inflammation in atopic dermatitis (AD). Dictamnine is one of the main ingredients in Cortex Dictamni, a widely used traditional Chinese medicine for the treatment of dermatitis. In the present study, we investigated the anti-inflammatory effects of dictamnine on AD like skin lesions and M1 macrophage polarization. A 2,4-dinitrofluorobenzene (DNFB) triggered AD like skin lesions models in mice was established to identify the ameliorative effects of dictamnine on AD in vivo. In addition, an M1 macrophage polarization model was co-stimulated by lipopolysaccharide (LPS) and interferon-γ (IFN-γ) using phorbol myristate acetate (PMA) differentiated THP-1 cells, to investigate the effect of dictamnine on promoting autophagy and inhibiting inflammatory factor release. Dictamnine suppressed DNFB-induced skin inflammation by inhibiting M1 macrophage polarization, up-regulating the expression of microtubule-associated protein 1A/1B-light chain 3 (LC3) expression, and promoting macrophage autophagy at inflammatory sites. Dictamnine also could reduce the release of interleukin-1ß (IL-1ß), tumor necrosis factor-α (TNF-α), interleukin-6 (IL-6), monocyte chemotactic protein-1 (MCP-1), and interleukin-8 (IL-8), and down-regulate the mRNA expression of these genes in LPS-IFN-γ triggered M1 polarized macrophages. Dictamnine ameliorates AD like skin lesions by inhibiting M1 macrophage polarization and promoting autophagy. Hence, dictamnine is expected to be a potential therapeutic candidate for AD.

Fine mapping identifies independent HLA associations in autoimmune hepatitis type 1.

Background & Aims: Association studies have greatly refined the important role of the major histocompatibility complex (MHC) region in autoimmune hepatitis (AIH). However, the effects of human leucocyte antigen (HLA) polymorphisms on AIH are not well established. The aim of this study is to systematically characterise the association of MHC variants with AIH in our well-defined cohort of patients. Methods: We performed an imputation-based analysis on the extensive association observed within the MHC region using the Han-MHC reference panel, and tested the comprehensive associations of HLA polymorphisms with AIH in 1622 Chinese AIH type 1 patients and 10,466 population controls. Results: A total of 588 HLA variants were significantly associated with AIH, with HLA-B∗35:01 (p = 8.17 × 10-304; odds ratio [OR] = 7.32) contributing the strongest signal. Stepwise conditional analysis revealed additional independent signals at HLA-B∗08:01 (p = 1.35 × 10-33; OR = 4.26) and rs7765379 (p = 5.08 × 10-18; OR = 1.66). A strong link between the lead HLA variant and clinical phenotypes of AIH was observed: patients with HLA-B∗35:01 were less frequently positive for ANA and tended to have higher serum AST and ALT levels at diagnosis, but lower serum IgG levels. Conclusions: Our study reveals three novel and independent variants at HLA-B∗35:01, HLA-B∗08:01, and rs7765379 associated with AIH across the whole MHC region in the Han Chinese population. The findings illustrate the value of the MHC region in AIH and provide a new perspective for the immunogenetics of AIH. Impact and implications: This study revealed three novel and independent variants associated with autoimmune hepatitis across the whole major histocompatibility complex region in the Han Chinese population. These findings are significant in identifying autoantigens, providing insights into the activation of the autoimmune processes, and further advancing our understanding of the immunogenetic basis underlying autoimmune hepatitis.

Combinatorial genetic strategies for dissecting cell lineages, cell types, and gene function in the mouse brain.

Research in neuroscience has greatly benefited from the development of genetic approaches that enable lineage tracing, cell type targeting, and conditional gene regulation. Recent advances in combinatorial strategies, which integrate multiple cellular features, have significantly enhanced the spatiotemporal precision and flexibility of these manipulations. In this minireview, we introduce the concept and design of these strategies and provide a few examples of their application in genetic fate mapping, cell type targeting, and reversible conditional gene regulation. These advancements have facilitated in-depth investigation into the developmental principles underlying the assembly of brain circuits, granting experimental access to highly specific cell lineages and subtypes, as well as offering valuable new tools for modeling and studying neurological diseases. Additionally, we discuss future directions aimed at expanding and improving the existing genetic toolkit for a better understanding of the development, structure, and function of healthy and diseased brains.

Biliary sepsis complication with congenital hepatic fibrosis: an unexpected outcome.

BACKGROUND: CHF (Congenital hepatic fibrosis) is a rare hereditary disease characterized by periportal fibrosis and ductal plate malformation. Little is known about the clinical presentations and outcome in CHF patients with an extraordinary complication with biliary sepsis. Our case described a 23-year-old female diagnosed as CHF combined with biliary sepsis. Her blood culture was positive for KP (Klebsiella pneumoniae), and with a high level of CA19-9 (> 1200.00 U/ml, ref: <37.00 U/ml). Meanwhile, her imaging examinations showed intrahepatic bile duct dilatation, portal hypertension, splenomegaly, and renal cysts. Liver pathology revealed periportal fibrosis and irregularly shaped proliferating bile ducts. Whole-exome sequencing identified two heterozygous missense variants c.3860T > G (p. V1287G) and c.9059T > C (p. L3020P) in PKHD1 gene. After biliary sepsis relieved, her liver function test was normal, and imaging examination results showed no significant difference with the results harvested during her biliary sepsis occurred. CONCLUSION: The diagnosis of CHF complicated with biliary sepsis in the patient was made. Severely biliary sepsis due to KP infection may not inevitably aggravate congential liver abnormality in young patients. Our case provides a good reference for timely treatment of CHF patients with biliary sepsis.

The Suppressive Basis of Ocular Dominance Changes Induced by Short-Term Monocular Deprivation in Normal and Amblyopic Adults.

Purpose: We aimed to study the effect of short-term monocular deprivation on the suppressive interocular interactions in normals and amblyopes by using a dichoptic masking paradigm. Methods: Nine adults with anisometropic or mixed amblyopia and 10 control adults participated in our study. The contrast sensitivity in discriminating a target Gabor dichoptically masked was measured before and after 2 hours of monocular deprivation. The mask consisted of bandpass-filtered noise. Both the target and the mask were horizontally oriented at the spatial frequency of 1.31 cpd. Deprivation was achieved using an opaque patch on the amblyopic eye of amblyopes and the dominant eye of controls. Results: Results were similar in both controls and amblyopes. After 2 hours of monocular deprivation, the previously patched eye showed a significant increase in contrast sensitivity under dichoptic masking, which also suggested reduced suppressive effect from the nonpatched eye. Meanwhile, the contrast sensitivity of the nonpatched eye remained almost unchanged under dichoptic masking. Conclusions: We demonstrate that the ocular dominance changes induced by short-term monocular deprivation-namely, the strengthening of the deprived eye's contribution-are associated with the unilateral and asymmetric changes in suppressive interaction. The suppression from the nondeprived eye is reduced after short-term monocular deprivation. This provides a better understanding of how inverse patching (patching of the amblyopic eye) could, by reducing the suppressive drive from the normally sighted (nondeprived) eye, form the basis of a new treatment for the binocular deficit in amblyopia.

Alleviated symptoms of SARS-CoV-2 Omicron variant infection in chronic hepatitis B patients with immune control.

The impact of hepatitis B virus (HBV) infection on the progression of coronavirus disease 2019 (COVID-19) disease remains controversial. We aimed to investigate whether pre-existing chronic HBV (CHB) infection and therapy with anti-HBV nucleos(t)ide analogs (NAs) influence the clinical presentation of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) Omicron variant infection. In this study, clinical information was collected via a questionnaire from patients with COVID-19, and their clinical symptoms were quantitatively assessed for comparative analyses. Additionally, hepatitis B-related laboratory data were collected for CHB patients. Propensity score matching (PSM) was used to minimize confounding biases. A total of 785 patients with COVID-19 were included in the cohort, of which 387 were identified as being infected with CHB infection and they were categorized as being in the immune control or clearance phase. After PSM, the CHB group (n = 222) had a shorter duration of fever and disease course, milder clinical symptoms, and lower incidence of pneumonia than the non-CHB group (n = 222) after Omicron variant infection (p < 0.05). After the adjustment of confounding factors, CHB patients showed a lower risk of prolonged fever, severe clinical symptoms, and pneumonia (p < 0.05). However, there were no statistically significant differences in the clinical symptoms and incidence of pneumonia between CHB patients who received and did not receive NAs, or CHB patients who received tenofovir disoproxil fumarate and entecavir (p > 0.05). In conclusion, our findings suggest that the crosstalk of anti-HBV immunity may contribute to the alleviated symptoms of SARS-CoV-2 Omicron variants infection in the CHB patients, independent of anti-HBV NA therapy.

Comparative analysis of clinical features of lower respiratory tract infection with respiratory syncytial virus and influenza virus in adults: a retrospective study.

BACKGROUND: Respiratory syncytial virus (RSV) infection in adults remains less recognized and understood, both socially and clinically, compared to influenza virus infection. This retrospective study aims to delineate and compare the clinical manifestations of adult RSV and influenza virus infections in the lower respiratory tract, thereby enhancing awareness of RSV lower respiratory tract infection and providing strategic insights for its prevention and treatment. METHODS: Clinical data from January 2019 to December 2020 were analyzed for 74 patients with RSV and 129 patients with influenza A/B virus lower respiratory tract infections who were admitted to respiratory or intensive care units. All patients had complete clinical data with positive IgM and negative IgG viral antibodies. Comparison parameters included onset timing, baseline data, clinical manifestations, supplementary examination results, treatment methods, and prognosis, while logistic regression was employed to ascertain the correlation of clinical features between the two patient groups. RESULTS: In comparison to the influenza group, the RSV group presented less frequently with fever at admission but exhibited a higher incidence of dyspnea and wheezing on pulmonary auscultation (P < 0.01). RSV infection was more prevalent among patients with underlying diseases, particularly chronic obstructive pulmonary disease (COPD) and demonstrated a higher probability of co-infections, most notably with Mycoplasma (P < 0.01). The RSV group had significantly higher lymphocyte counts (P < 0.01) and exhibited more incidences of pleural thickening, pulmonary fibrosis, and emphysema (P < 0.05). The use of non-invasive mechanical ventilation was more common, and hospital stays were longer in the RSV group compared to the influenza group (P < 0.05). Logistic multivariate regression analysis further revealed that age and tachypnea incidence were significantly higher in the RSV group (P < 0.05). CONCLUSION: Compared to influenza virus infection, adults with COPD are more susceptible to RSV infection. Moreover, RSV infection elevates the risk of co-infection with Mycoplasma and may lead to conditions such as pleural thickening, pulmonary fibrosis, and emphysema. The requirement for non-invasive mechanical ventilation is higher in RSV-infected patients, who also tend to have longer hospital stays. Therefore, greater awareness and preventive strategies against RSV infection are imperative.

Analysis of the detection rate and related factors of fatty liver disease in physical examination of healthy population in Chengdu district.

BACKGROUND: In the present study, we analyzed the detection rate and related influencing factors of fatty liver in the health examination population in Chengdu area. METHODS: The case-control study was performed to compare the gender, age (years), body mass index (BMI), smoking, drinking, abnormal lipid metabolism, hypertension, hyperglycemia, hyperuricemia Is there any statistically significant difference in the detection rate of diseases such as metabolic syndrome, and logistic regression analysis is conducted to analyze the comprehensive impact of each influencing factor on the prevention of fatty liver disease. RESULTS: Among 14,426 survey subjects, a total of 6717 patients with fatty liver were detected, with a detection rate of 47.22%. There are significant differences in the incidence of fatty liver disease among different gender groups, with the incidence rate in males being significantly higher than that in females (P < .05); The incidence of fatty liver in elderly subjects was significantly higher than that in middle-aged and young subjects (P < .05); The prevalence rate of individuals with a BMI > 24 was significantly higher than that of individuals with a BMI < 24 (P < .05). The prevalence of fatty liver in the population with abnormal lipid metabolism, hypertension, hyperglycemia, hyperuricemia, metabolic syndrome and other diseases was significantly higher (P < .05); After stratified analysis by gender and age, the incidence of fatty liver in males was significantly higher than that in females in the 3 age groups < 60 years old (P < .05); In the age group ≥ 60 years old, the difference in the incidence of fatty liver disease between males and females was significantly reduced, and the difference was not statistically significant (P > .05). CONCLUSION: The health screening of patients with fatty liver should be carried out regularly, and attention should be paid to the intervention and prevention of overweight people and people with basal metabolism diseases such as hyperglycemia and hypertension, so as to reduce the incidence of fatty liver.

Natural product P57 induces hypothermia through targeting pyridoxal kinase.

Induction of hypothermia during hibernation/torpor enables certain mammals to survive under extreme environmental conditions. However, pharmacological induction of hypothermia in most mammals remains a huge challenge. Here we show that a natural product P57 promptly induces hypothermia and decreases energy expenditure in mice. Mechanistically, P57 inhibits the kinase activity of pyridoxal kinase (PDXK), a key metabolic enzyme of vitamin B6 catalyzing phosphorylation of pyridoxal (PL), resulting in the accumulation of PL in hypothalamus to cause hypothermia. The hypothermia induced by P57 is significantly blunted in the mice with knockout of PDXK in the preoptic area (POA) of hypothalamus. We further found that P57 and PL have consistent effects on gene expression regulation in hypothalamus, and they may activate medial preoptic area (MPA) neurons in POA to induce hypothermia. Taken together, our findings demonstrate that P57 has a potential application in therapeutic hypothermia through regulation of vitamin B6 metabolism and PDXK serves as a previously unknown target of P57 in thermoregulation. In addition, P57 may serve as a chemical probe for exploring the neuron circuitry related to hypothermia state in mice.

Acid ground nano-realgar processed product inhibits breast cancer by inducing mitophagy via the p53/BNIP3/NIX pathway.

Breast cancer is a highly prevalent malignancy with the first morbidity and the primary reason for female cancer-related deaths worldwide. Acid ground nano-realgar processed product (NRPP) could inhibit breast cancer cell proliferation and induce autophagy in our previous research; however, the underlying mechanisms are still unclear. Therefore, this research aimed to verify whether NRPP induces breast cancer mitophagy and explore the mitophagy-mediated mechanism. Primarily, rhodamine-123 assay and transmission electron microscopy were applied to detect mitochondrial membrane potential (MMP) and ultrastructural changes in the MDA-MB-435S cells, respectively. Mito-Tracker Green/Lyso-Tracker Red staining, western blot, immunofluorescence and RT-PCR were used to explore molecular mechanisms of NRPP-induced mitophagy in vitro. MDA-MB-435S breast cancer xenograft models were established to assess the activity and mechanisms of NRPP in vivo. Our results showed that NRPP decreased MMP and increased autophagosome numbers in MDA-MB-435S cells and activated mitophagy. Furthermore, mitophagy was consolidated because mitochondria and lysosomes colocalized phenomenology were observed, and the expression of LC3II/I and COXIV was upregulated. Additionally, we found the p53/BNIP3/NIX pathway was activated. Finally, NRPP inhibited tumour growth and downregulated the levels of TNF-α, IL-1ß and IL-6. Necrosis, damaged mitochondria and autophagosomes were observed in xenograft tumour cells, and proteins and mRNA levels of LC3, p53, BNIP3 and NIX were increased. Overall, NRPP inhibited MDA-MB-435S cell proliferation and tumour growth by inducing mitophagy via the p53/BNIP3/NIX pathway. Thus, NRPP is a promising candidate for breast cancer treatment.

Proteomic Analysis of Pediatric Hemophagocytic Lymphohistiocytosis: a Comparative Study with Healthy Controls, Sepsis, Critical Ill, and Active Epstein-Barr virus Infection to Identify Altered Pathways and Candidate Biomarkers.

Hemophagocytic lymphohistiocytosis (HLH) is a life-threatening hyperinflammatory syndrome characterized by excessive activation of the immune system, along with uncontrolled proliferation of activated macrophages and lymphocytes. The clinical features of HLH often overlap with the clinical features of other severe inflammatory conditions such as sepsis, hindering accurate and timely diagnosis. In this study, we performed a data-independent acquisition mass spectrometry-based plasma proteomic analysis of 33 pediatric patients with HLH compared with four control groups: 39 healthy children, 43 children with sepsis, 39 children hospitalized in the pediatric intensive care unit without confirmed infections, and 21 children with acute Epstein-Barr virus infection. Proteomic comparisons between the HLH group and each of the control groups showed that HLH was characterized by alterations in complement and coagulation cascades, neutrophil extracellular trap formation, and platelet activation pathways. We identified eight differentially expressed proteins in patients with HLH, including plastin-2 (LCP1), vascular cell adhesion protein 1, fibrinogen beta chain, fibrinogen gamma chain, serum amyloid A-4 protein, extracellular matrix protein 1, apolipoprotein A-I, and albumin. LCP1 emerged as a candidate diagnostic marker for HLH with an area under the curve (AUC) of 0.97 in the original cohort and an AUC of 0.90 (sensitivity = 0.83 and specificity = 1.0) in the validation cohort. Complement C1q subcomponent subunit B was associated with disease severity in patients with HLH. Based on comparisons with multiple control groups, this study provides a proteomic profile and candidate biomarkers of HLH, offering researchers novel information to improve the understanding of this condition.

Metaplasticity: Dark exposure boosts local excitability and visual plasticity in adult human cortex.

An interlude of dark exposure for about 1 week is known to shift excitatory/inhibitory (E/I) balance of the mammalian visual cortex, promoting plasticity and accelerating visual recovery in animals that have experienced cortical lesions during development. However, the translational impact of our understanding of dark exposure from animal studies to humans remains elusive. Here, we used magnetic resonance spectroscopy as a probe for E/I balance in the primary visual cortex (V1) to determine the effect of 60 min of dark exposure, and measured binocular combination as a behavioural assay to assess visual plasticity in 14 normally sighted human adults. To induce neuroplastic changes in the observers, we introduced 60 min of monocular deprivation, which is known to temporarily shift sensory eye balance in favour of the previously deprived eye. We report that prior dark exposure for 60 min strengthens local excitability in V1 and boosts visual plasticity in normal adults. However, we show that it does not promote plasticity in amblyopic adults. Nevertheless, our findings are surprising, given the fact that the interlude is very brief. Interestingly, we find that the increased concentration of the excitatory neurotransmitter is not strongly correlated with the enhanced functional plasticity. Instead, the absolute degree of change in its concentration is related to the boost, suggesting that the dichotomy of cortical excitation and inhibition might not explain the physiological basis of plasticity in humans. We present the first evidence that an environmental manipulation that shifts cortical E/I balance can also act as a metaplastic facilitator for visual plasticity in humans. KEY POINTS: A brief interlude (60 min) of dark exposure increased the local concentration of glutamine/glutamate but not that of GABA in the visual cortex of adult humans. After dark exposure, the degree of the shift in sensory eye dominance in favour of the previously deprived eye from short-term monocular deprivation was larger than that from only monocular deprivation. The neurochemical and behavioural measures were associated: the magnitude of the shift in the concentration of glutamine/glutamate was correlated with the boost in perceptual plasticity after dark exposure. Surprisingly, the increase in the concentration of glutamine/glutamate was not correlated with the perceptual boost after dark exposure, suggesting that the physiological mechanism of how E/I balance regulates plasticity is not deterministic. In other words, an increased excitation did not unilaterally promote plasticity.

Stimulation of Liver Fibrosis by N2 Neutrophils in Wilson's Disease.

BACKGROUND & AIMS: Wilson's disease is an inherited hepatoneurologic disorder caused by mutations in the copper transporter ATP7B. Liver disease from Wilson's disease is one leading cause of cirrhosis in adolescents. Current copper chelators and zinc salt treatments improve hepatic presentations but frequently worsen neurologic symptoms. In this study, we showed the function and machinery of neutrophil heterogeneity using a zebrafish/murine/cellular model of Wilson's disease. METHODS: We investigated the neutrophil response in atp7b-/- zebrafish by live imaging, movement tracking, and transcriptional analysis in sorted cells. Experiments were conducted to validate liver neutrophil heterogeneity in Atp7b-/- mice. In vitro experiments were performed in ATP7B-knockout human hepatocellular carcinomas G2 cells and isolated bone marrow neutrophils to reveal the mechanism of neutrophil heterogeneity. RESULTS: Recruitment of neutrophils into the liver is observed in atp7b-/- zebrafish. Pharmacologic stimulation of neutrophils aggravates liver and behavior defects in atp7b-/- zebrafish. Transcriptional analysis in sorted liver neutrophils from atp7b-/- zebrafish reveals a distinct transcriptional profile characteristic of N2 neutrophils. Furthermore, liver N2 neutrophils also were observed in ATP7B-knockout mice, and pharmacologically targeted transforming growth factor ß1, DNA methyltransferase, or signal transducer and activator of transcription 3 reduces liver N2 neutrophils and improves liver function and alleviates liver inflammation and fibrosis in ATP7B-knockout mice. Epigenetic silencing of Socs3 expression by transforming growth factor ß1 contributes to N2-neutrophil polarization in isolated bone marrow neutrophils. CONCLUSIONS: Our findings provide a novel prospect that pharmacologic modulation of N2-neutrophil activity should be explored as an alternative therapeutic to improve liver function in Wilson's disease.

PROS1 variant c.1574C>T p.Ala525Val causes portal vein thrombosis with protein S deficiency.

BACKGROUND: Protein S (PS) is a vitamin K-dependent plasma glycoprotein, and the deficiency of PS increases the risk of venous thromboembolism (VTE). PS deficiency has been found in 1.5-7% of selected groups of thrombophilic patients. However, the reported PS deficiency patients with portal vein thrombosis are scarce. CASE REPORT AND RESULTS: Our case described a 60-year-old male patient presented portal vein thrombosis with protein S deficiency. Imaging findings of the patient revealed extensive thrombosis involving the portal vein and superior mesenteric vein. His medical history revealed lower extremity venous thrombosis 10 years ago. The level of PS activity was greatly reduced (14%, reference: 55-130%). Acquired thrombophilia caused by antiphospholipid syndrome, hyperhomocysteinemia, or malignancy were excluded. Whole exome sequencing revealed a heterozygous missense variation c.1574C>T, p.Ala525Val in the PROS1 gene. The in-silico analysis of the variant was performed by SIFT and PolyPhen-2. The results showed that the variant is a pathogenic and likely pathogenic variation respectively (SIFT, -3.404; PolyPhen-2, 0.892), the amino acid substitution A525V is presumed to result in unstable PS protein which is degraded intracellularly. Mutation site of the proband and his family members was validated by Sanger sequencing. CONCLUSION: According to the clinical manifestation, imaging findings, protein S level, and the genetic results, a diagnosis of portal vein thrombosis with PS deficiency was made. To the best of our knowledge, our case is the second reported PS deficiency patient caused by PROS1 c.1574C>T, p.Ala525Val variant in Asia, and the case is also the only reported case with PROS1 c.1574C>T, p.Ala525Val variant presents portal vein thrombosis.

Evaluating the optimised font size and viewing time of online learning in young children: a multicentre cross-sectional study.

OBJECTIVES: Near viewing distance (VD) and longer viewing times are associated with myopia. This study aimed to identify the font size and viewing time that guarantee the appropriate VD and pixels per degree (PPD) for children's online learning. DESIGN: This cross-sectional study comprised two experiments. In experiment A, participants read text in five font sizes on three backlit displays (a personal computer, a smartphone and a tablet), an E-ink display and paper for 5 min per font size. In experiment B, participants watched videos for 30 min on three backlit displays. SETTING: The Peking University People's Hospital in Beijing (China) and the School of Ophthalmology and Optometry, Wenzhou Medical University (Zhejiang Province, China). PARTICIPANTS: Thirty-five participants completed experiment A. Ten of them participated in experiment B. PRIMARY AND SECONDARY OUTCOME MEASURES: VDs were measured by Clouclip. The corresponding PPD was calculated. RESULTS: In experiment A, font size and display type significantly affected VD (F(4840)=149.44, p<0.001, ES (Effect size)=0.77; F(4840), p<0.001, ES=0.37). VDs were >33 cm for all five font sizes on the PC, the tablet and paper and for 18-pt on the smartphone and 16-pt on E-ink. PPD for 16-pt on the PC, 14-pt on the tablet and all five font sizes on the phone were >60. In experiment B, VD increased over the four previous 5 min periods but decreased slightly on tablets and PCs in the fifth 5 min period. PPD was >60. CONCLUSION: Children demonstrated different VDs and PPDs based on font size and display type. To ensure a 33 cm VD and 60 PPD, the minimum font size for online reading should be 18-pt on smartphones, 16-pt on PCs and E-ink, 10.5-pt on tablets and 9-pt on paper. More attention should be given to children's VD with continuous video viewing of more than 25 min. TRIAL REGISTRATION NUMBER: ChiCTR2100049584.

A Three-Step Screening Procedure for Early Identification of Children at High Risk of Hemophagocytic Lymphohistiocytosis.

PURPOSE: The first step in diagnosing hemophagocytic lymphohistiocytosis (HLH) is to suspect its presence and then order the appropriate diagnostic tests. The development of screening procedures for HLH could facilitate early diagnosis. In this study, we evaluated the utility of fever, splenomegaly, and cytopenias as screening criteria for identifying pediatric HLH at an early stage, built a screening model using commonly measured laboratory parameters, and developed a step-wise screening procedure for pediatric HLH. METHODS: The medical records of 83,965 pediatric inpatients, including 160 patients with HLH, were collected retrospectively. The utility of fever, splenomegaly, hemoglobin level, and platelet and neutrophil counts at hospital admission as screening criteria for HLH was evaluated. For HLH patients who might be missed by screening based on the presence of fever, splenomegaly, and cytopenias, a screening model using common laboratory parameters was developed. Following that, a three-step screening procedure was then developed. RESULTS: The criteria of cytopenias affecting two or more lineages plus fever or splenomegaly had a sensitivity of 51.9% and a specificity of 98.4% for identifying HLH in pediatric inpatients. Our screening score model comprises six parameters: splenomegaly, platelet count, neutrophil count, albumin level, total bile acid level, and lactate dehydrogenase level. The use of the validation set had a sensitivity of 87.0% and a specificity of 90.6%. A three-step screening procedure has been developed: Step 1: Is fever or splenomegaly present? (Yes: risk for HLH should be considered, go to Step 2; No: less likely HLH); Step 2: Are cytopenias affecting at least two lineages? (Yes: consider HLH; No: go to Step 3); Step 3: Calculate the screening score. Is the sum of the score greater than 37? (Yes: consider HLH; No: less likely HLH). The overall sensitivity and specificity of the three-step screening procedure were 91.9% and 94.4%, respectively. CONCLUSION: A significant proportion of pediatric HLH patients present at the hospital without having all three symptoms: fever, splenomegaly, and cytopenias. Our three-step screening procedure, utilizing commonly available clinical and laboratory parameters, can effectively identify pediatric patients who may be at high risk for HLH.

Insights into the impacts of autotoxic allelochemicals from rhizosphere of Atractylodes lancea on soil microenvironments.

Atractylodes lancea suffers from continuous cropping obstacles that have become a major constraint in its cultivation, but there is still little information on the autotoxic allelochemicals and their interaction with soil microorganisms. In this study, we firstly identified the autotoxic allelochemicals from rhizosphere of A. lancea and determined their autotoxicity. Third-year continuous A. lancea cropping soils, i.e., rhizospheric soil and bulk soil, compared with control soil and one-year natural fallow soil were used to determine soil biochemical properties and microbial community. Eight allelochemicals from A. lancea roots were detected and exhibited significant autotoxicity effects on seed germination and seedling growth of A. lancea with the highest content of dibutyl phthalate in rhizospheric soil and lowest IC50 value of 2,4-di-tert-butylphenol inhibiting seed germination. The contents of soil nutrients and organic matter, pH value, and enzyme activity were altered between different soils, and the parameters of fallow soil were close to those of the unplanted soil. The PCoA analysis indicated that the community composition of both bacteria and fungi were differed significantly among the soil samples. Continuous cropping decreased OTUs numbers of bacterial and fungal communities, and natural fallow restored them. The relative abundance of Proteobacteria, Planctomycetes, and Actinobacteria decreased, and that of Acidobacteria and Ascomycota increased after three years cultivation. The LEfSe analysis identified 115 and 49 biomarkers for bacterial and fungal communities, respectively. The results suggested that natural fallow restored the structure of soil microbial community. Overall, our results revealed that autotoxic allelochemicals caused the variations of soil microenvironments and resulted in replantation problem of A. lancea, and natural fallow alleviated the soil deterioration by remodeling the rhizospheric microbial community and restoring soil biochemical properties. These findings provide important insights and clues for solving the continuous cropping problems and guiding the management of sustainable farmland.