bluuebunny/crossref_metadata_2025_split huggingface dataset:
Detailed imaging and genetic analysis reveal a secondary BRAFL505H resistance mutation and extensive intrapatient heterogeneity in metastatic BRAF mutant melanoma patients treated with vemurafenib
Authors: Hoogstraat Marlous , Gadellaa‐van Hooijdonk Christa G. , Ubink Inge , Besselink Nicolle J. M. , Pieterse Mark , Veldhuis Wouter , van Stralen Marijn , Meijer Eelco F. J. , Willems Stefan M. , Hadders Michael A. , Kuilman Thomas , Krijgsman Oscar , Peeper Daniel S. , Koudijs Marco J. , Cuppen Edwin , Voest Emile E. , Lolkema Martijn P. 
Published: December 2014

SummaryResistance to treatment is the main problem of targeted treatment for cancer. We followed ten patients during treatment with vemurafenib, by three‐dimensional imaging. In all patients, only a subset of lesions progressed. Next‐generation DNA sequencing was performed on sequential biopsies in four patients to uncover mechanisms of resistance. In two patients, we identified mutations that explained resistance to vemurafenib; one of these patients had a secondary BRAF L505H mutation. This is the first observation of a secondary BRAF mutation in a vemurafenib‐resistant patient‐derived melanoma sample, which confirms the potential importance of the BRAF L505H mutation in the development of therapy resistance. Moreover, this study hints toward an important role for tumor heterogeneity in determining the outcome of targeted treatments.
The response of Chlamydomonas reinhardtii to nitrogen deprivation: a systems biology analysis
Authors: Park Jeong‐Jin , Wang Hongxia , Gargouri Mahmoud , Deshpande Rahul R. , Skepper Jeremy N. , Holguin F. Omar , Juergens Matthew T. , Shachar‐Hill Yair , Hicks Leslie M. , Gang David R. 
Published: December 2014

SummaryDrastic alteration in macronutrients causes large changes in gene expression in the photosynthetic unicellular alga Chlamydomonas reinhardtii. Preliminary data suggested that cells follow a biphasic response to this change hinging on the initiation of lipid accumulation, and we hypothesized that drastic repatterning of metabolism also followed this biphasic modality. To test this hypothesis, transcriptomic, proteomic, and metabolite changes that occur under nitrogen (N) deprivation were analyzed. Eight sampling times were selected covering the progressive slowing of growth and induction of oil synthesis between 4 and 6 h after N deprivation. Results of the combined, systems‐level investigation indicated that C. reinhardtii cells sense and respond on a large scale within 30 min to a switch to N‐deprived conditions turning on a largely gluconeogenic metabolic state, which then transitions to a glycolytic stage between 4 and 6 h after N depletion. This nitrogen‐sensing system is transduced to carbon‐ and nitrogen‐responsive pathways, leading to down‐regulation of carbon assimilation and chlorophyll biosynthesis, and an increase in nitrogen metabolism and lipid biosynthesis. For example, the expression of nearly all the enzymes for assimilating nitrogen from ammonium, nitrate, nitrite, urea, formamide/acetamide, purines, pyrimidines, polyamines, amino acids and proteins increased significantly. Although arginine biosynthesis enzymes were also rapidly up‐regulated, arginine pool size changes and isotopic labeling results indicated no increased flux through this pathway.
THE RELATION OF PROTEINS TO CRYSTALLOIDS. I. THE OSMOTIC PRESSURE OF HÆMOGLOBIN AND THE “LAKING” OF RED BLOOD CORPUSCLES
Authors: Roaf H. E. 
Published: December 2014

1. The relation of the osmotic pressure of hæmoglobin to the “laking” of red blood corpuscles is briefly discussed.2. A simple method is described for direct measurement of the osmotic pressure of a series of solutions, when the solute does not pass through parchment paper.3. Measurements of the osmotic pressure of “laked” corpuscles and “crystallised” hæmoglobin have been made.4. Under conditions which limit ionisation, yet promote the solubility of hæmoglobin, pressures corresponding to the molecular weight calculated from other data have been obtained.5. Pressures considerably higher than can be accounted for by the molecular weight of hæmoglobin have been found, although the hæmoglobin was unchanged spectroscopically. It is suggested that this is due to ionising salts of hæmoglobin. Both acid and alkali increase the pressure, and, as with serum proteins, a minimal pressure is found near the neutral point.6. Many substances lower the osmotic pressure, and thus might help to prevent “laking” of red blood corpuscles.7. Pressures have been obtained with corpuscles “laked” by freezing and thawing up to 282 and 256. If ionisation occurred, the calculated pressure might be as high as 960 millimeters of mercury.8. With such a range of pressure the osmotic pressure of hæmoglobin should be considered in discussing the “laking” of corpuscles, but until further experiment has determined the pressures in mixed solutions containing the various crystalloids of the corpuscle it cannot be decided what part is played by hæmoglobin and how much is due to other factors.This work is an independent continuation of work begun originally with Professor B. Moore, and I wish to thank him for his continued interest in my experiments.I also wish to thank Professor F. G. Donnan for advice during this research.
EXPERIMENTS ON THE PATHS TAKEN BY VOLITIONAL IMPULSES PASSING FROM THE CEREBRAL CORTEX TO THE CORD: THE PYRAMIDS AND THE VENTRO‐LATERAL DESCENDING TRACTS
Authors: Schäfer E. A. 
Published: December 2014

1. As has been previously found by other observers, the paralysis which results from section of the pyramid tracts in the medulla oblongata is not complete and persistent. There is therefore some other path by which volitional impulses arising in the cortex reach the motor cells of the cord.2. Such an alternative path appears to be furnished by the descending fibres of the ventral columns and of the ventral parts of the lateral columns of the cord. Section of these parts produces at least as complete and persistent paralysis in the monkey as does section of the pyramid tracts themselves.3. This result is not due to the inclusion of the prepyramidal tracts in the section, since it is produced when these are not involved.4. The question is discussed whether the paralysis produced by section of the ventro‐lateral tracts is due to the severance of an encephalo‐spinal path, or to loss of tone of the neuro‐muscular apparatus of the cord. The conclusion arrived at is, that such loss of tone as might result from the section would be insufficient to produce so complete a block to impulses emanating from the motor cortex as results from the section of these tracts, and that the ventro‐lateral descending fibres therefore constitute an alternative path by which volitional impulses pass from the brain to the ventral horn cells of the cord, although in a less direct manner than by the pyramid tracts themselves.5. In vertebrata below mammals this probably represents the only path between the higher centres in the brain and the lower motor centres in the cord.6. There is no evidence of any permanent sensory paralysis resulting from section of the ventral column and ventral part of the lateral column, even although the injury may include the tract of Gowers.
ON THE REACTIONS OF THE SALIVARY CENTRES
Authors: Miller F. R. 
Published: December 2014

I. The Lingualis Reflex.1. Stimulation of the central end of the lingual nerve (lingualis reflex) causes abundant secretion from the ipsilateral submaxillary gland, and less secretion from the ipsilateral parotid.2. Slight secretion (about one drop) takes place from the contralateral submaxillary and parotid glands.3. The threshold of the reflex is very low (sec. coil at 30 cm.).4. The threshold of the lingualis reflex is lower than that of the peripheral chordo‐lingual nerve.5. The ipsilateral submaxillary latency is less than the parotid latency. The ipsilateral submaxillary latency is less than the contralateral submaxillary latency.II. The Glossopharyngeus Reflex.1. Stimulation of the central end of the glossopharyngeal nerve (glossopharyngeus reflex) causes abundant secretion from the ipsilateral parotid gland, less secretion from the ipsilateral submaxillary.2. Slight contralateral effects are produced.3. The ipsilateral parotid latency is less than the submaxillary latency.III. The Gastric Vagus Reflex.1. Stimulation of the central end of the gastric vagus (gastric vagus reflex) causes secretion from the submaxillary and parotid glands.2. The threshold is high.IV. Stimulation of a sensory nerve (sciatic) causes a slight submaxillary secretion.V. The salivary reflexes are independent of the associated muscular reflexes.VI. Afferent fibres for the salivary reflex are contained in the chorda tympani.VII. The salivary secretion of curare poisoning is caused by asphyxia.VIII. Two points may be localised by unipolar faradisation of the surface of the medulla oblongata. Stimulation of the one causes parotid secretion; of the other, submaxillary secretion. The stimulus threshold is very low (sec. coil at 80 cm.). The results agree, in the main, with those of previous anatomical work.I take pleasure in thanking Professor Sherrington for advice and assistance during the course of this work. My best thanks are also due to Dr Potter of Amsterdam for aid in identifying certain of the structures in the sections.
STUDIES ON THE ENDOCRINE GLANDS:—III.: THE EFFECTS ON THE THYROID AND PARATHYROID OF THE RAT OF ADMINISTERING THYROID EXTRACT AND CERTAIN OTHER AUTACOIDS AND SALTS
Authors: Kojima Masaharu 
Published: December 2014

1. Administration of thyroid and of sodium and potassium iodides causes accumulation of colloid in the vesicles of the thyroid of rats. The epithelial cells lining the vesicles are flattened. The cells of the parathyroid are generally swollen.2. Administration of posterior lobe of pituitary gives the epithelial cells of the thyroid a swollen, barrel‐like appearance; their nuclei are shrunken. The structure of the parathyroid becomes loose. Its cells are also swollen and their nuclei shrunken.3. Administration of adrenalin causes somewhat similar changes in the thyroid and parathyroid to those produced by posterior lobe of pituitary, but they are less marked.
THE ADRENALIN CONTENT OF THE SUPRARENALS OF THE FEMALE WHITE RAT, AND THE CHANGES BROUGHT ABOUT BY THYROID FEEDING AND OTHER CONDITIONS
Authors: Herring P. T. 
Published: December 2014

The suprarenals of the young adult female white rat are normally some 40 per cent. heavier than the suprarenals of the male animals of the same body‐weight.The adrenalin content of the suprarenals of the female white rat is rather more than twice as large as that of the suprarenals of the male animal of the same size.Per 100 grm. body‐weight the amount of adrenalin in the suprarenals of the female white rat averages 0–073 mg. in the twenty animals examined. The corresponding figure for the adrenalin content of the male suprarenals is given as 0·034 mg.The larger suprarenals and adrenalin content of the female white rat are associated with sex differences in the other endocrine glands and organs of the body.The adrenalin content of the suprarenals is increased during pregnancy, but is not perinanently altered by the occurrence of this condition.The female white rat does not tolerate thyroid feeding as well as the male animal of the same weight. A daily dosage of 0·2 grm. fresh ox‐thyroid continued for any length of time is too high, and checks the rate of growth of the animal.The administration of thyroid causes a rapid increase in the weight of the suprarenals, though not as great a proportional increase in the case of the female as it does in the male.The amount of adrenalin is less constantly increased in the female by thyroid feeding. Some female rats thrive well and show an increased adrenalin content, while others do badly and show a reduction in the amount of adrenalin in their suprarenals.The chromaphil tissue of the female white rat normally maintains a much higher level of adrenalin production than it does in the male, but its reserve power of increase under the stimulus of thyroid is proportionally less than it is in the male.The increased size of the suprarenals brought about by thyroid feeding is mainly due to hypertrophy of the cortex. The percentage amount of adrenalin in the suprarenals is always diminished by thyroid feeding.I have to thank Mrs Donald Mills for her help in looking after the animals. To Mr Niven of Strathkinness I am indebted for a regular supply of fresh ox‐thyroid.The expenses of the research have been met by a grant from the Research Fund of the Carnegie Trust for the Universities of Scotland.
THE ACTION OF THE BLOOD SERUM OF ANIMALS IN TETANIA PARATHYREOPRIVA ON MOTOR NERVE AND STRIATED MUSCLE
Authors: Yoshimoto Misao 
Published: December 2014

The serum of thyro‐parathyroidectomized dogs and cats produces some increase of excitability in the isolated nerve of the frog, but has no special effect on the contraction of isolated muscle, nor does it cause tremors in the frog's sartorius muscle.The serum of both thyroidectomized and normal dogs and cats has no effect or a very feeble (depressive or excitatory) effect on frog's nerve, thus showing itself much more inert than the serum of thyro‐parathyroidectomized animals. But on muscle the effect is the same in all.A solution of guanidine carbonate above.01 % causes some increase of nervous excitability, approaching that caused by the serum of the thyro‐parathyroidectomized animals. On muscle, guanidine carbonate solutions above .025 % show a depressive effect, while a .001 % solution produced no effect. None of the solutions of guanidine carbonate within the concentration range studied produced any spontaneous twitching in the muscle. It is already known that nerve is affected by a guanidine solution of lower concentration than affects muscles. In these experiments the muscle preparation was not denervated, so that the correct expression would be muscle with its neural elements.These experimental results taken in conjunction with the results of the ivestigations of previous workers on the problem of tetany give reason for supposing that the serum of animals in a condition of tetania parathyreopriva may contain some exciting substance which is present in just sufficient amount to affect the excitability of motor nerves but not of muscles. This conclusion is put forward with reserve, since my experiments on this subject are not yet complete.The similarity in the action on nerve and muscle of guanidine carbonate and or the serum from animals in a condition of tetania parathyreopriva lends support to the experimental conclusions adduced by previous investigators that some guanidine‐like body may be an agent in producing the hyperexcitability of peripheral motor nerves which occurs in the condition of tetany.
THE NATURE OF THE SERUM CONSTITUENT AFFECTING PLAIN MUSCLE
Authors: Ponder Eric 
Published: December 2014

The constituent of serum which produces increased contraction of plain muscle is not protein, is dialysable, not volatile with steam, not destroyed by boiling or by drying, but is destroyed by ashing. It is insoluble in ether, acetone and chloroform, but is soluble in boiling alcohol, and with difficulty in cold alcohol. It is not destroyed by 1 per cent alkali in the cold or at 100° C., nor by 1 per cent sulphuric acid in the cold ; but sulphuric acid at 100° C, rapidly destroys it. It may be removed from solution by certain adsorbents. It exists in the human red cells as well as in the serum.This research was aided by a grant from the Earl of Moray Fund of the University of Edinburgh.
STUDIES IN THE PHYSIOLOGY OF THE NERVOUS SYSTEM. XXVIII.: ABSENCE OF ALGEBRAIC EQUALITY BETWEEN THE MAGNITUDES OF CENTRAL EXCITATION AND EFFECTIVE CENTRAL INHIBITION GIVEN IN THE REFLEX CENTRE OF A SINGLE LIMB BY THE SAME REFLEX STIMULUS
Authors: Brown T. Graham 
Published: December 2014

I. Two reflex stimuli which evoke antagonistic reflexes in the same pair of antagonistic muscles yield a compound reflex when applied synchronously. At certain intensities of the two stimuli both of the antagonistic muscles contract more in the compound reflex than they were contracted in the state preceding all stimulation.2. Each reflex stimulus excites one half‐centre (e.g. flexor), and tends to inhibit any discharge present in the antagonistic half‐centre (e.g. extensor). The magnitude of the inhibition which actually falls upon any discharging neurones in the inhibited half‐centre may be termed the “effective inhibition” conditioned by the stimulus in question.3. If excitation is measured in terms of number of synchronous nerve‐impulses by which the discharge of a half‐centre is increased, and effective inhibition in terms of the number of synchronous nerve‐impulses suppressed in the discharge of the antagonistic half‐centre, a direct deduction may be drawn from the observation in paragraph 1. At certain intensities of stimulation, and in the case of at least one of two antagonistic stimuli, the effective inhibition conditioned by it in one half‐centre is less than the excitation conditioned by it in the antagonistic half‐centre. This means that, in the case (for example) of an extension‐reflex, the inhibition of the previously discharging flexor motor neurones is less than the excitation of the extensor motor neurones.4. The magnitude of inhibition which falls upon any neurones in a half‐centre (whether they be discharging or not) may be termed the “total inhibition” conditioned by a reflex stimulus.5. If total inhibition is so distributed in a half‐centre that it first falls only upon discharging neurones (and then upon non‐discharging neurones only when all the discharging neurones have been inhibited), the above deduction applies to total inhibition as well as to effective inhibition. But this cannot at present be assumed, for there is no proof that inhibition is so distributed.6. If total inhibition is so distributed that it falls proportionally upon discharging and non‐discharging neurones in a half‐centre, then some of the inhibition may be spent upon non‐discharging neurones. In this case the effective and the total inhibition in a half‐centre will be of different magnitudes (if the inhibition and excitation in it are sub‐maximal), and inequality between the excitation (in one half‐centre) and the effective inhibition (in the other) given by a single reflex stimulus will not necessarily imply inequality between the excitation and total inhibition given by the same stimulus. That problem remains at issue.
THE MEASUREMENT OF THE DIAMETERS OF ERYTHROCYTES. I. THE MEAN DIAMETER OF THE RED CELLS IN MAN
Authors: Ponder Eric , Millar W. G. 
Published: December 2014

1. A method is described in detail for the measurement of erythrocytes in plasma. The cells are photographed under suitable optical conditions, and measured from the negative. The error in measurement does not exceed 0·2µ.2. The mean size of the diameter of the red cells in man is 8·8µ.3. Erythrocytes which are dried or stained are of smaller diameter, the difference being about 1·0µ.4. The frequency distribution of the sizes of the red cells in man closely approximates to the symmetrical type.
EXPERIMENTS ON CONTRACTION OF WHITE CONNECTIVE TISSUE FIBRES
Authors: Tidmarsh C. J. , Tait John 
Published: December 2014

1. In heat contraction of mouse‐tail tendon, localised swellings commence at certain points along the tendon. A partially contracted tendon has the appearance of a knotted cord with normal portions of tendon between the knots. Only when contraction is maximal is the whole tendon swollen.2. Immersion of the tendon in solutions of CaCl2 markedly affects the temperature at which contraction is induced. The higher the concentration of calcium salt, the lower the temperature at which the tendon will contract; with 48 per cent. of CaCl2 the tendon will contract at 0°C. The relation between concentration and temperature is approximately linear.3. Immersion in solutions of BaCl2 likewise affects the temperature at which contraction is induced. Thirty per cent. BaCl2 causes contraction at 38°C. The relation between concentration and temperature is again linear.The expenses of this research were defrayed by a grant from the James Cooper Fund of M'Gill University for Research in Experimental Medicine.
AN INVESTIGATION INTO THE SIZE OF HUMAN ERYTHROCYTES BEFORE AND AFTER EXERCISE
Authors: Dryerre Henry , Millar W. G. , Ponder Eric 
Published: December 2014

A method for investigating the mean size of human erythrocytes before and after exercise is described. In this method the cells are measured without having been exposed to any atmosphere other than one such as would be in equilibrium with the gaseous content of the blood in the vessel from which they were withdrawn.By this method no difference has been found between the mean diameter of the cells before and after violent exercise.
STUDIES ON THE ARNETH COUNT.—IV. THE DEFLECTION OF THE COUNT BY THYROID INJECTIONS
Authors: Ponder Eric 
Published: December 2014

1. By means of a single injection of thyroid a deflection of the Arneth count is produced, a large number of cells of Class I. being introduced into the circulation. The subsequent changes in the count are followed, and it is shown that the cells of Class I. develop in the blood‐stream into cells of Class II., these into cells of Class III., and so on until Class V. is reached.2. In animals under the conditions of these experiments, the cells leave the blood‐stream principally from Classes IV. and V.3. In the experimental animals used, the duration of time which a polymorph spends in the circulation is from two to three weeks. About 107 polymorphs are produced by the marrow per diem.This research was carried out under a grant from the Government Grants Committee of the Royal Society, and some of the earlier experimental work under a grant from the Medical Research Council.I have to thank Mr K.
Newstead Flint for his careful carrying out of much of the routine work associated with this investigation.
THE ACTION OF dl‐GLYCERIC ALDEHYDE ON THE ISOLATED HEART
Authors: Reeves H. Gordon 
Published: December 2014

Glyceric aldehyde is definitely toxic to the rabbit's heart, and hence it is unlikely that the aldehyde is an intermediate in the utilisation of glucose by mammalian cardiac muscle.In the amphibian, however, glyceric aldehyde is efficient in maintaining, and even increasing, the rhythmic contractions of the excised heart.The expenses of this work were defrayed by a grant from the Government Grants Committee of the Royal Society.
THE ACTION OF DRUGS UPON THE MOVEMENTS OF THE STOMACH
Authors: M'Crea E. D. , Macdonald A. D. 
Published: December 2014

1. Adrenaline may produce both inhibitory or augmentor effects on the stomach of the cat and dog, but its action is chiefly inhibitory. It cannot be said to duplicate the effects of faradic stimulation of the splanchnic nerves.2. Pilocarpine, physostigmine, and acetyl‐choline, like the vagus, can be both augmentor and depressor to the stomach, according to its condition of tonus. Pilocarpine and physostigmine often cause irregular after‐contractions of considerable duration.3. Atropine relaxes and paralyses the stomach‐musculature and abolishes all response to nervous stimulation or to other drugs.4. The effects of ephedrine, ergotamine, strychnine, histamine, and pituitary extracts are briefly described.5. An explanation is advanced of the varying results of nerve‐stimulation and of drugs.