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Aging is a physiological process that leads to a higher risk for the most devastating diseases. There are a number of theories of human aging proposed, and many of them are directly or indirectly linked to mitochondria. Here, we used mesenchymal stem cells (MSCs) from young and older donors to study age‐related changes in mitochondrial metabolism. We have found that aging in MSCs is associated with a decrease in mitochondrial membrane potential and lower NADH levels in mitochondria. Mitochondrial DNA content is higher in aged MSCs, but the overall mitochondrial mass is decreased due to increased rates of mitophagy. Despite the higher level of ATP in aged cells, a higher rate of ATP consumption renders them more vulnerable to energy deprivation compared to younger cells. Changes in mitochondrial metabolism in aged MSCs activate the overproduction of reactive oxygen species in mitochondria which is compensated by a higher level of the endogenous antioxidant glutathione. Thus, energy metabolism and redox state are the drivers for the aging of MSCs/mesenchymal stromal cells. [ABSTRACT FROM AUTHOR]

Introduction The increasing longevity of the Western population means patients with a more advanced age are being diagnosed with resectable disease. With improvements in imaging and diagnostic capabilities, this trend is likely to develop further. As a unit operating on a higher proportion of older patients and with limited literature regarding the population of older than 85 years, we retrospectively compared the outcomes of patients older than 85 years in our unit treated with elective lung resection for non-small cell lung cancer (NSCLC) with those between the age of 80 and 84 years inclusive. Methods All patients who underwent elective lung cancer resection between the years 2012 and 2015 were identified from the National Thoracic Surgical Database. Results A total of 701 elective lung resections were performed during this time frame; 76 patients between the ages of 80 and 84 years and 18 patients older than 85 years. The follow-up period was 3 to 7 years. There was a significant increase in the Thoracic Surgery Scoring System (2.04; 2.96%, p = 0.0015) and a significant reduction in the transfer factor (94.7; 69.5%, p = 0.0001) between the younger and older groups. There were three (3.9%) in-hospital deaths in the 80 to 84 years age group and no in-hospital deaths in the 85 years and older age group. Conclusion This study demonstrates that surgery for early NSCLC can be safely performed in 85 years and older population. This is a higher risk population and parenchymal-sparing procedures should be considered. [ABSTRACT FROM AUTHOR]

Objective: To identify the genetic cause of complex neuropathy in two siblings from a consanguineous family. Methods: The patients were recruited from our clinic. Muscle biopsy and whole-exome sequencing (WES) were performed. Fibroblasts cell lines from the index patient, unaffected parents, and three normal controls were used for cDNA analysis and western blot. Results: The index patient was a 29-year-old male with clinical phenotype of syndactyly, pes cavus, swallowing difficulties, vision problem, imbalance, and muscle weakness. The sibling had similar, but milder symptoms. Nerve conduction studies and electromyography of both patients suggested sensory-motor axonal neuropathy. Muscle biopsy showed a feature of necklace fibres. WES identified a novel homozygous frameshift deletion (c.5477-5478del; p.1826-1826del) in exon 40 of the SBF1 gene in the two siblings, while both parents and the unaffected sibling were heterozygous carriers. Functional analysis showed a markedly reduced level of MTMR5 protein encoded by SBF1 in the index case. The levels of MTMR5 protein in unaffected parents were similar to those found in controls. Conclusion: A novel homozygous frameshift deletion in SBF1 was identified in this family. Sensory-motor axonal neuropathy and necklace fibres in biopsy were the major features expanding the phenotypic spectrum of SBF1-related recessive syndromic neuropathy. [ABSTRACT FROM AUTHOR]

Spectra were recorded in the H-F stretching fundamental region for O[sub 2]-HF and in the D-F region for O[sub 2]-DF, using a laser difference-frequency spectrometer coupled to a slit-nozzle expansion. By varying the ratio of oxygen to carrier gas, beam temperatures ranging from 5 to 16 K were obtained. One standard uncertainty for the relative frequency position of unblended lines is 0.0001 cm[sup -1]. Each spectrum was visually subdivided into a stronger (cold) spectrum and a weaker (hot) spectrum. Lines in the cold spectrum were fit to nearly experimental error, using a rotational Hamiltonian for open-shell complexes taken from the literature. For O[sub 2]-DF, 21 rotational and spin-rotational parameters (10 each for the upper and lower state plus the band origin) were used to fit 86 transitions to a standard deviation of 0.0002 cm[sup -1]. For O[sub 2]-HF, 23 rotational and spin-rotational parameters were used to fit 83 transitions to a standard deviation of 0.0003 cm[sup -1]. The slightly poorer quality of the fit for O[sub 2]-HF than for O[sub 2]-DF is probably related to the somewhat larger vibrational amplitudes expected for the van der Waals motions in the protonated species. In spite of strenuous efforts, a simultaneous global fit to measurement error of the eight cold-spectrum branches and fourteen hot-spectrum branches could not be achieved, suggesting some improvement in the model used to derive the fitting Hamiltonian may be necessary. [ABSTRACT FROM AUTHOR]

An extensive series of near-infrared absorption spectra are recorded for jet-cooled (6–14 K) hydrogen chloride dimer (HCl)2. Both ΔKa=0 and ΔKa=±1 bands are observed for both the free (ν1) and bonded (ν2) HCl stretches; all three chlorine isotopomers (H 35Cl–H 35Cl, H 35Cl–H 37Cl, and H 37Cl–H 37Cl) are observed and analyzed for K‘a ≤ 2. The slit jet spectrum extends significantly the previous cooled cell infrared study of this complex and provides a measure of tunneling splittings for Ka=0 and 1 for each of the HCl ground (v=0) and excited (v=1) states. Mode specific vibrational predissociation is observed via analysis of the absorption line shapes, with Lorentzian contributions to the line profiles of Δν1<=1.6 MHz and Δν2=5.1±1.2 (2σ) MHz full width at half-maximum for ν1 and ν2 excitation, respectively. Stronger coupling in (HCl)2 of the bonded (ν2) vs free (ν1) HCl vibration to the dissociation coordinate is consistent with the comparable trends observed in other hydrogen bonded dimers. Quantum mechanical variational calculations on an electrostatic angular potential energy surface are used to model the internal HCl rotor dynamics using a coupled rotor formalism; analysis of the internal rotor eigenfunctions provides direct evidence for large amplitude ‘‘geared’’ internal rotation of the HCl subunits. [ABSTRACT FROM AUTHOR]

High resolution ir data on weakly bound OCOHF complexes formed in a slit supersonic expansion reveal a progression of extremely low frequency vibrational levels associated with the bending of the OCO–HF hydrogen bond. In a previous paper [J. Chem. Phys. 93, 7716 (1990)], we presented a spectroscopic analysis of the fundamental, combination and hot bands observed, corresponding to transitions between vlbend=00, 11, 20, 22, and 31, where vlbend denotes quanta of OCOHF skeletal bend excitation with l units of vibrational angular momentum. In this paper, we analyze the rotationally resolved data in terms of the rigid bender formalism of Hougen, Bunker and Johns to determine an explicit angular potential, V(θ), for the OCOHF complex in both the HF ground (vHF=0) and vibrationally excited (vHF=1) state.The OCOHF ground state (vHF=0) potential is dominated by quartic and sextic angular terms, and thus is surprisingly shallow with respect to the bending angle. This quasilinear vibrational behavior is characterized by wide amplitude bending wave functions with zero point motion extending from -38° to +38°. In contrast, the OCOHF excited state (vHF=1) exhibits a significantly bent equilibrium geometry with a hydrogen bond bend angle of 31°±5°, corresponding to a cylindrically symmetric, noncolinear minimum in the potential. This shift in equilibrium geometry upon vHF excitation is quantitatively responsible for promoting Δvbend=0,2,... combination band vibrational modes, in analogy with Franck–Condon progressions in a bent←linear electronic transition.The predissociation lifetimes for vHF=1 excited OCOHF vary systematically with vlbend, and can be analyzed in terms of a geometry dependent predissociation rate which increases with bending of the hydrogen bond angle. These empirical bending potentials are in qualitative agreement with, but quantitatively much shallower than predicted by previous electrostatic and ab... [ABSTRACT FROM AUTHOR]

The near-infrared spectrum of NeDF formed in a slit free jet expansion is recorded with a high resolution, tunable laser spectrometer. Four bands, consisting of the DF stretching fundamental and three internal rotation and van der Waals stretch combination bands, are observed and analyzed for both the 20Ne and 22Ne isotopomers. All three combination bands reveal a sudden onset of rotational predissociation at modest J, which is modeled with effective one-dimensional potentials to determine the binding energy D0=34.7±0.8 cm-1 for 20NeDF (v=0) and D0=35.1±0.8 cm-1 for 20 NeDF (v=1). The experimental results are compared with predictions of a recently published ab initio anisotropic potential surface, and an improved potential is developed and tested. This refined potential has an absolute minimum of -86 cm-1 in the linear Ne–D–F geometry, a secondary minimum at -55 cm-1 in the inverted linear Ne–F–D geometry, and an intervening saddle point at -39 cm-1 near the perpendicular geometry. The lowest bound state lies ≊4 cm-1 above the saddle so internal DF rotation is only slightly hindered in this complex. [ABSTRACT FROM AUTHOR]

We report the use of near infrared tunable difference frequency laser absorption methods to investigate low-frequency bending of the intermolecular hydrogen bond in OCOHF complexes. By deliberate thermal warming of the slit jet expansion to 16 K, we observe bending ‘‘hot band’’ transitions built on the fundamental vHF=1←0 HF stretch from the lowest five internally excited bending states (i.e., vlbend=00←00, 11←11, 20←20, 22←22, and 31←31) which correspond to low-frequency, skeletal bending of the intermolecular hydrogen bond. In addition, much weaker parallel (Δl=0) combination band transitions (vlbend=20←00 and 31←11 ) are observed at ≲5% of the 00←00 intensity. Furthermore, measurements of the extremely weak 11←00 perpendicular (Δl=1) band are obtained at ≲1% of the 00←00 intensity. The fundamental, hot band, and combination band data permit quantitative measurement of the absolute vibrational energies of all vibrational levels for the l=0 and 1 manifolds in both HF excited (vHF=1) and ground-state (vHF=0) complexes.The bending frequencies are surprisingly low (∼10 cm-1 ) and exhibit positive anharmonicity (i.e., the energy level spacings increase with vlbend ). The results suggest nearly unrestricted bending of the hydrogen bond in a very flat, highly anharmonic angular potential. In contrast with many other weakly bound complexes, the lowest bending frequency decreases dramatically upon HF excitation, which signals a vHF vibrationally induced shift from a linear to a nonlinear equilibrium geometry for the vHF=1 excited OCOHF potential surface. Excess Lorentzian line widths are observed in all OCOHF transitions, attributable to vibrational predissociation lifetimes that vary smoothly from 1.2 ns (vlbend=00) to 650 ps (vlbend=31) as a function of intermolecular bending excitation. [ABSTRACT FROM AUTHOR]

The near-infrared vibration–rotation spectra of the weakly bound complexes HeHF, HeDF, and HeHCl are observed in a slit supersonic expansion. The spectra correspond to simultaneous excitation of vibration and internal rotation of the H(D)X subunit within the complex. The HeHF and HeDF P/R branch transitions show J-dependent excess linewidths, which are attributed to rapid predissociation of the excited states from intramolecular rotation–translation energy transfer. The corresponding P/R branch transitions in HeHCl are not observed despite good S/N on the Q branch, suggesting even more rapid predissociation for the upper state of this complex. The Q branch transitions for all three complexes abruptly terminate at low J, yielding lower limits to the number of bound rotational states and good estimates of the dissociation energies D0=7.1±0.1 cm-1 for HeHF and HeDF, and 10.1±1.2 cm-1 for HeHCl. In addition to isotropic intermolecular potentials, the HeHF/HeDF data yield considerable information on the potential anisotropy in the region sampled by the bound and quasibound states. The information so obtained is complementary to results from scattering studies and provides sensitive tests for refining trial potential energy surfaces. [ABSTRACT FROM AUTHOR]

The near-infrared spectrum of ArHF prepared in a slit supersonic expansion is recorded with a difference frequency infrared laser spectrometer. By virtue of the high sensitivity of the technique, and the lack of appreciable spectral congestion at the 10 K jet temperature, we observe 9 of the 11 vibrational states with energies below the Ar+HF(v=1, j=0) dissociation limit. These include (1000), the lowest bound HF (v=1) state, the singly, doubly, and quadruply van der Waals stretch excited states (1001) (1002), and (1004), both the Σ bend (1200) and Π bend (111e,f 0), and the multiply excited, Π bend plus van der Waals stretch (111e,f 1). Two Ar+HF(v=0) states, (0000) and (0001), are also characterized. This spectroscopic information is quite sensitive to the Ar+HF potential energy surface away from the equilibrium configuration, and thus provides a rigorous test of trial potential energy surfaces. Excellent agreement is obtained between experiment and the predictions of a recently reported Ar+HF(v=1) potential. [ABSTRACT FROM AUTHOR]

Two spectroscopically distinct isomers of a hydrogen bonded complex between nitrous oxide and hydrogen fluoride are observed by direct infrared laser absorption detection in a slit supersonic expansion. The linear isomer FH–NNO contains a relatively rigid hydrogen bond to the nitrogen end of NNO. The bent isomer NNO–HF has a stronger hydrogen bond to the oxygen end of NNO, but this bond is characterized by a softer bending potential and thus the complex exhibits evidence of large amplitude bending motion. Rapid vibrational predissociation, as determined from the homogeneous broadening of the rovibrational absorption structure, is evidenced in both isomers. The linear isomer exhibits predissociation lifetimes which show structure as a function of the upper J’ rotational level, including narrow resonances which suggest excitation of NNO fragment vibrational modes. [ABSTRACT FROM AUTHOR]

Ultrasensitive infrared laser absorption spectroscopy in a slit supersonic expansion is used to obtain the spectrum of the HF stretching fundamental of D2HF. Both a Π←Π band due to para-D2HF and a ∑←∑ band due to ortho-D2HF are observed, in contrast to the H2HF spectrum which consists of the Π←Π band alone. Analysis of the spectrum indicates that the D2HF Π states are more strongly bound than the ∑ states. Doublet splittings in the Π←Π band are analyzed to determine barriers to internal rotation of D2 within the complex. The vibrationa1 predissociation rate of D2HF is approximately 25 times faster than that of H2HF, suggesting the opening of a channel which results in vibrational excitation of the D2 fragment. [ABSTRACT FROM AUTHOR]

The vibration–rotation spectrum of the HF stretch mode in ortho-H2HF complexes has been obtained via infrared laser direct absorption detection in a slit supersonic jet expansion. The spectrum resembles a Ka =1←1 parallel band of a prolate near-symmetric top and can be reasonably well fit with a Watson A-type Hamiltonian; however, no rigid molecular structure can reproduce the observed Ka splittings without invoking unphysically large changes in the constituent bond lengths upon complexation. The splittings are more correctly analyzed in terms of a j=1 hindered H2 rotor in an anisotropic potential, with a minimum energy T-shaped geometry. Matrix calculations determine barriers to H2 rotation between 120 and 170 cm-1 that depend systematically both on vibrational and rotational state in the complex. These data are consistent with a strong increase in potential anisotropy with decreasing intermolecular separation, with both upper and lower vibrational states close to the dissociation limit. No evidence for a corresponding Σ←Σ para-H2HF spectrum is observed, despite adequate experimental sensitivity. The matrix calculations indicate that the ground Σ state of para-H2HF is less stabilized by the potential anisotropy than the ground Π state in ortho-H2HF, and may therefore be much less efficiently formed in the jet expansion. The preferential observation of a ground Π vs Σ state in ortho-H2HF clearly indicates a minimum in the potential surface for a T-shaped vs collinear geometry. The observed rotational constants strongly suggest a H2···H–F ordering. The results provide direct evidence for vibrationally averaged structure, internal rigidity, and intermolecular bond strength that are significantly quantum state dependent, but can be qualitatively understood in terms of simple steric interactions between the H2 and HF subunits. [ABSTRACT FROM AUTHOR]

High sensitivity, tunable laser direct absorption methods are exploited to obtain high resolution IR spectra (Δν≾0.001 cm-1) of weakly bound CO2HF complexes in a pulsed supersonic slit jet expansion. Transitions from the ground vibrational state corresponding to a single quantum excitation of the ν1 HF stretch are observed and analyzed with a semirigid linear molecule Hamiltonian. The observed increase in both B (+1.75%) and D (+55%) upon ν1 excitation is inconsistent with the commonly used diatomic approximation, and is not possible to rationalize for a nearly linear upper state geometry with small amplitude zero point motion of the intermolecular CO2 bend coordinate. We consider an alternative centrifugal straightening mechanism which predicts large centrifugal distortion effects due to end over end rotation of a complex with a nonlinear vibrationally averaged geometry in a weak bending potential. In support of this interpretation, hot band spectra are observed arising from bend excited complexes significantly populated in the 16 K expansion; intensity based estimates of the internal excitation indicate a surprisingly low bend frequency of 10±5 cm-1. A preliminary analysis of the spectra as l doubling in a Π←Π vibrational hot band for a linear equilibrium geometry is presented. An alternative interpretation of the spectrum as asymmetry doubling of a K=1←1 rotational hot band for a bent geometry is also considered. This latter interpretation is more consistent with the data and predicts a CO2 bend angle in the complex for K=1 between 25° and 30°. Linewidths for the upper vibrational states in CO2HF exhibit homogeneous broadening 3–4 times in excess of the apparatus resolution. Voigt analysis of the absorption line shapes indicates linewidths (FWHM) of 136±16 MHz and independent of J state; this corresponds to a relaxation lifetime of 1.1±0.2 ns for HF in the complex. [ABSTRACT FROM AUTHOR]

A difference frequency IR spectrometer is combined with a slit supersonic expansion for high-resolution (≤50 MHz FWHM) direct absorption investigations of jet-cooled species. The 1.25 cm long nozzle provides a long path length and high densities suitable for synthesis and observation of van der Waals clusters, with a gradual spatial temperature gradient that permits experimental control of low frequency vibrational populations. Due to collisional quenching of velocity distributions, absorption linewidths are reduced and peak absorbance increased five- to sevenfold compared to pinhole expansions. Minimum detectable concentrations of HF containing complexes are 2×109 molecules/cm3/quantum state in a 2.5 cm path length. The combination of high sensitivity, sub-Doppler resolution, long path lengths, and temperature control make direct absorption in slit nozzle expansions a powerful and general technique for high-resolution study of jet-cooled species. The spectometer is used to obtain the near-infrared spectrum of N2HF. The ν1 (HF stretch) fundamental is observed at 3918.2434(2) cm-1, red shifted by 43.1795(2) cm-1 from the HF origin. In the warmer regions of the expansion close to the nozzle the ν5+ν1-ν5 Π←Π hot band is also observed, blue shifted by 2.7160(4) from the ν1 fundamental. Rotational analysis of these spectra reveals changes in vibrationally averaged molecular geometries upon excitation that are consistent with a near linear equilibrium geometry. The ν5 (N2 bend) frequency is estimated at 85±20 cm-1, based on the relative intensities of the two bands and on an analysis of the l doubling. The linewidths of the N2HF transitions show no increase over the HF monomer and are limited by instrumental resolution to 50 MHz FWHM; the lifetime of the upper level is therefore at least ≥3 ns. [ABSTRACT FROM AUTHOR]

IR spectra of jet cooled ArHF are obtained via direct absorption of a high resolution tunable difference frequency laser in a 2.54 cm path length, slit supersonic pulsed expansion at <10 K. Detection limits of 2×109 molecules/cm3/quantum state permit observation of the high frequency ν1 fundamental stretch (1000) ← (0000), the ν1+ν2 van der Waals bend plus stretch combination band (1110) ← (0000), as well as transitions to the (1002) triply vibrationally excited state that are weakly allowed via Coriolis interactions with the Π+ component of the (1110) manifold. The ground state (0000) molecular constants are in excellent agreement with previous microwave data. From the changes in rotational and centrifugal distortion constants, the vibrationally averaged van der Waals well depth is estimated to increase (+15%) with ν1 excitation, but decrease dramatically (-42%) upon subsequent excitation of the l=1 ν2 bend. L-doubling in the ν1+ν2 (1110) perpendicular bending state is large and negative [-69.8(18) MHz] and indicates the presence of a near resonant Coriolis coupledvibration of Σ+ symmetry at lower energy. A second, localized Coriolis perturbation is observed in the (1110) state and assigned to the near resonant (1002) Σ+ fundamental plus van der Waals stretch overtone at higher energy. Analysis of this Coriolis interaction indicates that coupling can be significant even for a three quantum change in vibration. However, a perturbative, small amplitude oscillator model predicts Coriolis matrix elements only 18% of the observed values, suggesting that large amplitude, bend–stretch interactions can strongly enhance Coriolis coupling. The decrease in the B rotational constant and the vibrationally averaged well depth upon ν2 excitation confirms the strong coupling between van der Waals stretch and bend coordinates. The slit expansion geometry quenches perpendicular velocity... [ABSTRACT FROM AUTHOR]

Carbon monoxide‐releasing molecules (CO‐RMs) induce nitric oxide (NO) release (which requires NADPH), and Ca2+‐dependent signalling; however, their contribution in mediating endothelial responses to CO‐RMs is not clear. Here, we studied the effects of CO liberated from CORM‐401 on NO production, calcium signalling and pentose phosphate pathway (PPP) activity in human endothelial cell line (EA.hy926). CORM‐401 induced NO production and two types of calcium signalling: a peak‐like calcium signal and a gradual increase in cytosolic calcium. CORM‐401‐induced peak‐like calcium signal, originating from endoplasmic reticulum, was reduced by thapsigargin, a SERCA inhibitor, and by dantrolene, a ryanodine receptors (RyR) inhibitor. In contrast, the phospholipase C inhibitor U73122 did not significantly affect peak‐like calcium signalling, but a slow and progressive CORM‐401‐induced increase in cytosolic calcium was dependent on store‐operated calcium entrance. CORM‐401 augmented coupling of endoplasmic reticulum and plasmalemmal store‐operated calcium channels. Interestingly, in the presence of NO synthase inhibitor ( l‐NAME) CORM‐401‐induced increases in NO and cytosolic calcium were both abrogated. CORM‐401‐induced calcium signalling was also inhibited by superoxide dismutase (poly(ethylene glycol)‐SOD). Furthermore, CORM‐401 accelerated PPP, increased NADPH concentration and decreased the ratio of reduced to oxidized glutathione (GSH/GSSG). Importantly, CORM‐401‐induced NO increase was inhibited by the PPP inhibitor 6‐aminonicotinamide (6‐AN), but neither by dantrolene nor by an inhibitor of large‐conductance calcium‐regulated potassium ion channel (paxilline). The results identify the primary role of CO‐induced NO increase in the regulation of endothelial calcium signalling, that may have important consequences in controlling endothelial function. [ABSTRACT FROM AUTHOR]

A major challenge to our understanding of the molecular mechanisms of Alzheimer's disease (AD) has been the lack of physiologically relevant in vitro models which capture the precise patient genome, in the cell type of interest, with physiological expression levels of the gene(s) of interest. Induced pluripotent stem cell (iPSC) technology, together with advances in 2D and 3D neuronal differentiation, offers a unique opportunity to overcome this challenge and generate a limitless supply of human neurons for in vitro studies. iPSC-neuron models have been widely employed to model AD and we discuss in this review the progress that has been made to date using patient-derived neurons to recapitulate key aspects of AD pathology and how these models have contributed to a deeper understanding of AD molecular mechanisms, as well as addressing the key challenges posed by using this technology and what progress is being made to overcome these. Finally, we highlight future directions for the use of iPSC-neurons in AD research and highlight the potential value of this technology to neurodegenerative research in the coming years. [ABSTRACT FROM AUTHOR]

The translational-to-vibrational and rotational (T-V,R) excitation of H2O with 2.2 eV hydrogen atoms is studied by time-resolved Fourier-transform infrared spectroscopy. Up to 2900 cm-1 of rotational excitation is observed in (001), with a strong preference for in-plane rather than out-of-plane rotation for J≥7, which implies a unique collision process leading to rotational alignment. [ABSTRACT FROM AUTHOR]

Artificial intelligence (AI) has seen increasing use across all sectors, as enabled by increasing volumes of data, greater computing power and novel algorithm architectures. Machine learning (ML) encompasses a group of AI methods by which computers can identify patterns and relationships between data (such as radiological images or blood tests) and outcomes of interest. Convolutional neural networks (CNNs) are specialized ML methods, excelling at imaging analysis, which may support assessment of respiratory disease on chest X-ray or CT scan. [Extracted from the article]

We describe a valve for production of jet-cooled species in a pulsed, long-path-length (1.2-cm) supersonic expansion. The valve produces 150–600-μs-duration pulses at repetition rates up to 60 Hz from a nozzle with variable slit width, and is suitable for use with corrosive gases and vapors. [ABSTRACT FROM AUTHOR]

The near-IR spectrum and equilibrium structure of a novel hydrogen bonded complex between nitrous oxide and hydrogen fluoride is described. In contrast to a previously reported structure, in which the HF bonds to the oxygen end of NNO, the present structure has the HF bonded to the nitrogen end of NNO. The structure is unambiguously confirmed by isotopic substitution. The identification of the two stable, spectroscopically distinct structures represents the first demonstration of geometric isomerism in a hydrogen-bonded complex. [ABSTRACT FROM AUTHOR]

Mutations in presenilin 1 (PSEN1) or presenilin 2 (PSEN2), the catalytic subunit of γ-secretase, cause familial Alzheimer's disease (fAD). We hypothesized that mutations in PSEN1 reduce Notch signaling and alter neurogenesis. Expression data from developmental and adult neurogenesis show relative enrichment of Notch and γ-secretase expression in stem cells, whereas expression of APP and β-secretase is enriched in neurons. We observe premature neurogenesis in fAD iPSCs harboring PSEN1 mutations using two orthogonal systems: cortical differentiation in 2D and cerebral organoid generation in 3D. This is partly driven by reduced Notch signaling. We extend these studies to adult hippocampal neurogenesis in mutation-confirmed postmortem tissue. fAD cases show mutation-specific effects and a trend toward reduced abundance of newborn neurons, supporting a premature aging phenotype. Altogether, these results support altered neurogenesis as a result of fAD mutations and suggest that neural stem cell biology is affected in aging and disease. • In neurogenesis, PSEN1 expression is enriched in progenitors, as it is for APP in neurons • Inhibiting β-secretase has little effect on neurogenesis, contrary to γ-secretase • Familial Alzheimer's disease mutations in PSEN1 cause premature neurogenesis • Trend toward fewer newborn neurons in familial AD postmortem hippocampi Arber et al. employ human iPSC neurogenesis to model adult hippocampal neurogenesis, investigating familial Alzheimer's disease (fAD) mutations. In contrast to APP , PSEN1 and γ-secretase components are enriched in neural progenitors and mutations drive premature neurogenesis. Postmortem fAD hippocampi show corresponding trends toward altered neurogenesis. [ABSTRACT FROM AUTHOR]

Background: Familial Alzheimer's disease (fAD) is caused by mutations in PSEN1, PSEN2 and APP. PSEN1 forms the catalytic core of g‐secretase, a membrane protease which cleaves numerous substrates including APP and Notch. We have previously shown that our panel of fAD patient‐derived iPSCs show altered APP processing and Ab generation. Here we investigated whether mutations led to altered Notch cleavage in neural precursors. We hypothesised that reduced Notch cleavage in fAD lines would promote premature differentiation during iPSC neuronal differentiation and during adult hippocampal neurogenesis. Method: We generated 2D cortical neurons and 3D cerebral organoids from a panel of 14 donor‐derived iPSC lines (5 controls, 2 APP mutation lines and 7 PSEN1 mutation lines). Neurogenesis was quantified via the proportion of neural precursors versus the number of post‐mitotic neurons at timepoints of neural commitment. In addition, we quantified newly generated neurons in the post‐mortem hippocampus of 3 control brains and 7 brains derived from fAD mutation carriers. Result: We describe a small, yet reproducible premature differentiation phenotype in lines containing mutations in PSEN1 during in vitro neurogenesis. This is, at least in part, due to reduced Notch signalling; which drives terminal differentiation. These findings are corroborated in independent orthogonal iPSC systems, namely 2D neurogenesis and 3D organoid differentiation. We see describe robust, quantifiable neurogenesis in post‐mortem tissue using b‐III‐tubulin immunohistochemistry. Results are suggestive of mutation‐specific effects and also a premature ageing phenotype in fAD tissue. Conclusion: These findings reveal insights into the functional outcomes of fAD mutations. Mutations in PSEN1, but not APP, alter Notch signalling in neural precursors, which in turn drives premature terminal differentiation. Premature differentiation and mutation‐specific differences both necessitate careful consideration for drug design and patient stratification. [ABSTRACT FROM AUTHOR]

Background: Familial Alzheimer's disease (fAD) is caused by mutations inPSEN1, PSEN2and APP. PSEN1forms the catalytic core of g‐secretase, a membrane protease which cleaves numerous substrates including APP and Notch. We have previously shown that our panel of fAD patient‐derived iPSCs show altered APP processing and Abgeneration. Here we investigated whether mutations led to altered Notch cleavage in neural precursors. We hypothesised that reduced Notch cleavage in fAD lines would promote premature differentiation during iPSC neuronal differentiation and during adult hippocampal neurogenesis. Methods: We generated 2D cortical neurons and 3D cerebral organoids from a panel of 14 donor‐derived iPSC lines (5 controls, 2 APPmutation lines and 7 PSEN1mutation lines). Neurogenesis was quantified via the proportion of neural precursors versus the number of post‐mitotic neurons at timepoints of neural commitment. In addition, we quantified newly generated neurons in the post‐mortem hippocampus of 3 control brains and 7 brains derived from fAD mutation carriers. Results: We describe a small, yet reproducible premature differentiation phenotype in lines containing mutations in PSEN1during in vitro neurogenesis. This is, at least in part, due to reduced Notch signalling; which drives terminal differentiation. These findings are corroborated in independent orthogonal iPSC systems, namely 2D neurogenesis and 3D organoid differentiation. Using immunohistochemistry against b‐III‐tubulin, we describe robust, quantifiable neurogenesis in post‐mortem tissue. Results are suggestive of mutation‐specific effects and also a premature ageing phenotype in fAD tissue. Conclusion: These findings reveal insights into the functional outcomes of fAD mutations. Mutations in PSEN1, but not APP, alter Notch signalling in neural precursors, which in turn drives premature terminal differentiation. Premature differentiation and mutation‐specific differences both necessitate careful consideration for drug design and patient stratification. [ABSTRACT FROM AUTHOR]

Background: Mutations in the microtubule‐associated protein tau (MAPT) are causative of Frontotemporal Dementia (FTD). Many of the features associated with the development of tau pathology, such as high levels of tau phosphorylation, are also present in early development. iPSC‐neurons have gene expression signatures similar to fetal neurons, and iPSC‐neurons with MAPT mutations do not develop tau aggregates. We hypothesise that iPSC‐neurons are resistant to developing tau aggregates due to high activity levels of the proteostasis network during early development. To test this hypothesis we investigated the RNA and protein levels of proteasome subunits (B5, RPT6, PSMD11) and associated proteins (TRIM11, BAG3) in developing MAPT mutated iPSC derived neurons. Methods: Human cortical neurons were derived from isogenic iPSCs with the following MAPT genotypes: WT, 10+16 monoallelic, 10+16 biallelic and 10+16/P301S biallelic. RNA and protein analysis of proteasome subunits was performed by qPCR and Western blot at Days 0, 10, 30 and 100, spanning the different stages of neurogenesis. Results: Gene and protein expression of the core proteasome subunit B5 remains consistent throughout development. The expression of regulatory proteasome subunits PSMD11 decreases at both the protein and RNA level. RPT6 decreases at the protein level but increases at the RNA level. BAG3 significantly decreases at the protein level. There is no significant difference in protein expression between disease and WT lines. Conclusion: This data indicates that the core 20S proteasome unit remains at consistent levels throughout development, however the expression of regulatory subunits differ. A change in regulatory subunit expression could have a direct impact on the ability of the proteasome to degrade proteins. Ongoing work is using proteasome activity assays to determine how this changes through development and is impacted by MAPT mutations. [ABSTRACT FROM AUTHOR]

Summary Virus infection is sensed by pattern recognition receptors (PRRs) detecting virus nucleic acids and initiating an innate immune response. DNA-dependent protein kinase (DNA-PK) is a PRR that binds cytosolic DNA and is antagonized by vaccinia virus (VACV) protein C16. Here, VACV protein C4 is also shown to antagonize DNA-PK by binding to Ku and blocking Ku binding to DNA, leading to a reduced production of cytokines and chemokines in vivo and a diminished recruitment of inflammatory cells. C4 and C16 share redundancy in that a double deletion virus has reduced virulence not seen with single deletion viruses following intradermal infection. However, non-redundant functions exist because both single deletion viruses display attenuated virulence compared to wild-type VACV after intranasal infection. It is notable that VACV expresses two proteins to antagonize DNA-PK, but it is not known to target other DNA sensors, emphasizing the importance of this PRR in the response to infection in vivo. Graphical Abstract Highlights • DNA-PK is a pattern recognition receptor that binds cytosolic DNA • Vaccinia virus proteins C4 and C16 antagonize DNA-PK by blocking DNA binding • C4 and C16 inhibit IRF3 signaling, cytokine production, and immune cell recruitment • C4 and C16 share redundant and non-redundant functions in vivo DNA-PK is a pattern recognition receptor (PRR) that binds cytosolic DNA and stimulates IRF3 signaling. Scutts et al. show that vaccinia virus antagonizes this DNA sensor with two proteins, C4 and C16, which both block DNA binding. [ABSTRACT FROM AUTHOR]