Three broad questions about China's “Belt and Road Initiative” are raised. First, what are likely to be the real objectives behind the Initiative? Second, are investment and trade, considered the ...“major task” of the Initiative by China, to be driven by market-based transactions, or will they be a form of foreign aid that is not based on economic calculation of gains and losses? Third, which of the 60 or so countries in Asia, Europe and Africa along the Belt and Road will likely be the Initiative's priority targets of economic cooperation?
•Three broad questions about China's “Belt and Road Initiative” are discussed.•The Initiative's official objectives would be achieved only in some countries.•Investment and trade under the Initiative will not be driven solely by market.•China should prevent rent-seeking behavior in its preferential policies.•The success of the Initiative will depend on many factors beyond China's control.
The intrinsic electrical characteristics of different types of neurons are shaped by the K
channels they express. From among the more than 70 different K
channel genes expressed in neurons, Kv3 ...family voltage-dependent K
channels are uniquely associated with the ability of certain neurons to fire action potentials and to release neurotransmitter at high rates of up to 1,000 Hz. In general, the four Kv3 channels Kv3.1-Kv3.4 share the property of activating and deactivating rapidly at potentials more positive than other channels. Each Kv3 channel gene can generate multiple protein isoforms, which contribute to the high-frequency firing of neurons such as auditory brain stem neurons, fast-spiking GABAergic interneurons, and Purkinje cells of the cerebellum, and to regulation of neurotransmitter release at the terminals of many neurons. The different Kv3 channels have unique expression patterns and biophysical properties and are regulated in different ways by protein kinases. In this review, we cover the function, localization, and modulation of Kv3 channels and describe how levels and properties of the channels are altered by changes in ongoing neuronal activity. We also cover how the protein-protein interaction of these channels with other proteins affects neuronal functions, and how mutations or abnormal regulation of Kv3 channels are associated with neurological disorders such as ataxias, epilepsies, schizophrenia, and Alzheimer's disease.
An important goal of biomedical research is to translate basic research findings into useful medical advances. In the field of neuropharmacology this requires understanding disease mechanisms as well ...as the effects of drugs and other compounds on neuronal function. Our hope is that this information will result in new or improved treatment for CNS disease. Despite great progress in our understanding of the structure and functions of the CNS, the discovery of new drugs and their clinical development for many CNS disorders has been problematic. As a result, CNS drug discovery and development programs have been subjected to significant cutbacks and eliminations over the last decade. While there has been recent resurgence of interest in CNS targets, these past changes in priority of the pharmaceutical and biotech industries reflect several well-documented realities. CNS drugs in general have higher failure rates than non-CNS drugs, both preclinically and clinically, and in some areas, such as the major neurodegenerative diseases, the clinical failure rate for disease-modifying treatments has been 100%. The development times for CNS drugs are significantly longer for those drugs that are approved, and post-development regulatory review is longer. In this introduction we review some of the reasons for failure, delineating both scientific and technical realities, some unique to the CNS, that have contributed to this. We will focus on major neurodegenerative disorders, which affect millions, attract most of the headlines, and yet have witnessed the fewest successes. We will suggest some changes that, when coupled with the approaches discussed in the rest of this special volume, may improve outcomes in future CNS-targeted drug discovery and development efforts.
This article is part of the Special Issue entitled “Beyond small molecules for neurological disorders”.
•CNS drug discovery and development has been problematic, particularly in the area of acute and chronic neurodegenerative disorders.•These difficulties have resulted in significant cutbacks in CNS drug programs.•Drug targets must be better understood in terms of their role in normal CNS function and in disease.•Animal models of disease and hypothetical drug regimens must better reflect the clinical condition.•Unique combinations may have to be tested, including combinations of drugs which have not independently demonstrated efficacy.•Clinical trials may have to be much longer.
The human superior temporal gyrus (STG) is critical for extracting meaningful linguistic features from speech input. Local neural populations are tuned to acoustic-phonetic features of all consonants ...and vowels and to dynamic cues for intonational pitch. These populations are embedded throughout broader functional zones that are sensitive to amplitude-based temporal cues. Beyond speech features, STG representations are strongly modulated by learned knowledge and perceptual goals. Currently, a major challenge is to understand how these features are integrated across space and time in the brain during natural speech comprehension. We present a theory that temporally recurrent connections within STG generate context-dependent phonological representations, spanning longer temporal sequences relevant for coherent percepts of syllables, words, and phrases.
The human superior temporal gyrus (STG) encodes phonological features relevant for speech perception. Yi et al. describe how direct human neurophysiology has revealed the local and context-dependent nature of STG representations and propose a theory for temporal binding in speech.
Potassium channels in auditory neurons are rapidly modified by changes in the auditory environment. In response to elevated auditory stimulation, short-term mechanisms such as protein phosphorylation ...and longer-term mechanisms such as accelerated channel synthesis increase the amplitude of currents that promote high-frequency firing. It has been suggested that this allows neurons to fire at high rates in response to high sound levels. We have carried out simple simulations of the response to postsynaptic neurons to patterns of neurotransmitter release triggered by auditory stimuli. These demonstrate that the amplitudes of potassium currents required for optimal encoding of a low-amplitude auditory signal differ from those for louder sounds. Specifically, the cross-correlation of the output of a neuron with an auditory stimulus is improved by increasing potassium currents as sound amplitude increases. Temporal fidelity for low-frequency stimuli is improved by increasing potassium currents that activate at negative potentials, while that for high-frequency stimuli requires increases in currents that activate at positive membrane potentials. These effects are independent of the firing rate. Moreover, levels of potassium currents that maximize the fidelity of the output of an ensemble of neurons differ from those that maximize fidelity for a single neuron. This suggests that the modulatory mechanisms must coordinate channel activity in groups of neurons or an entire nucleus. The simulations provide an explanation for the modulation of the intrinsic excitability of auditory brainstem neurons by changes in environmental sound levels, and the results may extend to information processing in other neural systems.
Mutations that increase sodium currents in excitatory neurons typically produce hyperexcitability and epileptic seizures. Paradoxically, mutations that reduce NaV1.2 sodium currents also have a ...similar effect. Two research groups (Spratt et al. and Zhang et al.) have now found that in some excitatory neurons, loss of NaV1.2 increases intrinsic excitability by altering activation and/or expression of potassium channels.
In recent years, high entropy alloys (HEAs) have attracted significant attention due to their excellent mechanical properties and good corrosion resistance, making them potential candidates for high ...temperature fission and fusion structural applications. However there is very little known about their radiation resistance, particularly at elevated temperatures relevant for energy applications. In the present study, a single phase (face centered cubic) concentrated solid solution alloy of composition 27%Fe-28%Ni-27%Mn-18%Cr was irradiated with 3 or 5.8 MeV Ni ions at temperatures ranging from room temperature to 700 °C and midrange doses from 0.03 to 10 displacements per atom (dpa). Transmission electron microscopy (TEM), scanning transmission electron microscopy with energy dispersive x-ray spectrometry (STEM/EDS) and X-ray diffraction (XRD) were used to characterize the radiation defects and microstructural changes. Irradiation at higher temperatures showed evidence of relatively sluggish solute diffusion with limited solute depletion or enrichment at grain boundaries. The main microstructural feature at all temperatures was high-density small dislocation loops. Voids were not observed at any irradiation condition. Nano-indentation tests on specimens irradiated at room temperature showed a rapid increase in hardness ∼35% and ∼80% higher than the unirradiated value at 0.03 and 0.3 dpa midrange doses, respectively. The irradiation-induced hardening was less pronounced for 500 °C irradiations (<20% increase after 3 dpa). Overall, the examined HEA material exhibits superior radiation resistance compared to conventional single phase Fe-Cr-Ni austenitic alloys such as stainless steels. The present study provides insight on the fundamental irradiation behavior of a single phase HEA material over a broad range of irradiation temperatures.
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•Detailed irradiation behavior of a high entropy alloy has been reported for a wide range of irradiation conditions.•Significant suppression in radiation-induced segregation was observed compared to irradiated conventional austenitic Fe-Cr-Ni alloys.•Voids were not observed up to midrange doses of 10 dpa over a wide range of irradiation temperatures.
Natural communication often occurs in dialogue, differentially engaging auditory and sensorimotor brain regions during listening and speaking. However, previous attempts to decode speech directly ...from the human brain typically consider listening or speaking tasks in isolation. Here, human participants listened to questions and responded aloud with answers while we used high-density electrocorticography (ECoG) recordings to detect when they heard or said an utterance and to then decode the utterance's identity. Because certain answers were only plausible responses to certain questions, we could dynamically update the prior probabilities of each answer using the decoded question likelihoods as context. We decode produced and perceived utterances with accuracy rates as high as 61% and 76%, respectively (chance is 7% and 20%). Contextual integration of decoded question likelihoods significantly improves answer decoding. These results demonstrate real-time decoding of speech in an interactive, conversational setting, which has important implications for patients who are unable to communicate.
In speech, the highly flexible modulation of vocal pitch creates intonation patterns that speakers use to convey linguistic meaning. This human ability is unique among primates. Here, we used ...high-density cortical recordings directly from the human brain to determine the encoding of vocal pitch during natural speech. We found neural populations in bilateral dorsal laryngeal motor cortex (dLMC) that selectively encoded produced pitch but not non-laryngeal articulatory movements. This neural population controlled short pitch accents to express prosodic emphasis on a word in a sentence. Other larynx cortical representations controlling voicing and longer pitch phrase contours were found at separate sites. dLMC sites also encoded vocal pitch during a non-speech singing task. Finally, direct focal stimulation of dLMC evoked laryngeal movements and involuntary vocalization, confirming its causal role in feedforward control. Together, these results reveal the neural basis for the voluntary control of vocal pitch in human speech.
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•A human brain area that controls vocal pitch in both speech and song is identified•Two laryngeal functions, voicing and pitch, are encoded by distinct neural populations•A causal role for larynx muscle control is demonstrated through cortical stimulation
The ability to control vocal pitch during speech and singing is encoded by the dorsal laryngeal motor cortex in humans.
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