Ablation of KIF2C in Purkinje cells impairs metabotropic glutamate receptor trafficking and motor coordination in male mice.

Kinesin family member 2C (KIF2C)/mitotic centromere-associated kinesin (MCAK), is thought to be oncogenic as it is involved in tumour progression and metastasis. Moreover, it also plays a part in neurodegenerative conditions like Alzheimer's disease and psychiatric disorders such as suicidal schizophrenia. Our previous study conducted on mice demonstrated that KIF2C is widely distributed in various regions of the brain, and is localized in synaptic spines. Additionally, it regulates microtubule dynamic properties through its own microtubule depolymerization activity, thereby affecting AMPA receptor transport and cognitive behaviour in mice. In this study, we show that KIF2C regulates the transport of mGlu1 receptors in Purkinje cells by binding to Rab8. KIF2C deficiency in Purkinje cells results in abnormal gait, reduced balance ability and motor incoordination in male mice. These data suggest that KIF2C is essential for maintaining normal transport and synaptic function of mGlu1 and motor coordination in mice. KEY POINTS: KIF2C is localized in synaptic spines of hippocampus neurons, and regulates excitatory transmission, synaptic plasticity and cognitive behaviour. KIF2C is extensively expressed in the cerebellum, and we investigated its functions in development and synaptic transmission of cerebellar Purkinje cells. KIF2C deficiency in Purkinje cells alters the expression of metabotropic glutamate receptor 1 (mGlu1) and the AMPA receptor GluA2 subunit at Purkinje cell synapses, and changes excitatory synaptic transmission, but not inhibitory transmission. KIF2C regulates the transport of mGlu1 receptors in Purkinje cells by binding to Rab8. KIF2C deficiency in Purkinje cells affects motor coordination, but not social behaviour in male mice.

Determination of electric and thermoelectric properties of molecular junctions by AFM in peak force tapping mode.

Molecular thin films, such as self-assembled monolayers (SAMs), offer the possibility of translating the optimised thermophysical and electrical properties of high-Seebeck-coefficient single molecules to scalable device architectures. However, for many scanning probe-based approaches attempting to characterise such SAMs, there remains a significant challenge in recovering single-molecule equivalent values from large-area films due to the intrinsic uncertainty of the probe-sample contact area coupled with film damage caused by contact forces. Here we report a new reproducible non-destructive method for probing the electrical and thermoelectric (TE) properties of small assemblies (10-103) of thiol-terminated molecules arranged within a SAM on a gold surface, and demonstrate the successful and reproducible measurements of the equivalent single-molecule electrical conductivity and Seebeck values. We have used a modified thermal-electric force microscopy approach, which integrates the conductive-probe atomic force microscope, a sample positioned on a temperature-controlled heater, and a probe-sample peak-force feedback that interactively limits the normal force across the molecular junctions. The experimental results are interpreted by density functional theory calculations allowing quantification the electrical quantum transport properties of both single molecules and small clusters of molecules. Significantly, this approach effectively eliminates lateral forces between probe and sample, minimising disruption to the SAM while enabling simultaneous mapping of the SAMs nanomechanical properties, as well as electrical and/or TE response, thereby allowing correlation of the film properties.

First evidence of occupational and residential exposure to bisphenols associated with an e-waste dismantling site: A case study in China.

Bisphenol A and its structural analogues (BPs) are widely used chemicals in electronics devices. To get insight into the occupational exposure to the full-time employees compared with the residents, urinary BPs in workers dismantling e-waste and in nearby residents were compared. Only 4 BPs among the tested 8 congeners, bisphenol AF (BPAF), bisphenol A, bisphenol S (BPS), and bisphenol F (BPF), were extensively detected with the detection frequencies of 100%, 99%, 98.7%, 51.3%. The median concentration of bisphenol A was 8.48 ng/mL, followed by BPAF (1.05 ng/mL), BPS (0.115 ng/mL), and BPF (0.110 ng/mL). The 4 detected BPs had a median concentration (Σ4BPs) ranging from 0.950 to 64.5 ng/mL in all volunteers, with a median value of 10.2 ng/mL. Result indicated the median concentration of ∑4BPs in worker's urine was significantly higher (14.2 ng/mL) than those in residents in nearby towns (4.52 ng/mL and 5.37 ng/mL) (p < 0.05), suggesting a BPs' occupational exposure risk related to e-waste dismantling. Besides, urinary ∑4BPs' median concentrations for the employees in family workshops (14.5 ng/mL) were significantly higher than those in plants with centralized management (9.36 ng/mL). Among volunteers, higher ∑4BPs were observed in groups of aged above 50 years, males, or body weight under average with no significant correlations. The estimated daily intake of bisphenol A did not exceed the reference dose (50 µg/kg bw/day) recommended by the U.S. Food and Drug Administration. In this research, excess levels of BPs were recorded for the full-time employees in e-waste dismantling sites. Strengthened standards could support public health initiatives for full-time worker protection and reduce take-home BPs to family members.

Potassium channel Kir 4.1 regulates oligodendrocyte differentiation via intracellular pH regulation.

In humans, loss-of-function mutations of Kcnj10 in SeSAME/EAST syndrome, which encodes the inwardly rectifying K+ channel 4.1 (Kir 4.1), causes progressive neurological decline. Despite its rich expression in oligodendrocyte (OL) lineage cells and an emerging link with demyelinating disease, the function of Kir 4.1 in OLs is unclear. Here we show a novel role of Kir 4.1 in OL development. Kir 4.1 expression is markedly greater in OLs than in OL precursor cells (OPCs), and the down-regulation of Kir 4.1 impairs OL maturation by affecting OPC differentiation. Interestingly, Kir 4.1 regulates the intracellular pH of OPCs and OLs via the Na+ /H+ exchanger, which underlies impeded OPC differentiation by Kir 4.1 inhibition. Furthermore, Kir 4.1 regulates GSK3ß and SOX10, two molecules critical to OPC development. Collectively, our work opens a new avenue to understanding the functions of Kir 4.1 and intracellular pH in OLs.

Scale-Up of Room-Temperature Constructive Quantum Interference from Single Molecules to Self-Assembled Molecular-Electronic Films.

The realization of self-assembled molecular-electronic films, whose room-temperature transport properties are controlled by quantum interference (QI), is an essential step in the scale-up of QI effects from single molecules to parallel arrays of molecules. Recently, the effect of destructive QI (DQI) on the electrical conductance of self-assembled monolayers (SAMs) has been investigated. Here, through a combined experimental and theoretical investigation, we demonstrate chemical control of different forms of constructive QI (CQI) in cross-plane transport through SAMs and assess its influence on cross-plane thermoelectricity in SAMs. It is known that the electrical conductance of single molecules can be controlled in a deterministic manner, by chemically varying their connectivity to external electrodes. Here, by employing synthetic methodologies to vary the connectivity of terminal anchor groups around aromatic anthracene cores, and by forming SAMs of the resulting molecules, we clearly demonstrate that this signature of CQI can be translated into SAM-on-gold molecular films. We show that the conductance of vertical molecular junctions formed from anthracene-based molecules with two different connectivities differ by a factor of approximately 16, in agreement with theoretical predictions for their conductance ratio based on CQI effects within the core. We also demonstrate that for molecules with thioether anchor groups, the Seebeck coefficient of such films is connectivity dependent and with an appropriate choice of connectivity can be boosted by ∼50%. This demonstration of QI and its influence on thermoelectricity in SAMs represents a critical step toward functional ultra-thin-film devices for future thermoelectric and molecular-scale electronics applications.

Carbazole-Based Tetrapodal Anchor Groups for Gold Surfaces: Synthesis and Conductance Properties.

As the field of molecular-scale electronics matures and the prospect of devices incorporating molecular wires becomes more feasible, it is necessary to progress from the simple anchor groups used in fundamental conductance studies to more elaborate anchors designed with device stability in mind. This study presents a series of oligo(phenylene-ethynylene) wires with one tetrapodal anchor and a phenyl or pyridyl head group. The new anchors are designed to bind strongly to gold surfaces without disrupting the conductance pathway of the wires. Conductive probe atomic force microscopy (cAFM) was used to determine the conductance of self-assembled monolayers (SAMs) of the wires in Au-SAM-Pt and Au-SAM-graphene junctions, from which the conductance per molecule was derived. For tolane-type wires, mean conductances per molecule of up to 10-4.37  G0 (Pt) and 10-3.78  G0 (graphene) were measured, despite limited electronic coupling to the Au electrode, demonstrating the potential of this approach. Computational studies of the surface binding geometry and transport properties rationalise and support the experimental results.

In-Place Modulation of Rectification in Tunneling Junctions Comprising Self-Assembled Monolayers.

This paper describes tunneling junctions comprising self-assembled monolayers that can be converted between resistor and diode functionality in-place. The rectification ratio is affected by the hydration of densely packed carboxylic acid groups at the interface between the top-contact and the monolayer. We studied this process by treatment with water and a water scavenger using three different top-contacts, eutectic Ga-In (EGaIn), conducting-probe atomic force microscopy (CP-AFM), and reduced graphene oxide (rGO), demonstrating that the phenomena is molecular in nature and is not platform-speciffc. We propose a mechanism in which the tunneling junctions convert to diode behavior through the lowering of the LUMO, which is suffcient to bring it close to resonance at positive bias, potentially assisted by a Stark shift. This shift in energy is supported by calculations and a change in polarization observed by X-ray photoelectron spectroscopy and Kelvin probe measurements. We demonstrate light-driven modulation using spiropyran as a photoacid, suggesting that any chemical process that is coupled to the release of small molecules that can tightly bind carboxylic acid groups can be used as an external stimulus to modulate rectification. The ability to convert a tunneling junction reversibly between a diode and a resistor via an effect that is intrinsic to the molecules in the junction extends the possible applications of Molecular Electronics to reconfigurable circuits and other new functionalities that do not have direct analogs in conventional semiconductor devices.

Ablation of TFR1 in Purkinje Cells Inhibits mGlu1 Trafficking and Impairs Motor Coordination, But Not Autistic-Like Behaviors.

Group 1 metabotropic glutamate receptors (mGlu1/5s) are critical to synapse formation and participate in synaptic LTP and LTD in the brain. mGlu1/5 signaling alterations have been documented in cognitive impairment, neurodegenerative disorders, and psychiatric diseases, but underlying mechanisms for its modulation are not clear. Here, we report that transferrin receptor 1 (TFR1), a transmembrane protein of the clathrin complex, modulates the trafficking of mGlu1 in cerebellar Purkinje cells (PCs) from male mice. We show that conditional knock-out of TFR1 in PCs does not affect the cytoarchitecture of PCs, but reduces mGlu1 expression at synapses. This regulation by TFR1 acts in concert with that by Rab8 and Rab11, which modulate the internalization and recycling of mGlu1, respectively. TFR1 can bind to Rab proteins and facilitate their expression at synapses. PC ablation of TFR1 inhibits parallel fiber-PC LTD, whereas parallel fiber-LTP and PC intrinsic excitability are not affected. Finally, we demonstrate that PC ablation of TFR1 impairs motor coordination, but does not affect social behaviors in mice. Together, these findings underscore the importance of TFR1 in regulating mGlu1 trafficking and suggest that mGlu1- and mGlu1-dependent parallel fiber-LTD are associated with regulation of motor coordination, but not autistic behaviors.SIGNIFICANCE STATEMENT Group 1 metabotropic glutamate receptor (mGlu1/5) signaling alterations have been documented in cognitive impairment, neurodegenerative disorders, and psychiatric diseases. Recent work suggests that altered mGlu1 signaling in Purkinje cells (PCs) may be involved in not only motor learning, but also autistic-like behaviors. We find that conditional knock-out of transferrin receptor 1 (TFR1) in PCs reduces synaptic mGlu1 by tethering Rab8 and Rab11 in the cytosol. PC ablation of TFR1 inhibits parallel fiber-PC LTD, whereas parallel fiber-PC LTP and PC intrinsic excitability are intact. Motor coordination is impaired, but social behaviors are normal in TFR1flox/flox;pCP2-cre mice. Our data reveal a new regulator for trafficking and synaptic expression of mGlu1 and suggest that mGlu1-dependent LTD is associated with motor coordination, but not autistic-like behaviors.

Peripheral inflammation activated focal adhesion kinase signaling in spinal dorsal horn of mice.

Focal adhesion kinase (FAK) is one of the nonreceptor protein tyrosine kinases critical for the dynamic regulation of cell adhesion structures. Recent studies have demonstrated that FAK is also localized at excitatory glutamatergic synapses and is involved in long-term modification of synaptic strength. However, whether FAK is engaged in nociceptive processing in the spinal dorsal horn remains unresolved. The current study shows that intraplantar injection of complete Freund's adjuvant (CFA) in mice significantly increases FAK autophosphorylation at Tyr397, indicating a close correlation of FAK activation with inflammatory pain. FAK activation depended on the activity of N-methyl-D-aspartate-subtype glutamate receptor (NMDAR) and metabotropic glutamate receptor (mGluR) because pharmacological inhibition of NMDAR or group I mGluR totally abolished FAK phosphorylation induced by CFA. The active FAK operated to stimulate extracellular signal-regulated kinase1/2 (ERK1/2), which boosted the protein expression of GluN2B subunit-containing NMDAR at the synaptosomal membrane fraction. Inhibition of FAK activity by spinal expression of a kinase-dead FAK(Y397F) mutant repressed ERK1/2 hyperactivity and reduced the synaptic concentration of NMDAR in CFA-injected mice. Electrophysiological recording demonstrated that intracellular loading of specific anti-FAK antibody significantly reduced the amplitudes of NMDAR-mediated excitatory postsynaptic currents on lamina II neurons from inflamed mice but not from naive mice. Behavioral tests showed that spinal expression of FAK(Y397F) generated a long-lasting alleviation of CFA-induced mechanical allodynia and thermal hyperalgesia. These data indicate that FAK might exaggerate NMDAR-mediated synaptic transmission in the spinal dorsal horn to sensitize nociceptive behaviors.

Mono- and bis(pyrrolo)tetrathiafulvalene derivatives tethered to C60: synthesis, photophysical studies, and self-assembled monolayers.

A series of mono- (MPTTF) and bis(pyrrolo)tetrathiafulvalene (BPTTF) derivatives tethered to one or two C60 moieties was synthesized and characterized. The synthetic strategy for these dumbbell-shaped compounds was based on a 1,3-dipolar cycloaddition reaction between aldehyde-functionalized MPTTF/BPTTF derivatives, two different tailor-made amino acids, and C60. Electronic communication between the MPTTF/BPTTF units and the C60 moieties was studied by a variety of techniques including cyclic voltammetry and absorption spectroscopy. These solution-based studies indicated no observable electronic communication between the MPTTF/BPTTF units and the C60 moieties. In addition, femtosecond and nanosecond transient absorption spectroscopy revealed, rather surprisingly, that no charge transfer from the MPTTF/BPTTF units to the C60 moieties takes place on excitation of the fullerene moiety. Finally, it was shown that the MPTTF-C60 and C60-BPTTF-C60 dyad and triad molecules formed self-assembled monolayers on a Au(111) surface by anchoring to C60.

Triazatriangulene as binding group for molecular electronics.

The triazatriangulene (TATA) ring system was investigated as a binding group for tunnel junctions of molecular wires on gold surfaces. Self-assembled monolayers (SAMs) of TATA platforms with three different lengths of phenylene wires were fabricated, and their electrical conductance was recorded by both conducting probe-atomic force microscopy (CP-AFM) and scanning tunneling microscopy (STM). Similar measurements were performed for phenylene SAMs with thiol anchoring groups as references. It was found that, despite the presence of a sp(3) hybridized carbon atom in the conduction path, the TATA platform displays a contact resistance only slightly larger than the thiols. This surprising finding has not been reported before and was analyzed by theoretical computations of the transmission functions of the TATA anchored molecular wires. The relatively low contact resistance of the TATA platform along with its high stability and directionality make this binding group very attractive for molecular electronic measurements and devices.

Immunoglobulin A Vasculitis With Intussusception in Children.

BACKGROUND: Immunoglobulin A (IgA) vasculitis with intussusception is acute and severe vasculitis combined with acute abdomen in children. The diagnosis of the disease depends on the results of imaging examinations, and its treatment mainly includes enema and surgery. The literature summarized the detailed diagnosis and treatment data in previous literature reports. METHODS: We described the clinical manifestations, ultrasonic features, and treatment of patients admitted to a single center and reviewed previous literature regarding cases with detailed clinical data in the PubMed database within the past 20 years. RESULTS: The review included 36 patients, including 22 boys and 14 girls. A total of 32 patients were diagnosed using ultrasound (88.9%). The main sites of intussusception were the ileum and ileocolon in 16 (44.4%) and 11 (30.6%) cases, respectively. Thirteen patients (36.1%) were treated with enema, with 6 responding to the treatment. 26 patients (72.2%) underwent surgical treatment. Patients with ileal intussusception were more likely to be treated with surgery than those with colonic intussusception (P < .05). The single-center clinical data of 23 patients showed that there was no significant difference in laboratory test findings between patients with and without surgical treatment (P > .05). Patients with long insertion lengths were more likely to require surgery and resection (P < .05). CONCLUSIONS: Ultrasonography is the first-line investigation for diagnosis. The main sites of intussusception were ileum and ileocolon. The length of intubation was related to surgery; treatment is according to the intussusception site. Air enema is not suitable for intussusception of the small intestine.

Aberrant outputs of cerebellar nuclei and targeted rescue of social deficits in an autism mouse model.

The cerebellum is heavily connected with other brain regions, sub-serving not only motor but also non-motor functions. Genetic mutations leading to cerebellar dysfunction are associated with mental diseases, but cerebellar outputs have not been systematically studied in this context. Here, we present three dimensional distributions of 50,168 target neurons of cerebellar nuclei (CN) from wild-type mice and Nlgn3R451C mutant mice, a mouse model for autism. Our results derived from 36 target nuclei show that the projections from CN to thalamus, midbrain and brainstem are differentially affected by Nlgn3R451C mutation. Importantly, Nlgn3R451C mutation altered the innervation power of CN→zona incerta (ZI) pathway, and chemogenetic inhibition of a neuronal subpopulation in the ZI that receives inputs from the CN rescues social defects in Nlgn3R451C mice. Our study highlights potential role of cerebellar outputs in the pathogenesis of autism and provides potential new therapeutic strategy for this disease.

Protein disulfide isomerase A3 as novel biomarker for endometrial cancer.

Objective: This study aims to investigate the potential of PDIA3 as a novel prognostic biomarker and therapeutic target for Endometrial Cancer (EC) with the ultimate goal of improving survival rates in EC patients. Methods: This study employed a combination of public database analysis and clinical tissue sample assays. The analysis included comparing the gene expression of PDIA3 between EC and adjacent paracancerous tissues, investigating this expression status using qPCR and immunohistochemistry (IHC) assays, studying the correlation of expression with different parameters using Chi-square test, Cox Regression, and log-rank test, as well as exploring the PDIA3-related immune infiltration and metabolic pathway using TIMER and GSEA. Results: The analysis of public datasets revealed that PDIA3 mRNA and protein expression was significantly higher in EC tissues compared to adjacent tissues (P = 4.1e-03, P = 1.95e-14, and P = 1.6e-27, respectively). The qPCR analysis supported this finding (P = 0.029). IHC analysis revealed a significant increase in PDIA3 expression in endometrial cancer (EC) tissues compared to adjacent normal tissues (P = 0.01). Furthermore, PDIA3 expression showed significant correlations with cancer stage and tumor grade. Multivariate Cox regression analysis suggested that the PDIA3 gene holds promise as a prognostic factor for EC patients (HR = 0.47, 95% CI [0.27, 0.82], P = 0.008). The results from TIMER demonstrated a positive correlation between PDIA3 and tumor-infiltrating CD8 T cells and macrophages, and a negative correlation with tumor-infiltrating CD4 T cells. Additionally, the GSEA results indicated that PDIA3 overexpression was associated with various metabolic processes in EC patients. Conclusion: PDIA3 has been validated as a potential biomarker for EC, and its expression is further associated with pathological staging and prognosis.

Acute pancreatitis associated with immunoglobulin A vasculitis: report of fifteen cases.

OBJECTIVE: Immunoglobulin A vasculitis (IgAV) is a systemic small vessel vasculitis common in children. Pancreatic involvement in IgAV is rare. The purpose of this study was to analyze the clinical characteristics of IgAV-related acute pancreatitis in children. METHODS: Records of patients with IgAV-related acute pancreatitis admitted to our institution between January 2016 and December 2019 were reviewed. We summarized the clinical characteristics, laboratory characteristics, imaging findings, treatment, and outcomes of 15 children with IgAV-related acute pancreatitis. RESULTS: The patients' median age was 9.6 years. Pancreatitis was the initial manifestation of IgAV in 3 patients. All patients had abdominal manifestations, including abdominal pain (15/15), vomiting (10/15), and gastrointestinal bleeding (7/15). Serum amylase and lipase levels were elevated in all patients. Serum amylase in 4 cases reached more than three-fold elevation and serum lipase in 14 cases reached more than three-fold elevation. Morphological abnormalities and abnormal signals of the pancreas were observed in 13 cases by magnetic resonance imaging. Pancreaticobiliary maljunction was seen in 3 cases by magnetic resonance cholangiopancreatography. Glucocorticoid therapy and intravenous immunoglobulins were used to treat acute pancreatitis in IgAV. All patients showed clinical improvement after treatment. During the follow-up period of 6-12 months, all 15 cases with pancreatitis were cured without recurrence. CONCLUSIONS: Pancreatic involvement is rare in IgAV; however, this should be considered in IgAV patients with severe abdominal pain. The timely application of steroid therapy is important for IgAV-associated pancreatitis. Key Points • Acute pancreatitis is a rare complication of immunoglobulin A vasculitis (IgAV). • Acute pancreatitis can be the initial manifestation of IgAV. It is important to evaluate for pancreatitis while IgAV patients with severe abdominal pain. • A common image finding of IgAV-associated pancreatitis was swelling of the pancreas. • Glucocorticoid therapy and intravenous immunoglobulins is helpful in alleviating acute pancreatitis in IgAV.

Urine metabolites and viral pneumonia among children: a case-control study in China.

Background: Viral pneumonia in children is common and has grave consequences. The study aims to better understand the pathophysiological processes involved in the onset and progression of viral pneumonia and identify common effects or biomarkers across different viruses. Methods: This study collected urine samples from 96 patients with viral pneumonia including respiratory syncytial virus (RSV) (n=30), influenza virus (IV) (n=23), parainfluenza virus (PIV) (n=24), and adenovirus (ADV) (n=19), and 31 age- and sex-matched normal control (NC) subjects. The samples were analyzed using liquid chromatography coupled with mass spectrometry (LC-MS) to identify endogenous substances. The XCMS Online platform was utilized for data processing and analysis , including feature detection, retention time correction, alignment, annotation, and statistical analysis for difference between groups and biomarker identification. Results: A total of 948 typical metabolites were identified using the XCMS Online platform with the Mummichog technique. After analyzing the data, 24 metabolites were selected as potential biomarkers for viral pneumonia, of which 16 were aspartate and asparagine metabolites, byproducts of alanine, leucine, and isoleucine degradation, and butanoate metabolites. Conclusions: This study specific metabolites and altered pathways in children with viral pneumonia and propose that these findings could contribute to the discovery of new treatments and the development of antiviral drugs.

Planar aromatic anchors control the electrical conductance of gold|molecule|graphene junctions.

The synthesis of a family of alkanethiol molecules with planar aromatic head groups, designed to anchor molecules effectively to graphene electrodes, is reported. Characterisation of self-assembled monolayers of these molecules on a gold surface via conductive atomic force microscopy shows that when an aromatic head group is present, the conductance G graphene obtained using a graphene coated probe is higher than the conductance G Pt obtained using a platinum (Pt) probe. For Pt probe and graphene probe junctions, the tunnelling decay constant of benzyl ether derivatives with an alkanethiol molecular backbone is determined as ß = 5.6 nm-1 and 3.5 nm-1, respectively. The conductance ratio G graphene/G Pt increases as the number of rings present in the aromatic head unit, n, increases. However, as the number of rings increases, the conductance path length increases because the planar head groups lie at an angle to the plane of the electrodes. This means that overall conductance decreases as n increases. Density functional theory-based charge transport calculations support these experimental findings. This study confirms that planar aromatic head groups can function as effective anchoring units for graphene electrodes in large area molecular junctions. However, the results also indicate that the size and geometry of these head groups must be considered in order to produce effective molecular designs.

Quantum Interference and Contact Effects in the Thermoelectric Performance of Anthracene-Based Molecules.

We report on the single-molecule electronic and thermoelectric properties of strategically chosen anthracene-based molecules with anchor groups capable of binding to noble metal substrates, such as gold and platinum. Specifically, we study the effect of different anchor groups, as well as quantum interference, on the electric conductance and the thermopower of gold/single-molecule/gold junctions and generally find good agreement between theory and experiments. All molecular junctions display transport characteristics consistent with coherent transport and a Fermi alignment approximately in the middle of the highest occupied molecular orbital/lowest unoccupied molecular orbital gap. Single-molecule results are in agreement with previously reported thin-film data, further supporting the notion that molecular design considerations may be translated from the single- to many-molecule devices. For combinations of anchor groups where one binds significantly more strongly to the electrodes than the other, the stronger anchor group appears to dominate the thermoelectric behavior of the molecular junction. For other combinations, the choice of electrode material can determine the sign and magnitude of the thermopower. This finding has important implications for the design of thermoelectric generator devices, where both n- and p-type conductors are required for thermoelectric current generation.

A patient-derived mutation of epilepsy-linked LGI1 increases seizure susceptibility through regulating Kv1.1.

BACKGROUND: Autosomal dominant lateral temporal epilepsy (ADLTE) is an inherited syndrome caused by mutations in the leucine-rich glioma inactivated 1 (LGI1) gene. It is known that functional LGI1 is secreted by excitatory neurons, GABAergic interneurons, and astrocytes, and regulates AMPA-type glutamate receptor-mediated synaptic transmission by binding ADAM22 and ADAM23. However, > 40 LGI1 mutations have been reported in familial ADLTE patients, more than half of which are secretion-defective. How these secretion-defective LGI1 mutations lead to epilepsy is unknown. RESULTS: We identified a novel secretion-defective LGI1 mutation from a Chinese ADLTE family, LGI1-W183R. We specifically expressed mutant LGI1W183R in excitatory neurons lacking natural LGI1, and found that this mutation downregulated Kv1.1 activity, led to neuronal hyperexcitability and irregular spiking, and increased epilepsy susceptibility in mice. Further analysis revealed that restoring Kv1.1 in excitatory neurons rescued the defect of spiking capacity, improved epilepsy susceptibility, and prolonged the life-span of mice. CONCLUSIONS: These results describe a role of secretion-defective LGI1 in maintaining neuronal excitability and reveal a new mechanism in the pathology of LGI1 mutation-related epilepsy.

Purkinje-cell-specific MeCP2 deficiency leads to motor deficits and autistic-like behavior due to aberrations in PTP1B-TrkB-SK signaling.

Patients with Rett syndrome suffer from a loss-of-function mutation of the Mecp2 gene, which results in various symptoms including autistic traits and motor deficits. Deletion of Mecp2 in the brain mimics part of these symptoms, but the specific function of methyl-CpG-binding protein 2 (MeCP2) in the cerebellum remains to be elucidated. Here, we demonstrate that Mecp2 deletion in Purkinje cells (PCs) reduces their intrinsic excitability through a signaling pathway comprising the small-conductance calcium-activated potassium channel PTP1B and TrkB, the receptor of brain-derived neurotrophic factor. Aberration of this cascade, in turn, leads to autistic-like behaviors as well as reduced vestibulocerebellar motor learning. Interestingly, increasing activity of TrkB in PCs is sufficient to rescue PC dysfunction and abnormal motor and non-motor behaviors caused by Mecp2 deficiency. Our findings highlight how PC dysfunction may contribute to Rett syndrome, providing insight into the underlying mechanism and paving the way for rational therapeutic designs.