Olenekian (Early Triassic) bivalves from the Salt Range and Surghar Range,Pakistan

Abstract: Based on newly collected material from the uppermost Smithian and lower to middle Spathian (Olenekian, Lower Triassic) of the Salt Range and Surghar Range (Pakistan), 15 bivalve species belonging to 11 genera are described, including two new genera, Eobuchia and Dimorphoconcha, and one new species, Palaeoneilo? fortistriata. Eobuchia gen. nov. is placed in a new subfamily, the Eobuchiinae, which differs from the Buchiinae in having an almost planar and only moderately inclined or offset right anterior auricle. Inclination of the right anterior auricle is proposed as a synapomorphy of the revised suborder Monotidina, which includes the Buchiidae, Monotidae, Oxytomidae and, tentatively, the Dolponellidae. The Pseudomonotidae, Chaenocardiidae and Claraiidae are discussed as candidate ancestors of the Monotidina. Dimorphoconcha gen. nov., provisionally placed in the Limidae, is a morphologically unusual genus characterized by a globose shell centre and a strongly plicate fringe. Permophorus costatus, which was previously known exclusively from Permian strata, is reported from the Spathian of the Surghar Range. This record extends the range of P. costatus for at least 8 Myr and makes it the first reported Lazarus species, with an outage of more than 2 Myr after the end‐Permian mass extinction. Ten of 15 species recognized in this study have not been reported from other regions, which may indicate increasing provincialism towards the end of the Early Triassic, or, alternatively, reflect the still insufficient knowledge of benthic faunas from the epoch that followed the greatest crisis in the history of life.     

Use of the PI index in predicting toxicity of nitrobenzene derivatives

The PI Index is a Szeged-like topological index developed very recently. It has useful applications in chemistry which are yet to be investigated thoroughly. Herein, we report quantitative structure-toxicity relationship (QSTR) study using the PI Index. We have used 41 monosubstituted nitrobenzene for this purpose. The results have shown that the PI Index alone is not an appropriate index for modelling toxicity of nitrobenzene derivatives. Combinations of the PI Index with other distance-based topological indices resulted into statistically significant models and excellent results are obtained in pentaparametric models. The predictive potential of the models is discussed on the basis of cross-validation method, as well as by estimating root-mean-square error (RMS).     

Mechanisms and significance of spike-timing dependent plasticity

Hebb's original postulate left two important issues unaddressed: (i) what is the effective time window between pre- and postsynaptic activity that will result in potentiation? and (ii) what is the learning rule that underlies decreases in synaptic strength? While research over the past 2 decades has addressed these questions, several studies within the past 5 years have shown that synapses undergo long-term depression (LTD) or long-term potentiation (LTP) depending on the order of activity in the pre- and postsynaptic cells. This process has been referred to as spike-timing dependent plasticity (STDP). Here we discuss the experimental data on STDP, and develop models of the mechanisms that may underlie it. Specifically, we examine whether the standard model of LTP and LTD in which high and low levels of Ca(2+) produce LTP and LTD, respectively, can also account for STDP. We conclude that the standard model can account for a type of STDP in which, counterintuitively, LTD will be observed at some intervals in which the presynaptic cell fires before the postsynaptic cell. This form of STDP will also be sensitive to parameters such as the presence of an after depolarization following an action potential. Indeed, the sensitivity of this type of STDP to experimental parameters suggests that it may not play an important physiological role in vivo. We suggest that more robust forms of STDP, which do not exhibit LTD at pre-before-post intervals, are not accounted for by the standard model, and are likely to rely on a second coincidence detector in addition to the NMDA receptor.     

Considerations for the Use of Anesthetics in Neurotoxicity Studies

Anesthetics are widely used in experiments investigating neurotoxicity and neuroprotection; however, these agents are known to interfere with the outcome of these experiments. The purpose of this overview is to review these effects and suggest methods for minimizing unintended consequences on experimental outcomes. Information on the neuroprotective and neurotoxic effects of isoflurane, dexmedetomidine, propofol, ketamine, barbiturates, halothane, xenon, carbon dioxide, and nitrous oxide is summarized. The pertinent cell signaling pathways of these agents are discussed. Methods of humane animal euthanasia without anesthetics are considered. Most anesthetics alter the processes of neuronal survival and death. When designing survival surgeries, sham controls subjected to anesthesia but not the surgical intervention should be compared with controls subjected to neither anesthesia nor surgery. Additional controls could include using an anesthetic with a different mechanism of action from the primary anesthetic used. Because the effects of anesthetics lessen with time after surgery, survival surgeries should include later time points until at least 7 d after the procedure. Humane methods of animal euthanasia that do not require anesthetics exist and should be used whenever appropriate.Abbreviations: Bcl2, B cell lymphoma 2 protein; CA1, cornu ammonis 1 region; ERK, extracellular regulated kinase; GABA_A, γ-amino butyric acid A receptor; NMDAR, N-methyl D-aspartate receptor; NR, NMDAR subunit; OGD, oxygen–glucose deprivationNumerous molecules, including anesthetics, have been examined for their neuroprotective action, although some studies report neurotoxicity of certain anesthetic agents.^12,34,36,55 Anesthetic agents are widely and appropriately used in the laboratory setting for the humane treatment of animals. However, at times investigators fail to give due consideration to the possibility that these agents may alter the outcome of the experiment. Numerous studies show that anesthetics alter the processes being studied in neurotoxicity experiments.^{1,2,8,10,15,21,25,28,30,32,33,35,61,62,64} In experimental models that use cell viability as an endpoint, anesthetics might interfere with the measurement of the outcome parameter. Anesthetics act through many of the same intracellular pathways involved in neurotoxicity and neuroprotection.¹² The purpose of this overview is to summarize the neuroprotective and neurotoxic effects of anesthetics and to suggest ways of managing their use in laboratory animal research.For obvious humane reasons, research animals are treated with anesthetic agent(s) during common surgical methods of inducing ischemia. Depending on the method, anesthesia may be continued for part or all of the procedure. Clearly any effect of the anesthetic on the processes being studied is important, and sham surgical controls are used to account in part for these undesired effects. Another useful strategy is to allow the animal to serve as its own control by comparing the ipsilateral to contralateral hemisphere in animals exposed to unilateral ischemia. This approach allows the direct effect of the ischemia to be differentiated from nonspecific activation of stress responses or individual genetic variations. To truly test the effects of the anesthetic, these controls should be compared with animals not subjected to either anesthesia or surgery.Often animals undergo surgical implantation of monitoring devices (such as arterial catheters or intracranial pressure monitors) a day or more before surgical ischemia. Although seemingly unrelated to the subsequent experimental paradigm, anesthesia used in these preparative procedures may produce an unintended effect known as preconditioning.⁶⁶ In preconditioning, a subthreshold or subtoxic treatment induces a cascade of neuroprotective mechanisms that lessen the effect of future neurotoxic insults; the preconditioning effect may last from 24 h to as long as 2 wk after the stimulus.⁴³ Obviously, a preconditioning stimulus may interfere with experimental outcomes and can be detrimental to animal studies involving neuronal death and survival. In any experiment in which surgical procedures must be done prior to the primary intervention, animals should be allowed to recover for 1 to 2 wk before proceeding.Animals often are euthanized under anesthesia prior to analysis of the effects of neurotoxic insults or in the determination of neuroprotective properties of a test drug. Although present in the animal''s system for only a short interval before death, an anesthetic may cause effects that persist in the tissue after circulation ceases, thereby potentially affecting cellular characteristics and processes. Appropriate and humane methods of euthanasia that do not require anesthesia, such as microwave irradiation, cervical dislocation or rapid decapitation,³ are sometimes available and should be used whenever possible.Clearly a thorough appreciation of the effects of anesthetics on neurotoxic or neuroprotective processes and information on how anesthesia may affect experimental outcome is essential for designing effective animal studies. Strategies to minimize unwanted influences of anesthetics are important. The anesthetic agents most commonly used in laboratory and clinical studies for which information on neuroprotective or neurotoxic effects exist are isoflurane, dexmedetomidine, propofol, ketamine, barbiturates, halothane, xenon, carbon dioxide (CO₂), and nitrous oxide (N₂O). Urethane, sevoflurane, fentanyl, chloral hydrate, and lidocaine are used less frequently and are less well-studied in regard to neurotoxicity and therefore are beyond the scope of this article. The following sections comprise a discussion of the neuroprotective or neurotoxic effects of each of the commonly used anesthetics.     

Magnetic resonance-guided, real-time targeted delivery and imaging of magnetocapsules immunoprotecting pancreatic islet cells

In type I diabetes mellitus, islet transplantation provides a moment-to-moment fine regulation of insulin. Success rates vary widely, however, necessitating suitable methods to monitor islet delivery, engraftment and survival. Here magnetic resonance-trackable magnetocapsules have been used simultaneously to immunoprotect pancreatic beta-cells and to monitor, non-invasively in real-time, hepatic delivery and engraftment by magnetic resonance imaging (MRI). Magnetocapsules were detected as single capsules with an altered magnetic resonance appearance on capsule rupture. Magnetocapsules were functional in vivo because mouse beta-cells restored normal glycemia in streptozotocin-induced diabetic mice and human islets induced sustained C-peptide levels in swine. In this large-animal model, magnetocapsules could be precisely targeted for infusion by using magnetic resonance fluoroscopy, whereas MRI facilitated monitoring of liver engraftment over time. These findings are directly applicable to ongoing improvements in islet cell transplantation for human diabetes, particularly because our magnetocapsules comprise clinically applicable materials.     

Late-onset adrenal hyperplasia in north Indian hirsute women

The occurrence of late-onset congenital adrenal hyperplasia (CAH) due to 21-hydroxylase deficiency was studied in 60 consecutive hirsute women by means of adrenocorticotrophin (ACTH)-stimulated serum 17-hydroxyprogesterone (17-OHP) levels. Five (8.3%) women had an exaggerated response (ACTH-stimulated 17-OHP 3,160 +/- 560 ng/dl). All of them had regular periods and 3 were virilized. The other 2 were indistinguishable from those with idiopathic hirsutism or polycystic ovarian disease.     

One circuit, two kinds of timing

In this issue of Neuron, Gabernet et al. report an elegant series of in vivo and in vitro experiments that dissect a disynaptic circuit dictating the dynamic transition of cortical spiking responses to whisker stimulation from coincidence detection to temporal integration.     

Timing in the absence of clocks: encoding time in neural network states

Decisions based on the timing of sensory events are fundamental to sensory processing. However, the mechanisms by which the brain measures time over ranges of milliseconds to seconds remain unclear. The dominant model of temporal processing proposes that an oscillator emits events that are integrated to provide a linear metric of time. We examine an alternate model in which cortical networks are inherently able to tell time as a result of time-dependent changes in network state. Using computer simulations we show that within this framework, there is no linear metric of time, and that a given interval is encoded in the context of preceding events. Human psychophysical studies were used to examine the predictions of the model. Our results provide theoretical and experimental evidence that, for short intervals, there is no linear metric of time, and that time may be encoded in the high-dimensional state of local neural networks.