Climate change, its impact on emerging infectious diseases and new technologies to combat the challenge.

Improved sanitation, increased access to health care, and advances in preventive and clinical medicine have reduced the mortality and morbidity rates of several infectious diseases. However, recent outbreaks of several emerging infectious diseases (EIDs) have caused substantial mortality and morbidity, and the frequency of these outbreaks is likely to increase due to pathogen, environmental, and population effects driven by climate change. Extreme or persistent changes in temperature, precipitation, humidity, and air pollution associated with climate change can, for example, expand the size of EID reservoirs, increase host-pathogen and cross-species host contacts to promote transmission or spillover events, and degrade the overall health of susceptible host populations leading to new EID outbreaks. It is therefore vital to establish global strategies to track and model potential responses of candidate EIDs to project their future behavior and guide research efforts on early detection and diagnosis technologies and vaccine development efforts for these targets. Multi-disciplinary collaborations are demanding to develop effective inter-continental surveillance and modeling platforms that employ artificial intelligence to mitigate climate change effects on EID outbreaks. In this review, we discuss how climate change has increased the risk of EIDs and describe novel approaches to improve surveillance of emerging pathogens that pose the risk for EID outbreaks, new and existing measures that could be used to contain or reduce the risk of future EID outbreaks, and new methods to improve EID tracking during further outbreaks to limit disease transmission.

CXCR4 overexpression in chronic lymphocytic leukemia associates with poorer prognosis: A prospective, single-center, observational study.

Controversial data have been reported on the prognostic value of C-X-C motif chemokine receptor 4 (CXCR4) in chronic lymphocytic leukemia (CLL). This prospective, single-center, observational study aimed to evaluate the role of CXCR4 in the pathophysiology of CLL and its prognostic role. A total of 158 patients of CLL were enrolled, and CXCR4 expression on CLL cells was detected by flow cytometry (FCM) at initial diagnosis. The patients were divided into 2 groups according to the CXCR4 mean fluorescence intensity (MFI) median. Also, four patient specimens from the CXCR4low and CXCR4high groups were selected for RNASeq analysis. The progression-free survival (PFS) of CLL patients in the CXCR4high group was significantly shorter than the CXCR4low group, with a median follow-up time of 27 months (log-rank P < 0.001). Moreover, CXCR4 overexpression (MFI > 3376) was an independent marker of poor PFS in CLL patients (P < 0.001). Analysis of RNASeq results revealed that CXCR4 plays an important role in the migration of CLL. Collectively, CXCR4 expression levels on leukemia cells can be detected rapidly by FCM. CXCR4 overexpression was significantly associated with poorer prognosis in CLL patients within a shorter follow-up time.

Micro-Red Blood Cell, Fragmented Red Blood Cell, Platelet Distribution Width, Mean Platelet Volume, and Platelet-Large Cell Ratio on Sysmex XN Series Hematology Analyzers Can Be Used for the Reflex Test of Impedance Platelet Count in Clinical Practice.

CONTEXT.­: Platelet (PLT) counting with impedance (PLT-I) is widely used but has low specificity. PLT counting with fluorescence (PLT-F), tested by the Sysmex XN series with high specificity, can be a complementary method to PLT-I. OBJECTIVE.­: To identify red blood cell (RBC)- and PLT-related parameters as potential influencing factors for PLT-I and establish PLT reflex test rules with PLT-F. DESIGN.­: We prospectively tested both PLT-I and PLT-F in all 3480 samples. In a development data set of 3000 samples, differences between the reflex and nonreflex groups were compared and influencing factors for PLT-I were identified by logistic regression. The area under the receiver operating characteristic (ROC) curve and cutoff values were obtained by ROC curve analysis. Validation was conducted in the remaining 480 samples (validation data set). RESULTS.­: PLT-F showed comparable results with immunoplatelet counting. In logistic regression, increased micro-RBC absolute count (micro-RBC#), fragmented RBC absolute count (FRC#), PLT distribution width (PDW), mean PLT volume (MPV), PLT-large cell ratio (P-LCR), and immature PLT fraction absolute count (IPF#) were influencing factors for PLT-I. In ROC curve analysis, the cutoff values of micro-RBC#, FRC#, PDW, MPV, and P-LCR were 0.64 × 106/µL, 0.082 × 106/µL, 15.40 fL, 11.15 fL, and 33.95%, respectively. The areas under the ROC curve of micro-RBC# and FRC# were 0.77 and 0.79, respectively. CONCLUSIONS.­: Micro-RBC#, FRC#, PDW, MPV, P-LCR, and IPF# were factors affecting PLT-I. Among them, micro-RBC# and FRC# were the most impactful factors. From our study results, micro-RBC#, FRC#, MPV, PDW, and P-LCR can be used to establish reflex test rules for PLT counting in clinical work.

A convolutional neural network-based, quantitative complete blood count scattergram-mapping framework promptly screens acute promyelocytic leukemia with high sensitivity.

BACKGROUND: Acute promyelocytic leukemia (APL) is a subtype of acute myeloid leukemia (AML) characterized by its rapidly progressive and fatal clinical course if untreated, although it is curable if treated in a timely manner. Promptly screening patients who have results that are suspicious for APL is vital to overcome early death. METHODS: The authors developed an innovative framework consisting of ResNet-18, a convolutional neural network architecture, with the objective of quantitatively mapping a complete blood count (CBC) scattergram to quickly and robustly indicate a probable susceptibility to APL. Three hundred and twenty scattergrams of the white blood cell differential channel from 51 patients with APL, 510 scattergrams from 105 patients who had non-APL AML, and 320 scattergrams from 320 healthy controls were randomly stratified at a ratio of 4:1 and split into training and testing data sets to accomplish five-fold cross-validation. RESULTS: Both the area under the curve and the average precision of >0.99 were achieved in each fold. Three hundred four of the 320 APL scattergrams (95%) were correctly flagged by the model, which outcompeted the CBC review rules recommended by the International Society of Laboratory Hematology (all p < .001). External validation based on an independent testing data set that included 56 scattergrams from 31 patients with APL, 56 scattergrams from 55 patients with non-APL AML, and 64 scattergrams from 64 healthy controls also confirmed the sensitivity and specificity of the framework. CONCLUSIONS: To the authors' knowledge, their convolutional neural network-based framework is the first to use scattergram output from routine CBC analysis to map suspicious APL early with outstanding sensitivity, specificity, and precision. The authors also describe a new CBC workflow incorporating this framework upstream of the morphologic review, which would provide the earliest flag for APL. PLAIN LANGUAGE SUMMARY: The authors propose an innovative way to visualize complete blood counts (CBCs) by mapping the difference in white blood cell counts using automated CBC analysis to identify potential acute promyelocytic leukemia (APL) using a convolutional neural network (CNN), which can eliminate the potential pitfalls of manual observation. Analyses of an unprecedented, realistic data set validated that the quantitative relationship between the CBC scattergram and an APL abnormality is highly consistent. This is the first study to date focusing on screening for APL using scattergrams of the difference in white blood cell counts from routine CBC tests and has significant clinical relevance. The authors recommend using this method even before analyzing cell images, which could provide the earliest way to screen for APL in a sensitive and accurate way.

Prognostic value of cross-lineage expression of the myeloid-associated antigens CD13 and CD33 in adult B-lymphoblastic leukemia: A large real-world study of 1005 patients.

BACKGROUND: Cross-lineage expression of the myeloid-associated antigens CD13/CD33 is common in adult B-lymphoblastic leukemia (B-ALL) patients, yet its prognostic value is still controversial. METHODS: We conducted a retrospective study of 1005 de novo adult B-ALL patients from January 2009 to December 2019 in our hospital. Logistic and Cox regression were used to analyze the prognostic value of CD13/CD33 expression in B-ALL. A Cox regression model was established to predict overall survival (OS) for B-ALL patients. RESULTS: Of the 1005 B-ALL patients, 53.7% (n = 540) aberrantly expressed CD13/CD33 (CD13/CD33+ ). Patients in the CD13/CD33+ group showed a higher incidence of BCR::ABL1 rearrangement and minimal/measurable residual disease (MRD) positivity but similar complete remission rate, relapse-free survival, mortality, and OS with CD13/CD33- . CD13/CD33+ patients had a higher risk of MRD positivity than CD13/CD33- patients. Notably, CD13/CD33+ patients who underwent tyrosine kinase inhibitor (TKI) therapy had a better long-term prognosis than those without TKI experience. Sex, group based on CD13/CD33 expression and TKI experience and white blood cell count were variables independently associated with OS. The Cox regression model integrating these three variables showed a moderate performance for OS prediction (C-index: 0.724). CONCLUSIONS: In real-world practice, CD13/CD33 expression can predict the risk of MRD in patients without TKI experience, but has no adverse effect on the prognosis of adult B-ALL patients. Incorporating CD13/CD33 into the standard antibody panels of B-ALL diagnosis and MRD measurements can help predict relapse risk and decisions on therapy options.

Resveratrol Inhibits Activation of Microglia after Stroke through Triggering Translocation of Smo to Primary Cilia.

Activated microglia act as a double-edged sword for stroke. In the acute phase of stroke, activated microglia might deteriorate neurological function. Therefore, it is of great clinical transforming potential to explore drugs or methods that can inhibit abnormal activation of microglia in the acute phase of stroke to improve neurological function after stroke. Resveratrol has a potential effect of regulating microglial activation and anti-inflammation. However, the molecular mechanism of resveratrol-inhibiting microglial activation has not been fully clarified. Smoothened (Smo) belongs to the Hedgehog (Hh) signaling pathway. Smo activation is the critical step that transmits the Hh signal across the primary cilia to the cytoplasm. Moreover, activated Smo can improve neurological function via regulating oxidative stress, inflammation, apoptosis, neurogenesis, oligodendrogenesis, axonal remodeling, and so on. More studies have indicated that resveratrol can activate Smo. However, it is currently unknown whether resveratrol inhibits microglial activation via Smo. Therefore, in this study, N9 microglia in vitro and mice in vivo were used to investigate whether resveratrol inhibited microglial activation after oxygen-glucose deprivation/reoxygenation (OGD/R) or middle cerebral artery occlusion/reperfusion (MCAO/R) injury and improved functional outcome via triggering translocation of Smo in primary cilia. We definitively found that microglia had primary cilia; resveratrol partially inhibited activation and inflammation of microglia, improved functional outcome after OGD/R and MCAO/R injury, and triggered translocation of Smo to primary cilia. On the contrary, Smo antagonist cyclopamine canceled the above effects of resveratrol. The study suggested that Smo receptor might be a therapeutic target of resveratrol for contributing to inhibit microglial activation in the acute phase of stroke.

Sirt1 regulates microglial activation and inflammation following oxygen-glucose deprivation/reoxygenation injury by targeting the Shh/Gli-1 signaling pathway.

BACKGROUND: Cerebral ischemic injury leads to over-activation of microglia, which release pro-inflammatory factors that deteriorate neurological function during the acute phase of stroke. Thus, inhibiting microglial over-activation is crucial for reducing ischemic injury. Sirtuin 1 (Sirt1) has been shown to play a critical role in stroke, neurodegenerative diseases and aging. However, the effect of Sirt1 on the regulation of microglial activation following cerebral ischemic injury, as well as the underlying mechanism, remain unknown. Therefore, the purpose of the present study is to mainly investigate the effect of Sirt1 on oxygen-glucose deprivation/reoxygenation (OGD/R)-treated N9 microglia following treatment with the Sirt1 agonists resveratrol and SRT1720 and the Sirt1 antagonist sirtinol. METHODS: Cell viability, Apoptosis, activation and inflammatory responses of microglia, expressions and activity of Shh signaling pathway proteins were detected by Cell Counting Kit 8, Flow Cytometry, immunocytochemistry, ELISA, and Western blotting, respectively. RESULTS: The results demonstrated that treatment with resveratrol or SRT1720 could inhibit the activation of microglia and inflammation during OGD/R. Moreover, these treatments also led to the translocation of the GLI family zinc finger-1 (Gli-1) protein from the cytoplasm to the nucleus and upregulated the expression of Sonic hedgehog (Shh), Patched homolog-1 (Ptc-1), smoothened frizzled class receptor and Gli-1. By contrast, the inhibition of Sirt1 using sirtinol had the opposite effect. CONCLUSION: These findings suggested that Sirt1 may regulate microglial activation and inflammation by targeting the Shh/Gli-1 signaling pathway following OGD/R injury. Schematic representation of Sirt1 regulating the microglial activation and inflammation following oxygen-glucose deprivation/reoxygenation injury via mediation of Shh/Gli-1 signaling pathway.

Association of Minimal Residual Disease by a Single-Tube 8-Color Flow Cytometric Analysis With Clinical Outcome in Adult B-Cell Acute Lymphoblastic Leukemia: A Real-World Study Based on 486 Patients.

CONTEXT.­: Minimal/measurable residual disease (MRD) measured by molecular and multiparametric flow cytometry (MFC) has been proven to be predictive of relapse and survival in patients with B-cell acute lymphoblastic leukemia (B-ALL). A universally applicable antibody panel at a low cost but without compromising sensitivity and power of prognosis prediction in adult B-ALL remains unestablished. OBJECTIVE.­: To report our experience of using a single-tube 8-color MFC panel to measure the MRD status as a prognostic indicator in adult B-ALL patients. DESIGN.­: We retrospectively analyzed the characteristics, MRD status, and prognosis of adult B-ALL based on a large real-world cohort of 486 patients during a 10-year period. RESULTS.­: MRD assessed by MFC and polymerase chain reaction (PCR) assays for BCR-ABL+ patients showed concordant results in 74.2% of cases. MRD- status by our MFC panel could clearly predict a favorable relapse-free survival (RFS) and overall survival (OS) both at the end of induction and at the end of 1 consolidation course. Patients with continuous MRD- and with at least 1 MRD- result showed a favorable RFS and OS compared with those with at least 1 MRD+ result and continuous MRD+, respectively. CONCLUSIONS.­: The single-tube 8-color MFC panel demonstrated a low cost, decent sensitivity, and comparability with polymerase chain reaction-MRD but an excellent performance in predicting RFS and OS, and thus could potentially be taken as a routine indicator in the evaluation of the treatment response for adult patients with B-ALL.

Resveratrol Inhibits Oxidative Stress and Regulates M1/M2-Type Polarization of Microglia via Mediation of the Nrf2/Shh Signaling Cascade after OGD/R Injury In Vitro.

AIMS: Microglia are closely related to the occurrence and development of oxidative stress. Cerebral ischemia leads to abnormal activation of microglia. Resveratrol can regulate M1/M2-type microglia polarization, but the underlying mechanism is not well understood, although the Nrf2 and Shh signaling pathways may be involved. Given that resveratrol activates Shh, the present study examined whether this is mediated by Nrf2 signaling. METHODS: N9 microglia were pretreated with drugs before oxygen-glucose deprivation/reoxygenation (OGD/R). HT22 neurons were also used for conditional co-culture with microglia. Cell viability was measured by CCK-8 assay. MDA levels and SOD activity in the supernatant were detected by TBA and WST-1, respectively. Immunofluorescence detected Nrf2 and Gli1 nuclear translocation. The levels of CD206, Arg1, iNOS, TNF-α, Nrf2, HO-1, NQO1, Shh, Ptc, Smo, Gli1 protein and mRNA were measured by Western blotting or RT-qPCR. Annexin V-FITC Flow Cytometric Analysis detected apoptosis. RESULTS: Resveratrol and Nrf2 activator RTA-408 enhanced the viability of microglia, reduced oxidative stress, promoted M2-type microglia polarization and activated Nrf2 and Shh signaling. ML385, a selective inhibitor of Nrf2, decreased the viability of microglia, aggravated oxidative stress, promoted M1-type microglia polarization and inhibited Nrf2 and Shh signaling. Moreover, resveratrol and RTA-408-treated microglia can reduce the apoptosis and increase the viability of HT22 neurons, while ML385-treated microglia aggravated the apoptosis and weakened the viability of HT22 neurons. CONCLUSIONS: These results demonstrated that resveratrol may inhibit oxidative stress, regulate M1/M2-type polarization of microglia and decrease neuronal injury in conditional co-culture of neurons and microglia via the mediation of the Nrf2/Shh signaling cascade after OGD/R injury in vitro.

Early T-cell precursor lymphoblastic leukemia accompanied by prominent blastic plasmacytoid dendritic cell proliferation mimicking blastic plasmacytoid dendritic cell neoplasm: an exceptional case report and literature review.

PURPOSE: Plasmacytoid dendritic cells (pDCs) are commonly associated with myeloid malignancies. The association between lymphoblastic leukemia and pDCs has been little explored. CASE PRESENTATION: Here, we report a novel case of early T-cell precursor lymphoblastic leukemia (ETP-ALL) accompanied by prominent proliferation of blastic pDCs mimicking BPDCN. The diagnosis was established based on a comprehensive analysis of morphology, immunophenotype and clinical implications. We also present a literature review and discussion on the differential expression of reactive and neoplastic pDCs, the functional role of pDCs in lymphoblastic leukemia, and the etiological association of normal pDCs and BPDCN. CONCLUSIONS: The current case demonstrates for the first time that prominent pDC proliferation can be associated with lymphoid neoplasms and can exhibit blastic morphology and immunophenotype. The underlying mechanism of the coexistence of these two blastic populations remains unknown. Further genetic profiling may be required to denote the progressive development of tumor stem cells to the lymphoid, myeloid or dendritic cell lineage. Moreover, the prognostic value of pDCs in hematological neoplasms needs further investigation.

CCDC88A Post-Transcriptionally Regulates VEGF via miR-101 and Subsequently Regulates Hepatocellular Carcinoma.

Background: miR-101 is one of the most abundantly expressed microRNA (miRNA) and exerst a critical role in hepatocellular carcinoma (HCC) by targeting to 3' -untranslated region (UTR) of Girders of actin filaments (CCDC88A) and Vascular endothelial growth factor (VEGF) mRNA, but the underlying molecular mechanism remains to be elucidated. This study aimed to investigate the potential role of CCDC88A on malignancies and stemness by regulating VEGF via miR-101 in HCC. Methods: Gene Expression Profiling Interactive Analysis (GEPIA) was employed to analyze the relevance of CCDC88A expression with prognosis in HCC. Tissue slides were performed to confirm the protein level of CCDC88A in HCC. Correlation between CCDC88A and VEGF was transcriptionally and post-transcriptionally detected, followed by evaluation of malignancies. Results: By employing Immunohistochemistry, we found CCDC88A protein was upregulated in HCC tissues, which is closely correlated to poor prognosis and survival rate. Employment of GEPIA revealed the positive correlation between CCDC88A and VEGF in HCC, but not in liver tissue. Silencing of CCDC88A in Huh-7 and SK-HEP-1 cells significantly decreased proliferation, cell cycle phases, migration, invasion, colony formation, and tumor formation. Introduction of miR-101 mimics specifically targeting CCDC88A and VEGF decreased protein levels of both CCDC88A and VEGFA. Notably, inhibition of miR-101 reversed the correlation between CCDC88A and VEGFA protein levels, indicating that CCDC88A and VEGF may exert as a miR-101 sponge. The addition of SKLB1002, a VEGFR2 inhibitor inhibited malignant behaviors, which was further inhibited by the introduction of miR-101 mimics, indicating that CCDC88A regulates malignant behaviors partially via regulating VEGF. Moreover, CCDC88A also promotes the stemness of cancer stem-like cells derived from HCC cells depending on VEGF modification. Conclusion: Taken together, our findings suggested that the miR-101/CCDC88A/VEGF axis could be a potential therapeutic target of HCC treatment.

Association of genetic polymorphisms in IL-23R and IL-17A with the susceptibility to IgA nephropathy in a Chinese Han population.

IgA Nephropathy (IgAN) is one of the most common causes of chronic kidney damage worldwide. Identifying new genetic factors associated with IgAN risk is of invaluable importance. To explore the association between polymorphisms of IL-23R and IL-17A and the susceptibility of IgAN, 164 IgAN patients and 192 healthy controls were genotyped for five SNPs in a Chinese Han population. A comparative analysis between genotype distributions, clinical indexes and pathological grades in the IgAN patients was also performed. The GG genotype and a G allele of rs7517847 were associated with a decreased IgAN risk (OR: 0.545; 95% CI: 0.299-0.993; p = 0.046; OR: 0.730; 95% CI: 0.541-0.984; p = 0.039) compared to the TT genotype and T allele respectively. Furthermore, the AA genotype of rs2275913 appeared to reduce the IgAN risk (OR: 0.405; 95% CI: 0.209-0.786; p = 0.007) compared to the GG genotype. Consistently, individuals harboring an AA genotype had a lower IgAN risk (OR: 0.380; 95% CI: 0.211-0.686; p = 0.001) under the recessive model. Our study demonstrated for the first time the significant associations of rs7517847 in IL-23R and rs2275913 in IL-17A with the risk of IgAN in Chinese Han.

[Effect of Chelated Iron on Nitrogen Removal Efficiency and Microbial Community Structure in the Anaerobic Ferric Ammonium Oxidation].

In order to understand the characteristics and interactions of the microbial community during the anaerobic ferric ammonium oxidation (FEAMMOX) process, this study investigated the effects of various forms of chelated iron on nitrogen removal efficiency and microbial community structure. After 77 days of reactor operation, the removal efficiency of total nitrogen was 83.32% for the ferric humate group, 43.67% for the ferric citrate group, 55.07% for the ferric sodium ethylene diamine tetraacetate group, and 12.65% for the ferric ammonium triacetate group. After the experiment, the abundance of denitrifying bacteria Comamonadaceae in ferric humate group was 17.57%, the abundance of Clostridium in ferric citrate group was 47.70%; and the abundance of denitrifying bacteria Thermomonas in the ferric sodium ethylene diamine tetraacetate group was 20.11%. This indicates that ferric humate is a more effective electron acceptor for the FEAMMOX process. The result of function prediction shows that the iron, sulfur, and nitrogen cycles are all closely related, with iron and sulfur metabolism playing an important role in nitrogen removal. In the humate group, iron respiration and the nitrogen cycle are more strongly correlated than other groups. Co-occurrence network analysis showed that the keystone species in the FEAMMOX process is Tessaracoccus.

Resveratrol-mediated neurorestoration after cerebral ischemic injury - Sonic Hedgehog signaling pathway.

AIMS: Resveratrol pretreatment can decrease ischemic cerebral injury and enhance proliferation of neural stem cells via mediation of Sonic Hedgehog signaling. However, it is relatively little known about whether neurorestorative effects of resveratrol are mediated by Shh signaling in ischemic cerebral injury. The present study tests whether the Shh signaling pathway mediates resveratrol to promote neurorestoration of ischemic cerebral injury. MATERIALS AND METHODS: Rats or neurons before middle cerebral artery occlusion/reperfusion (MCAO/R) or oxygen-glucose deprivation/reoxygenation (OGD/R) injury were pretreated with resveratrol. Immunohistochemistry is used to be determined BrdU+/DCX+, BrdU+/Nestin+ and BrdU+/NG2+ cell (markers of new proliferated neural stem/progenitor and oligodendrocyte precursor cell, respectively), BrdU+/MAP2+ and BrdU+/CNPase+ cell (markers of new mature neuron and oligodendrocyte, respectively), BrdU+/TUNEL+ cell (marker of apoptosis for new proliferated cell), SY, NF200, Iba-1 and GFAP (markers of synaptogenesis, axon, microglia and astrocyte, respectively). Shh and Gli-1 mRNAs were detected by RT-PCR assay. Iba-1, GFAP, Shh and Gli-1 proteins were detected by Western blot. KEY FINDINGS: Resveratrol pretreatment significantly reduced neurological deficit scores, promoted proliferation, differentiation, migration and survival of neural stem/progenitor and oligodendrocyte precursor cells, inhibited astrocyte and microglia activation, strengthened synaptophysin and NF200 expression, at the same time, promoted neurite outgrowth of neurons. Meanwhile, expression levels of Shh and Gli-1 proteins were significantly increased and Gli-1 translocated into the nucleus. However, cyclopamine, a Smo inhibitor, canceled the above effects of resveratrol. CONCLUSIONS: It may be mediated, at least partly, by the Shh signaling pathway that resveratrol pretreament promote neurorestoration of ischemic cerebral injury.

Micro-Heterogeneous Annihilation Dynamics of Self-Trapped Excitons in Hematite Single Crystals.

The Auger recombination in bulk semiconductors can quickly depopulate the charge carriers in a nonradiative way, which, fortunately, only has a detrimental impact on optoelectronic device performance under the condition of high carrier density because the restriction arising from concurrent momentum and energy conservation limits the Auger rate. Here, we surprisingly observed enhanced Auger recombination in an α-Fe2O3 single crystal, a wide bandgap semiconductor with low carrier mobility. The Auger process was ascribed to the Coulombically coupled self-trapped excitons (STEs), and the relaxation of momentum conservation due to the strong spatial localization of these STEs should account for the enhancement. The STE-density dependent kinetics suggested that the strong polaronic effect could cause a micro-heterogeneous distribution of STEs in a high-quality bulk single crystal, which also gave rise to the micro-heterogeneous annihilation dynamics, and a stochastic recombination model was developed and successfully described the STE annihilation dynamics.

Production of Autoreactive Heavy Chain-Only Antibodies in Systemic Lupus Erythematosus.

Systemic lupus erythematosus (SLE) is characterized by the overproduction of high-affinity autoreactive antibodies. Here, we show that more than 65.8% of 222 recombinant antibodies derived from 8 SLE patients can be secreted as heavy chain-only antibodies (HCAbs) when expressed in HEK-293T cells. The secretion of HCAbs follows the conventional endoplasmic reticulum-Golgi apparatus pathway, despite triggering a weaker unfolded protein response (UPR). Many of the purified SLE HCAbs remain autoreactive and have an even higher affinity for dsDNA, Sm, nucleosome, and cardiolipin than HCAbs from healthy individuals. Extended analyses of the CDR3 region and the heavy chain variable (VH) region of HCAb F3 show that the VH region is responsible for IgH secretion, while the CDR3 region determines its reactivity. Such a high frequency of HCAb secretion cannot fully concur with our current understanding of antibody assembly and secretion. The presence of a large proportion of autoreactive HCAbs in SLE reveals a novel mechanism for the generation of autoreactive antibodies in lupus.

The prognosis predictive value of FMS-like tyrosine kinase 3-internal tandem duplications mutant allelic ratio (FLT3-ITD MR) in patients with acute myeloid leukemia detected by GeneScan.

INTRODUCTION: This study aimed to explore the significance and cut-off values of FMS-like tyrosine kinase 3-internal tandem duplications mutant allelic ratio (FLT3-ITD MR) in prognostic evaluation of acute myeloid leukemia (AML) patients. METHODS: This study enrolled 249 Chinese AML patients. The exons 14 and 15 of FLT3 gene were amplified by genomic polymerase chain reaction. GeneScan and single nucleotide sequencing were also performed. Participants were grouped into high- and low-ratio FLT3-ITD MR (FLT3-ITD MRhigh and FLT3-ITD MRlow) applying the median of FLT3-ITD MR as the cut-off ratio, and patients without FLT3-ITD were grouped as FLT3-wild type (wt). Duration of complete remission (CR), relapsed remission and overall survival (OS) were examined. RESULTS: FLT3-ITD was detected in 58 patients. The medians of FLT3-ITD MR were 0.31 and 0.29 for all AML and non-M3 patients, respectively. For all patients, FLT3-ITD MRhigh group had the lowest CR rate among these 3 groups (p < 0.001). The FLT3-wt group, FLT3-ITD MRlow and FLT3-ITD MRhigh group had the median OS of 36.00 months (range: 2.00-92.00 months), 12.00 months (range: 1.00-78.00 months) and 14.00 months (range: 0.00-79.00 months), respectively. Subjects in FLT3-ITD MRhigh group had 2.675 times (95% CI: 1.726-4.146; p < 0.001) and 1.879 times (95% CI: 1.061-3.328; p = 0.031) higher death risk than those in FLT3-wt group and FLT3-ITD MRlow group, respectively. For non-M3 patients, the median OS was 35.00 months (range: 2.00-92.00 months), 9.5 months (range: 1.00-74.00 months) and 10.00 months (range: 1.00-38.00 months) in the FLT3-wt group, FLT3-ITD MRlow group and FLT3-ITD MRhigh group, respectively. Non-M3 patients in FLT3-ITD MRhigh group had 3.301 times (95% CI: 1.423-7.661; p = 0.005) higher death risk than those in FLT3-wt group. CONCLUSION: The present study found that FLT3-ITD MR is closely related to CR and OS in AML patients. Furthermore, FLT3-ITD MR may serve as an independent prognostic factor for OS in non-M3 AML patients. Classifying risk grades based on FLT3-ITD MR is crucial for individualized treatment and prognostic evaluation.