Connections to the Electrodes Control the Transport Mechanism in Single-Molecule Transistors.

When designing a molecular electronic device for a specific function, it is necessary to control whether the charge-transport mechanism is phase-coherent transmission or particle-like hopping. Here we report a systematic study of charge transport through single zinc-porphyrin molecules embedded in graphene nanogaps to form transistors, and show that the transport mechanism depends on the chemistry of the molecule-electrode interfaces. We show that van der Waals interactions between molecular anchoring groups and graphene yield transport characteristic of Coulomb blockade with incoherent sequential hopping, whereas covalent molecule-electrode amide bonds give intermediately or strongly coupled single-molecule devices that display coherent transmission. These findings demonstrate the importance of interfacial engineering in molecular electronic circuits

Effects of the mGluR2/3 agonist LY354740 on computerized tasks of attention and working memory in marmoset monkeys

Rationale: LY354740 is a recently developed metabotropic glutamatergic receptor 2 and 3 (mGluR2/3) agonist. A high density of mGluR2 has been reported in terminal fields of the perforant path in rodents and humans, suggesting its involvement in cognitive functions mediated by the temporal lobe, including memory. A small number of in vivo studies in rodents have assessed the effects of LY354740 on memory tasks, reporting the induction of impaired memory for spatial orientation in a water maze task and for delayed match and non-match to position in an operant version of these tasks. Objective: In the present primate study, we used radioautography to describe the distribution and intensity of 3H-LY354740 binding in the hippocampal formation of the common marmoset monkey (Callithrix jacchus) relative to the rat. In the major, in vivo part of the study, the effects of systemic LY354740 on computerized tasks of attention and memory were investigated. Methods: Adult common marmosets were trained to perform a five-choice serial reaction time (5-CSRT) task and a concurrent delayed match-to-position (CDMP) task from the Cambridge Neuropsychological Automated test Battery (CANTAB). Filter tests of LY354740 effects on motor dexterity and motivation for reward revealed high inter-individual variation in sensitivity; therefore, on the 5-CSRT, subjects were tested at a dose range of 3-10mg/kg, and on the CDMP, subjects were tested at 1-3 or 3-10mg/kg. Results: Radioautography revealed a relatively low level of 3H-LY354740 binding in the marmoset hippocampal formation compared to the rat. Despite low binding, LY354740 reduced sustained-attention accuracy in the 5-CSRT, and reduced accuracy in two stages of the CDMP. Conclusions: The current study provides novel evidence for the importance of mGluR2/3 in the regulation of primate cognitive functionin

Quantum interference enhances the performance of single-molecule transistors.

Quantum effects in nanoscale electronic devices promise to lead to new types of functionality not achievable using classical electronic components. However, quantum behaviour also presents an unresolved challenge facing electronics at the few-nanometre scale: resistive channels start leaking owing to quantum tunnelling. This affects the performance of nanoscale transistors, with direct source-drain tunnelling degrading switching ratios and subthreshold swings, and ultimately limiting operating frequency due to increased static power dissipation. The usual strategy to mitigate quantum effects has been to increase device complexity, but theory shows that if quantum effects can be exploited in molecular-scale electronics, this could provide a route to lower energy consumption and boost device performance. Here we demonstrate these effects experimentally, showing how the performance of molecular transistors is improved when the resistive channel contains two destructively interfering waves. We use a zinc-porphyrin coupled to graphene electrodes in a three-terminal transistor to demonstrate a >104 conductance-switching ratio, a subthreshold swing at the thermionic limit, a >7 kHz operating frequency and stability over >105 cycles. We fully map the anti-resonance interference features in conductance, reproduce the behaviour by density functional theory calculations and trace back the high performance to the coupling between molecular orbitals and graphene edge states. These results demonstrate how the quantum nature of electron transmission at the nanoscale can enhance, rather than degrade, device performance, and highlight directions for future development of miniaturized electronics

Quantum Interference Enhances the Performance of Single-Molecule Transistors

An unresolved challenge facing electronics at a few-nm scale is that resistive channels start leaking due to quantum tunneling. This affects the performance of nanoscale transistors, with single-molecule devices displaying particularly low switching ratios and operating frequencies, combined with large subthreshold swings.1 The usual strategy to mitigate quantum effects has been to increase device complexity, but theory shows that if quantum effects are exploited correctly, they can simultaneously lower energy consumption and boost device performance.2-6 Here, we demonstrate experimentally how the performance of molecular transistors can be improved when the resistive channel contains two destructively-interfering waves. We use a zinc-porphyrin coupled to graphene electrodes in a three-terminal transistor device to demonstrate a >104 conductance-switching ratio, a subthreshold swing at the thermionic limit, a > 7 kHz operating frequency, and stability over >105 cycles. This performance is competitive with the best nanoelectronic transistors. We fully map the antiresonance interference features in conductance, reproduce the behaviour by density functional theory calculations, and trace back this high performance to the coupling between molecular orbitals and graphene edge states. These results demonstrate how the quantum nature of electron transmission at the nanoscale can enhance, rather than degrade, device performance, and highlight directions for future development of miniaturised electronics.Comment: 11 pages, 4 figure

Molecular characterisation of sporadic endolymphatic sac tumours and comparison to von Hippel–Lindau disease‐related tumours

Aims: Although inactivation of the von Hippel-Lindau gene (VHL) on chromosome 3p25 is considered to be the major cause of hereditary endolymphatic sac tumours (ELSTs), the genetic background of sporadic ELST is largely unknown. The aim of this study was to determine the prevalence of VHL mutations in sporadic ELSTs and compare their characteristics to VHL-disease-related tumours. Methods: Genetic and epigenetic alterations were compared between 11 sporadic and 11 VHL-disease-related ELSTs by targeted sequencing and DNA methylation analysis. Results: VHL mutations and small deletions detected by targeted deep sequencing were identified in 9/11 sporadic ELSTs (82%). No other cancer-related genetic pathway was altered except for TERT promoter mutations in two sporadic ELST and one VHL-disease-related ELST (15%). Loss of heterozygosity of chromosome 3 was found in 6/10 (60%) VHL-disease-related and 10/11 (91%) sporadic ELSTs resulting in biallelic VHL inactivation in 8/10 (73%) sporadic ELSTs. DNA methylation profiling did not reveal differences between sporadic and VHL-disease-related ELSTs but reliably distinguished ELST from morphological mimics of the cerebellopontine angle. VHL patients were significantly younger at disease onset compared to sporadic ELSTs (29 vs. 52 years, p < 0.0001, Fisher's exact test). VHL-disease status was not associated with an increased risk of recurrence, but the presence of clear cells was found to be associated with shorter progression-free survival (p = 0.0002, log-rank test). Conclusion: Biallelic inactivation of VHL is the main mechanism underlying ELSTs, but unknown mechanisms beyond VHL may rarely be involved in the pathogenesis of sporadic ELSTs

ATRT–SHH comprises three molecular subgroups with characteristic clinical and histopathological features and prognostic significance

Atypical teratoid/rhabdoid tumor (ATRT) is an aggressive central nervous system tumor characterized by loss of SMARCB1/INI1 protein expression and comprises three distinct molecular groups, ATRT–TYR, ATRT–MYC and ATRT–SHH. ATRT–SHH represents the largest molecular group and is heterogeneous with regard to age, tumor location and epigenetic profile. We, therefore, aimed to investigate if heterogeneity within ATRT–SHH might also have biological and clinical importance. Consensus clustering of DNA methylation profiles and confirmatory t-SNE analysis of 65 ATRT–SHH yielded three robust molecular subgroups, i.e., SHH-1A, SHH-1B and SHH-2. These subgroups differed by median age of onset (SHH-1A: 18 months, SHH-1B: 107 months, SHH-2: 13 months) and tumor location (SHH-1A: 88% supratentorial; SHH-1B: 85% supratentorial; SHH-2: 93% infratentorial, often extending to the pineal region). Subgroups showed comparable SMARCB1 mutational profiles, but pathogenic/likely pathogenic SMARCB1 germline variants were over-represented in SHH-2 (63%) as compared to SHH-1A (20%) and SHH-1B (0%). Protein expression of proneural marker ASCL1 (enriched in SHH-1B) and glial markers OLIG2 and GFAP (absent in SHH-2) as well as global mRNA expression patterns differed, but all subgroups were characterized by overexpression of SHH as well as Notch pathway members. In a Drosophila model, knockdown of Snr1 (the fly homologue of SMARCB1) in hedgehog activated cells not only altered hedgehog signaling, but also caused aberrant Notch signaling and formation of tumor-like structures. Finally, on survival analysis, molecular subgroup and age of onset (but not ASCL1 staining status) were independently associated with overall survival, older patients (> 3 years) harboring SHH-1B experiencing relatively favorable outcome. In conclusion, ATRT–SHH comprises three subgroups characterized by SHH and Notch pathway activation, but divergent molecular and clinical features. Our data suggest that molecular subgrouping of ATRT–SHH has prognostic relevance and might aid to stratify patients within future clinical trials. SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1007/s00401-022-02424-5

A Negative Regulatory Loop between MicroRNA and Hox Gene Controls Posterior Identities in Caenorhabditis elegans

MicroRNAs (miRNAs) have been found to regulate gene expression across eukaryotic species, but the function of most miRNA genes remains unknown. Here we describe how the analysis of the expression patterns of a well-conserved miRNA gene, mir-57, at cellular resolution for every minute during early development of Caenorhabditis elegans provided key insights in understanding its function. Remarkably, mir-57 expression shows strong positional bias but little tissue specificity, a pattern reminiscent of Hox gene function. Despite the minor defects produced by a loss of function mutation, overexpression of mir-57 causes dramatic posterior defects, which also mimic the phenotypes of mutant alleles of a posterior Hox gene, nob-1, an Abd homolog. More importantly, nob-1 expression is found in the same two posterior AB sublineages as those expressing mir-57 but with an earlier onset. Intriguingly, nob-1 functions as an activator for mir-57 expression; it is also a direct target of mir-57. In agreement with this, loss of mir-57 function partially rescues the nob-1 allele defects, indicating a negative feedback regulatory loop between the miRNA and Hox gene to provide positional cues. Given the conservation of the miRNA and Hox gene, the regulatory mechanism might be broadly used across species. The strategy used here to explore mir-57 function provides a path to dissect the regulatory relationship between genes

Hox cluster duplication in the basal teleost Hiodon alosoides (Osteoglossomorpha)

Large-scale—even genome-wide—duplications have repeatedly been invoked as an explanation for major radiations. Teleosts, the most species-rich vertebrate clade, underwent a “fish-specific genome duplication” (FSGD) that is shared by most ray-finned fish lineages. We investigate here the Hox complement of the goldeye (Hiodon alosoides), a representative of Osteoglossomorpha, the most basal teleostean clade. An extensive PCR survey reveals that goldeye has at least eight Hox clusters, indicating a duplicated genome compared to basal actinopterygians. The possession of duplicated Hox clusters is uncoupled to species richness. The Hox system of the goldeye is substantially different from that of other teleost lineages, having retained several duplicates of Hox genes for which crown teleosts have lost at least one copy. A detailed analysis of the PCR fragments as well as full length sequences of two HoxA13 paralogs, and HoxA10 and HoxC4 genes places the duplication event close in time to the divergence of Osteoglossomorpha and crown teleosts. The data are consistent with—but do not conclusively prove—that Osteoglossomorpha shares the FSGD