Differences in Topography of Individual Amyloid Brain Networks by Amyloid PET Images in Healthy Control, Mild Cognitive Impairment, and Alzheimer's Disease.

Amyloid plaques, implicated in Alzheimer's disease, exhibit a spatial propagation pattern through interconnected brain regions, suggesting network-driven dissemination. This study utilizes PET imaging to investigate these brain connections and introduces an innovative method for analyzing the amyloid network. A modified version of a previously established method is applied to explore distinctive patterns of connectivity alterations across cognitive performance domains. PET images illustrate differences in amyloid accumulation, complemented by quantitative network indices. The normal control group shows minimal amyloid accumulation and preserved network connectivity. The MCI group displays intermediate amyloid deposits and partial similarity to normal controls and AD patients, reflecting the evolving nature of cognitive decline. Alzheimer's disease patients exhibit high amyloid levels and pronounced disruptions in network connectivity, which are reflected in low levels of global efficiency (Eg) and local efficiency (Eloc). It is mostly in the temporal lobe where connectivity alterations are found, particularly in regions related to memory and cognition. Network connectivity alterations, combined with amyloid PET imaging, show potential as discriminative markers for different cognitive states. Dataset-specific variations must be considered when interpreting connectivity patterns. The variability in MCI and AD overlap emphasizes the heterogeneity in cognitive decline progression, suggesting personalized approaches for neurodegenerative disorders. This study contributes to understanding the evolving network characteristics associated with normal cognition, MCI, and AD, offering valuable insights for developing diagnostic and prognostic markers.

Altered assembly paths mitigate interference among paralogous complexes.

Protein complexes are fundamental to all cellular processes, so understanding their evolutionary history and assembly processes is important. Gene duplication followed by divergence is considered a primary mechanism for diversifying protein complexes. Nonetheless, to what extent assembly of present-day paralogous complexes has been constrained by their long evolutionary pathways and how cross-complex interference is avoided remain unanswered questions. Subunits of protein complexes are often stabilized upon complex formation, whereas unincorporated subunits are degraded. How such cooperative stability influences protein complex assembly also remains unclear. Here, we demonstrate that subcomplexes determined by cooperative stabilization interactions serve as building blocks for protein complex assembly. We further develop a protein stability-guided method to compare the assembly processes of paralogous complexes in cellulo. Our findings support that oligomeric state and the structural organization of paralogous complexes can be maintained even if their assembly processes are rearranged. Our results indicate that divergent assembly processes by paralogous complexes not only enable the complexes to evolve new functions, but also reinforce their segregation by establishing incompatibility against deleterious hybrid assemblies.

Long-Term Survival and Regeneration Following Transplantation of 3D-Printed Biodegradable PCL Tracheal Grafts in Large-Scale Porcine Models.

Polycaprolactone (PCL) implants in large animals show great promise for tracheal transplantation. However, the longest survival time achieved to date is only about three weeks. To meet clinical application standards, it is essential to extend the survival time and ensure the complete integration and functionality of the implant. Our study investigates the use of three-dimensional (3D)-printed, biodegradable, PCL-based tracheal grafts for large-scale porcine tracheal transplantation, assessing the feasibility and early structural integrity crucial for long-term survival experiments. A biodegradable PCL tracheal graft was fabricated using a BIOX bioprinter and transplanted into large-scale porcine models. The grafts, measuring 20 × 20 × 1.5 mm, were implanted following a 2 cm circumferential resection of the porcine trachea. The experiment design was traditionally implanted in eight porcines to replace four-ring tracheal segments, only two of which survived more than three months. Data were collected on the graft construction and clinical outcomes. The 3D-printed biosynthetic grafts replicated the native organ with high fidelity. The implantations were successful, without immediate complications. At two weeks, bronchoscopy revealed significant granulation tissue around the anastomosis, which was managed with laser ablation. The presence of neocartilage, neoglands, and partial epithelialization near the anastomosis was verified in the final pathology findings. Our study demonstrates in situ regenerative tissue growth with intact cartilage following transplantation, marked by neotissue formation on the graft's exterior. The 90-day survival milestone was achieved due to innovative surgical strategies, reinforced with strap muscle attached to the distal trachea. Further improvements in graft design and granulation tissue management are essential to optimize outcomes.

Mechanisms of mitochondrial resilience in teleostean radial glia under hypoxic stress.

Radial glial cells (RGCs) are remarkable cells, essential for normal development of the vertebrate central nervous system. In teleost fishes, RGCs play a pivotal role in neurogenesis and regeneration of injured neurons and glia. RGCs also exhibit resilience to environmental stressors like hypoxia via metabolic adaptations. In this study, we assessed the physiology of RGCs following varying degrees of hypoxia, with an emphasis on reactive oxygen species (ROS) generation, mitochondrial membrane potential (MMP), mitophagy, and energy metabolism. Our findings demonstrated that hypoxia significantly elevated ROS production and induced MMP depolarization in RGCs. The mitochondrial disturbances were closely associated with increased mitophagy, based on the co-localization of mitochondria and lysosomes. Key mitophagy-related genes were also up-regulated, including those of the BNIP3/NIX mediated pathway as well as the FUNDC1 mediated pathway. Such responses suggest robust cellular mechanisms are initiated to counteract mitochondrial damage due to increasing hypoxia. A significant metabolic shift from oxidative phosphorylation to glycolysis was also observed in RGCs, which may underlie an adaptive response to sustain cellular function and viability following a reduction in oxygen availability. Furthermore, hypoxia inhibited the synthesis of mitochondrial complexes subunits in RGCs, potentially related to elevated HIF-2α expression with 3 % O2. Taken together, RGCs appear to exhibit complex adaptive responses to hypoxic stress, characterized by metabolic reprogramming and the activation of mitophagy pathways to mitigate mitochondrial dysfunction.

Study of Power Equivalent Continuous Approximation Based on the Recent Consensus Recommendations for Brain Tumor Imaging with Pulsed Chemical Exchange Saturation Transfer at 3T.

The quantitative analysis of pulsed-chemical exchange saturation transfer (CEST) using a full model-based method is computationally challenging, as it involves dealing with varying RF values in pulsed saturation. A power equivalent continuous approximation of B1 power was usually applied to accelerate the analysis. In line with recent consensus recommendations from the CEST community for pulsed-CEST at 3T, particularly recommending a high RF saturation power (B1 = 2.0 µT) for the clinical application in brain tumors, this technical note investigated the feasibility of using average power (AP) as the continuous approximation. The simulated results revealed excellent performance of the AP continuous approximation in low saturation power scenarios, but discrepancies were observed in the z-spectra for the high saturation power cases. Cautions should be taken, or it may lead to inaccurate fitted parameters, and the difference can be more than 10% in the high saturation power cases.

Severe Occlusive Retinal Vasculitis in an Immunocompetent Patient with Chronic CMV Anterior Uveitis.

PURPOSE: We report a unique case of non-necrotizing occlusive retinal vasculitis presenting two years following chronic hypertensive uveitis. METHODS: Case Report. RESULTS: A 32-year-old Iraqi woman with a history of Posner-Schlossman Syndrome diagnosed 10 years prior presented with blurred vision and redness in her left eye. Examination demonstrated ocular hypertension, keratic precipitates, and inflammatory cells in the anterior chamber. Quantitative real-time PCR confirmed the presence of cytomegalovirus in the aqueous humor, and dilated posterior segment examination was negative for any signs of intraocular inflammation, retinitis, or vasculitis. Her uveitis workup was otherwise negative, and she was treated with valganciclovir for 6 months. Two years after her initial presentation, she was noted to have a new vitreous hemorrhage in the left eye. Fluorescein angiography demonstrated an occlusive retinal vasculitis with extensive neovascularization without retinitis. Quantitative real-time PCR again demonstrated the presence of cytomegalovirus in the anterior chamber. Her uveitis workup was repeated, which has now returned positive for HLA-B51. She otherwise did not demonstrate any systemic signs of Behcet's Disease. She was restarted on valganciclovir and oral prednisone and referred to rheumatology for consideration of adalimumab initiation. Thus far she has responded very well to treatment. CONCLUSION: This case highlights the importance of serial posterior segment examinations and HLA-B51 testing in individuals with cytomegalovirus anterior uveitis.

Mitigating environmental pollution in China: Unlocking the potential for high-quality innovation.

The nexus between environmental pollution (EP) and technological innovation is crucial for achieving sustainable development. However, existing literature has paid less attention to the new form of high-quality innovation (HI) in environmental management. This paper uses panel data from 31 Chinese provinces from 2008 to 2020, employing the two-stage least squares method to investigate the relationship between HI and EP. The empirical results reveal that HI can effectively reduce the EP, which holds after multiple robustness tests, and this effect is more obvious in southern China. Meanwhile, HI drives clean and efficient energy transition and decreases EP. Moreover, increased environmental regulation weakens the influence of HI on EP. The major contributions of this study are constructing an HI index including innovation, human capital, and government support and examining its influence on EP in China. The findings encourage government to implement policies of innovation-driven transformation, energy conservation and emissions reduction.

Substitutions in the nonactive site of the passenger domain on the activity of Haemophilus influenzae immunoglobulin A1 protease.

Immunoglobulin A1 (IgA1) protease is a critical virulence factor of Haemophilus influenzae that facilitates bacterial mucosal infection. This study investigates the effect of iga gene polymorphism on the enzymatic activity of H. influenzae IgA1 protease. The IgA1 protease activity was examined in the H. influenzae Rd KW20 strain and 51 isolates. Genetic variations in iga and deduced amino acid substitutions affecting IgA1 protease activity were assessed. Machine learning tools and functional complementation assays were used to analyze the effects of identified substitutions on the stability and activity of IgA1 protease, respectively. All 51 isolates exhibited similar iga expression levels. No igaB expression was detected. According to comparisons with the reference Rd KW20 strain, four substitutions in the protease domain, 26 in the nonprotease passenger domain, and two in the ß-barrel domain were associated with the change in IgA1 protease activity. No substitutions in the catalytic site of IgA1 protease were observed. Logistic regression, receiver operating characteristic curves, Venn diagrams, and protein stability analyses revealed that the substitutions Asn352Lys, Pro353Ala, Lys356Asn, Gln916Lys, and Gly917Ser, which were located in the nonactive site of the passenger domain, were associated with decreases in IgA1 protease activity and stability, whereas Asn914Lys was associated with an increase in these events. Functional complementation assays revealed that the Asn914Lys substitution increased IgA1 protease activity in the Rd KW20 strain. This study identified substitutions in the nonactive site of the passenger domain that affect both the activity and stability of H. influenzae IgA1 protease.

Evaluation and validation of a PrintrLab-based LAMP assay to identify Trypanosoma cruzi in newborns in Bolivia: a proof-of-concept study.

BACKGROUND: Vertical transmission of Trypanosoma cruzi represents approximately 20% of new Chagas disease cases. Early detection and treatment for women of childbearing age and newborns is a public health priority, but the lack of a simple and reliable diagnostic test remains a major barrier. We aimed to evaluate the performance of a point-of-care loop-mediated isothermal amplification (LAMP) assay for the detection of T cruzi. METHODS: In this proof-of-concept study, we coupled a low-cost 3D printer repurposed for sample preparation and amplification (PrintrLab) to the Eiken T cruzi-LAMP prototype to detect vertically transmitted T cruzi, which we compared with standardised PCR and with the gold-standard algorithm (microscopy at birth and 2 months and serological study several months later). We screened pregnant women from two hospitals in the Bolivian Gran Chaco province, and those who were seropositive for T cruzi were offered the opportunity for their newborns to be enrolled in the study. Newborns were tested by microscopy, LAMP, and PCR at birth and 2 months, and by serology at 8 months. FINDINGS: Between April 23 and Nov 17, 2018, 986 mothers were screened, among whom 276 were seropositive for T cruzi (28·0% prevalence, 95% CI 25·6-31·2). In total, 224 infants born to 221 seropositive mothers completed 8 months of follow-up. Congenital transmission was detected in nine of the 224 newborns (4·0% prevalence, 1·9-7·5) by direct microscopy observation, and 14 more cases were diagnosed serologically (6·3%, 3·6-10·3), accounting for an overall vertical transmission rate of 10·3% (6·6-15·0; 23 of 224). All microscopy-positive newborns were positive by PrintrLab-LAMP and by PCR, while these techniques respectively detected four and five extra positive cases among the remaining 215 microscopy-negative newborns. INTERPRETATION: The PrintrLab-LAMP yielded a higher sensitivity than microscopy-based analysis. Considering the simpler use and expected lower cost of LAMP compared with PCR, our findings encourage its evaluation in a larger study over a wider geographical area. FUNDING: Inter-American Development Bank.

Using ensemble learning and hierarchical strategy to predict the outcomes of ESWL for upper ureteral stone treatment.

Urinary tract stones are a common and frequently recurring medical issue. Accurately predicting the success rate after surgery can help avoid ineffective medical procedures and reduce unnecessary healthcare costs. This study collected data from patients with upper ureter stones who underwent extracorporeal shock wave lithotripsy, including cases of successful as well as unsuccessful stone removal after the first and second lithotripsy procedures, and constructed prediction systems for the outcomes of the first and second lithotripsy procedures. Features were extracted from three categories of information: patient characteristics, stone characteristics, and extracorporeal shock wave lithotripsy machine data, and additional features were created using Feature Creation. Finally, the impact of features on the models was analyzed using six methods to calculate feature importance. Our prediction model for the first lithotripsy, selected from among 43 methods and seven ensemble learning techniques, achieves an AUC of 0.91. For the second lithotripsy, the AUC reaches 0.76. The results indicate that the detailed and binary information provided by patients regarding their history of stone experiences contributes differently to the predictive accuracy of the first and second lithotripsy procedures. The prediction tool is available at https://predictor.isu.edu.tw/ks.

Cetacean Stranding Response Program and Spatial-Temporal Analysis in Taiwan, 1994-2018.

A national cetacean stranding response program in Taiwan has evolved significantly in the past three decades. Initially co-ordinated by National Taiwan University from 1994, the program transitioned to the Taiwan Cetacean Society in 1999, and local governments took on a more prominent role after 2009. A comprehensive stranding database (1994-2018) has been maintained, which documented 1320 stranding events involving 1698 animals from at least 27 species. The most commonly stranded species include finless porpoises, bottlenose dolphins, Kogia spp., and Risso's dolphins. The stranding rates varied annually and seasonally, with increases noted from an average of 16 events per year for the first 3 years to 44-58 events per year between 1997 and 2015, and a sharp rise to over 90 events per year for the period of the last three years. Seasonal variations were also significant, with higher stranding rates during the northeastern monsoon (NEM, October to next April) than that during southwestern monsoon (SWM, May to September). From the aspect of distribution, more frequent and even strandings occurred along the coast of northern Taiwan, while mass strandings were concentrated in the southwestern counties during NEM. Among all strandings, 390 events (29.5%) and 660 animals (38.9%) were live ones. Under great effort in rescuing and rehabilitating 52 cases, 15 cetacean individuals have been released since 2000. Additionally, there have been 56 mass strandings involving at least 11 species since 1994, predominated by pygmy killer whales, particularly during the NEM season along the southwest coast. This study not only contributes to our understanding of the stranding patterns and diversity of the cetaceans in Taiwan, but also provides valuable insights for future conservation strategies on cetaceans in the western Pacific.

Effects of Visual Art Therapy on Positive Symptoms, Negative Symptoms, and Emotions in Individuals with Schizophrenia: A Systematic Review and Meta-Analysis.

Schizophrenia is characterized by psychiatric symptoms and emotional issues. While pharmacological treatments have limitations, non-pharmacological interventions are essential. Art therapy has the potential to enhance emotional expression, communication, and health; however, the effectiveness of visual art therapy remains uncertain. This systematic review and meta-analysis synthesizes the findings of randomized controlled trials (RCTs) of visual art therapy on positive symptoms, negative symptoms, and emotions in patients with schizophrenia. This study reviews RCTs published prior to February, 2024. The PubMed, Embase, Cochrane Library, CEPS, CNKI, Wanfang, and Yiigle databases were searched, and three independent researchers screened the studies. In this meta-analysis, standardized mean difference (SMD) was employed as a measure to calculate effect sizes for continuous variables using a random effects model, while the meta-regression and subgroup analyses were performed with patient and intervention characteristics. A total of 31 studies revealed visual art therapy had a significant small-to-moderate effect on positive symptoms (SMD = 0.407, 95% CI 0.233 to 0.581), a moderate effect on negative symptoms (SMD = 0.697, 95% CI 0.514 to 0.880), a moderate effect on depression (SMD = 0.610, 95% CI 0.398 to 0.821), and a large effect on anxiety (SMD = 0.909, 95% CI 0.386 to 1.433). The subgroup analysis revealed painting and handcrafts had significant effects on positive symptoms, negative symptoms, and emotions. Combined Chinese calligraphy and painting had significant effects on positive symptoms, depression, and anxiety. Better improvement was noted among the Asian population, and a longer weekly treatment duration was associated with better improvement in positive symptoms. Female participants tended to have more improvements in negative symptoms and anxiety through visual art therapy. The results indicate that visual art therapy has positive effects on the psychiatric symptoms and emotions of individuals with schizophrenia. We recommend future research further investigate art therapy modalities and durations.

Clinical Significance of the Plasma Biomarker Panels in Amyloid-Negative and Tau PET-Positive Amnestic Patients: Comparisons with Alzheimer's Disease and Unimpaired Cognitive Controls.

The purpose of this study was to investigate whether plasma biomarkers can help to diagnose, differentiate from Alzheimer disease (AD), and stage cognitive performance in patients with positron emission tomography (PET)-confirmed primary age-related tauopathy, termed tau-first cognitive proteinopathy (TCP) in this study. In this multi-center study, we enrolled 285 subjects with young-onset AD (YOAD; n = 55), late-onset AD (LOAD; n = 96), TCP (n = 44), and cognitively unimpaired controls (CTL; n = 90) and analyzed plasma Aß42/Aß40, pTau181, neurofilament light (NFL), and total-tau using single-molecule assays. Amyloid and tau centiloids reflected pathological burden, and hippocampal volume reflected structural integrity. Receiver operating characteristic curves and areas under the curves (AUCs) were used to determine the diagnostic accuracy of plasma biomarkers compared to hippocampal volume and amyloid and tau centiloids. The Mini-Mental State Examination score (MMSE) served as the major cognitive outcome. Logistic stepwise regression was used to assess the overall diagnostic accuracy, combining fluid and structural biomarkers and a stepwise linear regression model for the significant variables for MMSE. For TCP, tau centiloid reached the highest AUC for diagnosis (0.79), while pTau181 could differentiate TCP from YOAD (accuracy 0.775) and LOAD (accuracy 0.806). NFL reflected the clinical dementia rating in TCP, while pTau181 (rho = 0.3487, p = 0.03) and Aß42/Aß40 (rho = -0.36, p = 0.02) were significantly correlated with tau centiloid. Hippocampal volume (unstandardized ß = 4.99, p = 0.01) outperformed all of the fluid biomarkers in predicting MMSE scores in the TCP group. Our results support the superiority of tau PET to diagnose TCP, pTau181 to differentiate TCP from YOAD or LOAD, and NFL for functional staging.

Neuromodulatory Responses Elicited by Intermittent versus Continuous Transcranial Focused Ultrasound Stimulation of the Motor Cortex in Rats.

Transcranial focused ultrasound stimulation (tFUS) has emerged as a promising neuromodulation technique that delivers acoustic energy with high spatial resolution for inducing long-term potentiation (LTP)- or depression (LTD)-like plasticity. The variability in the primary effects of tFUS-induced plasticity could be due to different stimulation patterns, such as intermittent versus continuous, and is an aspect that requires further detailed exploration. In this study, we developed a platform to evaluate the neuromodulatory effects of intermittent and continuous tFUS on motor cortical plasticity before and after tFUS application. Three groups of rats were exposed to either intermittent, continuous, or sham tFUS. We analyzed the neuromodulatory effects on motor cortical excitability by examining changes in motor-evoked potentials (MEPs) elicited by transcranial magnetic stimulation (TMS). We also investigated the effects of different stimulation patterns on excitatory and inhibitory neural biomarkers, examining c-Fos and glutamic acid decarboxylase (GAD-65) expression using immunohistochemistry staining. Additionally, we evaluated the safety of tFUS by analyzing glial fibrillary acidic protein (GFAP) expression. The current results indicated that intermittent tFUS produced a facilitation effect on motor excitability, while continuous tFUS significantly inhibited motor excitability. Furthermore, neither tFUS approach caused injury to the stimulation sites in rats. Immunohistochemistry staining revealed increased c-Fos and decreased GAD-65 expression following intermittent tFUS. Conversely, continuous tFUS downregulated c-Fos and upregulated GAD-65 expression. In conclusion, our findings demonstrate that both intermittent and continuous tFUS effectively modulate cortical excitability. The neuromodulatory effects may result from the activation or deactivation of cortical neurons following tFUS intervention. These effects are considered safe and well-tolerated, highlighting the potential for using different patterns of tFUS in future clinical neuromodulatory applications.

Defining breast cancer-related lymphedema (BCRL) prevalence and risk factors: A pragmatic approach to lymphedema surveillance.

Introduction: We presented the key findings from Singapore's Changi General Hospital Breast Centre's lymphedema surveillance strategy that used patients' reported symptoms, standard arm circumference measurements and clinical assessment in the diagnosis of breast cancer-related lymphedema (BCRL). Our secondary aim was to highlight and discuss important elements of a surveillance strategy that can be implemented to track this outcome measure of breast cancer treatment for future research. Method: We conducted a cross-sectional study of 511 breast cancer patients to assess the prevalence of BCRL and its associated risk factors. We defined BCRL prevalence rates based on patients' self-reporting, objective arm circumference measure-ments and clinical diagnosis based on International Society of Lymphology (ISL) staging. Results: The median follow-up of patients was 88.8 months. The cumulative prevalence rate in the cohort was 30.9%. The cohort of BCRL patients were older (58.4 versus [vs] 54.9 years), had higher mean Body Mass Index (27.7 vs 25.2), higher proportion of mastectomy (77% vs 64.3%), axillary clearance, less likely breast reconstruction, higher-grade tumour, more lymph nodes excised, more advanced nodal disease, and had undergone adjuvant chemotherapy. However, clinically apparent BCRL was only 6.5% (33 out of 511 patients). The proportion of clinically significant BCRL in patients undergoing sentinel lymph node biopsy (SLNB) or axillary sampling was 1.7% compared to 9.9% in patients who had undergone axillary clearance. Majority of the BCRL were subclinical or mild in severity. Conclusion: Our study showed that our rates of BCRL were comparable to international rates and highlighted similar patient profiles who were at risk of developing the disease. Having a comprehensive lymphedema surveillance strategy is paramount in paving the way for future studies.

Membranome-based identification of amino acid substitution in Haemophilus influenzae multidrug efflux pump HmrM for reduced chloramphenicol susceptibility.

A decreased chloramphenicol susceptibility in Haemophilus influenzae is commonly caused by the activity of chloramphenicol acetyltransferases (CATs). However, the involvement of membrane proteins in chloramphenicol susceptibility in H. influenzae remains unclear. In this study, chloramphenicol susceptibility testing, whole-genome sequencing, and analyses of membrane-related genes were performed in 51 H. influenzae isolates. Functional complementation assays and structure-based protein analyses were conducted to assess the effect of proteins with sequence substitutions on the minimum inhibitory concentration (MIC) of chloramphenicol in CAT-negative H. influenzae isolates. Six isolates were resistant to chloramphenicol and positive for type A-2 CATs. Of these isolates, A3256 had a similar level of CAT activity but a higher chloramphenicol MIC relative to the other resistant isolates; it also had 163 specific variations in 58 membrane genes. Regarding the CAT-negative isolates, logistic regression and receiver operator characteristic curve analyses revealed that 48T > G (Asn16Lys), 85 C > T (Leu29Phe), and 88 C > A (Leu30Ile) in HI_0898 (emrA), and 86T > G (Phe29Cys) and 141T > A (Ser47Arg) in HI_1177 (artM) were associated with enhanced chloramphenicol susceptibility, whereas 997G > A (Val333Ile) in HI_1612 (hmrM) was associated with reduced chloramphenicol susceptibility. Furthermore, the chloramphenicol MIC was lower in the CAT-negative isolates with EmrA-Leu29Phe/Leu30Ile or ArtM-Ser47Arg substitution and higher in those with HmrM-Val333Ile substitution, relative to their counterparts. The Val333Ile substitution was associated with enhanced HmrM protein stability and flexibility and increased chloramphenicol MICs in CAT-negative H. influenzae isolates. In conclusion, the substitution in H. influenzae multidrug efflux pump HmrM associated with reduced chloramphenicol susceptibility was characterised.