Differential effects of anticytoskeletal compounds on the localization and chemical patterns of actin in germinating conidia of Neurospora crassa

Abstract Anti-actin drugs, cytochalasins A and B, inhibited both normal single, and benomyl-induced multiple, germ tube outgrowth from conidia of Neurospora crassa . Actin was cytochemically found to be concentrated in each of the benomyl-induced germ tube tips. No significant quantitative changes either in total actin or its isoforms were measured in the inhibitor-treated germlings. While intact microtubules are required for normal, monopolar axiation of the germ tube, they appear not to be necessary for benomyl-induced multipolar outgrowth which, in contrast, still requires intact actin microfilaments. Microfilaments and microtubules thus play complementary roles in the normal germination of conidia.     

GLUT2 in pancreatic and extra-pancreatic gluco-detection

Detection of variations in blood glucose concentrations by pancreatic &#103 -cells and a subsequent appropriate secretion of insulin are key events in the control of glucose homeostasis. Because a decreased capability to sense glycemic changes is a hallmark of type 2 diabetes, the glucose signalling pathway leading to insulin secretion in pancreatic &#103 -cells has been extensively studied. This signalling mechanism depends on glucose metabolism and requires the presence of specific molecules such as GLUT2, glucokinase and the K ATP channel subunits Kir6.2 and SUR1. Other cells are also able to sense variations in glycemia or in local glucose concentrations and to modulate different physiological functions participating in the general control of glucose and energy homeostasis. These include cells forming the hepatoportal vein glucose sensor, which controls glucose storage in the liver, counterregulation, food intake and glucose utilization by peripheral tissues and neurons in the hypothalamus and brainstem whose firing rates are modulated by local variations in glucose concentrations or, when not protected by a blood-brain barrier, directly by changes in blood glucose levels. These glucose-sensing neurons are involved in the control of insulin and glucagon secretion, food intake and energy expenditure. Here, recent physiological studies performed with GLUT2 -/- mice will be described, which indicate that this transporter is ess ential for glucose sensing by pancreatic &#103 -cells, by the hepatoportal sensor and by sensors, probably located centrally, which control activity of the autonomic nervous system and stimulate glucagon secretion. These studies may pave the way to a fine dissection of the molecular and cellular components of extra-pancreatic glucose sensors involved in the control of glucose and energy homeostasis.     

Snap,crackle, and pop: Acoustic-based model estimation of snapping shrimp populations in healthy and degraded hard-bottom habitats

Human use of the ocean and its ecosystems continues to degrade coastal habitats around the world. Assessing anthropogenic impacts on these environments can be costly and manpower-intensive; thus, the development of rapid, remote techniques to assess habitat quality is important. We employed autonomous hydrophone receivers to record the soundscapes of healthy, sponge-rich hard-bottom habitat in Florida Bay, Florida (USA) and hard-bottom areas impacted by sponge die-offs. We also recorded sounds emanating from individual sponges of three species that were isolated in underwater sound booths, and then enumerated the invertebrates (mostly snapping shrimp) dwelling within the canals of each sponge. From these recordings, a modified cylindrical sound propagation model was used to estimate distances to individual snapping shrimp snaps. Using the program Distance, we estimated snapping shrimp population density and abundance within both habitat types. More snapping shrimp snaps per unit time were recorded in healthy hard-bottom areas as compared to degraded hard-bottom areas. In addition, the average distance to a snap source was greater within degraded hard-bottom areas than within healthy hard-bottom areas. As a consequence, the estimated density and abundance of snapping shrimp were one to two orders of magnitude greater within healthy habitat than within degraded habitat. This study demonstrates the feasibility of using acoustic sampling and modeling to rapidly assess populations of soniferous benthic indicator species, whose vocalizations may yield indirect estimates of habitat quality.     

Direct and indirect effects of microbiota-derived metabolites on neuroinflammation in multiple sclerosis

Multiple sclerosis (MS) and experimental autoimmune encephalomyelitis (EAE) are highly influenced by changes in the microbiota and of microbiota-derived metabolites, including short chain fatty acids, bile acids, and tryptophan derivatives. This review will discuss the effects of microbiota-derived metabolites on neuroinflammation driven by central nervous system-resident cells and peripheral immune cells, and their influence on outcomes of EAE and MS.     

Inhibition of Neuronal Degenerin/Epithelial Na+ Channels by the Multiple Sclerosis Drug 4-Aminopyridine

The voltage-gated K⁺ (Kv) channel blocker 4-aminopyridine (4-AP) is used to target symptoms of the neuroinflammatory disease multiple sclerosis (MS). By blocking Kv channels, 4-AP facilitates action potential conduction and neurotransmitter release in presynaptic neurons, lessening the effects of demyelination. Because they conduct inward Na⁺ and Ca²⁺ currents that contribute to axonal degeneration in response to inflammatory conditions, acid-sensing ion channels (ASICs) contribute to the pathology of MS. Consequently, ASICs are emerging as disease-modifying targets in MS. Surprisingly, as first demonstrated here, 4-AP inhibits neuronal degenerin/epithelial Na⁺ (Deg/ENaC) channels, including ASIC and BLINaC. This effect is specific for 4-AP compared with its heterocyclic base, pyridine, and the related derivative, 4-methylpyridine; and akin to the actions of 4-AP on the structurally unrelated Kv channels, dose- and voltage-dependent. 4-AP has differential actions on distinct ASICs, strongly inhibiting ASIC1a channels expressed in central neurons but being without effect on ASIC3, which is enriched in peripheral sensory neurons. The voltage dependence of the 4-AP block and the single binding site for this inhibitor are consistent with 4-AP binding in the pore of Deg/ENaC channels as it does Kv channels, suggesting a similar mechanism of inhibition in these two classes of channels. These findings argue that effects on both Kv and Deg/ENaC channels should be considered when evaluating the actions of 4-AP. Importantly, the current results are consistent with 4-AP influencing the symptoms of MS as well as the course of the disease because of inhibitory actions on Kv and ASIC channels, respectively.     

Effect of the time of day on central and peripheral fatigue during 2-min maximal voluntary contractions in persons with multiple sclerosis: gender differences

There is a lack of data on fatigue changes within 24 h among patients with multiple sclerosis. The purpose of this study was to evaluate the effect of time of day on central and peripheral fatigue during a continuous 2-min maximal voluntary contraction of the quadriceps muscle in women and men with multiple sclerosis (MS). We studied age-matched MS patients (range, 40–50 years). The inclusion criteria for patients were: a Kurtzke Expanded Disability Status score and a Fatigue Severity Scale score. We found a significant gender difference in central activation ratio (CAR) in the evening. At the end of the 2-min maximal voluntary contraction (MVC), the voluntary torque decreased by about 65% in men and women with MS in both the morning and evening. We also observed that, in women, CAR decreased markedly during the first 30 s in the evening test. The most interesting finding of our study is that central fatigue increased, whereas peripheral fatigue decreased markedly in the evening only in women. It remains unclear why women’s central fatigue is greater in the evening than in the morning.     

Extending the Horizon of Homology Detection with Coevolution-based Structure Prediction

Traditional sequence analysis algorithms fail to identify distant homologies when they lie beyond a detection horizon. In this review, we discuss how co-evolution-based contact and distance prediction methods are pushing back this homology detection horizon, thereby yielding new functional insights and experimentally testable hypotheses. Based on correlated substitutions, these methods divine three-dimensional constraints among amino acids in protein sequences that were previously devoid of all annotated domains and repeats. The new algorithms discern hidden structure in an otherwise featureless sequence landscape. Their revelatory impact promises to be as profound as the use, by archaeologists, of ground-penetrating radar to discern long-hidden, subterranean structures. As examples of this, we describe how triplicated structures reflecting longin domains in MON1A-like proteins, or UVR-like repeats in DISC1, emerge from their predicted contact and distance maps. These methods also help to resolve structures that do not conform to a “beads-on-a-string” model of protein domains. In one such example, we describe CFAP298 whose ubiquitin-like domain was previously challenging to perceive owing to a large sequence insertion within it. More generally, the new algorithms permit an easier appreciation of domain families and folds whose evolution involved structural insertion or rearrangement. As we exemplify with α1-antitrypsin, coevolution-based predicted contacts may also yield insights into protein dynamics and conformational change. This new combination of structure prediction (using innovative co-evolution based methods) and homology inference (using more traditional sequence analysis approaches) shows great promise for bringing into view a sea of evolutionary relationships that had hitherto lain far beyond the horizon of homology detection.