Iterative Design of Near-Infrared Fluorescent Probes for Early Diagnosis of Alzheimer's Disease by Targeting Aß Oligomers.

Amyloid-ß oligomers (AßOs), crucial toxic proteins in early Alzheimer's disease (AD), precede the formation of Aß plaques and cognitive impairment. In this context, we present our iterative process for developing novel near-infrared fluorescent (NIRF) probes specifically targeting AßOs, aimed at early AD diagnosis. An initial screening identified compound 18 as being highly selective for AßOs. Subsequent analysis revealed that compound 20 improved serum stability while retaining affinity for AßOs. The most promising iteration, compound 37, demonstrated exceptional qualities: a high affinity for AßOs, emission in the near-infrared region, and good biocompatibility. Significantly, ex vivo double staining indicated that compound 37 detected AßOs in AD mouse brain and in vivo imaging experiments showed that compound 37 could differentiate between 4-month-old AD mice and age-matched wild-type mice. Therefore, compound 37 has emerged as a valuable NIRF probe for early detection of AD and a useful tool in exploring AD's pathological mechanisms.

A unique subseafloor microbiosphere in the Mariana Trench driven by episodic sedimentation.

Hadal trenches are characterized by enhanced and infrequent high-rate episodic sedimentation events that likely introduce not only labile organic carbon and key nutrients but also new microbes that significantly alter the subseafloor microbiosphere. Currently, the role of high-rate episodic sedimentation in controlling the composition of the hadal subseafloor microbiosphere is unknown. Here, analyses of carbon isotope composition in a ~ 750 cm long sediment core from the Challenger Deep revealed noncontinuous deposition, with anomalous 14C ages likely caused by seismically driven mass transport and the funneling effect of trench geomorphology. Microbial community composition and diverse enzyme activities in the upper ~ 27 cm differed from those at lower depths, probably due to sudden sediment deposition and differences in redox condition and organic matter availability. At lower depths, microbial population numbers, and composition remained relatively constant, except at some discrete depths with altered enzyme activity and microbial phyla abundance, possibly due to additional sudden sedimentation events of different magnitude. Evidence is provided of a unique role for high-rate episodic sedimentation events in controlling the subsurface microbiosphere in Earth's deepest ocean floor and highlight the need to perform thorough analysis over a large depth range to characterize hadal benthic populations. Such depositional processes are likely crucial in shaping deep-water geochemical environments and thereby the deep subseafloor biosphere. Supplementary Information: The online version contains supplementary material available at 10.1007/s42995-023-00212-y.

Assessment of alterations in the retina and vitreous in pre- and post-COVID-19 patients using swept-source optical coherence tomography and angiography: A comparative study.

Ocular manifestations have been well recognized in coronavirus disease 2019 (COVID-19) outbreak. Several studies have detected ocular manifestations in patients after COVID-19. However, little is known about the retinal and vitreal alterations in patients before and after COVID-19 infection. This study aimed to investigate the retinal and vitreal alterations in patients before and after contracting COVID-19 infection using swept-source optical coherence tomography (SS-OCT) and angiography (SS-OCTA). A total of 38 participants (76 eyes) were enrolled and followed-up 1 month after COVID-19 infection. Then, 26 patients (52 eyes) were evaluated 3 months after COVID-19 infection. Compared with the pre-COVID-19 status, patients with 1- and 3-month post-COVID-19 statuses had significant thinning of ganglion cell and inner plexiform layer, thickening of inner nuclear layer, a decrease in the vessel density (VD) of superficial vascular complex, and an increase in the VD of deep vascular complex. Meanwhile, alteration in parameters of foveal avascular zone (all p < 0.05) and hyper-reflective dots in the vitreous of 27 patients (54 eyes) (71.1% vs. pre-COVID-19, 34.2%, p = 0.006) were observed. These findings suggest significantly retinal and vitreal alterations occurred in patients after COVID-19 infection, possibly due to direct or indirect virus-induced injuries. Further longitudinal studies are required to investigate the long-term effects of COVID-19 infection on the human eyes.

Assessment of Outer Retina and Choroid Using Swept Source Optical Coherence Tomography and Angiography in Patients With Multiple Sclerosis.

BACKGROUND: For patients with multiple sclerosis (MS), both structure and microvasculature alterations in the inner retina have been investigated in several studies. However, little is known about the alterations in the outer retina and choroid. Hence, this study aimed to assess the outer retinal and choroidal changes in patients with MS with no history of optic neuritis (ON). METHODS: Patients with MS and healthy control participants were enrolled in this cross-sectional study. Quantitative analyses were performed using swept source optical coherence tomography and swept source optical coherence tomography angiography images to assess outer retina thickness (ORT) and choroid thickness (CT), vessel density (VD) of choriocapillaris, and choroidal vascularity index (CVI), which were then compared between the groups. RESULTS: A total of 37 participants with MS (72 eyes) and 74 healthy control participants (148 eyes) were included in this study. Compared with healthy controls, patients with MS with no history of ON showed reduced VD of the choriocapillaris and CVI. There was no significant difference in ORT and CT between 2 groups. Meanwhile, in patients with MS, no correlation between OCTA parameters and expanded disability status scale score were found in this study. CONCLUSIONS: Our study indicates that patients with MS with no history of optical neuritis have reduced choriocapillaris vessel density and decreased choroidal vascularity index without detectable alteration in outer retina thickness and choroid thickness. The findings complement the outer retinal and choroidal component of MS, providing deeper insight into the pathophysiology of MS.

Effect of CDK7 inhibitor on MYCN-amplified retinoblastoma.

Retinoblastoma (RB) is a common malignancy that primarily affects pediatric populations. Although a well-known cause of RB is RB1 mutation, MYCN amplification can also lead to the disease, which is a poor prognosis factor. Studies conducted in various tumor types have shown that MYCN inhibition is an effective approach to impede tumor growth. Various indirect approaches have been developed to overcome the difficulty of directly targeting MYCN, such as modulating the super enhancer (SE) upstream of MYCN. The drug used in this study to treat MYCN-amplified RB was THZ1, a CDK7 inhibitor that can effectively suppress transcription by interfering with the activity of SEs. The study findings confirmed the anticancer activity of THZ1 against RB in both in vitro and in vivo experiments. Therapy with THZ1 was found to affect numerous genes in RB according to the RNA-seq analysis. Moreover, the gene expression changes induced by THZ1 treatment were enriched in ribosome, endocytosis, cell cycle, apoptosis, etc. Furthermore, the combined analysis of ChIP-Seq and RNA-seq data suggested a potential role of SEs in regulating the expression of critical transcription factors, such as MYCN, OTX2, and SOX4. Moreover, ChIP-qPCR experiments were conducted to confirm the interaction between MYCN and SEs. In conclusion, THZ1 caused substantial changes in gene transcription in RB, resulting in inhibited cell proliferation, interference with the cell cycle, and increased apoptosis. The efficacy of THZ1 is positively correlated with the degree of MYCN amplification and is likely exerted by interfering with MYCN upstream SEs.

Triplex-Loop-Mediated Isothermal Amplification Combined with a Lateral Flow Immunoassay for the Simultaneous Detection of Three Pathogens of Porcine Viral Diarrhea Syndrome in Swine.

Porcine epidemic diarrhea virus (PEDV), porcine bocavirus (PBoV), and porcine rotavirus (PoRV) are associated with porcine viral diarrhea. In this study, triplex loop-mediated isothermal amplification (LAMP) combined with a lateral flow dipstick (LFD) was established for the simultaneous detection of PEDV, PoRV, and PBoV. The PEDV-gp6, PoRV-vp6, and PBoV-vp1 genes were selected to design LAMP primers. The amplification could be carried out at 64 °C using a miniature metal bath within 30 min. The triplex LAMP-LFD assay exhibited no cross-reactions with other porcine pathogens. The limits of detection (LODs) of PEDV, PoRV, and PBoV were 2.40 × 101 copies/µL, 2.89 × 101 copies/µL, and 2.52 × 101 copies/µL, respectively. The consistency between rt-qPCR and the triplex LAMP-LFD was over 99% in field samples testing. In general, the triplex LAMP-LFD assay was suitable for the rapid and simultaneous detection of the three viruses in the field.

Europium Nanoparticle-Based Lateral Flow Strip Biosensors Combined with Recombinase Polymerase Amplification for Simultaneous Detection of Five Zoonotic Foodborne Pathogens.

The five recognized zoonotic foodborne pathogens, namely, Listeria monocytogenes, Staphylococcus aureus, Streptococcus suis, Salmonella enterica and Escherichia coli O157:H7, pose a major threat to global health and social-economic development. These pathogenic bacteria can cause human and animal diseases through foodborne transmission and environmental contamination. Rapid and sensitive detection for pathogens is particularly important for the effective prevention of zoonotic infections. In this study, rapid and visual europium nanoparticle (EuNP)-based lateral flow strip biosensors (LFSBs) combined with recombinase polymerase amplification (RPA) were developed for the simultaneous quantitative detection of five foodborne pathogenic bacteria. Multiple T lines were designed in a single test strip for increasing the detection throughput. After optimizing the key parameters, the single-tube amplified reaction was completed within 15 min at 37 °C. The fluorescent strip reader recorded the intensity signals from the lateral flow strip and converted the data into a T/C value for quantification measurement. The sensitivity of the quintuple RPA-EuNP-LFSBs reached a level of 101 CFU/mL. It also exhibited good specificity and there was no cross-reaction with 20 non-target pathogens. In artificial contamination experiments, the recovery rate of the quintuple RPA-EuNP-LFSBs was 90.6-101.6%, and the results were consistent with those of the culture method. In summary, the ultrasensitive bacterial LFSBs described in this study have the potential for widespread application in resource-poor areas. The study also provides insights in respect to multiple detection in the field.

The Associations Between Cataracts and Alzheimer's Disease: A Bidirectional Two-Sample Mendelian Randomization Study.

BACKGROUND: The relationship between cataracts and Alzheimer's disease (AD) has been reported in recent observational studies. However, it is still unclear whether a causal effect of cataracts on AD or reverse causation exists. OBJECTIVE: To explore the association between cataracts and AD genetically, we performed a bidirectional two-sample Mendelian randomization study. METHODS: We obtained genetic instrumental variables related to cataracts and AD from recently published genome-wide association studies (GWASs). SNP-outcome associations for AD were obtained from a GWAS with 111,326 cases and 677,663 controls. SNP-outcome associations for cataracts were drawn from two sources: a GWAS with 67,844 cases and 517,399 controls and the FinnGen consortium (42,843 cases and 262,698 controls). Inverse variance weighted (IVW) was used as the primary method for Mendelian randomization (MR) analyses. RESULTS: No genetic evidence suggested that cataracts were associated with the risk of AD (IVW odds ratio =1.04, 95% confidence interval: 0.98-1.10, p=0.199). In contrast, an effect of genetically determined AD on a decreased risk of cataract was observed with suggestive evidence (IVW odds ratio =0.96, 95% confidence interval: 0.93-0.99, p=0.004). However, this result might be distorted by survival bias. CONCLUSION: Genetically determined cataracts were not related to AD, as demonstrated by our study. In contrast, there was suggestive evidence that AD might prevent cataract development, but there might be potential survival bias. To define the exact association between the two diseases, more prospective research and studies on the pathogenesis are needed.

Efficacy and safety of the dexamethasone implant in vitrectomized and nonvitrectomized eyes with diabetic macular edema: A systematic review and meta-analysis.

Purpose: To compare the efficacy and safety of the intravitreal dexamethasone (DEX) implant for the treatment of diabetic macular edema (DME) in vitrectomized and nonvitrectomized eyes. Methods: We performed a literature search in four electronic databases (PubMed, EMBASE, MEDLINE, and Cochrane Library) from inception to 22 May 2022. Studies comparing the efficacy of the DEX implant in vitrectomized and nonvitrectomized eyes with DME with at least 3 months of follow-up were included. The main outcomes included comparison of the mean change in the best-corrected visual acuity (BCVA) and central macular thickness (CMT) from baseline to different follow-up endpoints between the vitrectomized and nonvitrectomized groups. The secondary outcomes were the mean duration of action for the first DEX implantation and the number of required injections throughout the follow-up period. Safety data were collected and compared. Results: The final analysis included 7 studies involving 582 eyes, 208 vitrectomized eyes and 374 nonvitrectomized eyes. The mean between-group differences in BCVA improvement were not significant at any endpoint, with averages difference of -0.07 logarithm of the minimum angle of resolution (logMAR) (p = 0.088) at 1 month, -0.03 logMAR (p = 0.472) 3 months, -0.07 logMAR (p = 0.066) 6 months, and -0.04 logMAR (p = 0.486) 12 months. The mean between-group differences in CMT reduction were not statistically significant, with mean differences of 7.17 µm (p = 0.685) at 1 month, 20.03 µm (p = 0.632) 3 months, -1.80 µm (p = 0.935) 6 months, and -25.65 µm (p = 0.542) 12 months. However, the vitrectomized group had a significantly shorter duration of action during the first DEX implantation than the nonvitrectomized group, with a mean difference of 0.8 months (p = 0.005). No significant between-group differences were detected for the number of required injections or safety profile. Conclusion: This meta-analysis showed similar efficacy and safety of the sustained-release DEX intravitreal implant for vitrectomized and nonvitrectomized eyes with DME. The intravitreal DEX implant could be considered an effective choice for DME treatment in eyes with prior vitrectomy.

Efficacy of single-dose intravitreal dexamethasone implantation for retinal vein occlusion patients with refractory macular edema: A systematic review and meta-analysis.

Purpose: To assess the functional and anatomical consequences of single-dose dexamethasone (DEX) implants for the treatment of refractory macular edema (ME) secondary to retinal vein occlusion (RVO) after anti-vascular endothelial growth factor agents. Methods: A literature search of studies on switching therapy to DEX implants from anti-VEGF agents in refractory RVO patients was performed with five electronic databases (PubMed, Embase, Web of Science, MEDLINE, and Cochrane Library) prior to January 2022. The main outcomes included best-corrected visual acuity (BCVA) and central macular thickness (CMT) changes at different follow-up endpoints from baseline. All analyses were performed using Stata version 15.0. Results: The final analysis included four eligible studies with a total of 99 patients. After single-dose DEX implant application, BCVA improved significantly at 2, 3, and 6 months with an average gain of -0.23 logarithm of the minimum angle of resolution (logMAR) (p = 0.004), -0.20 logMAR (p = 0.027), and -0.09 logMAR (p = 0.021), respectively. Mean CMT reduction was also significant from baseline to 2 months (-241.89 µm, p < 0.001), 3 months (-222.61 µm, p < 0.001), and 6 months (-90.49 µm, p < 0.001). No serious adverse events were observed in any of the included studies. Conclusion: This meta-analysis showed that RVO patients with refractory ME could benefit significantly from switching therapy to DEX implantation, with efficacy lasting 6 months after a single-dose application. Intravitreal DEX implantation is a safe and effective option for refractory cases.

Safety and efficacy profile of Trastuzumab deruxtecan in solid cancer: pooled reanalysis based on clinical trials.

PURPOSE: This study aimed to explore the efficiency and safety of the new generation antibody-drug conjugate Trastuzumab deruxtecan (DS-8201a) in treating HER2-positive solid cancers. METHOD: By searching PubMed, Medline and Ovid for all clinical trials related to the safety and efficacy of DS-8201a. Event rates were calculated for all adverse events (AEs) to evaluate the safety of DS-8201a. Objective response rate (ORR) and progression-free survival (PFS) were summarized to assess the potency of DS-8201a. RESULT: The AEs with event rates greater than 30% regardless of grades were nausea, decreased appetite, vomiting, fatigue, anemia, decreased neutrophil count, alopecia and diarrhea. In the grade 3 or more, decreased neutrophil count, anemia and decreased white blood cell count were the only three AEs with event rates greater than 10% (20.3, 15.0 and 10.3%). The median PFS of patients with breast cancer, gastric cancer and other HER2-positive solid cancers were 9.0-22.1, 3.0-8.3 and 4.1-11.9 months. The median ORR was 37-79.9% in patients with breast and gastric cancer and 28.3-55% in patients with other HER2-positive cancers. CONCLUSION: DS-8201a plays an active role in treating HER2-positive cancers, especially breast and gastric cancer, which have HER2 amplification. The most common AEs of DS-8201a were related to gastrointestinal and hematological system. Decreased white blood cell count and appetite were the AEs occurred with high grades.

Choroid and choriocapillaris changes in early-stage Parkinson's disease: a swept-source optical coherence tomography angiography-based cross-sectional study.

BACKGROUND: Parkinson's disease (PD) is one of the most common neurodegenerative diseases in the aging population. Previous literature has reported thinning of the retinal nerve fiber layer, ganglion cell layer, inner plexiform layer, and photoreceptor layer in PD patients. However, very few studies have used swept-source optical coherence tomography (SS-OCT) to study the choroid and choriocapillaris vascular changes in PD and their correlations with altered contrast sensitivity. METHODS: PD patients and controls were enrolled in the current study. We used a CSV-1000E instrument to assess contrast sensitivity and performed SS-OCT and SS-OCTA to measure outer retinal thickness, choroidal thickness, choriocapillaris flow density, choroidal vascular volume (CVV), and choroidal vascular index (CVI). RESULTS: One hundred eyes of 52 PD patients and 200 eyes of 100 healthy controls were recruited in the present study. Our study found remarkably impaired contrast sensitivity in PD patients (all P < 0.05). Significant thinning of the outer retinal layer and the choroid was appreciated in the PD group compared with the healthy controls (all P < 0.05). Choriocapillaris flow density, CVI, and CVV were significantly decreased in PD patients compared with healthy controls (all P < 0.05). Contrast sensitivity was weakly associated with outer retina thickness in the 3 mm circular area, with 3 cycles per degree being the most relevant (r = 0.535, P < 0.001). CONCLUSION: Our study indicates that there is a significant decrease in contrast sensitivity, outer retina thickness, choriocapillaris flow density, CVI, and CVV in PD patients. This research has also identified a positive correlation between outer retina thickness and contrast sensitivity.

Retinal microvascular changes in white matter hyperintensities investigated by swept source optical coherence tomography angiography.

BACKGRO: To assess the microvascular changes in the macular region and the foveal avascular zone (FAZ) area in participants with white matter hyperintensities (WMHs) using swept source optical coherence tomography angiography (SS OCTA). METHODS: This cross-sectional study included a total of 23 WMH participants (45 eyes) and 20 age-matched healthy participants (40 eyes). SS OCTA (VG200; SVision Imaging, Ltd., Luoyang, China) was used to assess the retinal vessel density (VD) and the FAZ area. VD was measured in the superficial vascular plexus (SVP), intermediate capillary plexus (ICP) and deep capillary plexus (DCP) within a 6 × 6-mm scan centred on the macula using a 5-mm Macula circle. The FAZ area was automatically measured on the inner retina layer within a 3 × 3-mm scan in the macular region. RESULTS: There was no significant difference in VD in the SVP between the two groups. However, VD in both the ICP and DCP was significantly decreased in WMH participants (P = 0.028, P = 0.016). The FAZ area was significantly enlarged in WMH participants (P = 0.030). The signal quality was significantly lower in WMH participants (P < 0.001). CONCLUSIONS: This study suggested that WMH participants have retinal microvascular and foveal avascular zone area changes compared with healthy controls. Further longitudinal studies with larger sample sizes are warranted to identify the value of our findings in the early evaluation of WMHs.

Efficacy and safety of single-dose dexamethasone implantation for patients with persistent diabetic macular edema: a systematic review and meta-analysis.

PURPOSE: This meta-analysis was conducted to evaluate the efficacy and safety of single-dose dexamethasone implantation for treating persistent DME (diabetic macular edema) refractory to anti-VEGF (anti-vascular endothelial growth factor) drugs over a period of 6 months. METHODS: All related clinical trials were reviewed by searching electronic databases of PubMed, Medline, Web of Science, Cochrane Library, and EMBASE. The primary outcome parameters were best-corrected visual acuity (BCVA) and central macular thickness (CMT). We performed this meta-analysis by using Stata15.0. RESULTS: Ten clinical trials involving 362 eyes from 328 patients were eligible in the final analysis. After single-dose dexamethasone implantation, there was a significant improvement in BCVA from baseline to 1, 3, and 6 months with an average increase of - 0.15 logMAR (p < 0.001), - 0.14 logMAR (p < 0.001), and - 0.07 logMAR (p = 0.004), respectively. Further, mean CMT decreased significantly with an average reduction of 249.18 µm (p < 0.001), 217.66 µm (p < 0.001), and 91.56 µm (p < 0.001) at months 1, 3, and 6, respectively. CONCLUSIONS: Our results indicate that switching to a dexamethasone implant could achieve significant anatomical and functional improvement among patients with refractory DME. Clinicians should be aware of this treatment option in refractory DME.

Differentiation of Intrahepatic Cholangiocarcinoma and Hepatic Lymphoma Based on Radiomics and Machine Learning in Contrast-Enhanced Computer Tomography.

Purpose: This study aimed to explore the ability of texture parameters combining with machine learning methods in distinguishing intrahepatic cholangiocarcinoma (ICCA) and hepatic lymphoma (HL). Method: A total of 28 patients with HL and 101 patients with ICCA were included. A total of 45 texture features were extracted by the software LifeX from contrast-enhanced computer tomography (CECT) images and 38 of them were eligible. A total of 5 feature selection methods and 9 feature classification methods were used to build the best diagnostic models, combining with the 10-fold cross-validation to assess the accuracy of these models. The discriminative ability of each model was evaluated by receiver operating characteristic analysis. Result: A total of 45 predictive models were built by the cross combination of each selection and classification method to differentiate ICCA from HL. According to the results of test group, most of the models performed well with a large area under the curve (AUC) (>0.85) and high accuracy (>0.85). Random Forest (RF)_Linear Discriminant Analysis (LDA) (AUC = 0.997, accuracy = 0.969) was the best model among all the 45 models. Conclusion: Combining texture parameters from CECT with multiple machine learning models can differentiate ICCA and HL effectively, and RF_LDA performed the best in this process.

Retinal Flow Density Changes in Early-stage Parkinson's Disease Investigated by Swept-Source Optical Coherence Tomography Angiography.

Background: Parkinson's Disease (PD) is the second-most common neurodegenerative disease affecting the elderly population. The eye has been referred to as a window to the brain due to its inseparable relationship with the central nervous system. The development of Swept-Source Optical Coherence Tomography (SS-OCT) and Optical Coherence Tomography Angiography (OCTA) technologies has offered us a better imaging modality to study the impact of PD on the retina.Method: Seventy-five eyes of 42 early-stage PD patients and 150 eyes of 75 matched healthy controls were enrolled in the current study. We performed SS-OCT and SS-OCTA to assess retinal nerve fiber layer (RNFL), ganglion cell layer (GCL) + inner plexiform layer (IPL), internal nuclear layer (INL) thickness, and retinal flow density and flow ratio.Results: Our study indicates decreasing superficial and deep flow density in most regions of the retina. Superficial and deep flow parameters were also associated with RNFL, GCL+IPL, and INL thickness. ROC analysis reveals superficial flow density demonstrated an Area Under Curve (AUC) of 0.688, which is greater than deep flow density and retinal thickness measurements.Conclusion: To the best of our knowledge, we are the first study using SS-OCT and SS-OCTA to study superficial and deep retinal flow changes in early-stage PD patients. Our study suggests decreasing retinal flow density provides greater diagnostic power than retinal thickness measurements in the early stage of PD. SS-OCTA parameters could potentially serve as imaging biomarkers in PD diagnosis and staging.