Astrocytes functionally interact with neurons and with other brain cells. Although not electrically excitable, astrocytes display a complex repertoire of intracellular Ca
signalling that evolves in ...space and time within single astrocytes and across astrocytic networks. Decoding the physiological meaning of these dynamic changes in astrocytic Ca
activity has remained a major challenge. This Review describes experimental preparations and methods for recording and studying Ca
activity in astrocytes, focusing on the analysis of Ca
signalling events in single astrocytes and in astrocytic networks. The limitations of existing experimental approaches and ongoing technical and conceptual challenges in the interpretation of astrocytic Ca
events and their spatio-temporal patterns are also discussed.
COVID-19 outbreak unfolds as the biggest challenge of this century by far. Virulence of the disease has compelled densely populated countries like India to impose severest measures, which include ...full or partial lockdown to contain the virus spread. The contagious virus has put the lives of many in urban cities on hold and forced them to abandon or restrict regular activities, which includes a basic human need to travel to satisfy one's daily needs. The eventual impact of the pandemic on individual mobility and the urban city's sustainability depends upon the resilience of medium and long-term policies during such disruptive events.
In order to gauge the impact of this unprecedented disease on travel behavior and mobility patterns of individuals, a web survey is conducted in urban agglomerations of India. The idea is to record travel mode choices before, during and after situations. The study also attempts to elicit responses towards a safer and disaster-resilient public transport, which can also cater to the needs of private vehicle-owning individuals. Further, the study presents and evaluates a set of medium to long-term policy prescriptions to negate the repercussions of this crisis and seize the opportunity it has created so that the long-held dream of sustainable and resilient cities in the context of urban mobility is realized in the best way possible.
The study findings indicate an increase in the car-dependency pan-India level post the COVID-19 crisis. Strikingly the captive users of public transport and non-motorized transport mode (walk) are also willing to make a shift towards private motorized vehicles (car, motorized two-wheeler). The eventual mobility shift will depend upon- (a) the recovery period of mass transportation systems to normalcy (b) investments and promotion of active travel modes (non-motorized transport, i.e., walk, bicycle). The findings also reveal that demand and the willingness to pay extra for a safer, faster, cleaner, comfortable, and most importantly, resilient public transport exists. Further, policy evaluations for sustainable and resilient recovery reveal - (a) the provision of bicycle superhighway will push the bicycle share from 31% to approximately 44% (b) travel demand moderation efforts such as (i) staggering of working days demonstrates the reduction in the congestion externalities. (ii) Flexible arrangements for educational activities (two shifts in a day) facilitates overall gain in the system welfare, and (c) incentive such as reducing public transport fare has a positive impact on its share due to the mobility-shift from the private motorized vehicle.
Investment and encouragement of active travel mode should be prioritized for personal well-being and disaster-resilient cities. Resilience planning should be an integral part of public transportation systems to handle the future shock of pandemics and other emergencies. Additionally, self-sustainable neighborhoods should be encouraged to reduce the trip lengths substantially or the need for private motorized transport for various secondary activities.
•Online survey to gauge COVID-19 disruptions on travel choices indicates mobility-shift in megacities of India.•Longer recovery for Mass Transit systems nudge to a rise in private motorized transport.•Demand as well as willingness to pay extra for resilient public transport exists.•In short-mid run, work from home, staggering of primary activities and incentivize PT are likely to be effective.•In long-run, investment in active travel modes can give significant returns for building sustainable and resilient cities.
We investigate the possibility of band structure engineering in the recently predicted 2D layered form of blue phosphorus via an electric field (E sub(z)) applied perpendicular to the layer(s). Using ...density functional theory, we study the effect of a transverse electric field in monolayer as well as three differently stacked bilayer structures of blue phosphorus. We find that for E sub(z) > 0.2 V/Angstrom the direct energy gap at the Gamma point, which is much larger than the default indirect band gap of mono- and bilayer blue phosphorus, decreases linearly with the increasing electric field, becomes comparable to the default indirect band gap at E sub(z) asymptotically = 0.45 (0.35) V/Angstrom for monolayer (bilayers), and decreases further until the semiconductor to metal transition of 2D blue phosphorus takes place at E sub(z) asymptotically = 0.7 (0.5) V/Angstrom for monolayer (bilayers). Calculated values of the electron and hole effective masses along various high symmetry directions in the reciprocal lattice suggests that the mobility of charge carriers is also influenced by the applied electric field.
Berry curvature in Weyl semimetals leads to intriguing magnetoconductivity and magnetothermal transport properties. Here, we explore the impact of the tilting of the Weyl nodes on the ...magnetoconductivity of type-I and type-II Weyl semimetals using the Berry-curvature-connected Boltzmann transport formalism. We find that in addition to the quadratic magnetic field (B) corrections induced by the tilt, there are also anisotropic and B-linear corrections in several elements of the conductivity matrix. For the case of magnetic field applied perpendicular to the tilt direction, we show the existence of previously unexplored B-linear transverse conductivity components. For the other case of magnetic field applied parallel to the tilt axis, the B-linear corrections appear in the longitudinal conductivity, giving rise to anisotropic magnetoresistance measurements. Our systematic analysis of the full magnetoconductivity matrix predicts several specific experimental signatures related to the tilting of the Weyl nodes in both type-I and type-II Weyl semimetals.
We present a detailed TCAD analysis of the impact of length scaling and the associated short-channel effects in the subthreshold regime of the two classes of double-gate negative capacitance ...transistors (NCFETs): metal-ferroelectric-metal-insulator-semiconductor (MFMIS) and metal-ferroelectric-insulator-semiconductor (MFIS). Our TCAD formulation takes into account both the out-of-plane and in-plane components of ferroelectric polarization. Contrary to the conventional FETs, both the configurations of NCFETs exhibit increase in the threshold voltage (<inline-formula> <tex-math notation="LaTeX">{V}_{t} </tex-math></inline-formula>), reduction in subthreshold swing (SS), and drain-induced barrier lowering with scaling due to inner and outer fringing electric field effects. The existence of the internal metal layer causes these effects to be significantly higher in the MFMIS structure than the MFIS, where the fringing field impact remains confined to the channel edges only. The above-mentioned unconventional short-channel effects increase with the inclusion of spacer regions of high permittivity in both the MFMIS and MFIS devices. We also analyze the impact of source/drain doping on fringing field coupling to the ferroelectric and find that a higher doping of these regions improves the subthreshold characteristics of NCFETs, in contrast to conventional FETs.
Issue Title: Special Issue on COLT 2006; Guest Editors: Avrim Blum, Gabor Lugosi and Hans Ulrich Simon In an online convex optimization problem a decision-maker makes a sequence of decisions, i.e., ...chooses a sequence of points in Euclidean space, from a fixed feasible set. After each point is chosen, it encounters a sequence of (possibly unrelated) convex cost functions. Zinkevich (ICML 2003) introduced this framework, which models many natural repeated decision-making problems and generalizes many existing problems such as Prediction from Expert Advice and Cover's Universal Portfolios. Zinkevich showed that a simple online gradient descent algorithm achieves additive regretO(SQRT T), for an arbitrary sequence of T convex cost functions (of bounded gradients), with respect to the best single decision in hindsight. In this paper, we give algorithms that achieve regret O(log(T)) for an arbitrary sequence of strictly convex functions (with bounded first and second derivatives). This mirrors what has been done for the special cases of prediction from expert advice by Kivinen and Warmuth (EuroCOLT 1999), and Universal Portfolios by Cover (Math. Finance 1:1-19, 1991). We propose several algorithms achieving logarithmic regret, which besides being more general are also much more efficient to implement. The main new ideas give rise to an efficient algorithm based on the Newton method for optimization, a new tool in the field. Our analysis shows a surprising connection between the natural follow-the-leader approach and the Newton method. We also analyze other algorithms, which tie together several different previous approaches including follow-the-leader, exponential weighting, Cover's algorithm and gradient descent. PUBLICATION ABSTRACT
Cigarette smoke (CS)-induced alveolar destruction and energy metabolism changes are known contributors to the pathophysiology of chronic obstructive pulmonary disease (COPD). This study examines the ...effect of CS exposure on metabolism in alveolar type II cells. Male A/J mice (8 wk old) were exposed to CS generated from a smoking machine for 4 or 8 weeks, and a recovery group was exposed to CS for 8 weeks and allowed to recover for 2 weeks. Alveolar type II cells were isolated from air- or CS- exposed mice. Acute CS exposure led to a reversible airspace enlargement in A/J mice as measured by the increase in mean linear intercept, indicative of alveolar destruction. The effect of CS exposure on cellular respiration was studied using the XF Extracellular Flux Analyzer. A decrease in respiration while metabolizing glucose was observed in the CS-exposed group, indicating altered glycolysis that was compensated by an increase in palmitate utilization; palmitate utilization was accompanied by an increase in the expression of CD36 and carnitine-palmitoyl transferase 1 in type II alveolar cells for the transport of palmitate into the cells and into mitochondria, respectively. The increase in palmitate use for energy production likely affects the surfactant biosynthesis pathway, as evidenced by the decrease in phosphatidylcholine levels and the increase in phospholipase A2 activity after CS exposure. These findings help our understanding of the mechanism underlying the surfactant deficiency observed in smokers and provide a target to delay the onset of COPD.
The antiapoptotic proteins BCL-2 and myeloid cell leukemia sequence 1 (MCL-1) promote multiple myeloma (MM) cell survival. Venetoclax is a selective, orally bioavailable small-molecule BCL-2 ...inhibitor; bortezomib can indirectly inhibit MCL-1. In preclinical studies, venetoclax enhanced bortezomib activity, suggesting that cotargeting of BCL-2 and MCL-1 could be an effective treatment strategy in myeloma. This phase 1b trial studied patients with relapsed/refractory MM receiving daily venetoclax (50-1200 mg per designated dose cohort; 800 mg in safety expansion) in combination with bortezomib and dexamethasone. A total of 66 patients were enrolled (54 in the dose-escalation cohorts and 12 in the safety expansion). Patients had received a median of 3 prior therapies (range, 1-13); 26 (39%) were refractory to prior bortezomib and 35 (53%) to lenalidomide; 39 (59%) had prior stem cell transplant. The combination was generally well tolerated, and common adverse events included mild gastrointestinal toxicities (diarrhea 46%, constipation 41%, and nausea 38%) and grade 3/4 cytopenias (thrombocytopenia 29% and anemia 15%). The overall response rate (ORR) was 67% (44/66); 42% achieved very good partial response or better (≥VGPR). Median time to progression and duration of response were 9.5 and 9.7 months, respectively. ORR of 97% and ≥VGPR 73% were seen in patients not refractory to bortezomib who had 1 to 3 prior therapies. Patients with high BCL2 expression had a higher ORR (94% 17/18) than patients with low BCL2 expression (59% 16/27). This novel combination of venetoclax with bortezomib and dexamethasone has an acceptable safety profile and promising efficacy in patients with relapsed/refractory MM. This trial was registered at www.clinicaltrials.gov as #NCT01794507.
•In relapsed/refractory MM, venetoclax plus bortezomib and dexamethasone appears to be safe and efficacious.•This is a novel therapeutic approach for MM.
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The inwardly rectifying K
channel K
4.1 is broadly expressed by CNS glia and deficits in K
4.1 lead to seizures and myelin vacuolization. However, the role of oligodendrocyte K
4.1 channels in ...controlling myelination and K
clearance in white matter has not been defined. Here, we show that selective deletion of K
4.1 from oligodendrocyte progenitors (OPCs) or mature oligodendrocytes did not impair their development or disrupt the structure of myelin. However, mice lacking oligodendrocyte K
4.1 channels exhibited profound functional impairments, including slower clearance of extracellular K
and delayed recovery of axons from repetitive stimulation in white matter, as well as spontaneous seizures, a lower seizure threshold, and activity-dependent motor deficits. These results indicate that K
4.1 channels in oligodendrocytes play an important role in extracellular K
homeostasis in white matter, and that selective loss of this channel from oligodendrocytes is sufficient to impair K
clearance and promote seizures.
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