For the past half century, the sliding filament-based cross-bridge theory has been the cornerstone of our understanding of how muscles contract. According to this theory, active force can only occur ...if there is overlap between the contractile filaments, actin and myosin. Otherwise, forces are thought to be caused by passive structural elements and are assumed to vary solely because of the length of the muscle. We observed increases in muscle force by a factor of 3 to 4 above the purely passive forces for activated and stretched myofibrils in the absence of actin-myosin overlap. We show that this dramatic increase in force is crucially dependent on the presence of the structural protein titin, cannot be explained with calcium activation, and is regulated by actin-myosin-based cross-bridge forces before stretching. We conclude from these observations that titin is a strong regulator of muscle force and propose that this regulation is based on cross-bridge force-dependent titin-actin interactions. These results suggest a mechanism for stability of sarcomeres on the "inherently unstable" descending limb of the force-length relationship, and they further provide an explanation for the protection of muscles against stretch-induced muscle injuries.
Bergmann’s and Allen’s rules were defined to describe macroecological patterns across latitudinal gradients. Bergmann observed a positive association between body size and latitude for endothermic ...species while Allen described shorter appendages as latitude increases. Almost two centuries later, there is still ongoing discussion about these patterns. Temperature, the common variable in these two rules, varies predictably across both latitude and elevation. Although these rules have been assessed extensively in mammals across latitude, particularly in regions with strong seasonality, studies on tropical montane mammals are scarce. We here test for these patterns and assess the variation of several other locomotory, diet-associated, body condition, and thermoregulatory traits across elevation in the Mountain Treeshrew (
Tupaia montana
) on tropical mountains in Borneo. Based on morphological measurements from both the field and scientific collections, we found a complex pattern: Bergmann’s rule was not supported in our tropical mountain system, since skull length, body size, and weight decreased from the lowest elevations (<1000 m) to middle elevations (2000–2500 m), and then increased from middle elevations to highest elevations. Allen’s rule was supported for relative tail length, which decreased with elevation, but not for ear and hindfoot length, with the former remaining constant and the latter increasing with elevation. This evidence together with changes in presumed diet-related traits (rostrum length, zygomatic breadth and upper tooth row length) along elevation suggest that selective pressures other than temperature, are playing a more important role shaping the morphological variation across the distribution of the Mountain Treeshrew. Diet, food acquisition, predation pressure, and/or intra- and inter-specific competition, are some of the potential factors driving the phenotypic variation of this study system. The lack of variation in body condition might suggest local adaptation of this species across its elevational range, perhaps due to generalist foraging strategies. Finally, a highly significant temporal effect was detected in several traits but not in others, representing the first phenotypic variation temporal trends described on treeshrews.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
A multidisciplinary panel of 18 physicians and 3 non-physicians from eight countries (Sweden, UK, Argentina, Australia, Italy, Finland, Norway and the USA) reviewed the literature on diagnosis and ...management of adult coeliac disease (CD). This paper presents the recommendations of the British Society of Gastroenterology. Areas of controversies were explored through phone meetings and web surveys. Nine working groups examined the following areas of CD diagnosis and management: classification of CD; genetics and immunology; diagnostics; serology and endoscopy; follow-up; gluten-free diet; refractory CD and malignancies; quality of life; novel treatments; patient support; and screening for CD.
The electrical conductivity of reduced graphene oxide (rGO) obtained from graphene oxide (GO) using sodium borohydride (NaBH
) as a reducing agent has been investigated as a function of time (2 min ...to 24 h) and temperature (20 °C to 80 °C). Using a 300 mM aqueous NaBH
solution at 80 °C, reduction of GO occurred to a large extent during the first 10 min, which yielded a conductivity increase of 5 orders of magnitude to 10 S m
. During the residual 1400 min of reaction, the reduction rate decreased significantly, eventually resulting in a rGO conductivity of 1500 S m
. High resolution XPS measurements showed that C/O increased from 2.2 for the GO to 6.9 for the rGO at the longest reaction times, due to the elimination of oxygen. The steep increase in conductivity recorded during the first 8-12 min of reaction was mainly due to the reduction of C-O (e.g., hydroxyl and epoxy) groups, suggesting the preferential attack of the reducing agent on C-O rather than Cdouble bond, length as m-dashO groups. In addition, the specular variation of the percentage content of C-O bond functionalities with the sum of Csp
and Csp
indicated that the reduction of epoxy or hydroxyl groups had a greater impact on the restoration of the conductive nature of the graphite structure in rGO. These findings were reflected in the dramatic change in the structural stability of the rGO nanofoams produced by freeze-drying. The reduction protocol in this study allowed to achieve the highest conductivity values reported so far for the aqueous reduction of graphene oxide mediated by sodium borohydride. The 4-probe sheet resistivity approach used to measure the electrical conductivity is also, for the first time, presented in detail for filtrate sheet assemblies' of stacked GO/rGO sheets.
Eccentric muscle properties are not well characterized by the current paradigm of the molecular mechanism of contraction: the cross-bridge theory. Findings of force contributions by passive ...structural elements a decade ago paved the way for a new theory. Here, we present experimental evidence and theoretical support for the idea that the structural protein titin contributes to active force production, thereby explaining many of the unresolved properties of eccentric muscle contraction.
It has been accepted for half a century that, for a given level of activation, the steady-state isometric force of a muscle sarcomere depends exclusively on the amount of overlap between the ...contractile filaments actin and myosin, or equivalently sarcomere length (Gordon AM et al., J Physiol 184: 170-192, 1966). Moreover, according to the generally accepted paradigm of muscle contraction, the cross-bridge theory (Huxley AF, Prog Biophys Biophys Chem 7: 255-318, 1957), this steady-state isometric sarcomere force is independent of the muscle's contractile history (Huxley AF, Prog Biophys Biophys Chem 7: 255-318, 1957; Walcott S and Herzog W, Math Biosci 216: 172-186, 2008); i.e., it is independent of whether a muscle is held at a constant length before and during the contraction or whether the muscle is shortened or lengthened to the same constant length. This, however, is not the case, as muscles and single fibers that are stretched show greatly increased steady-state isometric forces compared with preparations that are held at a constant length (Abbott BC and Aubert XM, J Physiol 117: 77-86, 1952; De Ruiter CJ et al., J Physiol 526.3: 671-681, 2000; Edman KAP et al., J Physiol 281: 139-155, 1978; Edman KAP et al., J Gen Physiol 80: 769-784, 1982; Edman KAP and Tsuchiya T, J Physiol 490.1: 191-205, 1996). This so-called "residual force enhancement" (Edman KAP et al., J Gen Physiol 80: 769-784, 1982) offers a perplexing puzzle for muscle physiologists. Many theories have been advanced to address the discrepancy between prediction and observation with the most popular and accepted being the sarcomere length nonuniformity theory (Morgan DL, Biophys J 57: 209-221, 1990), which explains the residual force enhancement with the development of large nonuniformities in sarcomere lengths during muscle stretching. Here, we performed experiments in mechanically isolated sarcomeres and observed that the residual force enhancement following active stretching is preserved. Since our preparation utilizes a single sarcomere, a redistribution of the length of neighboring sarcomeres to produce the higher force following stretch is, by design, precluded. Furthermore, the enhanced forces in the single sarcomeres always exceed the isometric forces on the plateau of the force-length relationship, thereby eliminating the possibility that our result might have been obtained because of a redistribution of half-sarcomere lengths. Since force enhancement in single myofibrils has been associated with actin-titin interactions (Kulke M et al., Circ Res 89: 874-881, 2001; Li Q et al., Biophys J 69: 1508-1518, 1995) and calcium binding to titin (Joumaa V et al., Am J Physiol Cell Physiol 294: C74-C78, 2008; Labeit D et al., Proc Natl Acad Sci USA 100: 13716-13721, 2003), titin may regulate the sarcomeric force enhancement observed here.
Sarcomere lengths are non-uniform on all structural levels of mammalian skeletal muscle. These non-uniformities have been associated with a variety of mechanical properties, including residual force ...enhancement and depression, creep, increased force capacity, and extension of the plateau of the force-length relationship. However, the nature of sarcomere length non-uniformities has not been explored systematically. The purpose of this study was to determine the properties of sarcomere length non-uniformities in active and passive muscle. Single myofibrils of rabbit psoas (
= 20; with 412 individual sarcomeres) were subjected to three activation/deactivation cycles and individual sarcomere lengths were measured at 4 passive and 3 active points during the activation/deactivation cycles. The myofibrils were divided into three groups based on their initial average sarcomere lengths: short, intermediate, and long average sarcomere lengths of 2.7, 3.2, and 3.6 µm. The primary results were that sarcomere length non-uniformities did not occur randomly but were governed by some structural and/or contractile properties of the sarcomeres and that sarcomere length non-uniformities increased when myofibrils went from the passive to the active state. We propose that the mechanisms that govern the systematic sarcomere lengths non-uniformities observed in active and passive myofibrils may be associated with the variable number of contractile proteins and the variable number and the adjustable stiffness of titin filaments in individual sarcomeres.
Summary Osteoarthritis (OA) in obese individuals is often attributed to joint loading. However, a subtype of OA, Metabolic OA, may be due to obesity-related intrinsic factors but remains to be ...evaluated experimentally against a known OA progression model. Objective To evaluate if obesity contributes to OA onset using a high fat/high sucrose diet-induced obesity (DIO) model with anterior cruciate ligament-transected rats (ACL-X). Methods Sprague Dawley rats ( n = 33) consumed high fat/high sucrose or chow diets for 12 weeks, were randomized to one of three groups: a unilateral ACL-X group, sham surgery group, or naïve non-surgical group. These animals were followed for an additional 16 weeks. At sacrifice, body composition, knee joint Modified Mankin scores, and 27 serum and synovial fluid cytokines and adipokines were measured. Results Experimental limbs of obese ACL-X, obese Sham, and lean ACL-X animals had similar Modified Mankin scores that were greater than those obtained from lean Sham and naïve animals. Obese contralateral limbs had similar OA damage as ACL-X and Sham limbs of obese and ACL-X limbs of lean animals. Obese contralateral limb Modified Mankin scores had a strong correlation ( r = 0.75, P < 0.001) with body fat percentage. Serum leptin and synovial fluid IP10/CXCL10 best described Modified Mankin scores in contralateral limbs of obese animals. Conclusions Mechanical factors produced OA damage in experimental limbs, as expected. Interestingly, OA damage in obese contralateral limbs was similar to mechanically perturbed limbs, suggesting that obesity may induce OA in a non-mechanical manner.
Aim
Understanding the biotic and abiotic mechanisms underlying the generation and maintenance of biogeographic transitions represent long‐standing topics in evolutionary biology. The Isthmus of Kra ...(IOK) divides Sundaland and Indochina and constitutes a poorly characterized terrestrial biogeographic transition. Here we looked at population genetic structure of three species that are distributed across the IOK to gain insights into the drivers that have shaped this transition and regional diversification patterns.
Location
Tropical east Asia: Sundaland and Indochina.
Taxa
Callosciurus caniceps, Tamiops mcclellandii, and Dremomys rufigenis‐ornatus species complex (Mammalia: Rodentia: Sciuridae).
Methods
We generated complete mitogenomes and sequences of 11 nuclear intron fragments from 61 and 67 museum specimen samples, respectively. We assessed population structure by constructing Maximum Likelihood mitogenome phylogenies (IQTREE2), and nuclear marker haplowebs and conspecificity matrices (HaplowebMaker and CoMa). We estimated divergence dates through Bayesian phylogenetic inference (BEAST2) and put these results in the context of climatic and geological history.
Results
High levels of mitochondrial and nuclear divergence were identified across the IOK in all three squirrels. Lineage turnover was consistent with the two major mammal species distribution transitions near the Kangar‐Pattani Line and at the juncture between the Thai‐Malay peninsula and the mainland. Divergence of mitochondrial lineages across Kra was estimated in the late Pliocene/ early Pleistocene for all three taxa. Older Miocene/Pliocene divergences were estimated within Indochina in D. rufigenis‐ornatus and T. mcclellandii, which were paraphyletic.
Main Conclusions
Sundaic and Indochinese populations have possibly diverged in allopatric habitat refugia in or around mountains during periods of increased aridity and evergreen forest contraction. Ecological differences and/or topography might have influenced genetic differentiation during periods of rainforest expansion. Alternative hypotheses remain to be tested with more informative nuclear markers and additional geographic sampling.
In vivo drug discovery in the zebrafish Peterson, Randall T; Zon, Leonard I
Nature reviews. Drug discovery,
200501, 2005-Jan, 2005-1-00, 20050101, Letnik:
4, Številka:
1
Journal Article
Recenzirano
Odprti dostop
The zebrafish has become a widely used model organism because of its fecundity, its morphological and physiological similarity to mammals, the existence of many genomic tools and the ease with which ...large, phenotype-based screens can be performed. Because of these attributes, the zebrafish might also provide opportunities to accelerate the process of drug discovery. By combining the scale and throughput of in vitro screens with the physiological complexity of animal studies, the zebrafish promises to contribute to several aspects of the drug development process, including target identification, disease modelling, lead discovery and toxicology.
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Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, UILJ, UKNU, UL, UM, UPUK
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