Effects of a periodic intermittent theta burst stimulation in Alzheimer's disease

Background Previous studies havedemonstrated that excitatory repetitive transcranial magnetic stimulation(rTMS)can improve the cognitive function of patients with Alzheimer's disease(AD).Intermittent theta burst stimulation(iTBS)is a novel excitatory rTMS protocol for brain activity stimulation with the ability to induce long-term potentiation-like plasticity and represents a promising treatment for AD.However,the long-term effects of iTBS on cognitive decline and brain structure in patients with AD areunknown.Aims We aimed to explore whether repeating accelerated iTBS every three months could slow down the cognitive decline in patients with AD.Methods In this randomised,assessor-blinded,controlled trial,iTBS was administered to the left dorsolateral prefrontal cortex(DLPFC)of 42 patients with AD for 14days every 13weeks.Measurements included the Montreal Cognitive Assessment(MoCA),a comprehensive neuropsychological battery,and the grey matter volume(GMV)of the hippocampus.Patients were evaluated at baseline and after follow-up.The longitudinal pipeline of the Computational Anatomy Toolbox for SPM was used to detect significant treatment-related changes over time.Results The iTBS group maintained MoCA scores relative to the control group(t=3.26,p=0.013)and reduced hippocampal atrophy,which was significantly correlated with global degeneration scale changes.The baseline Mini-Mental State Examination(MMSE)score,apolipoprotein E genotype and Clinical Dementia Rating were indicative of MoCA scores at follow-up.Moreover,the GMV of the left(t=0.08,p=0.996)and right(t=0.19,p=0.977)hippocampus were maintained in the active group but significantly declined in the control group(left:t=4.13,p<0.001;right:t=5.31,p<0.001).GMV change in the left(r=0.35,p=0.023)and right(r=0.36,p=0.021)hippocampus across the intervention positively correlated with MoCA changes;left hippocampal GMV change was negatively correlated with global degeneration scale(r=-0.32,p=0.041)changes.Conclusions DLPFC-iTBS maybe a feasible and easy-to-implement non-pharmacological intervention to slow down the progressive decline of overall cognition and quality of life in patients with AD,providing a new AD treatment option.Trial registration number NCT04754152.

Microneedle array facilitates hepatic sinusoid construction in a large-scale liver-acinus-chip microsystem

Hepatic sinusoids play a key role in maintaining high activities of liver cells in the hepatic acinus.However,the construction of hepatic sinusoids has always been a challenge for liver chips,especially for large-scale liver microsystems.Herein,we report an approach for the construction of hepatic sinusoids.In this approach,hepatic sinusoids are formed by demolding a self-developed microneedle array from a photocurable cell-loaded matrix in a large-scale liver-acinus-chip microsystem with a designed dual blood supply.Primary sinusoids formed by demolded microneedles and spontaneously self-organized secondary sinusoids can be clearly observed.Benefiting from significantly enhanced interstitial flows by formed hepatic sinusoids,cell viability is witnessed to be considerably high,liver microstructure formation occurs,and hepatocyte metabolism is enhanced.In addition,this study preliminarily demonstrates the effects of the resulting oxygen and glucose gradients on hepatocyte functions and the application of the chip in drug testing.This work paves the way for the biofabrication of fully functionalized large-scale liver bioreactors.

Magnetic and optical properties of NaGdF4：Nd^3＋, Yb^3＋, Tm^3＋ nanocrystals with upconversion/downconversion luminescence from visible to the near-infrared second window

We have designed and synthesized NaGdF4：Nd^3＋, Yb^3＋, Tm^3＋. magnetic nano- phosphors with combined dual-mode downconversion （DC） and upconversion （UC） photoluminescence upon 800 run excitation. Hexagonal-phase NaGdF4：Nd^3＋, Yb^3＋, Tm^3＋ nanocrystals （NCs） with an average size of 21 nm were synthesized using a solvothermal approach. Nd^3＋, Yb^3＋, Tm^3＋ triple-doped NaGdF4 NCs exhibit a broad range of photoluminescence peaks covering a near infrared first/second window （860-900, 1,000, and 1,060 nm）, and visible emission including blue （475 nm）, green （520 and 542 nm） and yellow （587 nm） after excitation at 800 nm. A mechanism involving circulation of energy over Gd^3＋ sublattices as bridge ions and final trapping by the initial activator ions （Nd^3＋） has been proposed. Penetration depth studies indicate that NIR emission is easily detected even at a large tissue thickness of 10 mm. These paramagnetic nanophosphors demonstrate a large magnetization value of 1.88 emu/g at 20 kOe and longitudinal relaxivity value of 1.2537 mM-1.S-1 as a Tl-weighted magnetic resonance imaging contrast agent. These NaGdF4：Nd^3＋, Yb^3＋ Tm^3＋ NCs are promising for applications in biological and magnetic resonance imaging.

Abnormal intra-network architecture in extra-striate cortices in amblyopia: a resting state fMRI study

Background:Amblyopia(lazy eye)is one of the most common causes of monocular visual impairment.Intensive investigation has shown that amblyopes suffer from a range of deficits not only in the primary visual cortex but also the extra-striate visual cortex.However,amblyopic brain processing deficits in large-scale information networks especially in the visual network remain unclear.Methods:Through resting state functional magnetic resonance imaging(rs-fMRI),we studied the functional connectivity and efficiency of the brain visual processing networks in 18 anisometropic amblyopic patients and 18 healthy controls(HCs).Results:We found a loss of functional correlation within the higher visual network(HVN)and the visuospatial network(VSN)in amblyopes.Additionally,compared with HCs,amblyopic patients exhibited disruptions in local efficiency in the V3v(third visual cortex,ventral part)and V4(fourth visual cortex)of the HVN,as well as in the PFt,hIP3(human intraparietal area 3),and BA7p(Brodmann area 7 posterior)of the VSN.No significant alterations were found in the primary visual network(PVN).Conclusion:Our results indicate that amblyopia results in an intrinsic decrease of both network functional correlations and local efficiencies in the extra-striate visual networks.

M2 macrophage-targeted iron oxide nanoparticles for magnetic resonance image-guided magnetic hyperthermia therapy

Tumor-associated macrophages(TAMs)play an important role in tumor development and progression.In particular,M2 TAMs can promote tumor growth by facilitating tumor progression and malignant behaviors.Selectively targeted elimination of M2 TAMs to inhibit tumor progression is of great significance for cancer treatment.Iron oxide nanoparticles based magnetic hyperthermia therapy(MHT)is a classical approach to destroy tumor tissue with deep penetration depth.In this study,we developed a typical M2 macrophage-targeted peptide(M2pep)functionalized superparamagnetic iron oxide nanoparticle(SPIO)for magnetic resonance imaging(MRI)-guided MHT in an orthotopic breast cancer mouse model.The obtained multifunctional SPIO-M2pep with a hydrodynamic diameter of 20 nm showed efficient targeting capability,high transverse relaxivity(149 mM^(-1) s^(-1))and satisfactory magnetic hyperthermia performance in vitro.In vivo studies demonstrated that the SPIO-M2pep based MRI can monitor the distribution of nanoparticles in tumor and indicate the suitable timing for MHT.The M2 macrophage-targeted MHT significantly reduced the tumor volume and the population of pro-tumoral M2 TAMs in tumor.In addition,the SPIO-M2pep based MHT can remodel the tumor immune microenvironment(TIME).The multifunctional SPIO-M2pep with M2 macrophage-targeting ability,high magnetic hyperthermia efficiency,MR imaging capability and effective role in remodeling the TIME hold great potential to improve clinical cancer therapy outcomes.