Lamivudine, a Reverse Transcriptase Inhibitor, Rescues Cognitive Deficits in a Mouse Model of Down Syndrome

An elevated activity of retrotransposons is increasingly recognized to be implicated in a wide range of neurodegenerative and neurodevelopmental diseases. Down syndrome (DS) is the most common genetic disorder associated with intellectual disability and a genetic form of Alzheimer’s disease. For this reason, we hypothesized that treatment with reverse transcriptase inhibitors could ameliorate DS phenotypes. In this proof of concept study, we treated trisomic (Ts65Dn) mice, a model of DS, with lamivudine, a reverse transcriptase inhibitor. We detected a significant improvement of neurobehavioral phenotypes, and a complete rescue of the hippocampal-dependent recognition memory upon treatment with lamivudine. Despite clinical studies in patients with DS are warranted, this study lays the groundwork for a novel and actionable therapeutic approach.

Excessive energy expenditure due to acute physical restraint disrupts Drosophila motivational feeding response

To study the behavior of Drosophila, it is often necessary to restrain and mount individual flies. This requires removal from food, additional handling, anesthesia, and physical restraint. We find a strong positive correlation between the length of time flies are mounted and their subsequent reflexive feeding response, where one hour of mounting is the approximate motivational equivalent to ten hours of fasting. In an attempt to explain this correlation, we rule out anesthesia side-effects, handling, additional fasting, and desiccation. We use respirometric and metabolic techniques coupled with behavioral video scoring to assess energy expenditure in mounted and free flies. We isolate a specific behavior capable of exerting large amounts of energy in mounted flies and identify it as an attempt to escape from restraint. We present a model where physical restraint leads to elevated activity and subsequent faster nutrient storage depletion among mounted flies. This ultimately further accelerates starvation and thus increases reflexive feeding response. In addition, we show that the consequences of the physical restraint profoundly alter aerobic activity, energy depletion, taste, and feeding behavior, and suggest that careful consideration is given to the time-sensitive nature of these highly significant effects when conducting behavioral, physiological or imaging experiments that require immobilization.

Satellite glia are essential modulators of sympathetic neuron survival, activity, and autonomic function

Satellite glia are the major glial cells in sympathetic ganglia, enveloping neuronal cell bodies. Despite this intimate association, how satellite glia contribute to sympathetic functions remain unclear. Here, we show that satellite glia are critical for metabolism, survival, and activity of sympathetic neurons and modulate autonomic behaviors in mice. Adult ablation of satellite glia results in impaired mTOR signaling, soma atrophy, reduced noradrenergic enzymes, and loss of sympathetic neurons. However, persisting neurons have elevated activity, and satellite glia-ablated mice show increased pupil dilation and heart rate, indicative of enhanced sympathetic tone. Satellite glia-specific deletion of Kir4.1, an inward-rectifying potassium channel, largely recapitulates the cellular defects observed in glia-ablated mice, suggesting that satellite glia act in part via extracellular K+ buffering. These findings highlight neuron-satellite glia as functional units in regulating sympathetic output, with implications for disorders linked to sympathetic hyper-activity such as cardiovascular disease and hypertension.

The Effect of Plasma Activated Water on Maize (Zea mays L.) under Arsenic Stress

Plasma activated water (PAW) is a source of various chemical species useful for plant growth, development, and stress response. In the present study, PAW was generated by a transient spark discharge (TS) operated in ambient air and used on maize corns and seedlings in the 3 day paper rolls cultivation followed by 10 day hydroponics cultivation. For 3 day cultivation, two pre-treatments were established, “priming PAW” and “rolls PAW”, with corns imbibed for 6 h in the PAW and then watered daily by fresh water and PAW, respectively. The roots and the shoot were then analyzed for guaiacol peroxidase (G-POX, POX) activity, root tissues for their lignification, and root cell walls for in situ POX activity. To evaluate the potential of PAW in the alleviation abiotic stress, ten randomly selected seedlings were hydroponically cultivated for the following 10 days in 0.5 Hoagland nutrient solutions with and without 150 μM As. The seedlings were then analyzed for POX and catalase (CAT) activities after As treatment, their leaves for photosynthetic pigments concentration, and leaves and roots for As concentration. The PAW improved the growth of the 3 day-old seedlings in terms of the root and the shoot length, while roots revealed accelerated endodermal development. After the following 10 day cultivation, roots from PAW pre-treatment were shorter and thinner but more branched than the control roots. The PAW also enhanced the POX activity immediately after the imbibition and in the 3 day old roots. After 10 day hydroponic cultivation, antioxidant response depended on the PAW pre-treatment. CAT activity was higher in As treatments compared to the corresponding PAW treatments, while POX activity was not obvious, and its elevated activity was found only in the priming PAW treatment. The PAW pre-treatment protected chlorophylls in the following treatments combined with As, while carotenoids increased in treatments despite PAW pre-treatment. Finally, the accumulation of As in the roots was not affected by PAW pre-treatment but increased in the leaves.

Digestive Enzyme Activity and Protein Degradation in Plasma of Heart Failure Patients

Introduction Heart failure is associated with degradation of cell functions and extracellular matrix proteins, but the trigger mechanisms are uncertain. Our recent evidence shows that active digestive enzymes can leak out of the small intestine into the systemic circulation and cause cell dysfunctions and organ failure. Methods Accordingly, we investigated in morning fasting plasma of heart failure (HF) patients the presence of pancreatic trypsin, a major enzyme responsible for digestion. Results Western analysis shows that trypsin in plasma is significantly elevated in HF compared to matched controls and their concentrations correlate with the cardiac dysfunction biomarker BNP and inflammatory biomarkers CRP and TNF-α. The plasma trypsin levels in HF are accompanied by elevated pancreatic lipase concentrations. The trypsin has a significantly elevated activity as determined by substrate cleavage. Mass spectrometry shows that the number of plasma proteins in the HF patients is similar to controls while the number of peptides was increased about 20% in HF patients. The peptides are derived from extracellular and intracellular protein sources and exhibit cleavage sites by trypsin as well as other degrading proteases (data are available via ProteomeXchange with identifier PXD026332). Connclusions These results provide the first evidence that active digestive enzymes leak into the systemic circulation and may participate in myocardial cell dysfunctions and tissue destruction in HF patients. Conclusions These results provide the first evidence that active digestive enzymes leak into the systemic circulation and may participate in myocardial cell dysfunctions and tissue destruction in HF patients.

Happy Enough to Relax? How Positive and Negative Emotions Activate Different Muscular Regions in the Back - an Explorative Study

Embodiment theories have proposed a reciprocal relationship between emotional state and bodily reactions. Besides large body postures, recent studies have found emotions to affect rather subtle bodily expressions, such as slumped or upright sitting posture. This study investigated back muscle activity as an indication of an effect of positive and negative emotions on the sitting position. The electromyography (EMG) activity of six back muscles was recorded in 31 healthy subjects during exposure to positive and negative affective pictures. A resting period was used as a control condition. Increased muscle activity patterns in the back were found during the exposure to negative emotional stimuli, which was mainly measured in the lumbar and thorax regions. The positive emotion condition caused no elevated activity. The findings show that negative emotions lead to increased differential muscle activity in the back and thus corroborate those of previous research that emotion affects subtle bodily expressions.

Resistance induction anthracnose control in pepper plants using acibenzolar-S-methyl

ABSTRACT: The resistance induction becomes an alternative to control microorganisms that attacks like plants. Little is known about the dose and its effect on the enzymatic activities associated with the induction of resistance of pepper plants under anthracnose attack. The objective of this study was to evaluate the severity and to estimate the enzymatic activity of Arcade F1 hybrid peppers infected with Colletotrichum gloeosporioides and submitted to different doses of the abiotic acibenzolar-S-methyl inducer. The experimental design was completely randomized blocks with five treatments, four doses of acibenzolar-S-methyl (0.15, 0.30, 0.45 and 0.60 g.L-1), and the control with distilled water only. The evaluation of leaf severity and collection for enzymatic activity of β-1,3-glucanase, catalase, peroxidase, polyphenoloxidase and ascorbate peroxidase were performed on the 4th, 8th and 12th day after inoculation of the phytopathogen. The application of acibenzolar-S-methyl provided a reduction in anthracnose severity, with an increase in all the enzymatic activities evaluated, but there was no prevalence of a specific dose. However, all doses of the evaluated inducers were able to delay the development of the phytopathogen with elevated activity of one or more antioxidant enzyme. KEYWORDS: Antioxidant enzymes, phytopathogenic fungus, Colletotrichum gloeosporioides.

Deletion of BDNF in Pax2 Lineage-Derived Interneuron Precursors in the Hindbrain Hampers the Proportion of Excitation/Inhibition, Learning, and Behavior

Numerous studies indicate that deficits in the proper integration or migration of specific GABAergic precursor cells from the subpallium to the cortex can lead to severe cognitive dysfunctions and neurodevelopmental pathogenesis linked to intellectual disabilities. A different set of GABAergic precursors cells that express Pax2 migrate to hindbrain regions, targeting, for example auditory or somatosensory brainstem regions. We demonstrate that the absence of BDNF in Pax2-lineage descendants of BdnfPax2KOs causes severe cognitive disabilities. In BdnfPax2KOs, a normal number of parvalbumin-positive interneurons (PV-INs) was found in the auditory cortex (AC) and hippocampal regions, which went hand in hand with reduced PV-labeling in neuropil domains and elevated activity-regulated cytoskeleton-associated protein (Arc/Arg3.1; here: Arc) levels in pyramidal neurons in these same regions. This immaturity in the inhibitory/excitatory balance of the AC and hippocampus was accompanied by elevated LTP, reduced (sound-induced) LTP/LTD adjustment, impaired learning, elevated anxiety, and deficits in social behavior, overall representing an autistic-like phenotype. Reduced tonic inhibitory strength and elevated spontaneous firing rates in dorsal cochlear nucleus (DCN) brainstem neurons in otherwise nearly normal hearing BdnfPax2KOs suggests that diminished fine-grained auditory-specific brainstem activity has hampered activity-driven integration of inhibitory networks of the AC in functional (hippocampal) circuits. This leads to an inability to scale hippocampal post-synapses during LTP/LTD plasticity. BDNF in Pax2-lineage descendants in lower brain regions should thus be considered as a novel candidate for contributing to the development of brain disorders, including autism.

A Cdc42-Borg4-Septin 7 axis regulates HSCs polarity and function

Aging of hematopoietic stem cells (HSCs) is caused by an elevated activity of the small RhoGTPase Cdc42 and an apolar distribution of proteins. Mechanisms by which Cdc42 activity controls polarity of HSCs are not known. Binder of RhoGTPases proteins (borgs) are known effector proteins of Cdc42 that are able to regulate the cytoskeletal septin network. Here we show that Cdc42 interacts with borg4, which in turn interacts with septin 7 to regulate the polar distribution of Cdc42, borg4 and septin 7 within HSCs. Genetic deletion of either borg4 or septin 7 in HSCs resulted in a reduced frequency of HSCs polar for Cdc42 or borg4 or septin 7 and a reduced engraftment potential and decreased lymphoid-primed multipotent progenitors (LMPPs) frequency in the bone marrow. In aggregation our data identify a Cdc42-borg4-septin 7 axis to be essential for maintenance of polarity within HSCs and for HSC function and provide rationale for further investigating the role of borgs and septins for the regulation of compartmentalization within stem cells.

Modeling earthquake occurrence and recurrence for supercycles and clusters

<p>Long records often show large earthquakes occurring in supercycles—temporal clusters of seismicity, cumulative displacement, and cumulative strain release separated by less active intervals. Presently used earthquake recurrence models do not account for the time dependence and clustering. Poisson models assume that earthquake recurrence is time-independent, but seismicity studies have shown that time is needed to accumulate strain along a fault before another large earthquake. Seismic cycle/renewal models account for this time-dependence but assume that all strain is released after large earthquakes and fail to replicate clustered earthquake behavior. The resulting probability estimates for recurrence of the next earthquake thus depend crucially on whether the cluster is treated as ongoing or over.</p><p>In this study, we have reformulated our previously developed Long-Term Fault Memory (LTFM) earthquake model as a Markov process to better quantify long-term earthquake behavior and the probability of future earthquakes. In the LTFM model, the probability of a large earthquake reflects accumulated strain rather than elapsed time. The probability increases with accumulated strain (and time) until an earthquake happens, after which the probability decreases, but not necessarily to zero. This simple, strain-driven recurrence model yields realistic sequences of large earthquakes with periods of elevated activity followed by longer quiescence. Using the Markov formulation, we explore long-term earthquake behavior and how to use paleoseismic records to better estimate the recurrence and probability of future large earthquakes.</p>