Targeting the autophagy-NAD axis protects against cell death in Niemann-Pick type C1 disease models.

Impairment of autophagy leads to an accumulation of misfolded proteins and damaged organelles and has been implicated in plethora of human diseases. Loss of autophagy in actively respiring cells has also been shown to trigger metabolic collapse mediated by the depletion of nicotinamide adenine dinucleotide (NAD) pools, resulting in cell death. Here we found that the deficit in the autophagy-NAD axis underpins the loss of viability in cell models of a neurodegenerative lysosomal storage disorder, Niemann-Pick type C1 (NPC1) disease.

Modulation of Mitochondrial Function as a Therapeutic Strategy for Neurodegenerative Diseases.

Despite recent FDA approval of anti-amyloid antibodies for Alzheimer's Disease, strategies that target early molecular mechanisms and could delay or change the disease trajectory are still needed. Mitochondria emerge as a signaling organelle that could modulate multiple molecular mechanisms to enhance cellular bioenergetics and promote neuronal survival. Approaches to enhance mitochondrial function could promote healthy aging delaying the onset of age-related diseases such as Alzheimer's Disease.

Partial Inhibition of Complex I Restores Mitochondrial Morphology and Mitochondria-ER Communication in Hippocampus of APP/PS1 Mice.

Alzheimer's disease (AD) has no cure. Earlier, we showed that partial inhibition of mitochondrial complex I (MCI) with the small molecule CP2 induces an adaptive stress response, activating multiple neuroprotective mechanisms. Chronic treatment reduced inflammation, Aβ and pTau accumulation, improved synaptic and mitochondrial functions, and blocked neurodegeneration in symptomatic APP/PS1 mice, a translational model of AD.

A Comprehensive Approach to Sample Preparation for Electron Microscopy and the Assessment of Mitochondrial Morphology in Tissue and Cultured Cells.

Mitochondria respond to metabolic demands of the cell and to incremental damage, in part, through dynamic structural changes that include fission (fragmentation), fusion (merging of distinct mitochondria), autophagic degradation (mitophagy), and biogenic interactions with the endoplasmic reticulum (ER). High resolution study of mitochondrial structural and functional relationships requires rapid preservation of specimens to reduce technical artifacts coupled with quantitative assessment of mitochondrial architecture. A practical approach for assessing mitochondrial fine structure using two dimensional and three dimensional high-resolution electron microscopy is presented, and a systematic approach to measure mitochondrial architecture, including volume, length, hyperbranching, cristae morphology, and the number and extent of interaction with the ER is described.

The evolution of operative access in lung surgery.

In modern surgical practice, considerable attention is paid to reducing surgical trauma and reducing the incidence of postoperative complications, which has a direct impact on the duration of hospitalization and patient recovery. In chest surgery, this problem is most significant, since to perform small interventions on the lungs and pleura, a wide thoracotomy was required with the transection of the chest muscles and the separation of the ribs. The article describes modern minimally invasive approaches used in lung surgery.

A genome-wide association study in human lymphoblastoid cells supports safety of mitochondrial complex I inhibitor.

Novel therapeutic strategies for Alzheimer's disease (AD) are of the greatest priority given the consistent failure of recent clinical trials focused on Aβ or pTau. Earlier, we demonstrated that mild mitochondrial complex I inhibitor CP2 blocks neurodegeneration and cognitive decline in multiple mouse models of AD. To evaluate the safety of CP2 in humans, we performed a genome-wide association study (GWAS) using 196 lymphoblastoid cell lines and identified 11 SNP loci and 64 mRNA expression probe sets that potentially associate with CP2 susceptibility.

Partial inhibition of mitochondrial complex I ameliorates Alzheimer's disease pathology and cognition in APP/PS1 female mice.

Alzheimer's Disease (AD) is a devastating neurodegenerative disorder without a cure. Here we show that mitochondrial respiratory chain complex I is an important small molecule druggable target in AD. Partial inhibition of complex I triggers the AMP-activated protein kinase-dependent signaling network leading to neuroprotection in symptomatic APP/PS1 female mice, a translational model of AD.

On-target temporal characterization of optical pulses at relativistic intensity.

High-field experiments are very sensitive to the exact value of the peak intensity of an optical pulse due to the nonlinearity of the underlying processes. Therefore, precise knowledge of the pulse intensity, which is mainly limited by the accuracy of the temporal characterization, is a key prerequisite for the correct interpretation of experimental data. While the detection of energy and spatial profile is well established, the unambiguous temporal characterization of intense optical pulses, another important parameter required for intensity evaluation, remains a challenge, especially at relativistic intensities and a few-cycle pulse duration.

[Preventive abdominal wall repair in high-risk groups of postoperative ventral hernia].

Aim: To identify the most important predictors of postoperative hernia and to determine the indications for preventive surgical repair of abdominal wall.

Material And Methods: Prospective analysis included 398 medical records of patients who underwent median laparotomy. Experimental tensiometry was applied to determine strength of intact fascia.

Differential effect of amyloid beta peptides on mitochondrial axonal trafficking depends on their state of aggregation and binding to the plasma membrane.

Inhibition of mitochondrial axonal trafficking by amyloid beta (Aβ) peptides has been implicated in early pathophysiology of Alzheimer's Disease (AD). Yet, it remains unclear whether the loss of motility inevitably induces the loss of mitochondrial function, and whether restoration of axonal trafficking represents a valid therapeutic target. Moreover, while some investigations identify Aβ oligomers as the culprit of trafficking inhibition, others propose that fibrils play the detrimental role.

[Treatment of rectal foreign bodies].

Aim: to present the results of treatment of rectal foreign bodies.

Material And Methods: 15-year outcomes of 112 patients with rectal foreign bodies were analyzed.

Results: Outpatient and hospital care were applied in 52 (46%) and 60 (54%) of cases respectively.

Interleukins 6 and 8 and abdominal fat depots are distinct correlates of lipid moieties in healthy pre- and postmenopausal women.

Unlabelled: Available data associate lipids concentrations in men with body mass index, anabolic steroids, age, and certain cytokines. Data were less clear in women, especially across the full adult lifespan, and when segmented by premenopausal and postmenopausal status.

Subjects: 120 healthy women (60 premenopausal and 60 postmenopausal) in Olmsted County, MN, USA, a stable well studied clinical population.

Attosecond nanoscale near-field sampling.

The promise of ultrafast light-field-driven electronic nanocircuits has stimulated the development of the new research field of attosecond nanophysics. An essential prerequisite for advancing this new area is the ability to characterize optical near fields from light interaction with nanostructures, with sub-cycle resolution. Here we experimentally demonstrate attosecond near-field retrieval for a tapered gold nanowire.

Carrier-envelope phase dependence of the directional fragmentation and hydrogen migration in toluene in few-cycle laser fields.

The dissociative ionization of toluene initiated by a few-cycle laser pulse as a function of the carrier envelope phase (CEP) is investigated using single-shot velocity map imaging. Several ionic fragments, CH3 (+), H2 (+), and H3 (+), originating from multiply charged toluene ions present a CEP-dependent directional emission. The formation of H2 (+) and H3 (+) involves breaking C-H bonds and forming new bonds between the hydrogen atoms within the transient structure of the multiply charged precursor.

Generation of multi-octave spanning high-energy pulses by cascaded nonlinear processes in BBO.

We present the generation of optical pulses with a spectral range of 500-2400 nm and energies up to 10 µJ at 1 kHz repetition rate by cascaded second-order nonlinear interaction of few-cycle pulses in beta-barium borate (BBO). Numerical simulations with a 1D+time split-step model are performed to explain the experimental findings. The large bandwidth and smooth spectral amplitude of the resulting pulses make them an ideal seed for ultra-broadband optical parametric chirped pulse amplification and an attractive source for spectroscopic applications.

Altered brain energetics induces mitochondrial fission arrest in Alzheimer's Disease.

Altered brain metabolism is associated with progression of Alzheimer's Disease (AD). Mitochondria respond to bioenergetic changes by continuous fission and fusion. To account for three dimensional architecture of the brain tissue and organelles, we applied 3-dimensional electron microscopy (3D EM) reconstruction to visualize mitochondrial structure in the brain tissue from patients and mouse models of AD.

Field propagation-induced directionality of carrier-envelope phase-controlled photoemission from nanospheres.

Near-fields of non-resonantly laser-excited nanostructures enable strong localization of ultrashort light fields and have opened novel routes to fundamentally modify and control electronic strong-field processes. Harnessing spatiotemporally tunable near-fields for the steering of sub-cycle electron dynamics may enable ultrafast optoelectronic devices and unprecedented control in the generation of attosecond electron and photon pulses. Here we utilize unsupported sub-wavelength dielectric nanospheres to generate near-fields with adjustable structure and study the resulting strong-field dynamics via photoelectron imaging.

Modulation of mitochondrial complex I activity averts cognitive decline in multiple animal models of familial Alzheimer's Disease.

Development of therapeutic strategies to prevent Alzheimer's Disease (AD) is of great importance. We show that mild inhibition of mitochondrial complex I with small molecule CP2 reduces levels of amyloid beta and phospho-Tau and averts cognitive decline in three animal models of familial AD. Low-mass molecular dynamics simulations and biochemical studies confirmed that CP2 competes with flavin mononucleotide for binding to the redox center of complex I leading to elevated AMP/ATP ratio and activation of AMP-activated protein kinase in neurons and mouse brain without inducing oxidative damage or inflammation.

Coherent electronic wave packet motion in C(60) controlled by the waveform and polarization of few-cycle laser fields.

Strong laser fields can be used to trigger an ultrafast molecular response that involves electronic excitation and ionization dynamics. Here, we report on the experimental control of the spatial localization of the electronic excitation in the C_{60} fullerene exerted by an intense few-cycle (4 fs) pulse at 720 nm. The control is achieved by tailoring the carrier-envelope phase and the polarization of the laser pulse.