Association between miR-365 polymorphism and ischemic stroke in a Chinese population.

Background: Ischemic stroke (IS) represents a major cause of morbidity and mortality across the globe. The aberrant expression of miR-365 has been found to be implicated in a wide array of human diseases, including atherosclerosis and cancer. Studies on single-nucleotide polymorphisms (SNPs) in miRNA genes can help gain insight into the susceptibility to the condition. This study aimed to examine the relationship between miR-365 SNPs and the risk of IS. Methods: The study recruited 215 IS patients and 220 controls. The SNPscans genotyping was employed to genotype three polymorphic loci (rs121224, rs30230, and rs178553) of miR-365. The relative expression of miR-365 in peripheral blood mononuclear cells of the patients and controls was determined by using real-time quantitative PCR. Results: The miR-365 rs30230 polymorphism exhibited a significant association with the risk of developing IS (TC vs. CC: adjusted OR = 0.55, 95% CI: 0.33-0.92, P = 0.022; TT vs. CC: adjusted OR = 0.34, 95% CI: 0.14-0.85, P = 0.021; TC +TT vs. CC: adjusted OR = 0.51, 95% CI: 0.31-0.83, P = 0.007; T vs. C: adjusted OR = 0.57, 95% CI: 0.39-0.83, P = 0.004). Haplotype analysis revealed that the C-T-G haplotype was associated with a decreased risk of IS (OR = 0.68, 95% CI: 0.46-1.00, P = 0.047). Furthermore, miR-365 expression was significantly higher in IS patients than in controls (P < 0.001). Interestingly, patients with rs30230 TC or TT genotypes had lower miR-365 levels compared to their counterparts with CC genotypes (P < 0.001). Conclusions: The miR-365 rs30230 polymorphism might bear an association with IS susceptibility in the Chinese population, and the rs30230 TC/TT genotype might be a protective factor against IS.

Adjunctive accelerated repetitive transcranial magnetic stimulation for older patients with depression: A systematic review.

Objective: We performed this systemic review to investigate the therapeutic potential and safety of adjunctive accelerated repetitive transcranial magnetic stimulation (aTMS) for older patients with depression. Methods: We included published randomized clinical trials (RCTs) and observational studies targeting adjunctive aTMS for older patients with depression. Results: Two open-label self-controlled studies (n = 29) fulfilled the criteria for inclusion. The included studies reported significant improvements in depressive symptoms from baseline to post-aTMS (all Ps < 0.05). One study reported a dropout rate of 10.5% (2/19). Mild headache was the most common adverse reaction. Conclusion: The currently available evidence from two open-label self-controlled studies indicates that adjunctive aTMS is a safe and effective therapy for older patients with depression.

Acinar ATP8b1/LPC pathway promotes macrophage efferocytosis and clearance of inflammation during chronic pancreatitis development.

Noninflammatory clearance of dying cells by professional phagocytes, termed efferocytosis, is fundamental in both homeostasis and inflammatory fibrosis disease but has not been confirmed to occur in chronic pancreatitis (CP). Here, we investigated whether efferocytosis constitutes a novel regulatory target in CP and its mechanisms. PRSS1 transgenic (PRSS1Tg) mice were treated with caerulein to mimic CP development. Phospholipid metabolite profiling and epigenetic assays were performed with PRSS1Tg CP models. The potential functions of Atp8b1 in CP model were clarified using Atp8b1-overexpressing adeno-associated virus, immunofluorescence, enzyme-linked immunosorbent assay(ELISA), and lipid metabolomic approaches. ATAC-seq combined with RNA-seq was then used to identify transcription factors binding to the Atp8b1 promoter, and ChIP-qPCR and luciferase assays were used to confirm that the identified transcription factor bound to the Atp8b1 promoter, and to identify the specific binding site. Flow cytometry was performed to analyze the proportion of pancreatic macrophages. Decreased efferocytosis with aggravated inflammation was identified in CP. The lysophosphatidylcholine (LPC) pathway was the most obviously dysregulated phospholipid pathway, and LPC and Atp8b1 expression gradually decreased during CP development. H3K27me3 ChIP-seq showed that increased Atp8b1 promoter methylation led to transcriptional inhibition. Atp8b1 complementation substantially increased the LPC concentration and improved CP outcomes. Bhlha15 was identified as a transcription factor that binds to the Atp8b1 promoter and regulates phospholipid metabolism. Our study indicates that the acinar Atp8b1/LPC pathway acts as an important "find-me" signal for macrophages and plays a protective role in CP, with Atp8b1 transcription promoted by the acinar cell-specific transcription factor Bhlha15. Bhlha15, Atp8b1, and LPC could be clinically translated into valuable therapeutic targets to overcome the limitations of current CP therapies.

St13 protects against disordered acinar cell arachidonic acid pathway in chronic pancreatitis.

BACKGROUND: Early diagnosis and treatment of chronic pancreatitis (CP) are limited. In this study, St13, a co-chaperone protein, was investigated whether it constituted a novel regulatory target in CP. Meanwhile, we evaluated the value of micro-PET/CT in the early diagnosis of CP. METHODS: Data from healthy control individuals and patients with alcoholic CP (ACP) or non-ACP (nACP) were analysed. PRSS1 transgenic mice (PRSS1Tg) were treated with ethanol or caerulein to mimic the development of ACP or nACP, respectively. Pancreatic lipid metabolite profiling was performed in human and PRSS1Tg model mice. The potential functions of St13 were investigated by crossing PRSS1Tg mice with St13-/- mice via immunoprecipitation and lipid metabolomics. Micro-PET/CT was performed to evaluate pancreatic morphology and fibrosis in CP model. RESULTS: The arachidonic acid (AA) pathway ranked the most commonly dysregulated lipid pathway in ACP and nACP in human and mice. Knockout of St13 exacerbated fatty replacement and fibrosis in CP model. Sdf2l1 was identified as a binding partner of St13 as it stabilizes the IRE1α-XBP1s signalling pathway, which regulates COX-2, an important component in AA metabolism. Micro-PET/CT with 68Ga-FAPI-04 was useful for evaluating pancreatic morphology and fibrosis in CP model mice 2 weeks after modelling. CONCLUSION: St13 is functionally activated in acinar cells and protects against the cellular characteristics of CP by binding Sdf2l1, regulating AA pathway. 68Ga-FAPI-04 PET/CT may be a very valuable approach for the early diagnosis of CP. These findings thus provide novel insights into both diagnosis and treatment of CP.

Impact of BRCA mutation on the survival and risk of contralateral breast cancer in Asian breast cancer patients.

PURPOSE: Breast cancer is increasing around the globe, including Asia. We aimed to examine the survival and risk of contralateral breast cancer (CBC) in Asian breast cancer patients with BRCA mutations. METHODS: A total of 128 breast cancer patients with germline BRCA mutations and 4,754 control breast cancer patients were enrolled. Data on clinical-pathologic characteristics, survival, and CBC were collected from the medical record. The rates of survival and CBC were estimated by Kaplan-Meier method. RESULTS: The mean age of onset in BRCA mutation carriers was significantly younger than control patients (BRCA vs. Non-BRCA: 43.9 vs. 53.2 years old). BRCA mutation carriers had a higher proportion of triple-negative breast cancer (TNBC) (52%) than control patients (12%, p < 0.001). The risk of CBC was significantly higher in BRCA mutation patients than in control cases (hazard ratio (HR) = 3.95, 95% CI 2.71-5.75); when stratified by genotype, the HRs (95%CI) were 4.84 (3.00-7.82) for BRCA1 and 3.13 (1.78-5.49) for BRCA2 carriers, respectively. Moreover, BRCA1 mutation patients with triple-negative breast cancer (TNBC) as their first breast cancer had the highest risk of CBC (HR = 5.55, 95% CI 3.29-9.34). However, we did not observe any differences in relapse-free survival and overall survival between mutation carriers and control patients. CONCLUSION: Our study suggest that BRCA patients had a significantly higher risk of developing CBC, particularly for BRCA1 mutation carriers with TNBC as the first breast cancer.

Frequent amplification of HDAC genes and efficacy of HDAC inhibitor chidamide and PD-1 blockade combination in soft tissue sarcoma.

BACKGROUND: The advent of immune checkpoint therapy has been a tremendous advance in cancer treatment. However, the responses are still insufficient in patients with soft tissue sarcoma (STS). We aimed to identify rational combinations to increase the response to immune checkpoint therapy and improve survival. METHODS: Whole-exome sequencing (WES) was performed in 11 patients with liposarcoma. Somatic copy number alterations (SCNAs) were analyzed at the gene level to identify obvious amplification patterns in drug-target genes. The expression and prognostic value of class I histone deacetylases (HDACs) was evaluated in 49 patients with sarcoma in our center and confirmed in 263 sarcoma samples from The Tumor Cancer Genome Atlas (TCGA) database. Q-PCR, flow cytometry and RNA-seq were performed to determine the correlations between class I HDACs, chidamide and PD-L1 in vitro and in vivo. The efficacy of combining chidamide with PD-1 blockade was explored in an immunocompetent murine model and a small cohort of patients with advanced sarcoma. Western blot, ChIP assay and dual luciferase assessment were applied in the mechanistic study. RESULTS: The HDAC gene family was frequently amplified in STS. SCNAs in the HDAC gene family were extensively amplified in 8 of 11 (73%) patients with liposarcoma, based on a drug-target gene set, and we verified amplification in 76.65% (197/257) of cases by analyzing TCGA sarcoma cohort. Class I HDAC expression is associated with a poor prognosis for patients with STS, and its inhibition is responsible for promoting apoptosis and upregulating of programmed cell death ligand 1 (PD-L1). The HDAC class I inhibitor chidamide significantly increases PD-L1 expression, increased the infiltration of CD8+ T cells and reduced the number of MDSCs in the tumor microenvironment. The combination of chidamide with an anti-PD-1 antibody significantly promotes tumor regression and improves survival in a murine model. Moreover, chidamide combined with the anti-PD-1 antibody toripalimab is effective in patients with advanced and metastatic sarcoma, and the side effects are tolerable. Mechanistically, chidamide increases histone acetylation at the PD-L1 gene through the activation of the transcriptional factor STAT1. CONCLUSIONS: The combination of chidamide and anti-programmed cell death 1 (PD-1) therapy represents a potentially important strategy for STS.

Adjunctive Magnetic Seizure Therapy for Schizophrenia: A Systematic Review.

Objective: The efficacy and safety of adjunctive magnetic seizure therapy (MST) for patients with schizophrenia are unclear. This systematic review was conducted to examine the efficacy and safety of adjunctive MST for schizophrenia. Methods: Chinese (WanFang and Chinese Journal Net) and English (PubMed, EMBASE, PsycINFO, and the Cochrane Library) databases were systematically searched. Results: Two open-label self-controlled studies (n = 16) were included and analyzed in this review. In these studies, the Positive and Negative Syndrome Scale (PANSS) total scores and Brief Psychiatric Rating Scale (BPRS) total scores significantly decreased from baseline to post-MST (all Ps < 0.05), without serious adverse neurocognitive effects. Mixed findings on the neurocognitive effects of adjunctive MST for schizophrenia were reported in the two studies. A discontinuation rate of treatment of up to 50% (4/8) was reported in both studies. The rate of adverse drug reactions (ADRs) was evaluated in only one study, where the most common ADRs were found to be dizziness (25%, 2/8) and subjective memory loss (12.5%, 1/8). Conclusion: There is inconsistent evidence for MST-related adverse neurocognitive effects and preliminary evidence for the alleviation of psychotic symptoms in schizophrenia.

EMC6 regulates acinar apoptosis via APAF1 in acute and chronic pancreatitis.

Treatment of acute pancreatitis (AP) and chronic pancreatitis (CP) remains problematic due to a lack of knowledge about disease-specific regulatory targets and mechanisms. The purpose of this study was to screen proteins related to endoplasmic reticulum (ER) stress and apoptosis pathways that may play a role in pancreatitis. Human pancreatic tissues including AP, CP, and healthy volunteers were collected during surgery. Humanized PRSS1 (protease serine 1) transgenic (PRSS1Tg) mice were constructed and treated with caerulein to mimic the development of human AP and CP. Potential regulatory proteins in pancreatitis were identified by proteomic screen using pancreatic tissues of PRSS1Tg AP mice. Adenoviral shRNA-mediated knockdown of identified proteins, followed by functional assays was performed to validate their roles. Functional analyses included transmission electron microscopy for ultrastructural analysis; qRT-PCR, western blotting, co-immunoprecipitation, immunohistochemistry, and immunofluorescence for assessment of gene or protein expression, and TUNEL assays for assessment of acinar cell apoptosis. Humanized PRSS1Tg mice could mimic the development of human pancreatic inflammatory diseases. EMC6 and APAF1 were identified as potential regulatory molecules in AP and CP models by proteomic analysis. Both EMC6 and APAF1 regulated apoptosis and inflammatory injury in pancreatic inflammatory diseases. Moreover, APAF1 was regulated by EMC6, induced apoptosis to injure acinar cells and promoted inflammation. In the progression of pancreatitis, EMC6 was activated and then upregulated APAF1 to induce acinar cell apoptosis and inflammatory injury. These findings suggest that EMC6 may be a new therapeutic target for the treatment of pancreatic inflammatory diseases.

A three serum miRNA panel as diagnostic biomarkers of radiotherapy-related metastasis in non-small cell lung cancer.

Serum microRNAs (miRNAs) have been implicated as noninvasive biomarkers for lung cancer diagnosis. However, there are no sensitive and specific biomarkers for the detection of radiotherapy-related non-small cell lung cancer (NSCLC) metastasis. The present study aimed to investigate the role of three serum miRNAs, namely miRNA (miR)-130a, miR-25 and miR-191*, in diagnosing NSCLC, and their biological functions in radiation-mediated development of metastatic properties in A549 cells. To determine this, serum samples were collected from 84 patients with NSCLC and 42 age- and sex-matched healthy controls. Differential expression of serum miRNAs was analyzed by quantitative PCR. Significant associations between miRNA expression and overall survival of patients with NSCLC were identified using the Cox proportional regression model. A receiver operating characteristic curve was generated to evaluate diagnostic accuracy. The functions of miR-130a, miR-25 and miR-191* in lung cancer cells were studied by transfecting A549 cells with miRNA mimics and inhibitors. The results of the present study demonstrated that the expression levels of miR-130a, miR-25 and miR-191* in the serum of patients with NSCLC were increased compared with those in healthy controls, and these increases were associated with advanced age (≥60 years), radiotherapy, histological type (squamous carcinoma), low survival rate and low median survival time. Additionally, irradiation induced the upregulation of miR-130a, miR-25 and miR-191* expression in A549 cells in vitro and in a xenograft mouse model. Irradiation also promoted the invasiveness of A549 cells in vitro and metastasis in vivo. In conclusion, miR-130a, miR-25 and miR-191* may be potential biomarkers for the diagnosis of patients with NSCLC and may serve oncogenic roles in radiation-mediated metastasis of NSCLC.

ATF6 aggravates acinar cell apoptosis and injury by regulating p53/AIFM2 transcription in Severe Acute Pancreatitis.

Background: There is no curative therapy for severe acute pancreatitis (SAP) due to poor understanding of its molecular mechanisms. Endoplasmic reticulum (ER) stress is involved in SAP and increased expression of ATF6 has been detected in SAP patients. Here, we aimed to investigate the role of ATF6 in a preclinical SAP mouse model and characterize its regulatory mechanism. Methods: Pancreatic tissues of healthy and SAP patients were collected during surgery. Humanized PRSS1 transgenic mice were treated with caerulein to mimic the SAP development, which was crossed to an ATF6 knockout mouse line, and pancreatic tissues from the resulting pups were screened by proteomics. Adenovirus-mediated delivery to the pancreas of SAP mice was used for shRNA-based knockdown or overexpression. The potential functions and mechanisms of ATF6 were clarified by immunofluorescence, immunoelectron microscopy, Western blotting, qRT-PCR, ChIP-qPCR and luciferase reporter assay. Results: Increased expression of ATF6 was associated with elevated apoptosis, ER and mitochondrial disorder in pancreatic tissues from SAP patients and PRSS1 mice. Knockout of ATF6 in SAP mice attenuated acinar injury, apoptosis and ER disorder. AIFM2, known as a p53 target gene, was identified as a downstream regulatory partner of ATF6, whose expression was increased in SAP. Functionally, AIFM2 could reestablish the pathological disorder in SAP tissues in the absence of ATF6. p53 expression was also increased in SAP mice, which was downregulated by ATF6 knockout. p53 knockout significantly suppressed acinar apoptosis and injury in SAP model. Mechanistically, ATF6 promoted AIFM2 transcription by binding to p53 and AIFM2 promoters. Conclusion: These results reveal that ATF6/p53/AIFM2 pathway plays a critical role in acinar apoptosis during SAP progression, highlighting novel therapeutic target molecules for SAP.

ALKATI interacts with c-Myc and promotes cancer stem cell-like properties in sarcoma.

Soft tissue sarcoma (STS) is a highly malignant tumor with limited targeted therapies. A novel anaplastic lymphoma kinase (ALK) transcript, ALKATI, was identified recently and could be targeted by ALK inhibitors in melanoma. However, the clinical and functional role of aberrant ALKATI expression in STS remains unknown. Here we demonstrate that as a new ALK transcript, ALKATI is frequently found in STS. ALKATI expression correlates with a lower probability of progression-free survival in STS patients. Compared with the other ALK isoforms, ALKATI expresses not only in the cytoplasm, but also in the nucleus of sarcoma cells. Functionally, overexpression of ALKATI promoted cancer stem cell (CSC)-like properties in sarcoma cells by promoting sphere formation and upregulating the expression of stem cell markers. Moreover, the ALK inhibitors not only suppressed the oncogenic functions of ALKATI but also attenuated ALKATI-induced CSC-like properties by reducing the expression of stem cell markers such as c-Myc, ABCG2, BMI1, and OCT4 both in vitro and in vivo. Furthermore, ALKATI interacted with c-Myc and increased the binding of c-Myc to the ABCG2 promoter, resulting in the induction of stem cell-like properties. Together, these findings indicate that ALKATI may be a potential prognostic marker and therapeutic target for STS patients harboring such ALK aberrations.

Author Correction: Efficient electron transfer across hydrogen bond interfaces by proton-coupled and -uncoupled pathways.

An amendment to this paper has been published and can be accessed via a link at the top of the paper.

Author Correction: Efficient electron transfer across hydrogen bond interfaces by proton-coupled and -uncoupled pathways.

The original version of this Article contained errors in the symbols displayed in the eighteenth sentence of the third paragraph of the 'Determination of Hab and kET data for the Mo2 dimers' section of the Results, and the third sentence of the Discussion. This has been corrected in both the PDF and HTML versions of the Article.

Efficient electron transfer across hydrogen bond interfaces by proton-coupled and -uncoupled pathways.

Thermal electron transfer through hydrogen bonds remains largely unexplored. Here we report the study of electron transfer through amide-amide hydrogen bonded interfaces in mixed-valence complexes with covalently bonded Mo2 units as the electron donor and acceptor. The rate constants for electron transfer through the dual hydrogen bonds across a distance of 12.5 Å are on the order of ∼ 1010 s-1, as determined by optical analysis based on Marcus-Hush theory and simulation of ν(NH) vibrational band broadening, with the electron transfer efficiencies comparable to that of π conjugated bridges. This work demonstrates that electron transfer across a hydrogen bond may proceed via the known proton-coupled pathway, as well as an overlooked proton-uncoupled pathway that does not involve proton transfer. A mechanistic switch between the two pathways can be achieved by manipulation of the strengths of electronic coupling and hydrogen bonding. The knowledge of the non-proton coupled pathway has shed light on charge and energy transport in biological systems.

Altered metabolites in guinea pigs with allergic asthma after acupoint sticking therapy: New insights from a metabolomics approach.

BACKGROUND: Clinical evidence gathered in Chinese communities suggested that acupoint sticking therapy could be an alternative treatment for asthma-related diseases. However, its underlying mechanism is still poorly understood. AIM/HYPOTHESIS: In this study, we aimed to investigate the mechanism of the anti-inflammatory effect of acupoint sticking application with 'Treatment of Winter Disease in Summer' (TWDS) prescription by using metabolomics. METHODS: Allergic asthma in guinea pig was sensitized and challenged by ovalbumin (OVA). Histopathological evaluation of the lung tissue was performed by hematoxylin and eosin (H&E) staining and Masson's trichrome staining. The levels of Th2 cytokine and IgE level in serum were measured using enzyme-linked immunoassay (ELISA). The mRNA expression levels of IL-4, IL-5, IL-13 and orosomucoid-like 3 (ORMDL3) were measured using quantitative reverse transcription polymerase chain reaction (RT-qPCR). Proteins of NF-κB signaling pathway were measured using western blot. The serum metabolomics profiles were obtained by using ultra-performance liquid chromatography combined with electrospray ionization quadrupole time-of-flight mass spectrometry (UPLC-ESI-QTOF-MS). RESULTS: The overall results confirmed that AST with TWDS prescription had a significant protective effect against OVA-induced allergic asthma in guinea pig. This treatment not only attenuated airway inflammation and collagen deposition in the airway, but also decreased the levels of IL-4, IL-5, IL-13 and IgE in serum. In addition, metabolomics results indicated that metabolisms of phospholipid, sphingolipid, purine, amino acid and level of epinephrine were restored back to the normal control level. Moreover, results of the gene expression of ORMDL3 in lung tissues indicated that AST using TWDS could alter the sphingolipid metabolism. Further western blotting analysis also showed that its anti-inflammatory mechanism was by decreasing the phosphorylation of p65 and IκB. CONCLUSION: The study demonstrated that metabolomics provides a better understanding of the actions of TWDS acupoint sticking therapy on OVA-induced allergic asthma.

Podocalyxin-like protein promotes gastric cancer progression through interacting with RUN and FYVE domain containing 1 protein.

Podocalyxin-like protein (PODXL), a transmembrane glycoprotein with anti-adhesive properties, is associated with an aggressive tumor phenotype and poor prognosis of several cancers. To elucidate the biological significance of PODXL and its molecular mechanism in gastric cancer (GC), we investigated the expression of PODXL in GC samples and assessed its effects on biological behaviors and the related signaling pathways in vitro and in vivo. Moreover, the possible and closely interacted partners of PODXL were identified. Our data showed that the protein or mRNA level of PODXL was significantly upregulated in tissues or serum of GC patients compared with normal-appearing tissues (NAT) or those of healthy volunteers. Overall survival (OS) curves showed that patients with high PODXL levels in tissues or serum had a worse 5-year OS. In vitro, restoring PODXL expression promoted tumor progression by increasing cell proliferation, colony formation, wound healing, migration and invasion, as well as suppressing the apoptosis. Furthermore, the PI3K/AKT, NF-κB and MAPK/ERK signaling pathways were activated. There was a significant positive correlation between PODXL and RUN and FYVE domain containing 1 (RUFY1) expression in tissues or serum. Subsequent mass spectrometry analysis, co-immunoprecipitation assays and western blot analysis identified PODXL/RUFY1 complexes in GC cells, and silencing RUFY1 expression in GC cells significantly attenuated PODXL-induced phenotypes and their underlying signaling pathways. Our results suggested that PODXL promoted GC progression via a RUFY1-dependent signaling mechanism. New GC therapeutic opportunities through PODXL and targeting the PODXL/RUFY1 complex might improve cancer therapy.

Electronic Coupling and Electron Transfer between Two Mo2 Units through meta- and para-Phenylene Bridges.

A series of three Mo2 dimers bridged by a meta-phenylene group has been studied in terms of electronic coupling (EC) and electron transfer (ET) in comparison with the para isomers. Optical analyses on the mixed-valence complexes indicate that by replacing a para-phenylene bridge with a meta one, the EC between the two Mo2 centers is dramatically weakened; consequently, the ET rates (ket ) are lowered by two to three orders of magnitude. In the para series, the EC parameters (Hab ) and ET rates (ket ) are greatly affected by O/S atomic alternation of the bridging ligand. However, for the meta analogues, similar EC and ET parameters are obtained, that is, Hab =300-400 cm-1 and ket ≈109  s-1 . These results suggest that through-σ-bond and/or through-space coupling channels become operative as the π conjugation is disabled. DFT calculations reveal that destructive quantum interference features seen for the meta series arise from the cancellation of two π-conjugated coupling pathways.

Mapping Bridge Conformational Effects on Electronic Coupling in Mo2-Mo2 Mixed-Valence Systems.

The large bridging ligand 9,10-anthracenedicarboxylate and its thiolated derivatives have been employed to assemble two dimolybdenum complex units and develop three Mo2 dimers, [Mo2(DAniF)3]2(µ-9,10-O2CC14H8CO2), [Mo2(DAniF)3]2(µ-9,10-OSCC14H8COS), and [Mo2(DAniF)3]2(µ-9,10-S2CC14H8CS2) (DAniF = N, N'-di( p-anisyl)formamidinate), for the study of conformation dependence of the electronic coupling between the two Mo2 centers. These compounds feature a large deviation of the central anthracene ring from the plane defined by the Mo-Mo bond vectors, with the torsion angles (ϕ = 50-76°) increasing as the chelating atoms of the bridging ligand vary from O to S. Consequently, the corresponding mixed-valence complexes do not exhibit characteristic intervalence charge transfer absorptions in the near-IR spectra, in contrast to the phenylene and naphthalene analogues, from which these systems are assigned to the Class I in Robin-Day's scheme. Together with the phenylene and naphthalene series, the nine total mixed-valence complexes in three series complete a transition from the electronically uncoupled Class I to the strongly coupled Class II-III borderline via moderately coupled Class II and permit a systematic mapping of the bridge conformation effects on electronic coupling. Density functional theory calculations show that the HOMO-LUMO energy gap, corresponding to the metal (δ) to ligand (π*) transition energy, and the magnitude of HOMO-HOMO-1 splitting in energy are linearly related to cos2 ϕ. Therefore, our experimental and theoretical results concur to indicate that the coupling strength decreases in the order of the bridging units: phenylene > naphthalene > anthracene, which verifies the through-bond superexchange mechanism for electronic coupling and electron transfer.