High-Precision Atom Interferometer-Based Dynamic Gravimeter Measurement by Eliminating the Cross-Coupling Effect.

A dynamic gravimeter with an atomic interferometer (AI) can perform absolute gravity measurements with high precision. AI-based dynamic gravity measurement is a type of joint measurement that uses an AI sensor and a classical accelerometer. The coupling of the two sensors may degrade the measurement precision. In this study, we analyzed the cross-coupling effect and introduced a recovery vector to suppress this effect. We improved the phase noise of the interference fringe by a factor of 1.9 by performing marine gravity measurements using an AI-based gravimeter and optimizing the recovery vector. Marine gravity measurements were performed, and high gravity measurement precision was achieved. The external and inner coincidence accuracies of the gravity measurement were ±0.42 mGal and ±0.46 mGal after optimizing the cross-coupling effect, which was improved by factors of 4.18 and 4.21 compared to the cases without optimization.

Intraneuronal ß-amyloid impaired mitochondrial proteostasis through the impact on LONP1.

Mitochondrial dysfunction plays a critical role in the pathogenesis of Alzheimer's disease (AD). Mitochondrial proteostasis regulated by chaperones and proteases in each compartment of mitochondria is critical for mitochondrial function, and it is suspected that mitochondrial proteostasis deficits may be involved in mitochondrial dysfunction in AD. In this study, we identified LONP1, an ATP-dependent protease in the matrix, as a top Aß42 interacting mitochondrial protein through an unbiased screening and found significantly decreased LONP1 expression and extensive mitochondrial proteostasis deficits in AD experimental models both in vitro and in vivo, as well as in the brain of AD patients. Impaired METTL3-m6A signaling contributed at least in part to Aß42-induced LONP1 reduction. Moreover, Aß42 interaction with LONP1 impaired the assembly and protease activity of LONP1 both in vitro and in vivo. Importantly, LONP1 knockdown caused mitochondrial proteostasis deficits and dysfunction in neurons, while restored expression of LONP1 in neurons expressing intracellular Aß and in the brain of CRND8 APP transgenic mice rescued Aß-induced mitochondrial deficits and cognitive deficits. These results demonstrated a critical role of LONP1 in disturbed mitochondrial proteostasis and mitochondrial dysfunction in AD and revealed a mechanism underlying intracellular Aß42-induced mitochondrial toxicity through its impact on LONP1 and mitochondrial proteostasis.

Bezafibrate confers neuroprotection in the 5xFAD mouse model of Alzheimer's disease.

Mitochondrial dysfunction plays an important role in the pathogenesis of Alzheimer's disease (AD), the most common neurodegenerative disease. Prior studies suggested impaired mitochondrial biogenesis likely contributes to mitochondrial dysfunction in AD. Bezafibrate, a peroxisome proliferator-activated receptor (PPAR) pan-agonist, has been shown to enhance mitochondrial biogenesis and increase oxidative phosphorylation capacity. In the present study, we investigated whether bezafibrate could rescue mitochondrial dysfunction and other AD-related deficits in 5xFAD mice. Bezafibrate was well tolerated by 5xFAD mice. Indeed, it rescued the expression of key mitochondrial proteins as well as mitochondrial dynamics and function in the brain of 5xFAD mice. Importantly, bezafibrate treatment led to significant improvement of cognitive/memory function in 5xFAD mice accompanied by alleviation of amyloid pathology and neuronal loss as well as reduced oxidative stress and neuroinflammation. Overall, this study suggests that bezafibrate improves mitochondrial function, mitigates neuroinflammation and improves cognitive functions in 5xFAD mice, thus supporting the notion that enhancing mitochondrial biogenesis/function is a promising therapeutic strategy for AD.

Accuracy Improvement of a Compact 85Rb Atom Gravimeter by Suppressing Laser Crosstalk and Light Shift.

We design and implement a compact 85Rb atom gravimeter (AG). The diameter of the sensor head is 35 cm and the height is 65 cm; the optical and electronic systems are installed in four standard 3U cabinets. The measurement accuracy of this AG is improved by suppress laser crosstalk and light shift. In addition, the angle of the Raman laser reflector is adjusted and locked, and the attitude of the sensing head is automatically adjusted, and the vibration noise is also compensated. The comparison measurement results between this AG and the superconducting gravimeter indicate that its long-term stability is 0.65 µGal @50000 s.

The space cold atom interferometer for testing the equivalence principle in the China Space Station.

The precision of the weak equivalence principle (WEP) test using atom interferometers (AIs) is expected to be extremely high in microgravity environment. The microgravity scientific laboratory cabinet (MSLC) in the China Space Station (CSS) can provide a higher-level microgravity than the CSS itself, which provides a good experimental environment for scientific experiments that require high microgravity. We designed and realized a payload of a dual-species cold rubidium atom interferometer. The payload is highly integrated and has a size of [Formula: see text]. It will be installed in the MSLC to carry out high-precision WEP test experiment. In this article, we introduce the constraints and guidelines of the payload design, the compositions and functions of the scientific payload, the expected test precision in space, and some results of the ground test experiments.

The space cold atom interferometer for testing the equivalence principle in the China Space Station.

The precision of the weak equivalence principle (WEP) test using atom interferometers (AIs) is expected to be extremely high in microgravity environment. The microgravity scientific laboratory cabinet (MSLC) in the China Space Station (CSS) can provide a higher-level microgravity than the CSS itself, which provides a good experimental environment for scientific experiments that require high microgravity. We designed and realized a payload of a dual-species cold rubidium atom interferometer. The payload is highly integrated and has a size of 460 mm × 330 mm × 260 mm. It will be installed in the MSLC to carry out high-precision WEP test experiment. In this article, we introduce the constraints and guidelines of the payload design, the compositions and functions of the scientific payload, the expected test precision in space, and some results of the ground test experiments.

Damaged mitochondria coincide with presynaptic vesicle loss and abnormalities in alzheimer's disease brain.

Loss of synapses is the most robust pathological correlate of Alzheimer's disease (AD)-associated cognitive deficits, although the underlying mechanism remains incompletely understood. Synaptic terminals have abundant mitochondria which play an indispensable role in synaptic function through ATP provision and calcium buffering. Mitochondrial dysfunction is an early and prominent feature in AD which could contribute to synaptic deficits. Here, using electron microscopy, we examined synapses with a focus on mitochondrial deficits in presynaptic axonal terminals and dendritic spines in cortical biopsy samples from clinically diagnosed AD and age-matched non-AD control patients. Synaptic vesicle density within the presynaptic axon terminals was significantly decreased in AD cases which appeared largely due to significantly decreased reserve pool, but there were significantly more presynaptic axons containing enlarged synaptic vesicles or dense core vesicles in AD. Importantly, there was reduced number of mitochondria along with significantly increased damaged mitochondria in the presynapse of AD which correlated with changes in SV density. Mitochondria in the post-synaptic dendritic spines were also enlarged and damaged in the AD biopsy samples. This study provided evidence of presynaptic vesicle loss as synaptic deficits in AD and suggested that mitochondrial dysfunction in both pre- and post-synaptic compartments contribute to synaptic deficits in AD.

Which Predictor, SctO2 or SstO2, Is more Sensitive for Postoperative Cognitive Dysfunction in Spine Surgery: A Prospective Observational Study?

OBJECTIVE: Patients undergoing spinal surgery in the prone position may experience venous stasis, often resulting in edema in dependent areas of the body, including the head, and increased postoperative cognitive dysfunction (POCD). Not only does POCD present challenges for post-operative care and recovery, it can also cause permanent damage to the patient's brain and increase mortality and social costs. We aimed to clarify the incidence of POCD in patients with hypertension after prone spine surgery and to further determine the association between intraoperative somatic tissue oxygen saturation (SstO2)/cerebral tissue oxygen saturation (SctO2) and POCD. METHODS: Patients with hypertension scheduled for open prone spine surgery from January 2020 to April 2021 were included in this single-center, prospective, observational study. SctO2 and SstO2 were monitored by near-infrared spectroscopy continuously throughout the surgery. The primary outcome was POCD assessed using the Mini-Mental Status Examination (MMSE). The association of SstO2 and SctO2 with POCD was evaluated with unadjusted analyses and multivariable logistic regression. RESULTS: One hundred and one of 112 identified patients were included, 28 (27.8%) of whom developed POCD. None of the investigated SctO2 indices were predictive of POCD. However, the patients with POCD had greater decreases in intraoperative absolute SstO2 and relative SstO2 than the patients without POCD (P = 0.037, P = 0.036). Moreover, three SstO2 indices were associated with POCD, including a greater absolute SstO2 decrease (P = 0.021), a greater relative SstO2 decrease (P = 0.032), and a drop below 90% of the baseline SstO2 (P = 0.002), independent of ASA III status, preoperative platelets and postoperative sepsis. In addition, there was no correlation between intraoperative SctO2 and intraoperative SstO2 or between their respective absolute declines. CONCLUSION: Twenty-eight (27.7%) of 101 patients developed POCD in patients with hypertension undergoing prone spine surgery, and intraoperative SstO2 is associated with POCD, whereas SctO2 shows no association with POCD. This study may initially provide a valuable new approach to the prevention of POCD in this population.

C19orf12 ablation causes ferroptosis in mitochondrial membrane protein-associated with neurodegeneration.

Mitochondrial membrane protein-associated with neurodegeneration (MPAN) is a rare genetic disease characterized by aggressive neurodegeneration and massive iron accumulation in patients' brains. Genetics studies identified defects in C19orf12 locus being associated with MPAN which likely caused loss of function although underlying pathogenic mechanism(s) remain elusive. In the present study, we investigated C19orf12 knockout (KO) M17 neuronal cells and primary skin fibroblasts from MPAN patients with C19orf12 homozygous G58S or heterozygous C19orf12 p99fs*102 mutations as cellular models of MPAN. C19orf12 KO cells and MPAN fibroblast cells demonstrated mitochondrial fragmentation and dysfunction, iron overload and increased oxidative damage. Antioxidant NAC and iron chelator DFO rescued both oxidative stress and mitochondrial deficits. Moreover, C19orf12 KO cells and MPAN fibroblast cells were susceptible to erastin- or RSL3-induced ferroptosis which could be almost completely prevented by pretreatment of iron chelator DFO. Importantly, we also found mitochondrial fragmentation and increased ferroptosis related oxidative damage in neurons in the biopsied cortical tissues from an MPAN patient. Collectively, these results supported the notion that iron overload and ferroptosis likely play an important role in the pathogenesis of MPAN.

METTL3-dependent RNA m6A dysregulation contributes to neurodegeneration in Alzheimer's disease through aberrant cell cycle events.

BACKGROUND: N6-methyladenosine (m6A) modification of RNA influences fundamental aspects of RNA metabolism and m6A dysregulation is implicated in various human diseases. In this study, we explored the potential role of RNA m6A modification in the pathogenesis of Alzheimer disease (AD). METHODS: We investigated the m6A modification and the expression of m6A regulators in the brain tissues of AD patients and determined the impact and underlying mechanism of manipulated expression of m6A levels on AD-related deficits both in vitro and in vivo. RESULTS: We found decreased neuronal m6A levels along with significantly reduced expression of m6A methyltransferase like 3 (METTL3) in AD brains. Interestingly, reduced neuronal m6A modification in the hippocampus caused by METTL3 knockdown led to significant memory deficits, accompanied by extensive synaptic loss and neuronal death along with multiple AD-related cellular alterations including oxidative stress and aberrant cell cycle events in vivo. Inhibition of oxidative stress or cell cycle alleviated shMettl3-induced apoptotic activation and neuronal damage in primary neurons. Restored m6A modification by inhibiting its demethylation in vitro rescued abnormal cell cycle events, neuronal deficits and death induced by METTL3 knockdown. Soluble Aß oligomers caused reduced METTL3 expression and METTL3 knockdown exacerbated while METTL3 overexpression rescued Aß-induced synaptic PSD95 loss in vitro. Importantly, METTL3 overexpression rescued Aß-induced synaptic damage and cognitive impairment in vivo. CONCLUSIONS: Collectively, these data suggested that METTL3 reduction-mediated m6A dysregulation likely contributes to neurodegeneration in AD which may be a therapeutic target for AD.

Oxidative Stress Signaling in Blast TBI-Induced Tau Phosphorylation.

Traumatic brain injury caused by blast is associated with long-term neuropathological changes including tau phosphorylation and pathology. In this study, we aimed to determine changes in initial tau phosphorylation after exposure to a single mild blast and the potential contribution of oxidative stress response pathways. C57BL/6 mice were exposed to a single blast overpressure (BOP) generated by a compressed gas-driven shock tube that recapitulates battlefield-relevant open-field BOP, and cortical tissues were harvested at different time points up to 24 h after blast for Western blot analysis. We found that BOP caused elevated tau phosphorylation at Ser202/Thr205 detected by the AT8 antibody at 1 h post-blast followed by tau phosphorylation at additional sites (Ser262 and Ser396/Ser404 detected by PHF1 antibody) and conformational changes detected by Alz50 antibody. BOP also induced acute oxidative damage at 1 h post-blast and gradually declined overtime. Interestingly, Extracellular signal-regulated kinase (ERK) and c-Jun N-terminal kinase (JNK) were acutely activated in a similar temporal pattern as the rise and fall in oxidative stress after blast, with p38 showing a similar trend. However, glycogen synthase kinase-3 ß (GSK3ß) was inhibited at 1 h and remained inhibited for 24 h post blast. These results suggested that mitogen-activated protein kinases (MAPKs) but not GSK3ß are likely involved in mediating the effects of oxidative stress on the initial increase of tau phosphorylation following a single mild blast.

VPS35 D620N knockin mice recapitulate cardinal features of Parkinson's disease.

D620N mutation in the vacuolar protein sorting 35 ortholog (VPS35) gene causes late-onset, autosomal dominant familial Parkinson's disease (PD) and contributes to idiopathic PD. However, how D620N mutation leads to PD-related deficits in vivo remains unclear. In the present study, we thoroughly characterized the biochemical, pathological, and behavioral changes of a VPS35 D620N knockin (KI) mouse model with chronic aging. We reported that this VPS35 D620N KI model recapitulated a spectrum of cardinal features of PD at 14 months of age which included age-dependent progressive motor deficits, significant changes in the levels of dopamine (DA) and DA metabolites in the striatum, and robust neurodegeneration of the DA neurons in the SNpc and DA terminals in the striatum, accompanied by increased neuroinflammation, and accumulation and aggregation of α-synuclein in DA neurons. Mechanistically, D620N mutation induced mitochondrial fragmentation and dysfunction in aged mice likely through enhanced VPS35-DLP1 interaction and increased turnover of mitochondrial DLP1 complexes in vivo. Finally, the VPS35 D620N KI mice displayed greater susceptibility to MPTP-mediated degeneration of nigrostriatal pathway, indicating that VPS35 D620N mutation increased vulnerability of DA neurons to environmental toxins. Overall, this VPS35 D620N KI mouse model provides a powerful tool for future disease modeling and pharmacological studies of PD. Our data support the involvement of VPS35 in the development of α-synuclein pathology in vivo and revealed the important role of mitochondrial fragmentation/dysfunction in the pathogenesis of VPS35 D620N mutation-associated PD in vivo.

Mfn2 Overexpression Attenuates MPTP Neurotoxicity In Vivo.

Mitochondrial dysfunction represents a critical event in the pathogenesis of Parkinson's disease (PD). Increasing evidence demonstrates that disturbed mitochondrial dynamics and quality control play an important role in mitochondrial dysfunction in PD. Our previous study demonstrated that MPP+ induces mitochondrial fragmentation in vitro. In this study, we aimed to assess whether blocking MPTP-induced mitochondrial fragmentation by overexpressing Mfn2 affords neuroprotection in vivo. We found that the significant loss of dopaminergic neurons in the substantia nigra (SN) induced by MPTP treatment, as seen in wild-type littermate control mice, was almost completely blocked in mice overexpressing Mfn2 (hMfn2 mice). The dramatic reduction in dopamine neuronal fibers and dopamine levels in the striatum caused by MPTP administration was also partially inhibited in hMfn2 mice. MPTP-induced oxidative stress and inflammatory response in the SN and striatum were significantly alleviated in hMfn2 mice. The impairment of motor function caused by MPTP was also blocked in hMfn2 mice. Overall, our work demonstrates that restoration of mitochondrial dynamics by Mfn2 overexpression protects against neuronal toxicity in an MPTP-based PD mouse model, which supports the modulation of mitochondrial dynamics as a potential therapeutic target for PD treatment.

Three-dimensional (3D)-printed titanium sternum replacement: A case report.

After sternal tumor resection, reconstruction of chest wall defects is still a challenging part of thoracic surgery. Three-dimensional (3D)-printed titanium alloy prosthesis implants provide an effective solution. The bionic bone trabecular micropore structure, which is beneficial to the human body, increases stability and robustness of the prosthesis. Here, we report a successful case of a customized prosthesis using a 3D-printed titanium alloy to repair and reconstruct bone defects in a patient with sternal osteosarcoma who underwent radical resection of the whole sternum.

Mitochondria dysfunction in the pathogenesis of Alzheimer's disease: recent advances.

Alzheimer's disease (AD) is one of the most prevalent neurodegenerative diseases, characterized by impaired cognitive function due to progressive loss of neurons in the brain. Under the microscope, neuronal accumulation of abnormal tau proteins and amyloid plaques are two pathological hallmarks in affected brain regions. Although the detailed mechanism of the pathogenesis of AD is still elusive, a large body of evidence suggests that damaged mitochondria likely play fundamental roles in the pathogenesis of AD. It is believed that a healthy pool of mitochondria not only supports neuronal activity by providing enough energy supply and other related mitochondrial functions to neurons, but also guards neurons by minimizing mitochondrial related oxidative damage. In this regard, exploration of the multitude of mitochondrial mechanisms altered in the pathogenesis of AD constitutes novel promising therapeutic targets for the disease. In this review, we will summarize recent progress that underscores the essential role of mitochondria dysfunction in the pathogenesis of AD and discuss mechanisms underlying mitochondrial dysfunction with a focus on the loss of mitochondrial structural and functional integrity in AD including mitochondrial biogenesis and dynamics, axonal transport, ER-mitochondria interaction, mitophagy and mitochondrial proteostasis.

Mfn2 Ablation in the Adult Mouse Hippocampus and Cortex Causes Neuronal Death.

It is believed that mitochondrial fragmentation cause mitochondrial dysfunction and neuronal deficits in Alzheimer's disease. We recently reported that constitutive knockout of the mitochondria fusion protein mitofusin2 (Mfn2) in the mouse brain causes mitochondrial fragmentation and neurodegeneration in the hippocampus and cortex. Here, we utilize an inducible mouse model to knock out Mfn2 (Mfn2 iKO) in adult mouse hippocampal and cortical neurons to avoid complications due to developmental changes. Electron microscopy shows the mitochondria become swollen with disorganized and degenerated cristae, accompanied by increased oxidative damage 8 weeks after induction, yet the neurons appear normal at the light level. At later timepoints, increased astrocyte and microglia activation appear and nuclei become shrunken and pyknotic. Apoptosis (Terminal deoxynucleotidyl transferase dUTP nick end labeling, TUNEL) begins to occur at 9 weeks, and by 12 weeks, most hippocampal neurons are degenerated, confirmed by loss of NeuN. Prior to the loss of NeuN, aberrant cell-cycle events as marked by proliferating cell nuclear antigen (PCNA) and pHistone3 were evident in some Mfn2 iKO neurons but do not colocalize with TUNEL signals. Thus, this study demonstrated that Mfn2 ablation and mitochondrial fragmentation in adult neurons cause neurodegeneration through oxidative stress and neuroinflammation in vivo via both apoptosis and aberrant cell-cycle-event-dependent cell death pathways.

Dynamin-like protein 1 cleavage by calpain in Alzheimer's disease.

Abnormal mitochondrial dynamics contributes to mitochondrial dysfunction in Alzheimer's disease (AD), yet the underlying mechanism remains elusive. In the current study, we reported that DLP1, the key mitochondrial fission GTPase, is a substrate of calpain which produced specific N-terminal DLP1 cleavage fragments. In addition, various AD-related insults such as exposure to glutamate, soluble amyloid-ß oligomers, or reagents inducing tau hyperphosphorylation (i.e., okadaic acid) led to calpain-dependent cleavage of DLP1 in primary cortical neurons. DLP1 cleavage fragments were found in cortical neurons of CRND8 APP transgenic mice which can be inhibited by calpeptin, a potent small molecule inhibitor of calpain. Importantly, these N-terminal DLP1 fragments were also present in the human brains, and the levels of both full-length and N-terminal fragments of DLP1 and the full-length and calpain-specific cleavage product of spectrin were significantly reduced in AD brains along with significantly increased calpain. These results suggest that calpain-dependent cleavage is at least one of the posttranscriptional mechanisms that contribute to the dysregulation of mitochondrial dynamics in AD.

The sterol regulatory element-binding protein 2 is dysregulated by tau alterations in Alzheimer disease.

Disturbed neuronal cholesterol homeostasis has been observed in Alzheimer disease (AD) and contributes to the pathogenesis of AD. As the master switch of cholesterol biosynthesis, the sterol regulatory element-binding protein 2 (SREBP-2) translocates to the nucleus after cleavage/activation, but its expression and activation have not been studied in AD which is the focus of the current study. We found both a significant decrease in the nuclear translocation of N-terminal SREBP-2 accompanied by a significant accumulation of C-terminal SREBP-2 in NFT-containing pyramidal neurons in AD. N-terminal- SREBP-2 is also found in dystrophic neurites around plaques in AD brain. Western blot confirmed a significantly reduced nuclear translocation of mature SREBP-2 (mSREBP-2) in AD brain. Interestingly, reduced nuclear mSREBP-2 was only found in animal models of tauopathies such as 3XTg AD mice and P301L Tau Tg mice but not in CRND8 APP transgenic mice, suggesting that tau alterations likely are involved in the changes of mSREBP-2 distribution and activation in AD. Altogether, our study demonstrated disturbed SREBP-2 signaling in AD and related models, and proved for the first time that tau alterations contribute to disturbed cholesterol homeostasis in AD likely through modulation of nuclear mSREBP-2 translocation.

HDL mimetic peptides affect apolipoprotein E metabolism: equal supplement or functional enhancer?: An Editorial for 'High-density lipoprotein mimetic peptide 4F mitigates amyloid-ß-induced inhibition of apolipoprotein E secretion and lipidation in primary astrocytes and microglia' on page 647.

ε4 allele of ApoE is the strongest genetic risk factor for late onset Alzheimer's disease (AD). Supplementation of ApoE proteins or mimetics has been pursued for drug developments against AD. A very low-density lipoprotein (HDL) mimetic peptide 4F was shown to alleviate AD-related deficits in APP transgenic mice, and this editorial highlights a study by Chernick et al. who use both mouse and human neuroglial cells to explore the mechanism underlying beneficial effects of this peptide. The authors demonstrate that 4F peptide significantly increased the secretion and lipidation of ApoE in the absence and presence of Aß independent of de novo transcription/translation, but requiring ABCA1 and the integrity of the secretory pathway between ER and Golgi. This study reveals a novel mechanism of HDL mimetic peptide as a functional ApoE enhancer and support further development of ApoA-I 4F peptide as effective ApoE modulating agents against AD.

Mfn2 ablation causes an oxidative stress response and eventual neuronal death in the hippocampus and cortex.

BACKGROUND: Mitochondria are the organelles responsible for energy metabolism and have a direct impact on neuronal function and survival. Mitochondrial abnormalities have been well characterized in Alzheimer Disease (AD). It is believed that mitochondrial fragmentation, due to impaired fission and fusion balance, likely causes mitochondrial dysfunction that underlies many aspects of neurodegenerative changes in AD. Mitochondrial fission and fusion proteins play a major role in maintaining the health and function of these important organelles. Mitofusion 2 (Mfn2) is one such protein that regulates mitochondrial fusion in which mutations lead to the neurological disease. METHODS: To examine whether and how impaired mitochondrial fission/fusion balance causes neurodegeneration in AD, we developed a transgenic mouse model using the CAMKII promoter to knockout neuronal Mfn2 in the hippocampus and cortex, areas significantly affected in AD. RESULTS: Electron micrographs of neurons from these mice show swollen mitochondria with cristae damage and mitochondria membrane abnormalities. Over time the Mfn2 cKO model demonstrates a progression of neurodegeneration via mitochondrial morphological changes, oxidative stress response, inflammatory changes, and loss of MAP2 in dendrites, leading to severe and selective neuronal death. In this model, hippocampal CA1 neurons were affected earlier and resulted in nearly total loss, while in the cortex, progressive neuronal death was associated with decreased cortical size. CONCLUSIONS: Overall, our findings indicate that impaired mitochondrial fission and fusion balance can cause many of the neurodegenerative changes and eventual neuron loss that characterize AD in the hippocampus and cortex which makes it a potential target for treatment strategies for AD.