Medin synergized with vascular amyloid-beta deposits accelerates cognitive decline in Alzheimer's disease:a potential biomarker

Brain vascular dysfunction in Alzheimer s disease(AD) pathogenesis has become increasingly clea r.Accumulating evidence shows that damaged vascular,including large or small vessels and even neurovascular unit,may accelerate the neuropathological process of AD via disrupting brain hypoperfusion,aberrant angiogenesis,and neuroinflammatory response,etc.Thus,vascular dysfunction makes a substantially contribution to the cognitive decline of AD patients.

Role of peripheral amyloid-β aggregates in Alzheimer’s disease: mechanistic, diagnostic, and therapeutic implications

Compelling evidence demonstrates that the levels of peripheral amyloid-β(Aβ)fluctuate in Alzheimer’s disease(AD)patients.Moreover,Aβdeposits have been identified in peripheral tissues.However,the relevance of peripheral Aβ(misfolded or not)in pathological situations,and the temporal appearance of these pathological fluctuations,are not well understood.The presence of misfolded Aβin peripheral compartments raises concerns on potential inter-individual transmissions considering the well-reported prion-like properties of this disease-associated protein.The latter is supported by multiple reports demonstrating that Aβmisfolding can be transmitted between humans and experimental animals through multiple routes of exposure.In this mini-review,we discuss the potential implications of peripheral,disease-associated Aβin disease mechanisms,as well as in diagnostic and therapeutic approaches.

Misfolded amyloid-beta conformational variants(strains)as drivers of Alzheimer's disease neuropathology

Pathological and clinical variability in Alzheimer's disease(AD):AD is clinically cha racterized by progressive memory loss and cognitive impairment.From a pathological point of view,the main features of AD are the deposition of amyloid plaques(composed of amyloid-beta,Aβ)and neurofibrillary tangles containing hyperphosphorylated Tau in the brain,accompanied by neu ronal and synaptic loss,neuroinflammation and brain atrophy(Jellinger,2022).Regardless of these common traits,growing evidence shows increased heterogen eity in the brain of AD patients considering both clinical manifestations and pathological features.

Corrigendum: Activation of autophagy by Citri Reticulatae Semen extract ameliorates amyloid-beta-induced cell death and cognition deficits in Alzheimer’s disease

In the article titled“Activation of autophagy by Citri Reticulatae Semen extract ameliorates amyloid-beta-induced cell death and cognition deficits in Alzheimer’s disease”published on pages 2467-2479,Issue 11,Volume 19 of Neural Regeneration Research(Tang et al.,2024),there are some errors in selecting the appropriate images in Figure 7 by authors during assembling the images.

Design and redesign journey of a drug for transthyretin amyloidosis

The misfolding and subsequent aggregation of proteins into amyloid fibrils underlie the onset of a variety of human disorders collectively known as amyloidosis.Transthyretin(TTR)is one of the>30 amyloidogenic proteins identified to date and is associated with a group of highly debilitating and life-threatening disorders called TTR amyloidosis(ATTR).ATTR comprises senile systemic amyloidosis,which is linked to wild-type(WT)TTR aggregation,and hereditary ATTR,a dominantly inherited disorder caused by the deposition of one of over 130 TTR genetic variants.Senile systemic amyloidosis is a prevalent age-related amyloidosis,affecting up to 25%of the population over 80 years of age,and is characterized by the build-up of TTR fibrils in the myocardium.Regarding hereditary ATTR,the clinical presentation is highly heterogeneous,primarily affecting the peripheral nervous system(familial amyloid polyneuropathy-FAP)or the heart(familial amyloid cardiomyopathy).In rare cases,aggregation develops in the central nervous system,giving rise to a phenotype known as familial leptomeningeal amyloidosis(Carroll et al.,2022).

Anti-amyloid antibodies in Alzheimer’s disease: what did clinical trials teach us?

Although many causes of Alzheimer’s disease(AD)may exist,both the original amyloid cascade and tau hypotheses posit that abnormal misfolding and accumulation of amyloid-β(Aβ)and tau protein is the central event causing the pathology.However,that conclusion could be only partly true,and there is conflicting evidence about the role of both proteins in AD,being able to precede and influence one another.Some researchers argue that these proteins are mere executors rather than primary causes of pathology.Therefore,there have been continuing refinements of both hypotheses,with alternative explanations proposed.Aβand tau proteins may be independently involved in specific neurotoxic pathways;yet there may be other crucial processes going on in early AD.Moreover,accumulating evidence suggests that Aβand tau act synergistically,rather than additively in disease onset(Jeremic et al.,2021,2023a).

Beyond neurodegeneration:engineering amyloids for biocatalysis

Amyloid fibrils are highly organized protein or peptide aggregates,often characterized by a distinctive supramolecular cross-β-sheet structure.The formation and accumulation of these structures have been traditionally associated with neural or systemic human diseases,such as Alzheimer’s disease,Parkinson’s disease,type-2 diabetes,or amyotrophic lateral sclerosis(Wei et al.,2017;Wittung-Stafshede,2023).

Impact of Pollutant Concentration and Particle Deposition on the Radiative Flow of Casson-Micropolar Fluid between Parallel Plates

Assessing the behaviour and concentration of waste pollutants deposited between two parallel plates is essential for effective environmental management.Determining the effectiveness of treatment methods in reducing pollution scales is made easier by analysing waste discharge concentrations.The waste discharge concentration analysis is useful for assessing how effectively wastewater treatment techniques reduce pollution levels.This study aims to explore the Casson micropolar fluid flow through two parallel plates with the influence of pollutant concentration and thermophoretic particle deposition.To explore the mass and heat transport features,thermophoretic particle deposition and thermal radiation are considered.The governing equations are transformed into ordinary differential equations with the help of suitable similarity transformations.The Runge-Kutta-Fehlberg’s fourthfifth order technique and shooting procedure are used to solve the reduced set of equations and boundary conditions.The integration of a neural network model based on the Levenberg-Marquardt algorithm serves to improve the accuracy of predictions and optimize the analysis of parameters.Graphical outcomes are displayed to analyze the characteristics of the relevant dimensionless parameters in the current problem.Results reveal that concentration upsurges as the micropolar parameter increases.The concentration reduces with an upsurge in the thermophoretic parameter.An upsurge in the external pollutant source variation and the local pollutant external source parameters enhances mass transport.The surface drag force declines for improved values of porosity and micropolar parameters.

Influence of laser shock peening on microstructure and high-temperature oxidation resistance of Ti45Al8Nb alloy fabricated via laser melting deposition

Laser shock peening(LSP)was used to enhance the high-temperature oxidation resistance of laser melting deposited Ti45Al8Nb alloy.The microstructure and high-temperature oxidation behavior of the as-deposited Ti45Al8Nb alloy before and after LSP were investigated by scanning electron microscopy,X-ray diffraction,and electron backscatter diffraction.The results indicated that the rate of mass gain in the as-deposited sample after LSP exhibited a decrease when exposed to an oxidation temperature of 900℃,implying that LSP-treated samples exhibited superior oxidation resistance at high temperatures.A gradient structure with a fine-grain layer,a deformed-grain layer,and a coarse-grain layer was formed in the LSP-treated sample,which facilitated the diffusion of the Al atom during oxidation,leading to the formation of a dense Al_(2)O_(3)layer on the surface.The mechanism of improvement in the oxidation resistance of the as-deposited Ti45Al8Nb alloy via LSP was discussed.

Vitreous amyloidosis caused by Lys55Asn mutation in TTR with peripheral neuropathy onset:a case report of FAP-related complications

Dear Editor,We present a case of vitreous amyloidosis in a patient who was previously confirmed as familial amyloidosis polyneuropathy(FAP)because of peripheral neuropathy symptom onset.Even though the patient had already undergone liver transplantation 5y prior,the extracellular deposition of amyloid in vitreous body greatly infected the patient’s visual function.

De novo intraocular amyloid deposition after hepatic transplantation in familial amyloidotic polyneuropathy

The familiar amyloid polyneuropathy(FAP) is a rare autosomal-dominant systemic amyloidosis. Amyloid deposition occurs more frequently and extensively in the vitq. The increase in intraocular pressure(IOP) is a result of deposition of transthyretin(TTR) in trabecular meshwork. Rarely, the amyloid deposition in anterior segment can be more exuberant than in posterior segment. A 42 years old man, with FAP(Val30Met mutation), liver transplantation in 1997. He was asymptomatic, without any significant ocular abnormality until 2011. In 2011 he had an episode of pain in right eye(RE). Scalloped pupils, pupillary amyloid deposits and subtle vitreous opacities were detected. The IOP was 40 mmHg in RE and 28 mmHg in left eye(LE) with open angle. Optical coherence tomography detected a temporal superior retinal nerve fiber layer defect in LE and perimetry was normal. Topical timolol was initiated, and brimonidine was subsequently added to improve IOP control, which was achieved with topical medication until last evaluation. No progression occurred since 2011. Actually, with longer life expectancies, there is an increased risk of ocular involvement in FAP, even after liver transplantation. Although rare, a more exuberant amyloid deposition in anterior segment vs posterior segment can occur, and supports an important role of amyloid production in ciliary pigment epithelium in these patients. Medical control of IOP and a stable course are unusual in this secondary glaucoma. Ophthalmologists have an important task in the follow-up of patients and early diagnosis of risk factors for secondary glaucoma, such as scalloped pupils with amyloid deposits.

Amyloid beta deposition related retinal pigment epithelium cell impairment and subretinal microglia activation in aged APPswePS1 transgenic mice

AIM：To identify the pathological role of amyloid beta（Aβ） deposition in retinal degeneration,and explore Aβ deposition on the retinal pigment epithelium cells（RPE） layer and the associated structural and functional changes in Alzheimer＇s disease transgenic mice.METHODS：RPE changes in the eyes of APPswe/PS1 transgenic and none transgenic（NTG） mice over 20 months old were examined.Histological changes were investigated via hematoxylin and eosin（H＆E） staining and transmission electron microscopy（TEM） examination,whereas the expression of amyloid precursor protein（APP）,Aβ,Zonula occludens-1（ZO-1） and Ionized calcium binding adaptor molecule-1（IBA-1） were investigated using immunohistochemistry and immunofluorescence techniques.All of the obtained results were quantitatively and statistically analyzed.RESULTS：In aged transgenic mice,an APP-positive immunoreaction and Aβ deposition were detected on the RPE layer but were undetectable in NTG mice.The RPE demonstrated some vacuole changes,shortened basal infoldings and basal deposition in histopathological examination and TEM tests,wherein irregular shapes were indicated by ZO-1 disorganization through fluorescence.Furthermore,IBA-1 positive cells were observed to have accumulated and infiltrated into the RPE layer and localized beneath the RPE/Bruch＇s membrane（Br M） complex,which was accompanied by an increase in BrM thickness in aged transgenic mice in comparison to NTG mice.The IBA-1 positive cells were found to be co-stained with Aβ deposition on the RPE flat mounts.CONCLUSION：The observed Aβ deposition in the RPE layer may cause RPE dysfunction,which is associated with microglia cells infiltration into the retina of aged transgenic mice,suggesting that Aβ deposition probably plays a significant role in RPE-related degenerative disease.

Regional differences in islet amyloid deposition in the residual pancreas with new-onset diabetes secondary to pancreatic ductal adenocarcinoma

BACKGROUND Islet amyloid deposition and reducedβ-cell mass are pathological hallmarks in type 2 diabetes mellitus subjects.To date,the pathological features of the islets in diabetes secondary to pancreatic ductal adenocarcinoma(PDAC)have not been specifically addressed.AIM To provide further insight into the relationship between islet amyloid deposition of the residual pancreas in PDAC patients and to explore whether regional differences(proximal vs distal residual pancreas)are associated with islet amyloid deposition.METHODS We retrospectively collected clinical information and pancreatic tissue removed from tumors of 45 PDAC patients,including 14 patients with normal glucose tolerance(NGT),16 patients with prediabetes and 15 new-onset diabetes(NOD)patients diagnosed before surgery by an oral glucose tolerance test at West China Hospital from July 2017 to June 2020.Pancreatic volume was calculated by multiplying the estimated area of pancreatic tissue on each image slice by the interval between slices based on abdominal computer tomography scans.Several sections of paraffin-embedded pancreas specimens from both the proximal and/or distal regions remote from the tumor were stained as follows:(1)Hematoxylin and eosin for general histological appearance;(2)hematoxylin and insulin for the determination of fractionalβ-cell area(immunohistochemistry);and(3)quadruple insulin,glucagon,thioflavin T and DAPI staining for the determination ofβ-cell area,α-cell area and amyloid deposits.RESULTS Screening for pancreatic histologic features revealed that duct obstruction with islet amyloid deposition,fibrosis and marked acinar atrophy were robust in the distal pancreatic regions but much less robust in the proximal regions,especially in the prediabetes and NOD groups.Consistent with this finding,the remnant pancreatic volume was markedly decreased in the NOD group by nearly one-half compared with that in the NGT group(37.35±12.16 cm^(3) vs 69.79±18.17 cm^(3),P<0.001).As expected,islets that stained positive for amyloid(islet amyloid density)were found in the majority of PDAC cases.The proportion of amyloid/islet area(severity of amyloid deposition)was significantly higher in both prediabetes and NOD patients than in NGT patients(P=0.002;P<0.0001,respectively).We further examined the regional differences in islet amyloid deposits.Islet amyloid deposit density was robustly increased by approximately 8-fold in the distal regions compared with that in the proximal regions in the prediabetes and NOD groups(3.98%±3.39%vs 0.50%±0.72%,P=0.01;12.03%vs 1.51%,P=0.001,respectively).CONCLUSION In conclusion,these findings suggest that robust alterations of the distal pancreas due to tumors can disturb islet function and structure with islet amyloid formation,which may be associated with the pathogenesis of NOD secondary to PDAC.

Investigation of amyloid deposition in uterine leiomyoma patients

Objects: To investigate the pathogenesis of amyloid presented in uterine leiomyoma. Methods: 36 uterine leiomyoma patients were recruited and divided into two groups according to Congo red staining results. 6 cases are Congo red staining-positive, and 30 cases Congo red staining-negative which represented amyloid positive and amyloid negative respectively. All patients’ serum total protein (TP), albumin (Alb) and prealbumin (PA) levels were measured as well as blood hemoglobin (Hb), cell counts of white blood cell (WBC), neutrophils (NEU) and lymphocyte (LYM). Glycogen in tissue was compared between amyloid accumulated and amyloid negative sections with periodic acid schiff staining (PAS) in leiomyoma patients. Results: All of blood Hb concentration, WBC, NEU and LYM have not been found significant differences between two groups. Also no obvious infiltration of inflammatory cells was observed in tissue with amyloid deposition in uterine leiomyoma patients. And levels of TP, Alb and prealbumin have not been found significant differences between two groups. The amyloid was negative in leiomyoma entity cells range by Congo red staining, while small blood vessels in myoma tissues were positively detected with high rate. Amyloid was found in normal tissue around myoma as well as in blood vessel of pseudo-capsule. Increased PAS-positive material induced by leiomyoma was not correlated with amyloid deposition. Conclusions: Metabolic changes in the setting of functional alterations of cell in local microenvironment with uterine leiomyoma, may be related to the amyloid deposition.

Primary Cutaneous MZL with Amyloid Deposition, Initially Misdiagnosed as Amyloidosis Mimics Primary Dural MZL upon Dural Dissemination

Primary cutaneous marginal zone B-cell lymphoma (MZL) is considered a cutaneous counterpart of extranodal MZL of mucosa-associated lymphoid tissue and an indolent lymphoma. Amyloid deposition in this tumor is very rare. We report here a case of primary cutaneous MZL with massive amyloid deposition. The tumor disseminated to the dura and mimicked primary dural MZL. The patient had a four year history of the recurrence cutaneous lesions with a misdiagnosis of amyloidosis. The correct diagnosis was made after the metastatic dural lesion was confirmed by radiology, pathology and molecular biology approaches. It is of crucial importance for differential diagnosis to avoid misdiagnosis and the patients are indeed required long-term regular examinations and treatment because of the possibility of recurrence or dissemination.

Jet formation and penetration performance of a double-layer charge liner with chemically-deposited tungsten as the inner liner

This paper proposes a type of double-layer charge liner fabricated using chemical vapor deposition(CVD)that has tungsten as its inner liner.The feasibility of this design was evaluated through penetration tests.Double-layer charge liners were fabricated by using CVD to deposit tungsten layers on the inner surfaces of pure T2 copper liners.The microstructures of the tungsten layers were analyzed using a scanning electron microscope(SEM).The feasibility analysis was carried out by pulsed X-rays,slug-retrieval test and static penetration tests.The shaped charge jet forming and penetration law of inner tungsten-coated double-layer liner were studied by numerical simulation method.The results showed that the double-layer liners could form well-shaped jets.The errors between the X-ray test results and the numerical results were within 11.07%.A slug-retrieval test was found that the retrieved slug was similar to a numerically simulated slug.Compared with the traditional pure copper shaped charge jet,the penetration depth of the double-layer shaped charge liner increased by 11.4% and>10.8% respectively.In summary,the test results are good,and the numerical simulation is in good agreement with the test,which verified the feasibility of using the CVD method to fabricate double-layer charge liners with a high-density and high-strength refractory metal as the inner liner.

Printability disparities in heterogeneous material combinations via laser directed energy deposition:a comparative study

Additive manufacturing provides achievability for the fabrication of bimetallic and multi-material structures;however,the material compatibility and bondability directly affect the parts’formability and final quality.It is essential to understand the underlying printability of different material combinations based on an adapted process.Here,the printability disparities of two common and attractive material combinations(nickel-and iron-based alloys)are evaluated at the macro and micro levels via laser directed energy deposition(DED).The deposition processes were captured using in situ high-speed imaging,and the dissimilarities in melt pool features and track morphology were quantitatively investigated within specific process windows.Moreover,the microstructure diversity of the tracks and blocks processed with varied material pairs was comparatively elaborated and,complemented with the informative multi-physics modeling,the presented non-uniformity in mechanical properties(microhardness)among the heterogeneous material pairs was rationalized.The differences in melt flow induced by the unlike thermophysical properties of the material pairs and the resulting element intermixing and localized re-alloying during solidification dominate the presented dissimilarity in printability among the material combinations.This work provides an in-depth understanding of the phenomenological differences in the deposition of dissimilar materials and aims to guide more reliable DED forming of bimetallic parts.

ZmbZIP27 regulates nitrogen-mediated leaf angle by modulating lignin deposition in maize

In grain crops such as maize(Zea mays),leaf angle(LA)is a key agronomic trait affecting light interception and thus planting density and yield.Nitrogen(N)affects LA in plants,but we lack a good understanding of how N regulates LA.Here,we report that N deficiency enhanced lignin deposition in the ligular region of maize seedlings.In situ hybridization showed that the bZIP transcription factor gene ZmbZIP27 is mainly expressed in the phloem of maize vascular bundles.Under N-sufficient conditions,transgenic maize overexpressing ZmbZIP27 showed significantly smaller LA compared with wild type(WT).By contrast,zmbzip27_(ems)mutant showed larger LA under both N-deficient and N-sufficient conditions compared with WT.Overexpression of ZmbZIP27 enhanced lignin deposition in the ligular region of maize in the field.We further demonstrated that ZmbZIP27 could directly bind the promoters of the microRNA genes ZmMIR528a and ZmMIR528b and negatively regulate the expression levels of ZmmiR528.ZmmiR528 knockdown transgenic maize displayed erect architecture in the field by increasing lignin content in the ligular region of maize.Taken together,these results indicate that ZmbZIP27 regulates N-mediated LA size by regulating the expression of ZmmiR528 and modulating lignin deposition in maize.

Tumor deposits in axillary adipose tissue in patients with breast cancer:Do they matter?

Tumor deposits(TDs)are defined as discrete,irregular clusters of tumor cells lying in the soft tissue adjacent to but separate from the primary tumor,and are usually found in the lymphatic drainage area of the primary tumor.By definition,no residual lymph node structure should be identified in these tumor masses.At present,TDs are mainly reported in colorectal cancer,with a few reports in gastric cancer.There are very few reports on breast cancer(BC).For TDs,current dominant theories suggest that these are the result of lymph node metastasis of the tumor with complete destruction of the lymph nodes by the tumor tissue.Even some pathologists classify a TD as two lymph node metastases for calculation.Some pathologists also believe that TDs belong to the category of disseminated metastasis.Therefore,regardless of the origin,TDs are an indicator of poor prognosis.Moreover,for BC,sentinel lymph node biopsy is generally used at present.Whether radical axillary lymph node dissection should be adopted for BC with TDs in axillary lymph nodes is still inconclusive.The present commentary of this clinical issue has certain guiding significance.It is aimed to increase the awareness of the scientific community towards this under-recognized problem in BC pathology.

Review on laser directed energy deposited aluminum alloys

Lightweight aluminum(Al)alloys have been widely used in frontier fields like aerospace and automotive industries,which attracts great interest in additive manufacturing(AM)to process high-value Al parts.As a mainstream AM technique,laser-directed energy deposition(LDED)shows good scalability to meet the requirements for large-format component manufacturing and repair.However,LDED Al alloys are highly challenging due to their inherent poor printability(e.g.low laser absorption,high oxidation sensitivity and cracking tendency).To further promote the development of LDED high-performance Al alloys,this review offers a deep understanding of the challenges and strategies to improve printability in LDED Al alloys.The porosity,cracking,distortion,inclusions,element evaporation and resultant inferior mechanical properties(worse than laser powder bed fusion)are the key challenges in LDED Al alloys.Processing parameter optimizations,in-situ alloy design,reinforcing particle addition and field assistance are the efficient approaches to improving the printability and performance of LDED Al alloys.The underlying correlations between processes,alloy innovation,characteristic microstructures,and achievable performances in LDED Al alloys are discussed.The benchmark mechanical properties and primary strengthening mechanism of LDED Al alloys are summarized.This review aims to provide a critical and in-depth evaluation of current progress in LDED Al alloys.Future opportunities and perspectives in LDED high-performance Al alloys are also outlined.