ZCCHC17 Modulates Neuronal RNA Splicing and Supports Cognitive Resilience in Alzheimer's Disease.

ZCCHC17 is a putative master regulator of synaptic gene dysfunction in Alzheimer's disease (AD), and ZCCHC17 protein declines early in AD brain tissue, before significant gliosis or neuronal loss. Here, we investigate the function of ZCCHC17 and its role in AD pathogenesis using data from human autopsy tissue (consisting of males and females) and female human cell lines. Co-immunoprecipitation (co-IP) of ZCCHC17 followed by mass spectrometry analysis in human iPSC-derived neurons reveals that ZCCHC17's binding partners are enriched for RNA-splicing proteins. ZCCHC17 knockdown results in widespread RNA-splicing changes that significantly overlap with splicing changes found in AD brain tissue, with synaptic genes commonly affected. ZCCHC17 expression correlates with cognitive resilience in AD patients, and we uncover an APOE4-dependent negative correlation of ZCCHC17 expression with tangle burden. Furthermore, a majority of ZCCHC17 interactors also co-IP with known tau interactors, and we find a significant overlap between alternatively spliced genes in ZCCHC17 knockdown and tau overexpression neurons. These results demonstrate ZCCHC17's role in neuronal RNA processing and its interaction with pathology and cognitive resilience in AD, and suggest that the maintenance of ZCCHC17 function may be a therapeutic strategy for preserving cognitive function in the setting of AD pathology.

ATP-binding cassette protein ABCA7 deficiency impairs sphingomyelin synthesis, cognitive discrimination, and synaptic plasticity in the entorhinal cortex.

Sphingomyelin (SM) is an abundant plasma membrane and plasma lipoprotein sphingolipid. We previously reported that ATP-binding cassette family A protein 1 (ABCA1) deficiency in humans and mice decreases plasma SM levels. However, overexpression, induction, downregulation, inhibition, and knockdown of ABCA1 in human hepatoma Huh7 cells did not decrease SM efflux. Using unbiased siRNA screening, here, we identified that ABCA7 plays a role in the biosynthesis and efflux of SM without affecting cellular uptake and metabolism. Since loss of function mutations in the ABCA7 gene exhibit strong associations with late-onset Alzheimer's disease across racial groups, we also studied the effects of ABCA7 deficiency in the mouse brain. Brains of ABCA7-deficient (KO) mice, compared with WT, had significantly lower levels of several SM species with long chain fatty acids. In addition, we observed that older KO mice exhibited behavioral deficits in cognitive discrimination in the active place avoidance task. Next, we performed synaptic transmission studies in brain slices obtained from older mice. We found anomalies in synaptic plasticity at the intracortical synapse in layer II/III of the lateral entorhinal cortex but not in the hippocampal CA3-CA1 synapses in KO mice. These synaptic abnormalities in KO brain slices were rescued with extracellular SM supplementation but not by supplementation with phosphatidylcholine. Taken together, these studies identify a role of ABCA7 in brain SM metabolism and the importance of SM in synaptic plasticity and cognition, as well as provide a possible explanation for the association between ABCA7 and late-onset Alzheimer's disease.

Role of External Field in Polymerization: Mechanism and Kinetics.

The past decades have witnessed an increasing interest in developing advanced polymerization techniques subjected to external fields. Various physical modulations, such as temperature, light, electricity, magnetic field, ultrasound, and microwave irradiation, are noninvasive means, having superb but distinct abilities to regulate polymerizations in terms of process intensification and spatial and temporal controls. Gas as an emerging regulator plays a distinctive role in controlling polymerization and resembles a physical regulator in some cases. This review provides a systematic overview of seven types of external-field-regulated polymerizations, ranging from chain-growth to step-growth polymerization. A detailed account of the relevant mechanism and kinetics is provided to better understand the role of each external field in polymerization. In addition, given the crucial role of modeling and simulation in mechanisms and kinetics investigation, an overview of model construction and typical numerical methods used in this field as well as highlights of the interaction between experiment and simulation toward kinetics in the existing systems are given. At the end, limitations and future perspectives for this field are critically discussed. This state-of-the-art research progress not only provides the fundamental principles underlying external-field-regulated polymerizations but also stimulates new development of advanced polymerization methods.

Amentoflavone Exerts Anti-Neuroinflammatory Effects by Inhibiting TLR4/MyD88/NF-κB and Activating Nrf2/HO-1 Pathway in Lipopolysaccharide-Induced BV2 Microglia.

Background: Amentoflavone, a natural biflavone, exerts anti-inflammation, antioxidation, and antiapoptosis effects on many diseases. However, the mechanism of amentoflavone on neuroinflammation-related diseases has not been comprehensively examined clearly. Methods: BV2 microglial cells were treated with amentoflavone (10 µM), followed by lipopolysaccharide (LPS). Microglial activation and migration ability and the expression of proinflammatory cytokines and other signaling proteins were determined using immunohistochemistry, immunofluorescence, quantitative real-time polymerase chain reaction, Western blotting, enzyme-linked immunosorbent assay, and wound-healing assays. Results: Amentoflavone restored LPS-induced microglia activation, migration, and inflammation response which depends on regulating toll-like receptor 4 (TLR4)/myeloid differentiation factor 88 (MyD88)/nuclear factor kappa B (NF-κB) pathway. In addition, amentoflavone also enhanced nuclear factor erythroid 2-related factor 2 (Nrf2)/heme oxygenase-1 (HO-1) levels in LPS-treated BV2 microglial cells. Conclusions: Amentoflavone ameliorated LPS-induced neuroinflammatory response and oxidative stress in BV2 microglia. These data provide new insight into the mechanism of amentoflavone in the treatment of neuroinflammation-related diseases. Therefore, amentoflavone may be a potential therapeutic option for neurological disorders.

Directional phase-unwrapping algorithm and phase shift technique on hydrogel.

Refractive index microstructures, which can be written by multiphoton absorption with femtosecond lasers, have many applications. Here we present a directional phase-unwrapping algorithm with phase-shifting technique and apply it to the metrology of hydrogel microstructures. A staircase phase-unwrapping algorithm is demonstrated. This fast quality-guided path phase-unwrapping applies well to situations that are geometrically well defined and is quite tolerant of phase noise. To achieve precise very small phase shifts, we also present a slant angle technique on a DC servo stage along with phase shift measurement, allowing us to achieve 6.5 nm step sizes.

Modification of surface morphology of hydrogels due to subsurface femtosecond laser micromachining.

In this paper, we studied the effects of subsurface femtosecond laser micromachining on surface morphology in hydrogels. Depending on material properties and writing conditions, we found surface bumps when materials were hydrated, and trenches when they were dehydrated, which can be attributed to the localized change in water concentration. Such wavy surfaces by laser-induced refractive index change are not desirable in clinical contact lenses. Therefore, the minimization of surface bumps is necessary to ensure the user eye wearing comfort. In addition, we examined the optical effects of the surface features using interferometry and the surface morphology using profilometry. Finally, we proposed a simplified mechanical model based on localized swelling.

Derivation and validation of the ED-SAS score for very early prediction of mortality and morbidity with acute pancreatitis: a retrospective observational study.

BACKGROUND: Existing scoring systems to predict mortality in acute pancreatitis may not be directly applicable to the emergency department (ED). The objective of this study was to derive and validate the ED-SAS, a simple scoring score using variables readily available in the ED to predict mortality in patients with acute pancreatitis. METHODS: This retrospective observational study was performed based on patient data collected from electronic health records across 2 independent health systems; 1 was used for the derivation cohort and the other for the validation cohort. Adult patients who were eligible presented to the ED, required hospital admission, and had a confirmed diagnosis of acute pancreatitis. Patients with chronic or recurrent episodes of pancreatitis were excluded. The primary outcome was 30-day mortality. Analyses tested and derived candidate variables to establish a prediction score, which was subsequently applied to the validation cohort to assess odds ratios for the primary and secondary outcomes. RESULTS: The derivation cohort included 599 patients, and the validation cohort 2011 patients. Thirty-day mortality was 4.2 and 3.9%, respectively. From the derivation cohort, 3 variables were established for use in the predictive scoring score: ≥2 systemic inflammatory response syndrome (SIRS) criteria, age > 60 years, and SpO2 < 96%. Summing the presence or absence of each variable yielded an ED-SAS score ranging from 0 to 3. In the validation cohort, the odds of 30-day mortality increased with each subsequent ED-SAS point: 4.4 (95% CI 1.8-10.8) for 1 point, 12.0 (95% CI 4.9-29.4) for 2 points, and 41.7 (95% CI 15.8-110.1) for 3 points (c-statistic = 0.77). CONCLUSION: An ED-SAS score that incorporates SpO2, age, and SIRS measurements, all of which are available in the ED, provides a rapid method for predicting 30-day mortality in acute pancreatitis.

[Value of serum miR-21-3p in predicting acute kidney injury in children with sepsis].

OBJECTIVE: To study the value of serum miR-21-3p combined with serum creatinine (Scr), cystatin C (Cys-C), and kidney injury molecule-1 (KIM-1) in predicting acute kidney injury (AKI) in children with sepsis. METHODS: A total of 142 children who were diagnosed with sepsis from January 2016 to March 2019 were enrolled. According to the presence or absence of AKI, they were divided into AKI group with 49 children and non-AKI group with 93 children. The serum levels of miR-21-3p, Scr, Cys-C, and KIM-1 were measured for the two groups. The receiver operating characteristic (ROC) curve was plotted to analyze the value of serum miR-21-3p, Scr, Cys-C, and KIM-1 in predicting AKI. A Pearson correlation analysis was used to evaluate the correlation of serum miR-21-3p with Scr, Cys-C, and KIM-1. RESULTS: The AKI group had significantly higher serum levels of miR-21-3p, Scr, Cys-C, and KIM-1 than the non-AKI group (P<0.05). The ROC curve analysis showed that the combination of serum miR-21-3p, Scr, Cys-C, and KIM-1 had an area under the ROC curve (AUC) of 0.962 (95%CI: 0.906-0.998), which was significantly larger than the AUC of each index alone (P<0.05), with a sensitivity of 97.0% and a specificity of 91.4%. The correlation analysis showed that the serum level of miR-21-3p was positively correlated with Scr, Cys-C, and KIM-1 in the AKI group (r=0.704, 0.812, and 0.863 respectively, P<0.01). CONCLUSIONS: There is a significant increase in the serum level of miR-21-3p in children with sepsis and AKI, and its combination with Scr, Cys-C, and KIM-1 has a high value in predicting AKI.

Genotypic and phenotypic characterization of Chinese patients with osteogenesis imperfecta.

Osteogenesis imperfecta (OI) is a rare hereditary skeletal dysplasia, characterized by recurrent fractures and bone deformity. This study presents a clinical characterization and mutation analysis of 668 patients, aiming to establish the mutation spectrum and to elucidate genotype-phenotype correlations in Chinese OI patients. We identified 274 sequence variants (230 in type I collagen encoding genes and 44 in noncollagen genes), including 102 novel variants, in 340 probands with a detection rate of 90%. Compared with 47 loss-of-function variants detected in COL1A1, neither nonsense nor frameshift variants were found in COL1A2 (p < 0.0001). The major cause of autosomal recessive OI was biallelic variants in WNT1 (56%, 20/36). It is noteworthy that three genomic rearrangements, including one gross deletion and one gross duplication in COL1A1 as well as one gross deletion in FKBP10, were detected in this study. Of ten individuals with glycine substitutions that lie towards the N-terminal end of the triple-helical region of the α1(I) chain, none exhibited hearing loss, suggesting a potential genotype-phenotype correlation. The findings in this study expanded the mutation spectrum and identified novel correlations between genotype and phenotype in Chinese OI patients.

Variations in right colic vascular anatomy observed during laparoscopic right colectomy.

BACKGROUND: This study aimed to analyze right colonic vascular variability. METHODS: The study included 60 consecutive patients who underwent laparoscopic radical right colectomy and D3 lymph node dissection for malignant colonic cancer on the ileocecal valve, ascending colon or hepatic flexure (March 2013 to October 2016). The videos of the 60 surgical procedures were collected. Variations of right colonic vascular anatomy were retrospectively analyzed based on 60 high-resolution surgical videos of laparoscopic surgery. RESULTS: The superior mesenteric artery and vein were present in all cases; 95.0% (57/60) had the superior mesenteric artery on the left side of the superior mesenteric vein. The ileocolic artery and vein occurred in 96.7% (58/60) and 100% (60/60) of cases, respectively; 50.0% (29/58) had the ileocolic artery passing the superior mesenteric vein anteriorly. Thirty-three (55.0%) cases had a right colic artery, and 2 (3.33%) had a double right colic artery; 90.9% (30/36) had the right colic vein passing anterior to the superior mesenteric artery. Fifty-six (93.3%) cases had a right colic vein; 7 (12.5%) had a right colic vein accompanied by a right colic artery, 66.1% (37/56) had the right colic vein draining into the gastrocolic trunk of Henle, 23.2% (13/56) had the right colic vein directly draining into superior mesenteric vein, and 10.7% (6/56) had one right colic vein draining into the superior mesenteric vein and the other into the gastrocolic trunk of Henle. Fifty-three (88.3%) cases had a gastrocolic trunk of Henle: a gastrocolic trunk in 35.8% (19/53), a gastropancreatic trunk in 9.4% (5/53), and a gastropancreaticocolic trunk in 54.7% (29/53). The frequencies of middle colic artery and vein were respectively 100% (60/60) and 93.3% (56/60). CONCLUSIONS: Right colonic vascular variations were classified in Chinese patients. Notable findings included a superior mesenteric artery positioned to the right of the superior mesenteric vein and variation in middle colic artery length. This knowledge may be helpful to colorectal surgeons and could potentially help to improve safety by reducing vascular complications during minimally invasive procedures.

TAF1 Variants Are Associated with Dysmorphic Features, Intellectual Disability, and Neurological Manifestations.

We describe an X-linked genetic syndrome associated with mutations in TAF1 and manifesting with global developmental delay, intellectual disability (ID), characteristic facial dysmorphology, generalized hypotonia, and variable neurologic features, all in male individuals. Simultaneous studies using diverse strategies led to the identification of nine families with overlapping clinical presentations and affected by de novo or maternally inherited single-nucleotide changes. Two additional families harboring large duplications involving TAF1 were also found to share phenotypic overlap with the probands harboring single-nucleotide changes, but they also demonstrated a severe neurodegeneration phenotype. Functional analysis with RNA-seq for one of the families suggested that the phenotype is associated with downregulation of a set of genes notably enriched with genes regulated by E-box proteins. In addition, knockdown and mutant studies of this gene in zebrafish have shown a quantifiable, albeit small, effect on a neuronal phenotype. Our results suggest that mutations in TAF1 play a critical role in the development of this X-linked ID syndrome.

Variation and treatment of vessels in laparoscopic right hemicolectomy.

BACKGROUND: With the introduction of complete mesocolic excision (CME) and the application of laparoscopic technique, surgery for colon cancer has become more standardized and the curative effect has improved [1]. The key points in laparoscopic right hemicolectomy are high ligation of main vessels and root dissection of lymph nodes. The wide range of variations in vascular architecture and intraoperative bleeding are common causes of prolonged surgical time, wound hemorrhage, and even transfer to the opening operation. METHODS: The superior mesenteric vein (SMV) is the most important anatomical landmark in CME for the right colon, and guides all the steps of lymph node dissection. The SMV appears as a pale blue bulge on laparoscopy, which enables accurate positioning. The ileocolic vessel pedicle is relatively constant and facilitates accurate positioning. The intersection of the ileocolic vessel pedicle and the SMV is the optimal starting point in laparoscopic right hemicolectomy using a medial-to-lateral approach. A sheath with an avascular plane can be reached after opening the SMV vascular sheath, which results in less bleeding and enables vascular root and thorough lymph node dissection. The first step is to manage the ileocolic vessels. The ileocolic artery (ICA) is located anterior to the ileocolic vein (ICV) for about one-third of the incidence. The ileocolic vessels are relatively long and are easy to work with. In the vast majority of cases, the ICV drains into the SMV, and into the gastrocolic trunk (GCT) in about 2.5% of cases. The reported incidence of a right colic artery (RCA) is controversial; the RCA is absent in about 50% of cases and often crosses the SMV. The right colic vein (RCV) usually drains into the GCT, but sometimes drains directly into the SMV. The middle colic vessels have great variability and a close anatomical relationship with the pancreas, duodenum, and GCT. Moreover, the transverse colon and mesentery are long, and root positioning and processing of the middle colic vein (MCV) are relatively difficult. With the SMV and pancreas as anatomic landmarks, it is more feasible to locate the blood vessels in the neck of the pancreas. The middle colic artery (MCA) originates from the superior mesenteric artery (SMA), and the distance from the inferior border of the pancreas differs slightly in the literature, but is at the most 5 cm. Identification of the MCA trunk and branches, as well as the common origin of the MCA and RCA, is of great importance for the maintaining the blood supply during surgery for primary colon cancer. The MCV mainly drains into the SMV and GCT; however, if branching variation drains into the jejunal vein, inferior mesenteric vein, or splenic vein, the effect is serious when a vessel is torn. Isolation of the GCT is the step at which bleeding will likely occur in standard right resection and is a difficult stage of the surgery. The GCT has five origins including the right gastroepiploic vein (RGV), right colic vein (RCV), accessory right colic vein (ARCV), pancreaticduodenal vein (PDV), and MCV, which can have 2, 3, or 4 branches; therefore, familiarity with variants may be helpful to avoid bleeding. Approximately 5-10% of colon cancers at the hepatic flexure have No. 6 group lymph node metastasis, and laparoscopic radical extended right hemicolectomy requires thorough dissection of No. 6 group lymph nodes and the omental arcade 10 cm from the pylorus. The inferior arteriovenous vessels are a common source of bleeding, and the RGV can serve as a clue to finding the artery. CONCLUSIONS: The core area of laparoscopic radical extended right hemicolectomy includes the pancreatic neck, duodenum, and right gastroepiploic vessels. The difficulty lies with the standard treatment of the GCT. A medial-to-lateral approach is more in line with the principle of no-touch in tumor surgery and is applied from lower to upper, inside to outside, and left to right, for both the vessels and plane of dissection. Familiarity with vascular variation and the management of vessels in key areas are essential for successful surgery.

Biochemical and cellular analysis of Ogden syndrome reveals downstream Nt-acetylation defects.

The X-linked lethal Ogden syndrome was the first reported human genetic disorder associated with a mutation in an N-terminal acetyltransferase (NAT) gene. The affected males harbor an Ser37Pro (S37P) mutation in the gene encoding Naa10, the catalytic subunit of NatA, the major human NAT involved in the co-translational acetylation of proteins. Structural models and molecular dynamics simulations of the human NatA and its S37P mutant highlight differences in regions involved in catalysis and at the interface between Naa10 and the auxiliary subunit hNaa15. Biochemical data further demonstrate a reduced catalytic capacity and an impaired interaction between hNaa10 S37P and Naa15 as well as Naa50 (NatE), another interactor of the NatA complex. N-Terminal acetylome analyses revealed a decreased acetylation of a subset of NatA and NatE substrates in Ogden syndrome cells, supporting the genetic findings and our hypothesis regarding reduced Nt-acetylation of a subset of NatA/NatE-type substrates as one etiology for Ogden syndrome. Furthermore, Ogden syndrome fibroblasts display abnormal cell migration and proliferation capacity, possibly linked to a perturbed retinoblastoma pathway. N-Terminal acetylation clearly plays a role in Ogden syndrome, thus revealing the in vivo importance of N-terminal acetylation in human physiology and disease.

Accurate de novo and transmitted indel detection in exome-capture data using microassembly.

We present an open-source algorithm, Scalpel (http://scalpel.sourceforge.net/), which combines mapping and assembly for sensitive and specific discovery of insertions and deletions (indels) in exome-capture data. A detailed repeat analysis coupled with a self-tuning k-mer strategy allows Scalpel to outperform other state-of-the-art approaches for indel discovery, particularly in regions containing near-perfect repeats. We analyzed 593 families from the Simons Simplex Collection and demonstrated Scalpel's power to detect long (≥30 bp) transmitted events and enrichment for de novo likely gene-disrupting indels in autistic children.

[Spectrum of COL1A1/2 mutations and gene diagnosis in Chinese patients with osteogenesis imperfecta].

OBJECTIVE: To identify mutations of the type I collagen genes (COL1A1 and COL1A2) in the affected with osteogenesis imperfecta (OI), to establish the spectrum of COL1A1/2 mutations in Chinese OI patients, and to provide prenatal gene diagnosis to the fetuses at high risk. METHODS: Genomic DNA was extracted from peripheral blood by the standard SDS-proteinase K-phenol/chloroform method. All the coding regions and exon/intron boundaries of COL1A1/2 were screened in 200 OI cases by conventional Sanger sequencing and targeted next-generation sequencing (NGS) on Ion Torrent-personalized genome sequencing operation (Ion PGM™). For familial cases, candidate mutations were validated in all available family members using high resolution melting analysis (HRM). In sporadic cases, only parents were examined to determine the origin of the identified mutation.Prenatal gene diagnosis was carried out by PCR direct sequencing and linkage analysis using microsatellite markers. RESULTS: In total, the authors identified 125 differently pathogenic mutations, including 74 in COL1A1 and 51 in COL1A2, in 158 probands, with a mutation detection rate of 79% (158/200). Among the 125 identified mutations, there were 63 novel mutations (33 in COL1A1 and 30 in COL1A2) and 13 recurrent mutations found in 46 probands (seven mutations recurring for two times, and the other six mutations recurring for more than 4 times). They performed prenatal genetic testing in 74 fetuses and found that 40 ones carried COL1A1/2 mutations identified in the corresponding probands. CONCLUSIONS: The authors have developed a combined approach for genetic testing of OI, extended the COL1A1/2 mutation spectrum in Chinese OI patients, and confirmed gene diagnosis in a relatively large cohort of OI probands and fetuses.

MRI-based Machine Learning Radiomics Can Predict CSF1R Expression Level and Prognosis in High-grade Gliomas.

The purpose of this study is to predict the mRNA expression of CSF1R in HGG non-invasively using MRI (magnetic resonance imaging) omics technology and to evaluate the correlation between the established radiomics model and prognosis. We investigated the predictive value of CSF1R in the Cancer Genome Atlas (TCGA) and The Cancer Imaging Archive (TCIA) database. The Support vector machine (SVM) and the Logistic regression (LR) algorithms were used to create a radiomics_score (Rad_score), respectively. The effectiveness and performance of the radiomics model was assessed in the training (n = 89) and tenfold cross-validation sets. We further analyzed the correlation between Rad_score and macrophage-related genes using Spearman correlation analysis. A radiomics nomogram combining the clinical factors and Rad_score was constructed to validate the radiomic signatures for individualized survival estimation and risk stratification. The results showed that CSF1R expression was markedly elevated in HGG tissues, which was related to worse prognosis. CSF1R expression was closely related to the abundance of infiltrating immune cells, such as macrophages. We identified nine features for establishing a radiomics model. The radiomics model predicting CSF1R achieved high AUC in training (0.768 in SVM and 0.792 in LR) and tenfold cross-validation sets (0.706 in SVM and 0.717 in LR). Rad_score was highly associated with tumor-related macrophage genes. A radiomics nomogram combining the Rad_score and clinical factors was constructed and revealed satisfactory performance. MRI-based Rad_score is a novel way to predict CSF1R expression and prognosis in high-grade glioma patients. The radiomics nomogram could optimize individualized survival estimation for HGG patients.

Association of 10 VEGF Family Genes with Alzheimer's Disease Endophenotypes at Single Cell Resolution.

The cell-type specific role of the vascular endothelial growth factors (VEGFs) in the pathogenesis of Alzheimer's disease (AD) is not well characterized. In this study, we utilized a single-nucleus RNA sequencing dataset from Dorsolateral Prefrontal Cortex (DLFPC) of 424 donors from the Religious Orders Study and Memory and Aging Project (ROS/MAP) to investigate the effect of 10 VEGF genes ( VEGFA, VEGFB, VEGFC, VEGFD, PGF, FLT1, FLT4, KDR, NRP1 , and NRP2 ) on AD endophenotypes. Mean age of death was 89 years, among which 68% were females, and 52% has AD dementia. Negative binomial mixed models were used for differential expression analysis and for association analysis with ß-amyloid load, PHF tau tangle density, and both cross-sectional and longitudinal global cognitive function. Intercellular VEGF-associated signaling was profiled using CellChat. We discovered prefrontal cortical FLT1 expression was upregulated in AD brains in both endothelial and microglial cells. Higher FLT1 expression was also associated with worse cross-sectional global cognitive function, longitudinal cognitive trajectories, and ß-amyloid load. Similarly, higher endothelial FLT4 expression was associated with more ß-amyloid load. In contrast to the receptors, VEGFB showed opposing effects on ß-amyloid load whereby higher levels in oligodendrocytes was associated with high amyloid burden, while higher levels in inhibitory neurons was associated with lower amyloid burden. Finally, AD cells showed significant reduction in overall VEGF signaling comparing to those from cognitive normal participants. Our results highlight key changes in VEGF receptor expression in endothelial and microglial cells during AD, and the potential protective role of VEGFB in neurons.

Hippocampus Glutathione S Reductase Potentially Confers Genetic Resilience to Cognitive Decline in the AD-BXD Mouse Population.

Alzheimer's disease (AD) is a prevalent and costly age-related dementia. Heritable factors account for 58-79% of variation in late-onset AD, but substantial variation remains in age-of- onset, disease severity, and whether those with high-risk genotypes acquire AD. To emulate the diversity of human populations, we utilized the AD-BXD mouse panel. This genetically diverse resource combines AD genotypes with multiple BXD strains to discover new genetic drivers of AD resilience. Comparing AD-BXD carriers to noncarrier littermates, we computed a novel quantitative metric for resilience to cognitive decline in the AD-BXDs. Our quantitative AD resilience trait was heritable and genetic mapping identified a locus on chr8 associated with resilience to AD mutations that resulted in amyloid brain pathology. Using a hippocampus proteomics dataset, we nominated the mitochondrial glutathione S reductase protein (GR or GSHR) as a resilience factor, finding that the DBA/2J genotype was associated with substantially higher GR abundance. By mapping protein QTLs (pQTLs), we identified synaptic organization and mitochondrial proteins coregulated in trans with a cis-pQTL for GR. We found four coexpression modules correlated with the quantitative resilience score in aged 5XFAD mice using paracliques, which were related to cell structure, protein folding, and postsynaptic densities. Finally, we found significant positive associations between human GSR transcript abundance in the brain and better outcomes on AD-related cognitive and pathology traits in the Religious Orders Study/Memory and Aging project (ROSMAP). Taken together, these data support a framework for resilience in which neuronal antioxidant pathway activity provides for stability of synapses within the hippocampus.

Accelerating the Design of Self-Guided Microrobots in Time-Varying Magnetic Fields.

Mobile robots combine sensory information with mechanical actuation to move autonomously through structured environments and perform specific tasks. The miniaturization of such robots to the size of living cells is actively pursued for applications in biomedicine, materials science, and environmental sustainability. Existing microrobots based on field-driven particles rely on knowledge of the particle position and the target destination to control particle motion through fluid environments. Often, however, these external control strategies are challenged by limited information and global actuation where a common field directs multiple robots with unknown positions. In this Perspective, we discuss how time-varying magnetic fields can be used to encode the self-guided behaviors of magnetic particles conditioned on local environmental cues. Programming these behaviors is framed as a design problem: we seek to identify the design variables (e.g., particle shape, magnetization, elasticity, stimuli-response) that achieve the desired performance in a given environment. We discuss strategies for accelerating the design process using automated experiments, computational models, statistical inference, and machine learning approaches. Based on the current understanding of field-driven particle dynamics and existing capabilities for particle fabrication and actuation, we argue that self-guided microrobots with potentially transformative capabilities are close at hand.