Asc-1 Transporter Regulation of Synaptic Activity via the Tonic Release of d-Serine in the Forebrain.

d-Serine is a co-agonist of NMDA receptors (NMDARs) whose activity is potentially regulated by Asc-1 (SLC7A10), a transporter that displays high affinity for d-serine and glycine. Asc-1 operates as a facilitative transporter and as an antiporter, though the preferred direction of d-serine transport is uncertain. We developed a selective Asc-1 blocker, Lu AE00527, that blocks d-serine release mediated by all the transport modes of Asc-1 in primary cultures and neocortical slices. Furthermore, d-serine release is reduced in slices from Asc-1 knockout (KO) mice, indicating that d-serine efflux is the preferred direction of Asc-1. The selectivity of Lu AE00527 is assured by the lack of effect on slices from Asc-1-KO mice, and the lack of interaction with the co-agonist site of NMDARs. Moreover, in vivo injection of Lu AE00527 in P-glycoprotein-deficient mice recapitulates a hyperekplexia-like phenotype similar to that in Asc-1-KO mice. In slices, Lu AE00527 decreases the long-term potentiation at the Schaffer collateral-CA1 synapses, but does not affect the long-term depression. Lu AE00527 blocks NMDAR synaptic potentials when typical Asc-1 extracellular substrates are present, but it does not affect AMPAR transmission. Our data demonstrate that Asc-1 mediates tonic co-agonist release, which is required for optimal NMDAR activation and synaptic plasticity.

From isolated diamondoids to a van-der-Waals crystal: A theoretical and experimental analysis of a trishomocubane and a diamantane dimer in the gas and solid phase.

The electronic properties of sp2/sp3 diamondoids in the crystalline state and in the gas phase are presented. Apparent differences in electronic properties experimentally observed by resonance Raman spectroscopy in the crystalline/gas phase and absorption measurements in the gas phase were investigated by density functional theory computations. Due to a reorganization of the molecular orbitals in the crystalline phase, the HOMO (highest occupied molecular orbital) and LUMO (lowest unoccupied molecular orbital) energy gaps are lowered significantly by 0.5 eV-1 eV. The π → π* transition is responsible for large absorption in both gas and crystalline phases. It further causes a large increase in the Raman intensity of the C=C stretch vibration when excited resonantly. By resonance Raman spectroscopy we were able to determine the C=C bond length of the trishomocubane dimer to exhibit 1.33 Å in the ground and 1.41 Å in the excited state.

Outcomes of Endobronchial Valve Treatment Based on the Precise Criteria of an Endobronchial Catheter for Detection of Collateral Ventilation under Spontaneous Breathing.

BACKGROUND: Endoscopic lung volume reduction with valves is a valid therapeutic option for COPD patients with severe emphysema. The exclusion of interlobar collateral ventilation (CV) is an important predictor of clinical success. OBJECTIVES: Recently, a catheter-based endobronchial in vivo measurement system (Chartis, Pulmonx, USA) has become routine in the clinical evaluation of CV status in target lobes, but the criteria for phenotyping CV by Chartis evaluation have not yet been defined. We asked the questions, how many phenotypes can be identified using Chartis, what are the exact criteria to distinguish them, and how do the Chartis phenotypes respond to valve insertion? METHODS: In a retrospective study, 406 Chartis assessments of 166 patients with severe COPD were analyzed. Four Chartis phenotypes, CV positive (CV+), CV negative (CV-), low flow (LF) and low plateau were identified. Fifty-two patients without CV were treated with valves and followed for 3 months. RESULTS: The Chartis phenotypes were discriminated with respect to decline in expiratory peak flow, increase in resistance index and change in total exhaled volume after 1, 2, 3, 4 and 5 min of measurement time (p < 0.0001, ANOVA), and the cutoff criteria were defined accordingly. To examine the application of these phenotyping criteria, students applied them to 100 Chartis assessments, and they demonstrated almost perfect inter- and intraobserver agreements (x03BA; > 0.9). Compared to baseline, CV- and LF patients with ipsilateral CV- lobe showed an improvement in FEV1 (p < 0.05), vital capacity (p < 0.05) and target lobe volume reduction (p < 0.005) after valve insertion. CONCLUSION: This study describes the most prevalent Chartis phenotypes.

Delayed myelination in a mouse model of fragile X syndrome.

Fragile X Syndrome is the most common inherited cause of autism. Fragile X mental retardation protein (FMRP), which is absent in fragile X, is an mRNA binding protein that regulates the translation of hundreds of different mRNA transcripts. In the adult brain, FMRP is expressed primarily in the neurons; however, it is also expressed in developing glial cells, where its function is not well understood. Here, we show that fragile X (Fmr1) knockout mice display abnormalities in the myelination of cerebellar axons as early as the first postnatal week, corresponding roughly to the equivalent time in human brain development when symptoms of the syndrome first become apparent (1-3 years of age). At postnatal day (PND) 7, diffusion tensor magnetic resonance imaging showed reduced volume of the Fmr1 cerebellum compared with wild-type mice, concomitant with an 80-85% reduction in the expression of myelin basic protein, fewer myelinated axons and reduced thickness of myelin sheaths, as measured by electron microscopy. Both the expression of the proteoglycan NG2 and the number of PDGFRα+/NG2+ oligodendrocyte precursor cells were reduced in the Fmr1 cerebellum at PND 7. Although myelin proteins were still depressed at PND 15, they regained wild-type levels by PND 30. These findings suggest that impaired maturation or function of oligodendrocyte precursor cells induces delayed myelination in the Fmr1 mouse brain. Our results bolster an emerging recognition that white matter abnormalities in early postnatal brain development represent an underlying neurological deficit in Fragile X syndrome.

UV resonance Raman analysis of trishomocubane and diamondoid dimers.

We present resonance Raman measurements of crystalline trishomocubane and diamantane dimers containing a C=C double bond. Raman spectra were recorded with excitation energies between 2.33 eV and 5.42 eV. The strongest enhancement is observed for the C=C stretch vibration and a bending mode involving the two carbon atoms of the C=C bond, corresponding to the B2g wagging mode of ethylene. This is associated with the localization of the π-HOMO and LUMO and the elongation of the C=C bond length and a pyramidalization of the two sp(2)-hybridized carbon atoms at the optical excitation. The observed Raman resonance energies of the trishomocubane and diamantane dimers are significantly lower than the HOMO-LUMO gaps of the corresponding unmodified diamondoids.

The role of the innate immune system in psychiatric disorders.

There is by now substantial clinical evidence for an association between specific mood disorders and altered immune function. More recently, a number of hypotheses have been forwarded to explain how components of the innate immune system can regulate brain function at the cellular and systems levels and how these may underlie the pathology of disorders such as depression, PTSD and bipolar disorder. In this review we draw reference to biochemical, cellular and animal disease models, as well as clinical observations to elucidate the role of the innate immune system in psychiatric disorders. Proinflammatory cytokines, such as IL-1ß IL-6 and TNFα, which feature prominently in the immune response to pathogen in the periphery, have unique and specific actions on neurons and circuits within the central nervous system. Effects of these signaling molecules on neurotransmission, memory, and glucocorticoid function, as well as animal behaviors such as social withdrawal and fear conditioning relevant to psychiatric disorders are elucidated. Finally, we highlight future directions for studies, including the use of peripheral biomarkers, relevant for developing new therapeutic approaches for treating psychiatric illnesses. This article is part of Special Issue entitled 'neuroinflammation in neurodegeneration and neurodysfunction'.

Biomechanical evaluation of macro and micro designed screw-type implants: an insertion torque and removal torque study in rabbits.

OBJECTIVE: To investigate the combined effect of macro and pitch shortened threads on primary and secondary stability during healing, but before dynamic loading. MATERIALS AND METHODS: Two sets of turned implants with different macro geometry were prepared. The test group possessed pitch shortened threads in between the large threads and the control group did not have thread alterations. The two implant groups were placed in both femur and tibiae of 10 lop-eared rabbits, and at the time of implant insertion, insertion torques were recorded. After 4 weeks, all implants were subjected to removal torque tests. RESULTS: The insertion torque values for the control and test groups for the tibia were 15.7 and 20.6 Ncm, respectively, and for the femur, 11.8, and 12.8 Ncm respectively. The removal torque values for the control and test groups in the tibia were 7.9 and 9.1 Ncm, respectively, and for the femur, 7.9 and 7.7 Ncm respectively. There was no statistically significant difference between the control and test groups. CONCLUSION: Under limited dynamic load, the addition of pitch shortened threads did not significantly improve either the primary or the secondary stability of the implants in bone.

Electronic structure and exciton-phonon interaction in two-dimensional colloidal CdSe nanosheets.

We study the electronic structure of ultrathin zinc-blende two-dimensional (2D)-CdSe nanosheets both theoretically, by Hartree-renormalized k·p calculations including Coulomb interaction, and experimentally, by temperature-dependent and time-resolved photoluminescence measurements. The observed 2D-heavy hole exciton states show a strong influence of vertical confinement and dielectric screening. A very weak coupling to phonons results in a low phonon-contribution to the homogeneous line-broadening. The 2D-nanosheets exhibit much narrower ensemble absorption and emission linewidths as compared to the best colloidal CdSe nanocrystallites ensembles. Since those nanoplatelets can be easily stacked and tend to roll up as they are large, we see a way to form new types of multiple quantum wells and II-VI nanotubes, for example, for fluorescence markers.

Immunohistochemical detection of double-stranded RNA in formalin-fixed paraffin-embedded tissue.

Double-stranded RNA (dsRNA) is produced during most viral infections, and immunohistochemical detection of dsRNA has been proposed as a potential screening marker for viral replication. The anti-dsRNA monoclonal antibody clone 9D5 is more sensitive than the established clone J2 but has not been validated in formalin-fixed paraffin-embedded (FFPE) tissue. This study aimed to test and compare the performance of the anti-dsRNA monoclonal antibodies, 9D5 and J2, in FFPE tissue using an automated staining platform. Archived clinical tissue samples with viral infections (n = 34) and uninfected controls (n = 30) were examined. Immunohistochemical staining for dsRNA (9D5 and J2) and virus-specific epitopes was performed. 9D5 provided a similar staining pattern but a higher signal-to-noise ratio than J2. The following proportions of virus-infected tissue samples were dsRNA-positive: SARS-CoV-2 (5/5), HPV (6/6), MCV (5/5), CMV (5/6), HSV (4/6), and EBV (0/6). Also, 18 of 30 uninfected samples were dsRNA positive, and an association between fixation time and intensity was observed. However, signals in all samples were markedly reduced by pretreatment with dsRNA-specific RNAse-III, indicating a specific reaction. In conclusion, dsRNA can be demonstrated in most viral infections with immunohistochemistry in FFPE tissue but with low clinical specificity. The antibody clone 9D5 performs better than clone J2.

Keratin 5 in Lung Cancer Specimens: Comparison of Four Antibody Clones and KRT5 mRNA-ISH.

Recent improvements in the medical treatment of non-small cell lung carcinoma have made the histopathological distinction between adenocarcinomas (ACs) and squamous cell carcinomas (SCCs) increasingly important. One immunohistochemical marker of squamous differentiation is Keratin 5 (K5). Several K5 antibody clones are commercially available, and data from external quality assessment (NordiQC) have shown large variations in their performance. However, comparing antibody performance characteristics of optimized K5 immunohistochemical assays in lung cancer specimens is needed. Tissue microarrays comprising 31 SCCs, 59 ACs, 17 large cell carcinomas, 8 large cell neuroendocrine carcinomas, 5 carcinosarcomas, and 10 small cell carcinomas were included. Serial sections from the tissue microarrays were stained using optimized assays based on the K5 mouse monoclonal antibodies D5/16 B4 and XM26, and the K5 rabbit monoclonal antibodies SP27 and EP1601Y, respectively. The staining reactions were assessed using H-score (0-300). In addition, p40 immunohistochemistry and KRT5 mRNA-ISH analyses were conducted. Clone SP27 showed significantly higher analytical sensitivity than the other 3 clones. However, a distinct positive reaction was observed in 25% of the ACs using clone SP27 but not with the other clones. Clone D5/16 B4 displayed granular staining in 14 ACs, probably representing Mouse Ascites Golgi-reaction. A weak, scattered expression of KRT5 mRNA was seen in 71% of the ACs. In conclusion, the K5 antibody clones D5/16 B4, EP1601Y, and XM26 showed equal sensitivity in lung cancer specimens, but D5/16 B4 also showed nonspecific Mouse Ascites Golgi-reaction. Clone SP27 demonstrated superior analytical sensitivity but lower clinical specificity in the differential diagnosis of SCC versus AC.

Tunable plasmon coupling in distance-controlled gold nanoparticles.

Plasmons are resonant excitations in metallic films and nanoparticles. For small enough static distances of metal nanoparticles, additional plasmon-coupled modes appear as a collective excitation between the nanoparticles. Here we show, by combining poly(N-isopropylacrylamide) micro- and nanospheres and Au nanoparticles, how to design a system that allows controllably and reversibly switching on and off, and tuning the plasmon-coupled mode.

Selective polycarboxylation of semiconducting single-walled carbon nanotubes by reductive sidewall functionalization.

The efficient and controllable synthesis, the detailed characterization, and the chemical postfunctionalization of polycarboxylated single-walled carbon nanotubes SWCNT(COOH)(n) are reported. This innovative covalent sidewall functionalization method is characterized by (a) the preservation of the integrity of the entire σ-framework of SWCNTs; (b) the possibility of achieving very high degrees of addition; (c) control of the functionalization degrees by the variation of the reaction conditions (reaction time, ultrasonic treatment, pressure); (d) the identification of conditions for the selective functionalization of semiconducting carbon nanotubes, leaving unfunctionalized metallic tubes behind; (e) the proof that the introduced carboxylic acid functionalities can serve as versatile anchor points for the coupling to functional molecules; and (f) the application of a subsequent thermal degradation step of the functionalized semiconducting tubes leaving behind intact metallic SWCNTs. Functional derivatives have been characterized in detail by means of Raman, UV-vis/nIR, IR, and fluorescence spectroscopy as well as by thermogravimetric analysis combined with mass spectrometry, atomic force microscopy, and zeta-potential measurements.

Raman and photoluminescence spectroscopic detection of surface-bound Li(+)O2(-) defect sites in Li-doped ZnO nanocrystals derived from molecular precursors.

We present a detailed study of Raman spectroscopy and photoluminescence measurements on Li-doped ZnO nanocrystals with varying lithium concentrations. The samples were prepared starting from molecular precursors at low temperature. The Raman spectra revealed several sharp lines in the range of 100-200 cm(-1), which are attributed to acoustical phonons. In the high-energy range two peaks were observed at 735 cm(-1) and 1090 cm(-1). Excitation-dependent Raman spectroscopy of the 1090 cm(-1) mode revealed resonance enhancement at excitation energies around 2.2 eV. This energy coincides with an emission band in the photoluminescence spectra. The emission is attributed to the deep lithium acceptor and intrinsic point defects such as oxygen vacancies. Based on the combined Raman and PL results, we introduce a model of surface-bound LiO(2) defect sites, that is, the presence of Li(+)O(2)(-) superoxide. Accordingly, the observed Raman peaks at 735 cm(-1) and 1090 cm(-1) are assigned to Li-O and O-O vibrations of LiO(2).

Adsorption behavior of 4-methoxypyridine on gold nanoparticles.

We demonstrate a phase transfer method to create stable colloidal solutions of Au nanoparticles with 4-methoxypyridine ligands. We then investigate the adsorption behavior of 4-methoxypyridine onto gold surfaces by Raman spectroscopy, DFT calculations, and (1)H NMR. In contrast to unsubstituted pyridine and the frequently used (N,N-dimethylamino)pyridine (DMAP), a flat adsorption of 4-methoxypyridine on gold was found.

High pressure Raman scattering of silicon nanowires.

We study the high pressure response, up to 8 GPa, of silicon nanowires (SiNWs) with ∼ 15 nm diameter, by Raman spectroscopy. The first order Raman peak shows a superlinear trend, more pronounced compared to bulk Si. Combining transmission electron microscopy and Raman measurements we estimate the SiNWs' bulk modulus and the Grüneisen parameters. We detect an increase of Raman linewidth at ∼ 4 GPa, and assign it to pressure induced activation of a decay process into LO and TA phonons. This pressure is smaller compared to the ∼ 7 GPa reported for bulk Si. We do not observe evidence of phase transitions, such as discontinuities or change in the pressure slopes, in the investigated pressure range.

Observation of breathing-like modes in an individual multiwalled carbon nanotube.

We study collective vibrational breathing modes in the Raman spectrum of a multiwalled carbon nanotube. In correlation with high-resolution transmission electron microscopy, we find that these modes have energies differing by more than 23% from the radial breathing modes of the corresponding single-walled nanotubes. This shift in energy is explained with intershell interactions using a model of coupled harmonic oscillators. The strength of this interaction is related to the coupling strength expected for few-layer graphene.

Estrogen modulates metabolic risk profile after resistance training in early postmenopausal women: a randomized controlled trial.

OBJECTIVE: Women experience an unhealthy change in metabolic risk profile at menopause. The purpose of the present study was to determine effects of resistance training with or without transdermal estrogen therapy (ET) on adipose tissue mass and metabolic risk profile in early postmenopausal women. METHODS: A double-blinded randomized controlled trial, where healthy, untrained postmenopausal women were allocated to supervised resistance training with placebo (PLC, n = 16) or transdermal ET (n = 15) for 12 weeks. Endpoints with prespecified hypotheses were the change in total fat mass (FM) (main endpoint) and the change in visceral FM (secondary endpoint) from before to after the intervention. Additionally, prespecified endpoints of body composition, metabolic health-related blood markers, fat%, fat cell size, and lipogenic markers in subcutaneous adipose tissue (SAT) from abdominal and femoral region were explored. RESULTS: Compared with the ET group, the PLC group experienced a greater reduction (time × treatment interaction P < 0.05) in total FM (PLC vs ET: -5.6% vs -1.1%) and visceral FM (-18.6% vs -6.8%), and femoral SAT (-5.6% vs 1.0%), but not abdominal SAT mass (-8.5% vs -2.8%, P = 0.15).The ET group improved their metabolic blood profile by reduced low-density lipoprotein, glucose and hemoglobin A1c compared with PLC (time × treatment interaction P < 0.05). The intervention induced changes in lipolytic markers of abdominal SAT, whereas no changes were detected in femoral SAT. CONCLUSION: Use of transdermal ET reduced adipose tissue loss, but improved metabolic blood markers when combined with 12 weeks of progressive resistance training in early postmenopausal women.

Synthesis and Characterization of the Novel Rodent-Active and CNS-Penetrant P2X7 Receptor Antagonist Lu AF27139.

There remains an insufficient number of P2X7 receptor antagonists with adequate rodent potency, CNS permeability, and pharmacokinetic properties from which to evaluate CNS disease hypotheses preclinically. Herein, we describe the molecular pharmacology, safety, pharmacokinetics, and functional CNS target engagement of Lu AF27139, a novel rodent-active and CNS-penetrant P2X7 receptor antagonist. Lu AF27139 is highly selective and potent against rat, mouse, and human forms of the receptors. The rat pharmacokinetic profile is favorable with high oral bioavailability, modest clearance (0.79 L/(h kg)), and good CNS permeability. In vivo mouse CNS microdialysis studies of lipopolysaccharide (LPS)-primed and 2'(3')-O-(benzoylbenzoyl)adenosine-5'-triphosphate (BzATP)-induced IL-1ß release demonstrate functional CNS target engagement. Importantly, Lu AF27139 was without effect in standard in vitro and in vivo toxicity studies. Based on these properties, we believe Lu AF27139 will be a valuable tool for probing the role of the P2X7 receptor in rodent models of CNS diseases.

Electronic properties of propylamine-functionalized single-walled carbon nanotubes.

We present resonant Raman measurements on single-walled carbon nanotubes (SWCNT) functionalized with propylamine groups at different degrees. Direct nucleophilic addition based on in situ generated primary amides is used for attaching n-propylamine to the sidewalls of SWCNTs. The influence of the amino functionalities on the electronic structure of the nanotubes is investigated. From the Raman resonance profiles of the radial breathing modes (RBMs), the chiral indices of the corresponding tubes are assigned. We observe significant redshifts of the transition energies and a broadening of the resonance windows due to chemical modification of SWCNTs. Similar redshifts are derived from the analysis of the NIR/Vis transmission spectrum. The relative Raman intensities of the functionalized samples and the evaluation of their transmission spectra indicate a diameter dependence of the reactivity as it has been observed for other moieties. By analyzing the defect induced D mode we observe a considerable degree of functionalization accompanied by an almost unharmed tube structure, which ensures that the observed effects are mainly driven by changes of the electronic structure.

Kohn anomaly and electron-phonon interaction at the K-derived point of the brillouin zone of metallic nanotubes.

We applied Raman spectroscopy to investigate the response to electrochemical doping of the second-order D* band in single-walled carbon nanotube (SWNT) bundles. Our study reveals a dramatic increase of the D* band sensitivity to doping upon moving the laser excitation to the red end of the visible spectrum and beyond. Using the double-resonance scattering model, we show that this phenomenon evidences a second Kohn anomaly in metallic SWNTs, located in the K-point-derived region of the Brillouin zone (BZ), which stems from the Kohn anomaly at the K-point of graphene. Our results will be compared to recent doping experiments on graphene with field-effect gating and can be used to investigate the wave-vector dependent electron-phonon coupling in the bulk of the BZ of metallic SWNTs.