Altered levels of CSF proteins in patients with FTD, presymptomatic mutation carriers and non-carriers

Background The clinical presentations of frontotemporal dementia(FTD)are diverse and overlap with other neurological disorders.There are,as of today,no biomarkers in clinical practice for diagnosing the disorders.Here,we aimed to find protein markers in cerebrospinal fluid(CSF)from patients with FTD,presymptomatic mutation carriers and non-carriers.Methods Antibody suspension bead arrays were used to analyse 328 proteins in CSF from patients with behavioural variant FTD(bvFTD,n=16)and progressive primary aphasia(PPA,n=13),as well as presymptomatic mutation carriers(PMC,n=16)and non-carriers(NC,n=8).A total of 492 antibodies were used to measure protein levels by direct labelling of the CSF samples.The findings were further examined in an independent cohort including 13 FTD patients,79 patients with Alzheimer’s disease and 18 healthy controls.Results We found significantly altered protein levels in CSF from FTD patients compared to unaffected individuals(PMC and NC)for 26 proteins.The analysis show patterns of separation between unaffected individuals and FTD patients,especially for those with a clinical diagnosis of bvFTD.The most statistically significant differences in protein levels were found for VGF,TN-R,NPTXR,TMEM132D,PDYN and NF-M.Patients with FTD were found to have higher levels of TN-R and NF-M,and lower levels of VGF,NPTXR,TMEM132D and PDYN,compared to unaffected individuals.The main findings were reproduced in the independent cohort.Conclusion In this pilot study,we show a separation of FTD patients from unaffected individuals based on protein levels in CSF.Further investigation is required to explore the CSF profiles in larger cohorts,but the results presented here has the potential to enable future clinical utilization of these potential biomarkers within FTD.

Elasto-inertial focusing and particle migration in high aspect ratio microchannels for highthroughput separation

The combination of flow elasticity and inertia has emerged as a viable tool for focusing and manipulating particles using microfluidics.Although there is considerable interest in the field of elasto-inertial microfluidics owing to its potential applications,research on particle focusing has been mostly limited to low Reynolds numbers(Re<1),and particle migration toward equilibrium positions has not been extensively examined.In this work,we thoroughly studied particle focusing on the dynamic range of flow rates and particle migration using straight microchannels with a single inlet high aspect ratio.We initially explored several parameters that had an impact on particle focusing,such as the particle size,channel dimensions,concentration of viscoelastic fluid,and flow rate.Our experimental work covered a wide range of dimensionless numbers(0.05<Reynolds number<85,1.5<Weissenberg number<3800,5<Elasticity number<470)using 3,5,7,and 10μm particles.Our results showed that the particle size played a dominant role,and by tuning the parameters,particle focusing could be achieved at Reynolds numbers ranging from 0.2(1μL/min)to 85(250μL/min).Furthermore,we numerically and experimentally studied particle migration and reported differential particle migration for high-resolution separations of 5μm,7μm and 10μm particles in a sheathless flow at a throughput of 150μL/min.Our work elucidates the complex particle transport in elasto-inertial flows and has great potential for the development of high-throughput and high-resolution particle separation for biomedical and environmental applications.

NDFIP1 limits cellular TAZ accumulation via exosomal sorting to inhibit NSCLC proliferation

NDFIP1 has been previously reported as a tumor suppressor in multiple solid tumors,but the function of NDFIP1 in NSCLC and the underlying mechanism are still unknown.Besides,the WW domain containing proteins can be recognized by NDFIP1,resulted in the loading of the target proteins into exosomes.However,whether WW domain-containing transcription regulator 1(WWTR1,also known as TAZ)can be packaged into exosomes by NDFIP1 and if so,whether the release of this oncogenic protein via exosomes has an effect on tumor development has not been investigated to any extent.Here,we first found that NDFIP1 was low expressed in NSCLC samples and cell lines,which is associated with shorter OS.Then,we confirmed the interaction between TAZ and NDFIP1,and the existence of TAZ in exosomes,which requires NDFIP1.Critically,knockout of NDFIP1 led to TAZ accumulation with no change in its mRNA level and degradation rate.And the cellular TAZ level could be altered by exosome secretion.Furthermore,NDFIP1 inhibited proliferation in vitro and in vivo,and silencing TAZ eliminated the increase of proliferation caused by NDFIP1 knockout.Moreover,TAZ was negatively correlated with NDFIP1 in subcutaneous xenograft model and clinical samples,and the serum exosomal TAZ level was lower in NSCLC patients.In summary,our data uncover a new tumor suppressor,NDFIP1 in NSCLC,and a new exosome-related regulatory mechanism of TAZ.