Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease characterized by progressive loss of motor neurons. Improving neuronal survival in ALS remains a significant challenge. Previously, we identified Lanthionine synthetase C-like protein 1 (LanCL1) as a neuronal antioxidant defense gene, the genetic deletion of which causes apoptotic neurodegeneration in the brain. Here, we report in vivo data using the transgenic SOD1G93A mouse model of ALS indicating that CNS-specific expression of LanCL1 transgene extends lifespan, delays disease onset, decelerates symptomatic progression, and improves motor performance of SOD1G93A mice. Conversely, CNS-specific deletion of LanCL1 leads to neurodegenerative phenotypes, including motor neuron loss, neuroinflammation, and oxidative damage. Analysis reveals that LanCL1 is a positive regulator of AKT activity, and LanCL1 overexpression restores the impaired AKT activity in ALS model mice. These findings indicate that LanCL1 regulates neuronal survival through an alternative mechanism, and suggest a new therapeutic target in ALS.

Despite the great progress on the cell biology of programmed cell death (PCD), its incidence and exact time course during embryonic and particular heart development are still unclear. This is also due to the lack of models enabling to directly identify and monitor PCD cells at different time points in vivo. Herein we report generation of transgenic murine embryonic stem cell and mouse models expressing secreted Annexin V-YFP under control of the CAG promoter. This enables to visualize and quantify PCD in vitro and in vivo during embryonic development. At early embryonic stages we found Annexin V-YFP+ fluorescent cells in known areas of PCD, such as the otic ring and at the site of neural tube closing, underscoring its specificity for detection of PCD. We have focused our detailed analysis primarily on PCD in the embryonic heart for a better understanding of its role during development. Our findings reveal that PCD peaks at early stages of cardiogenesis (E9.5-E13.5) and strongly decreases thereafter. Moreover, the PCD cells in the heart are predominantly cardiomyocytes, and an unexpected area of prominent cardiac PCD are the ventricular trabeculae (E9.5-E14.5). Thus, the sA5-YFP mouse line provides novel insight into the incidence and relevance of cardiac PCD during embryonic development ex- and in vivo.

When making decisions we often face the need to adjudicate between conflicting strategies or courses of action. Our ability to understand the neuronal processes underlying conflict processing is limited on the one hand by the spatiotemporal resolution of functional MRI and, on the other hand, by imperfect cross-species homologies in animal model systems. Here we examine the responses of single neurons and local field potentials in human neurosurgical patients in two prefrontal regions critical to controlled decision-making, the dorsal anterior cingulate cortex (dACC) and dorsolateral prefrontal cortex (dlPFC). While we observe typical modest conflict-related firing rate effects, we find a widespread effect of conflict on spike-phase coupling in the dACC and on driving spike-field coherence in the dlPFC. These results support the hypothesis that a cross-areal rhythmic neuronal coordination is intrinsic to cognitive control in response to conflict, and provide new evidence to support the hypothesis that conflict processing involves modulation of the dlPFC by the dACC.

No abstract available

It was recently reported that a magnetic actuator, Magneto, can control neuronal firings at magnetic strength as low as 50 mT (ref. 1), offering an exciting non-invasive approach to manipulating neuronal activity in a variety of research and clinical applications. We investigated whether Magneto can be used to manipulate electric properties of Purkinje cells in the cerebellum, which play critical roles in motor learning and emotional behaviors2. Surprisingly, we found that the application of a magnetic field did not change any electrical properties of Purkinje cells expressing Magneto, raising serious doubt about the previous claim that Magneto can readily be used as a magnetic actuator1.

Nipah virus (NiV) and Hendra virus (HeV) are zoonotic henipaviruses (HNVs) responsible for outbreaks of encephalitis and respiratory illness with fatality rates of 50-100%. No vaccines or licensed therapeutics currently exist to protect humans against NiV or HeV. HNVs enter host cells by fusing the viral and cellular membranes via the concerted action of the attachment (G) and fusion (F) glycoproteins, the main targets of the humoral immune response. Here, we describe the isolation and humanization of a potent monoclonal antibody cross-neutralizing NiV and HeV. Cryo-electron microscopy, triggering and fusion studies show the antibody binds to a prefusion-specific quaternary epitope, conserved in NiV F and HeV F glycoproteins, and prevents membrane fusion and viral entry. This work supports the importance of the HNV prefusion F conformation for eliciting a robust immune response and paves the way for using this antibody for prophylaxis and post-exposure therapy with NiV- and HeV-infected individuals.

Olfaction is critical for survival in neonatal mammals. However, little is known about the neural substrate for this ability as few studies of synaptic development in several olfactory processing regions have been reported. Odor information detected in the nasal cavity is first processed by the olfactory bulb and then sent via the lateral olfactory tract to a series of olfactory cortical areas. The first of these, the anterior olfactory nucleus pars principalis (AONpP), is a simple, two layered cortex with an outer plexiform and inner cell zone (Layers 1 and 2, respectively). Five sets of studies examined age-related changes in the AONpP. First, immunocytochemistry for glutamatergic (VGlut1 and VGlut2) and GABAergic (VGAT) synapses demonstrated that overall synaptic patterns remained uniform with age. The second set quantified synaptic development with electron microscopy and found different developmental patterns between Layers 1 and 2. As many of the interhemispheric connections in the olfactory system arise from AONpP, the third set examined the development of crossed projections using anterograde tracers and electron microscopy to explore the maturation of this pathway. A fourth study examined ontogenetic changes in immunostaining for the proteoglycans aggrecan and brevican, markers of mesh-like extracellular structures known as perineuronal nets whose maturation is associated with the end of early critical periods of synaptogenesis. A final study found no age-related changes in the density of vasculature in the peduncle from P5 to P30. This work is among the first to examine early postnatal changes in this initial cortical region of the olfactory system.

The BTB domain of B-cell lymphoma 6 (BCL6) protein was identified as a therapeutic target for B-cell lymphoma. This study compared the pharmacokinetics (PK) of the BCL6 BTB inhibitor (FX1) between mice and macaques, as well as evaluating its lymphoid suppressive effect in uninfected macaques with lymphoid hyperplasia.

Pediatric refractory solid tumors are aggressive malignant diseases, resulting in an extremely poor prognosis. KOC1, FOXM1, and KIF20A are cancer antigens that could be ideal targets for anticancer immunotherapy against pediatric refractory solid tumors with positive expression for these antigens. This nonrandomized, open-label, phase I clinical trial evaluated the safety and efficacy of the NCCV Cocktail-1 vaccine, which is a cocktail of cancer peptides derived from KOC1, FOXM1, and KIF20A, in patients with pediatric refractory solid tumors. Twelve patients with refractory pediatric solid tumors underwent NCCV Cocktail-1 vaccination weekly by intradermal injections. The primary endpoint was the safety of the NCCV Cocktail-1 vaccination, and the secondary endpoints were the immune response, as measured by interferon-r enzyme-linked immunospot assay, and the clinical outcomes including tumor response and progression-free survival. The NCCV Cocktail-1 vaccine was well tolerated. The clinical response of this trial showed that 4 patients had stable disease after 8 weeks and 2 patients maintained remission for >11 months. In 4, 8, and 5 patients, the NCCV Cocktail-1 vaccine induced the sufficient number of peptide-specific CTLs for KOC1, FOXM1, and KIF20A, respectively. Patients with high peptide-specific CTL frequencies for KOC1, FOXM1, and KIF20A had better progression-free survival than those with low frequencies. The findings of this clinical trial showed that the NCCV Cocktail-1 vaccine could be a novel therapeutic strategy, with adequate effects against pediatric refractory solid tumors. Future large-scale trials should evaluate the efficacy of the NCCV Cocktail-1 vaccination.

We aimed to compare frailty status between patients with head and neck cancer (HNC) and other solid malignancies.

The hippocampus is linked to the formation and retrieval of episodic memories and spatial navigation. In rats, it is an elongated structure divided into dorsal (septal) and ventral (temporal) regions paralleling the respective division in the posterior and anterior hippocampus in humans. The dorsal hippocampus has been suggested to be more important for spatial processing and the ventral to processing anxiety-based behaviors. Far less is known regarding the degree to which these different regions interact during information processing. The anatomical connectivity suggests a flow of information between the dorsal and ventral regions; conversely, there are also commissural connections to the contralateral hippocampus. The current study examined the extent to which information from the dorsal hippocampus interacts with processing in the ipsilateral and contralateral ventral hippocampus following the acquisition of a spatial task.

Taxane-based chemotherapy is widely used in lung cancer. ABCB1 have a role in the prediction of treatment response and toxicity of chemotherapy in solid tumors. In this retrospective study, we investigated ABCB1 polymorphism on response and toxicity in taxane-based chemotherapy in lung cancer patients.

Hirschmanniella mucronata is a plant-parasitic nematode that is widespread in rice production areas and causes 10-25% yield losses a year on average. Here, we investigated the mechanism of resistance to this nematode by comparing the transcriptomes of roots from resistant (Jiabali) and susceptible (Bawangbian) varieties of rice. Of 39 233 unigenes, 2243. exhibited altered total expression levels between control and infected resistant and susceptible varieties. Significant differences were observed in the expression levels of genes related to stress, peptidase regulation or inhibition, oxidoreductase activity, peroxidase activity and antioxidant activity. The up-regulated genes related to plant secondary metabolites, such as phenylpropanoid, lignin, cellulose or hemicellulose, may result in an increase in the degree of resistance of Jiabali to the H. mucronata infection compared with that of Bawangbian by affecting cell wall organization or biogenesis. Of the genes that responded similarly to H. mucronata infection, ~252 (~76.59%) showed greater changes (whether induced or suppressed) in RN155 (susceptible varieties infected by rice root nematode) than in RN51 (resistance varieties infected by rice root nematode). Nineteen pathogenesis-related genes belonging to nine pathogenesis-related gene families were significantly induced by H. mucronata in the infected roots of Jiabali and Bawangbian, and 13 differentially expressed genes showed changes in their abundance only in the susceptible Bawangbian variety. This study may help enhance our understanding of the mechanisms underlying plant resistance to nematodes.

Rapid detection of drug resistance in Mycobacterium tuberculosis (MTB) is essential for the efficient control of tuberculosis. Hence, in this study a nested-allele-specific (NAS) PCR, nested multiple allele-specific PCR (NMAS-PCR) and multiple allele-specific (MAS) PCR assays were evaluated that enabled detection of the most common mutations responsible for isoniazid (INH) and rifampicin (RIF) resistance in MTB isolates directly from clinical specimens.

To critically assess the neurological recovery and antioxidant effects of resveratrol in rat models of spinal cord injury.

Studies have shown that docosahexaenoic acid (DHA) has a beneficial effect in the treatment of spinal cord injury. A meta-analysis was used to study the effect of DHA on the neurological recovery in the rat spinal cord injury model, and the relationship between the recovery of motor function after spinal cord injury and the time and method of administration and the dose of DHA.

Ubenimex, an aminopeptidase N (APN) inhibitor, is widely known for its use as an adjunct therapy for cancer therapy. However, in recent studies, it has also conferred antitumour effects in many cancers, but its anticancer mechanism is largely unknown. This study aims to investigate the specific anticancer activities and mechanisms of ubenimex in GH3 and MMQ cells.

Nonadherence to indicated therapy reduces treatment effectiveness and may increase cost of care. HUMIRA Complete, a Patient Support Program (PSP), aims to reduce nonadherence in patients prescribed adalimumab (ADA). The objective of this study was to assess the relationship between participation in the PSP and prescription abandonment rates among ADA-treated patients.

Glioblastoma mutliforme is the most common and has the poorest prognosis of any malignant tumor of the central nervous system. Luteolin, the most abundant xanthone extracted from vegetables and medicinal plants, has been shown to have treatment effects in various cancer cell types. Luteolin is however, hydrophobic and has poor biocompatibility, which leads to low bioavailability.

Videolaryngoscopy in nasotracheal intubation has been reported to be better than direct laryngoscopy. The most suitable type of videolaryngoscope remains unknown. This study aimed to compare two videolaryngoscopes (McGrath MAC and Pentax AWS) with a Macintosh laryngoscope during nasotracheal intubation.