Do fossorial water voles have a functional vomeronasal organ? A histological and immunohistochemical study.

The fossorial water vole, Arvicola scherman, is an herbivorous rodent that causes significant agricultural damages. The application of cairomones and alarm pheromones emerges as a promising sustainable method to improve its integrated management. These chemical signals would induce stress responses that could interfere with the species regular reproductive cycles and induce aversive reactions, steering them away from farmlands and meadows. However, there is a paucity of information regarding the water vole vomeronasal system, both in its morphological foundations and its functionality, making it imperative to understand the same for the application of chemical communication in pest control. This study fills the existing gaps in knowledge through a morphological and immunohistochemical analysis of the fossorial water vole vomeronasal organ. The study is primarily microscopic, employing two approaches: histological, using serial sections stained with various dyes (hematoxylin-eosin, Periodic acid-Schiff, Alcian blue, Nissl), and immunohistochemical, applying various markers that provide morphofunctional and structural information. These procedures have confirmed the presence of a functional vomeronasal system in fossorial water voles, characterized by a high degree of differentiation and a significant expression of cellular markers indicative of active chemical communication in this species.

Highly Concentrated Emulsions Containing High Loads of Pterostilbene.

Pterostilbene is a highly researched molecule due to its bioactivity. However, its hydrophobicity limits its application. For this reason, researchers have sought to encapsulate pterostilbene (namely, in oil-in-water emulsion) to increase its availability. Studies are lacking when it comes to the effects of pterostilbene and its concentration at the oil/water interface. This paper discusses the effects of oil types, storage temperature, and pterostilbene concentration on the stability of the emulsions, as well as the interactions between encapsulated pterostilbene and the oil and water phases. Results showed that pterostilbene is present at the oil/water interface, affecting the interfacial tension and consequently the droplet size. It was also shown that encapsulation efficiency is affected by the storage temperature and oil type. Finally, it was proven that, according to oil types and storage temperature, the stability of pterostilbene to light is affected.

Periaqueductal gray matter echogenicity as a marker of migraine chronification: a case control study.

BACKGROUND: Migraine is one of the most prevalent and disabling medical diseases in the world. The periaqueductal gray matter and the red nucleus play an important role in its pathogenesis. Our aim was to evaluate the echogenicity of the periaqueductal gray matter and the red nucleus in patients with migraine, by means of transcranial ultrasound. METHODS: In this cross-sectional study, a group of patients with migraine (according to the International Classification of Headache Disorders) and a group of control subjects with comparable age-and-sex distribution were prospectively included. We evaluated the area and echogenicity of the periaqueductal gray matter and the red nucleus by means of transcranial ultrasound, both bedside and posteriorly analyzed with the medical image viewer Horos. RESULTS: We included 115 subjects: 65 patients with migraine (39 of them with chronic migraine and 26 with episodic migraine), and 50 controls. Median disease duration in patients with chronic migraine was 29 (IQR: 19; 40) years, with a median of 18 (IQR: 14; 27) days of migraine per month. The area of the periaqueductal gray matter was larger in patients with chronic migraine compared to episodic migraine and controls (0.15[95%CI 0.12;0.22]cm2; 0.11[95%CI 0.10;0.14]cm2 and 0.12[95%CI 0.09;0.15]cm2, respectively; p = 0.043). Chronic migraine patients showed an intensity of the periaqueductal gray matter echogenicity lower than controls (90.57[95%CI 70.87;117.26] vs 109.56[95%CI 83.30;122.64]; p = 0.035). The coefficient of variation of periaqueductal gray matter echogenicity was the highest in chronic migraine patients (p = 0.009). No differences were observed regarding the area or intensity of red nucleus echogenicity among groups. CONCLUSION: Patients with chronic migraine showed a larger area of echogenicity of periaqueductal gray matter, a lower intensity of its echogenicity and a higher heterogenicity within this brainstem structure compared to patients with episodic migraine and controls. The echogenicity of the periaqueductal gray matter should be further investigated as a biomarker of migraine chronification.

Fish By-Product Valorization as Source of Bioactive Compounds for Food Enrichment: Characterization, Suitability and Shelf Life.

Fish processing generates many by-products, which are mainly destined for aquaculture feed. However, these by-products have interesting nutritional properties and could still be used for human consumption, thus promoting circular economy. Therefore, this study focused on evaluating the shelf life of mechanically deboned and dried meat (MDDM) of sea bass based on the lipid oxidation criterion (TBARS). The effect of a tocopherol-based antioxidant was also evaluated, and changes in the fatty acid profile were studied. For that, samples with and without antioxidant were stored at three temperatures (37, 55, and 65 °C) for 50 days. This allowed its modelling according to the Arrhenius model. The results showed a shelf life for MDDM of 220 days at 20 °C without the addition of antioxidant. When antioxidant was added, a high protective effect against oxidation and preservation of unsaturated fatty acids was perceived, avoiding nutritional losses and negative sensory effects, reducing EPA and DHA losses by 75% and 72%, respectively. In conclusion, the stability of MDDM from sea bass was demonstrated, making possible its incorporation into other food matrices.

Monocyte-to-Lymphocyte Ratio in Clot Analysis as a Marker of Cardioembolic Stroke Etiology.

The aim of the study was to find markers of high-risk cardioembolic etiology (HRCE) in patients with cryptogenic strokes (CS) through the analysis of intracranial clot by flow cytometry (FC). A prospective single-center study was designed including patients with large vessel occlusion strokes. The percentage of granulocytes, monocytes, lymphocytes, and monocyte-to-lymphocyte ratio (MLr) were analyzed in clots extracted after endovascular treatment (EVT) and in peripheral blood. Large arterial atherosclerosis (LAA) strokes and high-risk cardioembolic (HRCE) strokes were matched by demographics and acute reperfusion treatment data to obtain FC predictors for HRCE. Multilevel decision tree with boosting random forest classifiers was performed with each feature importance for HRCE diagnosis among CS. We tested the validity of the best FC predictor in a cohort of CS that underwent extensive diagnostic workup. Among 211 patients, 178 cases underwent per-protocol workup. The percentage of monocytes (OR 1.06, 95% CI 1.01-1.11) and MLr (OR 1.83, 95% CI 1.12-2.98) independently predicted HRCE diagnosis when LAA clots (n = 28) were matched with HRCE clots (n = 28). Among CS (n = 82), MLr was the feature with the highest weighted importance in the multilevel decision tree as a predictor for HRCE. MLr cutoff point of 1.59 yield sensitivity of 91.23%, specificity of 44%, positive predictive value of 78.79%, and negative predictive value of 68.75 for HRCE diagnosis among CS. MLr ≥ 1.6 in clot analysis predicted HRCE diagnosis (OR, 6.63, 95% CI 1.85-23.71) in a multivariate model adjusted for age. Clot analysis by FC revealed high levels of monocyte-to-lymphocyte ratio as an independent marker of cardioembolic etiology in cryptogenic strokes.

Predictors of Functional Outcome After Thrombectomy in Patients With Prestroke Disability in Clinical Practice.

BACKGROUND AND PURPOSE: Mechanical thrombectomy (MT) in ischemic stroke patients with poor prestroke conditions remains controversial. We aimed to analyze the frequency of previously disabled patients treated with MT in clinical practice, the safety and clinical response to MT of patients with preexisting disability, and the disabled patient characteristics associated with a better response to MT. METHODS: We studied all consecutive patients with anterior circulation occlusion treated with MT from January 2017 to December 2019 included in the Codi Ictus Catalunya registry-a government-mandated, prospective, hospital-based data set. Prestroke disability was defined as modified Rankin Scale score 2 or 3. Functional outcome at 90 days was centrally assessed by a blinded evaluator of the Catalan Stroke Program. Favorable outcome (to return at least to prestroke modified Rankin Scale at 90 days) and safety and secondary outcomes were compared with patients without previous disability. Logistic regression analysis was used to assess the association between prestroke disability and outcomes and to identify a disabled patient profile with favorable outcome after MT. RESULTS: Of 2487 patients included in the study, 409 (17.1%) had prestroke disability (313 modified Rankin Scale score 2 and 96 modified Rankin Scale score 3). After adjustment for covariates, prestroke disability was not associated with a lower chance of achieving favorable outcome at 90 days (24% versus 30%; odds ratio, 0.79 [0.57-1.08]), whereas it was independently associated with a higher risk of symptomatic intracranial hemorrhage (5% versus 3%; odds ratio, 2.04 [1.11-3.72]) and long-term mortality (31% versus 18%; odds ratio, 1.74 [1.27-2.39]) compared with patients without disability. Prestroke disabled patients without diabetes, Alberta Stroke Program Early CT Score >8 and National Institutes of Health Stroke Scale score <17 showed similar safety and outcome results after MT as patients without prestroke disability. CONCLUSIONS: Despite a higher mortality and risk of symptomatic intracranial hemorrhage, prestroke-disabled patients return as often as independent patients to their prestroke level of function, especially those nondiabetic patients with favorable early ischemic signs profile. These data support a potential benefit of MT in patients with previous mild or moderate disability after large anterior vessel occlusion stroke.

Strain Improvement Program of Streptomyces roseosporus for Daptomycin Production.

Daptomycin is a cyclic lipopeptide antibiotic with potent activity against gram-positive bacteria. It has a calcium-dependent mechanism of action that disrupts multiple features of the bacterial membrane function. This antibiotic is highly demanded due to its effectiveness against to microorganisms resistant to other antibiotics, including vancomycin-resistant Staphylococcus aureus (VRSA) and methicillin-resistant S. aureus (MRSA). Daptomycin is produced by fermentation of Streptomyces roseosporus, currently identified as Streptomyces filamentosus. However, low fermentation yields and high production costs are reported. This chapter describes a method of strain improvement involving random mutagenesis, rational screening by bioassay, and flask fermentation. The ultimate objective is to select mutants of S. roseosporus overproducing daptomycin in order to design a more cost-effective daptomycin production.

Melatonin Induces Melanogenesis in Human SK-MEL-1 Melanoma Cells Involving Glycogen Synthase Kinase-3 and Reactive Oxygen Species.

Melatonin is present in all living organisms where it displays a diversity of physiological functions. Attenuation of melanogenesis by melatonin has been reported in some mammals and also in rodent melanoma cells. However, melatonin may also stimulate melanogenesis in human melanoma cells through mechanisms that have not yet been revealed. Using the human melanoma cells SK-MEL-1 as a model, an increase in both tyrosinase activity and melanin was already observed at 24 h after melatonin treatment with maximal levels of both being detected at 72 h. This effect was associated with the induction in the expression of the enzymes involved in the synthesis of melanin. In this scenario, glycogen synthase kinase-3ß seems to play a significant function since melatonin decreased its phosphorylation and preincubation with specific inhibitors of this protein kinase (lithium or BIO) reduced the expression and activity of tyrosinase. Blocking of PI3K/AKT pathway stimulated melanogenesis and the effect was suppressed by the inhibitors of glycogen synthase kinase-3ß. Although melatonin is a recognized antioxidant, we found that it stimulates reactive oxygen species generation in SK-MEL-1 cells. These chemical species seem to be an important signal in activating the melanogenic process since the antioxidants N-acetyl-l-cysteine and glutathione decreased both the level and activity of tyrosinase stimulated by melatonin. Our results support the view that regulation of melanogenesis involves a cross-talk between several signaling pathways.

Cytotoxicity of the Sesquiterpene Lactone Spiciformin and Its Acetyl Derivative against the Human Leukemia Cell Lines U-937 and HL-60.

Spiciformin (1) is a sesquiterpene lactone with a germacrane skeleton that is found in two Tanacetum species endemic to the Canary Islands. In this study, the cytotoxicities of 1 and its acetyl derivative (2) were evaluated against human tumor cells. These sesquiterpene lactones were cytotoxic against human acute myeloid leukemia (U-937 and HL-60) cells, even in cells over-expressing the pro-survival protein Bcl-2, but melanoma (SK-MEL-1) and human mononuclear cells isolated from blood of healthy donors were more resistant. Both compounds are apoptotic inducers in human leukemia U-937 cells. Cell death was mediated by the processing and activation of initiator and effector caspases and the cleavage of poly(ADP-ribose) polymerase, and it was blocked by a broad-spectrum caspase inhibitor and (in the case of sesquiterpene lactone 2) by the selective caspase-3/7, -8, and -9 inhibitors. In addition, certainly in the case of compound 2, this was found to be associated with a decrease in mitochondrial membrane potential, downregulation of the anti-apoptotic protein Bcl-2, activation of the mitogen-activated protein kinases signaling pathway, and generation of reactive oxygen species. It will, therefore, be relevant to continue characterization of this class of compounds.

Helios modulates the maturation of a CA1 neuronal subpopulation required for spatial memory formation.

Currently, molecular, electrophysiological and structural studies delineate several neural subtypes in the hippocampus. However, the precise developmental mechanisms that lead to this diversity are still unknown. Here we show that alterations in a concrete hippocampal neuronal subpopulation during development specifically affect hippocampal-dependent spatial memory. We observed that the genetic deletion of the transcription factor Helios in mice, which is specifically expressed in developing hippocampal calbindin-positive CA1 pyramidal neurons (CB-CA1-PNs), induces adult alterations affecting spatial memory. In the same mice, CA3-CA1 synaptic plasticity and spine density and morphology in adult CB-CA1-PNs were severely compromised. RNAseq experiments in developing hippocampus identified an aberrant increase on the Visinin-like protein 1 (VSNL1) expression in the hippocampi devoid of Helios. This aberrant increase on VSNL1 levels was localized in the CB-CA1-PNs. Normalization of VSNL1 levels in CB-CA1-PNs devoid of Helios rescued their spine loss in vitro. Our study identifies a novel and specific developmental molecular pathway involved in the maturation and function of a CA1 pyramidal neuronal subtype.

A civilian tactical survival chain for incidents involving multiple intentionalinjury victims: the Victory I Consensus Report. / Consenso Victoria I: la cadena de supervivencia táctica civil ante incidentes de múltiples víctimas intencionados.

EN: International guidelines recommend adapting military health care protocols to emergencies involving multiple intentional-injury victims in civilian environments. Adaptations can reflect similarities in types of injuries or issues of provider safety and that arise in military and some civilian emergencies. Because more experience with such incidents has been gained in the United States, most of the literature on this topic discusses emergency medical systems that differ from the ones operating in the autonomous communities of Spain, where varying resources and procedures are mandated by local authorities charged with preparing for emergencies. However, common elements are present, offering a framework and principles to apply when drafting evidence-based plans for effective, efficient response to multiple-victim emergencies. We think that participants at each point in the chain of survival must have clear missions and understand the roles they play in the various zones that comprise the scene of an emergency. Therefore this consensus paper attempts to define the relevant principles and roles for participants at all levels, from occasional first responders up to staff at trauma referral centers.

ES: Son múltiples las recomendaciones internacionales que aconsejan adaptar modelos asistenciales del entorno militar a incidentes de múltiples víctimas intencionados (IMVI) ocurridos en el entorno civil, bien por el tipo de patrón lesional, bien por aspectos de seguridad y autoprotección. Debido a la experiencia en Norteamérica, donde este tipo de situaciones son más frecuentes, casi toda la bibliografía y referencias existentes no se corresponden con un modelo de sistemas de emergencias médicas como el que existe en las distintas comunidades autónomas españolas, con sus diferentes medios y procedimientos tal y como viene estipulado por sus competencias exclusivas en esta materia. No obstante, se han detectado una serie de elementos comunes que pueden servir de referencia para elaborar un plan de respuesta a los IMVI, basados en la evidencia y utilizando principios de actuación dirigidos a una acción eficaz y eficiente. Pensamos que cada actor de los eslabones de esta cadena asistencial debe tener clara su misión, su rol y su función en las diferentes zonas de la escena, y así se intentan definir en este documento de consenso, desde un primer interviniente ocasional hasta la asistencia definitiva en los centros de referencia para pacientes traumatizados.

Consenso Victoria I: la cadena de supervivencia táctica civil ante incidentes de múltiples víctimas intencionados / A civilian tactical survival chain for incidents involving multiple intentionalinjury victims: the Victory I Consensus Report

Son múltiples las recomendaciones internacionales que aconsejan adaptar modelos asistenciales del entorno militar a incidentes de múltiples víctimas intencionados (IMVI) ocurridos en el entorno civil, bien por el tipo de patrón lesional, bien por aspectos de seguridad y autoprotección. Debido a la experiencia en Norteamérica, donde este tipo de situaciones son más frecuentes, casi toda la bibliografía y referencias existentes no se corresponden con un modelo de sistemas de emergencias médicas como el que existe en las distintas comunidades autónomas españolas, con sus diferentes medios y procedimientos tal y como viene estipulado por sus competencias exclusivas en esta materia. No obstante, se han detectado una serie de elementos comunes que pueden servir de referencia para elaborar un plan de respuesta a los IMVI, basados en la evidencia y utilizando principios de actuación dirigidos a una acción eficaz y eficiente. Pensamos que cada actor de los eslabones de esta cadena asistencial debe tener clara su misión, su rol y su función en las diferentes zonas de la escena, y así se intentan definir en este documento de consenso, desde un primer interviniente ocasional hasta la asistencia definitiva en los centros de referencia para pacientes traumatizados

International guidelines recommend adapting military health care protocols to emergencies involving multiple intentional-injury victims in civilian environments. Adaptations can reflect similarities in types of injuries or issues of provider safety and that arise in military and some civilian emergencies. Because more experience with such incidents has been gained in the United States, most of the literature on this topic discusses emergency medical systems that differ from the ones operating in the autonomous communities of Spain, where varying resources and procedures are mandated by local authorities charged with preparing for emergencies. However, common elements are present, offering a framework and principles to apply when drafting evidence-based plans for effective, efficient response to multiple-victim emergencies. We think that participants at each point in the chain of survival must have clear missions and understand the roles they play in the various zones that comprise the scene of an emergency. Therefore this consensus paper attempts to define the relevant principles and roles for participants at all levels, from occasional first responders up to staff at trauma referral centers

An Input-Specific Orphan Receptor GPR158-HSPG Interaction Organizes Hippocampal Mossy Fiber-CA3 Synapses.

Pyramidal neuron dendrites integrate synaptic input from multiple partners. Different inputs converging on the same dendrite have distinct structural and functional features, but the molecular mechanisms organizing input-specific properties are poorly understood. We identify the orphan receptor GPR158 as a binding partner for the heparan sulfate proteoglycan (HSPG) glypican 4 (GPC4). GPC4 is enriched on hippocampal granule cell axons (mossy fibers), whereas postsynaptic GPR158 is restricted to the proximal segment of CA3 apical dendrites receiving mossy fiber input. GPR158-induced presynaptic differentiation in contacting axons requires cell-surface GPC4 and the co-receptor LAR. Loss of GPR158 increases mossy fiber synapse density but disrupts bouton morphology, impairs ultrastructural organization of active zone and postsynaptic density, and reduces synaptic strength of this connection, while adjacent inputs on the same dendrite are unaffected. Our work identifies an input-specific HSPG-GPR158 interaction that selectively organizes synaptic architecture and function of developing mossy fiber-CA3 synapses in the hippocampus.

Lycopene Production by Mated Fermentation of Blakeslea trispora.

Lycopene is a carotenoid mainly present in red-colored fruits and vegetables. Its value in the pharmaceutical and food industry is linked to its benefits for the human health, including properties against cancer and cardiovascular diseases, and its use as a food colorant. Lycopene can be produced either by synthetic or natural means, but there is a preference for the second, since it is considered a more eco-friendly and less harmful process. Among natural methods for obtaining lycopene, microbial fermentation is a good alternative to extraction from plants that naturally contain lycopene, since it implies obtaining higher and more specific amounts of this carotenoid. This chapter describes lycopene production by fermentation of the fungus Blakeslea trispora, a naturally carotenoid producer, at 30 L scale. This procedure involves separated growth of the two sexual mating types of B. trispora during the vegetative stages and the use of a lycopene cyclase inhibitor to achieve lycopene accumulation during the production stage.

The GABAergic septohippocampal connection is impaired in a mouse model of tauopathy.

Alzheimer's disease (AD), the most common cause of dementia nowadays, has been linked to alterations in the septohippocampal pathway (SHP), among other circuits in the brain. In fact, the GABAergic component of the SHP, which controls hippocampal rhythmic activity crucial for learning and memory, is altered in the J20 mouse model of AD-a model that mimics the amyloid pathology of this disease. However, AD is characterized by another pathophysiological hallmark: the hyperphosphorylation and aggregation of the microtubule-associated protein Tau. To evaluate whether tauopathies alter the GABAergic SHP, we analyzed transgenic mice expressing human mutated Tau (mutations G272V, P301L, and R406W, VLW transgenic strain). We show that pyramidal neurons, mossy cells, and some parvalbumin (PARV)-positive hippocampal interneurons in 2- and 8-month-old (mo) VLW mice accumulate phosphorylated forms of Tau (P-Tau). By tract-tracing studies of the GABAergic SHP, we describe early-onset deterioration of GABAergic septohippocampal (SH) innervation on PARV-positive interneurons in 2-mo VLW mice. In 8-mo animals, this alteration was more severe and affected mainly P-Tau-accumulating PARV-positive interneurons. No major loss of GABAergic SHP neurons or PARV-positive hippocampal interneurons was observed, thereby indicating that this decline is not caused by neuronal loss but by the reduced number and complexity of GABAergic SHP axon terminals. The decrease in GABAergic SHP described in this study, targeted onto the PARV-positive/P-Tau-accumulating inhibitory neurons in the hippocampus, establishes a cellular correlation with the dysfunctions in rhythmic neuronal activity and excitation levels in the hippocampus. These dysfunctions are associated with the VLW transgenic strain in particular and with AD human pathology in general. These data, together with our previous results in the J20 mouse model, indicate that the GABAergic SHP is impaired in response to both amyloid-ß and P-Tau accumulation. We propose that alterations in the GABAergic SHP, together with a dysfunction of P-Tau-accumulating PARV-positive neurons, contribute to the cognitive deficits and altered patterns of hippocampal activity present in tauopathies, including AD.

The eudesmanolide tanapsin from Tanacetum oshanahanii and its acetate induce cell death in human tumor cells through a mechanism dependent on reactive oxygen species.

In this study the cytotoxicities of two species of Tanacetum were evaluated against human tumor cells. Tanacetum oshanahanii extract was more cytotoxic than Tanacetum ptarmiciflorum. Analyses of both extracts of Tanacetum by ultrahigh performance liquid chromatography-tandem mass spectrometry revealed that T. oshanahanii extract contains the eudesmanolide tanapsin, while T. ptarmiciflorum lacks this sesquiterpene lactone. Tanapsin was cytotoxic against leukemia and melanoma cells, including cells that overexpress Bcl-2 and Bcl-xL, with IC50 values of approximately 10 µM, but not against quiescent or proliferating human peripheral blood mononuclear cells. Treatment of cells with tanapsin induced apoptosis. This was prevented by the non-specific caspase inhibitor z-VAD-fmk, and reduced by the selective caspase-3/7 inhibitor z-DEVD-fmk. Tanapsin acetate was also cytotoxic against leukemia and melanoma cells and a potent apoptotic inducer. Tanapsin-induced cell death was found to be associated with (i) the loss of inner mitochondrial membrane potential (ΔΨm) and release of mitochondrial cytochrome c, (ii) the activation of multiple caspases and the mitogen-activated protein kinase pathway, and (iii) an increase in reactive oxygen species generation. Generation of reactive oxygen species in response to tanapsin seems to play a crucial role in the cell death process since the antioxidant N-acetyl-l-cysteine blocked both ROS generation and cell death.

Somatic signature of brain-specific single nucleotide variations in sporadic Alzheimer's disease.

BACKGROUND: Although genome-wide association studies have shown that genetic factors increase the risk of suffering late-onset, sporadic Alzheimer's disease (SAD), the molecular mechanisms responsible remain largely unknown. OBJECTIVE: The aim of the study was to investigate the presence of somatic, brain-specific single nucleotide variations (SNV) in the hippocampus of SAD samples. METHODS: By using bioinformatic tools, we compared whole exome sequences in paired blood and hippocampal genomic DNAs from 17 SAD patients and from 2 controls and 2 vascular dementia patients. RESULTS: We found a remarkable number of SNVs in SAD brains (~575 per patient) that were not detected in blood. Loci with hippocampus-specific (hs)-SNVs were common to several patients, with 38 genes being present in 6 or more patients out of the 17. While some of these SNVs were in genes previously related to SAD (e.g., CSMD1, LRP2), most hs-SNVs occurred in loci previously unrelated to SAD. The most frequent genes with hs-SNVs were associated with neurotransmission, DNA metabolism, neuronal transport, and muscular function. Interestingly, 19 recurrent hs-SNVs were common to 3 SAD patients. Repetitive loci or hs-SNVs were underrepresented in the hippocampus of control or vascular dementia donors, or in the cerebellum of SAD patients. CONCLUSION: Our data suggest that adult blood and brain have different DNA genomic variations, and that somatic genetic mosaicism and brain-specific genome reshaping may contribute to SAD pathogenesis and cognitive differences between individuals.

The GABAergic septohippocampal pathway is directly involved in internal processes related to operant reward learning.

We studied the role of γ-aminobutyric acid (GABA)ergic septohippocampal projections in medial septum (MS) self-stimulation of behaving mice. Self-stimulation was evoked in wild-type (WT) mice using instrumental conditioning procedures and in J20 mutant mice, a type of mouse with a significant deficit in GABAergic septohippocampal projections. J20 mice showed a significant modification in hippocampal activities, including a different response for input/output curves and the paired-pulse test, a larger long-term potentiation (LTP), and a delayed acquisition and lower performance in the MS self-stimulation task. LTP evoked at the CA3-CA1 synapse further decreased self-stimulation performance in J20, but not in WT, mice. MS self-stimulation evoked a decrease in the amplitude of field excitatory postsynaptic potentials (fEPSPs) at the CA3-CA1 synapse in WT, but not in J20, mice. This self-stimulation-dependent decrease in the amplitude of fEPSPs was also observed in the presence of another positive reinforcer (food collected during an operant task) and was canceled by the local administration of an antibody-inhibiting glutamate decarboxylase 65 (GAD65). LTP evoked in the GAD65Ab-treated group was also larger than in controls. The hippocampus has a different susceptibility to septal GABAergic inputs depending on ongoing cognitive processes, and the GABAergic septohippocampal pathway is involved in consummatory processes related to operant rewards.

Cell death triggered by synthetic flavonoids in human leukemia cells is amplified by the inhibition of extracellular signal-regulated kinase signaling.

A new class of methyl esters of flavonoids, with different substituents on the B ring were synthesized and evaluated for their antiproliferative activity against the human leukemia cell line HL-60. The presence of either a methyl group (1f) or a chlorine atom (1o) at position 2' of the B ring played an important role in affecting antiproliferative activity. The cytotoxic effects of these compounds were accompanied by the concentration- and time-dependent appearance of DNA- and nuclear-fragmentation, increase in the percentage of sub-G(1) cells, and processing of multiple caspases and poly(ADP-ribose)polymerase cleavage. Pretreatment of cells with the specific mitogen-activated extracellular kinases (MEK) 1/2 inhibitor PD98059, together with 1f and 1o, resulted in an important enhancement of cell death, which might have clinical implications for the use of both compounds in combination with MEK 1/2 inhibitors as potential therapeutic agents.

Accelerated aging of the GABAergic septohippocampal pathway and decreased hippocampal rhythms in a mouse model of Alzheimer's disease.

Patients with Alzheimer's disease (AD) display altered functioning of cortical networks, including altered patterns of synchronous activity and a serious deficit in cholinergic septohippocampal (SH) innervation. However, the mechanisms underlying these alterations and the implication of the GABAergic SH component in AD are largely unknown. In addition, the GABAergic septohippocampal pathway (SHP) is believed to regulate synchronous hippocampal activity by controlling the activity of interneurons. Here we show, using well-characterized pathway tracing experiments, that innervation of the GABAergic SHP decreases during normal aging. Furthermore, in an AD mouse model (hAPP(Sw,Ind); J20 mice), the GABAergic SHP shows a dramatic and early onset of this decrease in 8-mo-old mice. This decline is not caused by neuronal loss, but by the reduced number and complexity of GABAergic SH axon terminals. Finally, we demonstrate that hippocampal θ and γ rhythm power spectra are markedly diminished in 8-mo-old behaving mice expressing mutated hAPP. In addition to the well-known loss of cholinergic input to the hippocampus in AD, these data suggest that the altered patterns of synchronous activity seen in patients with AD could be caused by the loss of GABAergic SH axons, which modulate hippocampal network activities.