Three-dimensional feedback processes in current-driven metal.

Using three-dimensional (3D) magnetohydrodynamic simulations, we study how a pit on a metal surface evolves when driven by intense electrical current density j. Redistribution of j around the pit initiates a feedback loop: j both reacts to and alters the electrical conductivity σ, through Joule heating and hydrodynamic expansion, so that j and σ are constantly in flux. Thus, the pit transforms into larger striation and filament structures predicted by the electrothermal instability theory. Both structures are important in applications of current-driven metal: The striation constitutes a density perturbation that can seed the magneto-Rayleigh-Taylor instability, while the filament provides a more rapid path to plasma formation, through 3D j redistribution. Simulations predict distinctive self-emission patterns, thus allowing for experimental observation and comparison.

Seeding the Electrothermal Instability through a Three-Dimensional, Nonlinear Perturbation.

Electrothermal instability plays an important role in applications of current-driven metal, creating striations (which seed the magneto-Rayleigh-Taylor instability) and filaments (which provide a more rapid path to plasma formation). However, the initial formation of both structures is not well understood. Simulations show for the first time how a commonly occurring isolated defect transforms into the larger striation and filament, through a feedback loop connecting current and electrical conductivity. Simulations have been experimentally validated using defect-driven self-emission patterns.

First-in-class Microbial Ecosystem Therapeutic 4 (MET4) in combination with immune checkpoint inhibitors in patients with advanced solid tumors (MET4-IO trial).

BACKGROUND: The intestinal microbiome has been associated with response to immune checkpoint inhibitors (ICIs) in humans and causally implicated in ICI responsiveness in animal models. Two recent human trials demonstrated that fecal microbiota transplant (FMT) from ICI responders can rescue ICI responses in refractory melanoma, but FMT has specific limitations to scaled use. PATIENTS AND METHODS: We conducted an early-phase clinical trial of a cultivated, orally delivered 30-species microbial consortium (Microbial Ecosystem Therapeutic 4, MET4) designed for co-administration with ICIs as an alternative to FMT and assessed safety, tolerability and ecological responses in patients with advanced solid tumors. RESULTS: The trial achieved its primary safety and tolerability outcomes. There were no statistically significant differences in the primary ecological outcomes; however, differences in MET4 species relative abundance were evident after randomization that varied by patient and species. Increases in the relative abundance of several MET4 taxa, including Enterococcus and Bifidobacterium, taxa previously associated with ICI responsiveness, were observed and MET4 engraftment was associated with decreases in plasma and stool primary bile acids. CONCLUSIONS: This trial is the first report of the use of a microbial consortium as an alternative to FMT in advanced cancer patients receiving ICI and the results justify the further development of microbial consortia as a therapeutic co-intervention for ICI treatment in cancer.

Effect of sex on torque, recovery, EMG, and MMG responses to fatigue.

OBJECTIVE: The purpose of the present investigation was to examine the effect of sex on maximal voluntary isometric contraction (MVIC) torque and the EMG and MMG responses as a result of fatiguing, intermittent, submaximal (65% of MVIC), isometric elbow flexion muscle contractions. METHODS: Eighteen men and women performed MVIC trials before (pretest), after (posttest), and 5-min after (5-min recovery) performing 50 intermittent, submaximal isometric muscle contractions. Surface electromyographic (EMG) and mechanomyographic (MMG) signals were simultaneously recorded from the biceps brachii muscle. RESULTS: As a result of the fatiguing workbout torque decreased similarly from pretest to posttest for both the men (24.0%) and women (23.3%). After 5-min of recovery, torque had partially recovered for the men, while torque had returned to pretest levels for the women. For both sexes, from pretest to posttest EMG mean power frequency and MMG amplitude decreased, but returned to pretest levels after 5-min of recovery. CONCLUSIONS: In the present study, there were sex-related differences in muscle fatigue that were not associated with the EMG or MMG responses.

Effects of fatiguing constant versus alternating intensity intermittent isometric muscle actions on maximal torque and neuromuscular responses.

OBJECTIVE: To determine the effects of constant versus alternating applications of torque during fatiguing, intermittent isometric muscle actions of the leg extensors on maximal voluntary isometric contraction (MVIC) torque and neuromuscular responses. METHODS: Sixteen subjects performed two protocols, each consisting of 50 intermittent isometric muscle actions of the leg extensors with equal average load at a constant 60% MVIC or alternating 40 then 80% (40/80%) MVIC with a work-to-rest ratio of 6-s on and 2-s off. MVIC torque as well as electromyographic signals from the vastus lateralis (VL), vastus medialis (VM), and rectus femoris (RF) and mechanomyographic signals from the VL were recorded pretest, immediately posttest, and 5-min posttest. RESULTS: The results indicated that there were no time-related differences between the 60% MVIC and 40/80% MVIC protocols. The MVIC torque decreased posttest (22 to 26%) and remained depressed 5-min posttest (9%). There were decreases in electromyographic frequency (14 to 19%) and mechanomyographic frequency (23 to 24%) posttest that returned to pretest levels 5-min posttest. There were no changes in electromyographic amplitude and mechanomyogrpahic amplitude. CONCLUSIONS: These findings suggested that these neuromuscular parameters did not track the fatigue-induced changes in MVIC torque after 5-min of recovery.

Four weeks of high- versus low-load resistance training to failure on the rate of torque development, electromechanical delay, and contractile twitch properties.

The purpose of this study was to investigate the effects of 4-weeks of high- versus low-load resistance training to failure on rate of torque development (RTD), electromechanical delay (EMD), and contractile twitch characteristics. Fifteen men (mean±SD; age=21.7±2.4 yrs) were randomly assigned to either a high- (80% 1RM; n=7) or low-load (30% 1RM; n=8) training group and completed elbow flexion resistance training to failure 3 times per week for 4 weeks. The participants were tested at baseline, 2-, and 4-weeks of training. Peak RTD (pRTDV) and RTD at 0-30 (RTD30V), 0-50 (RTD50V), 0-100 (RTD100V), and 0-200 (RTD200V) ms, integrated EMG amplitude (iEMG) at 0-30, 0-50, and 0-100 ms, and EMD were quantified during maximal voluntary isometric muscle actions. Peak twitch torque, peak RTD, time to peak twitch, 1/2 relaxation time and the peak relaxation rate were quantified during evoked twitches. Four weeks of high-load, but not low-load resistance training, increased RTD200V. There were also increases in iEMG during the first 30 ms of muscle activation for the high- and low-load groups, which may have indirectly indicated increases in early phase motor unit recruitment and/or firing frequency. There were no significant training-induced adaptations in EMD or contractile twitch properties.

Electromyographic Responses from the Vastus Medialis during Isometric Muscle Actions.

This study examined the electromyographic (EMG) responses from the vastus medialis (VM) for electrodes placed over and away from the innervation zone (IZ) during a maximal voluntary isometric contraction (MVIC) and sustained, submaximal isometric muscle action. A linear electrode array was placed on the VM to identify the IZ and muscle fiber pennation angle during an MVIC and sustained isometric muscle action at 50% MVIC. EMG amplitude and frequency parameters were determined from 7 bipolar channels of the electrode array, including over the IZ, as well as 10 mm, 20 mm and 30 mm proximal and distal to the IZ. There were no differences between the channels for the patterns of responses for EMG amplitude or mean power frequency during the sustained, submaximal isometric muscle action; however, there were differences between channels during the MVIC. The results of the present study supported the need to standardize the placement of electrodes on the VM for the assessment of EMG amplitude and mean power frequency. Based on the current findings, it is recommended that electrode placements be distal to the IZ and aligned with the muscle fiber pennation angle during MVICs, as well as sustained, submaximal isometric muscle actions.

Pronounced polarization-induced energy level shifts at boundaries of organic semiconductor nanostructures.

Organic semiconductor devices rely on the movement of charge at and near interfaces, making an understanding of energy level alignment at these boundaries an essential element of optimizing materials for electronic and optoelectronic applications. Here we employ low temperature scanning tunneling microscopy and spectroscopy to investigate a model system: two-dimensional nanostructures of the prototypical organic semiconductor, PTCDA (3,4,9,10-perylenetetracarboxylic dianhydride) adsorbed on NaCl (2 ML)/Ag(111). Pixel-by-pixel scanning tunneling spectroscopy allows mapping of occupied and unoccupied electronic states across these nanoislands with sub-molecular spatial resolution, revealing strong electronic differences between molecules at the edges and those in the centre, with energy level shifts of up to 400 meV. We attribute this to the change in electrostatic environment at the boundaries of clusters, namely via polarization of neighbouring molecules. The observation of these strong shifts illustrates a crucial issue: interfacial energy level alignment can differ substantially from the bulk electronic structure in organic materials.

HIGH-PRESSURE PHYSICS. Direct observation of an abrupt insulator-to-metal transition in dense liquid deuterium.

Eighty years ago, it was proposed that solid hydrogen would become metallic at sufficiently high density. Despite numerous investigations, this transition has not yet been experimentally observed. More recently, there has been much interest in the analog of this predicted metallic transition in the dense liquid, due to its relevance to planetary science. Here, we show direct observation of an abrupt insulator-to-metal transition in dense liquid deuterium. Experimental determination of the location of this transition provides a much-needed benchmark for theory and may constrain the region of hydrogen-helium immiscibility and the boundary-layer pressure in standard models of the internal structure of gas-giant planets.

Physiological Responses during Cycle Ergometry at a Constant Perception of Effort.

13 subjects performed an incremental test to exhaustion, 4, 8-min submaximal rides, and a 1-h ride at the rating of perceived exertion (RPE) that corresponded to the physical working capacity at the OMNI threshold (PWC(OMNI)) to examine: 1) the oxygen consumption (V̇O2), heart rate (HR), minute ventilation (+V̇(E)), respiratory frequency (FR), and power output responses during 1-h work bouts at a constant RPE that corresponded to the PWC(OMNI); and 2) the ability of current models to explain the responses for physiological and perceptual parameters during the 1-h work bouts. The RPE that corresponded to the PWC(OMNI) represented a sustainable exercise intensity (56±5% (V̇O(2Peak)) within the moderate-intensity domain. The mean, normalized slope coefficients for the V̇O2, +V̇(E), and power output vs. time relationships during the 1-h rides were significantly less than zero. The mean, normalized slope coefficient for the FR vs. time relationship during the 1-h rides, however, was not significantly different from zero. Thus, RPE most clearly tracked FR responses during the 1-h rides. It was hypothesized that afferent feedback from respiratory muscles may have mediated the perception of effort during cycle ergometry at a constant RPE in the moderate-intensity domain.

The rate of torque development: a unique, non-invasive indicator of eccentric-induced muscle damage?

This study examined the time courses of recovery for isometric peak torque and rate of torque development (RTD) after eccentric-induced muscle damage. 18 men completed 6 sets of 10 maximal eccentric isokinetic muscle actions at 30° · s(-1). Peak torque, peak RTD and RTD at 10 (RTD10), 50 (RTD50), 100 (RTD100) and 200 ms (RTD200), serum creatine kinase and lactate dehydrogenase were measured before (PRE), immediately after (POST), 24, 48 and 72 h after eccentric exercise. Creatine kinase and lactate dehydrogenase increased from 139 to 6 457 and from 116 to 199 IU · L(-1) from PRE to 72 h, respectively. Peak torque and all RTDs decreased at POST. Peak torque and RTD200 remained lower than PRE through 72 h. Peak RTD remained lower than PRE through 48 h, but was not different from PRE at 72 h. RTD10 and RTD100 were lower than PRE through 24 h, but were not different from PRE at 48 and 72 h. RTD50 decreased at POST, but was not different from PRE at 24 h. Early phase RTDs recovered more quickly than PT and RTD200. Early phase RTDs may reflect neural mechanisms underlying eccentric-induced force decrements, while late RTDs may describe the same physiological mechanisms as PT.

Nanosecond electrical explosion of thin aluminum wires in a vacuum: experimental and computational investigations.

Experimental and computational investigations of nanosecond electrical explosion of a thin Al wire in vacuum are presented. We have demonstrated that increasing the current rate leads to increased energy deposited before voltage collapse. The experimental evidence for synchronization of the wire expansion and light emission with voltage collapse is presented. Hydrocarbons are indicated in optical spectra and their influence on breakdown physics is discussed. The radial velocity of low-density plasma reaches a value of approximately 100 km/s. The possibility of an over-critical phase transition due to high pressure is discussed. A one-dimensional magnetohydrodynamic (MHD) simulation shows good agreement with experimental data. The MHD simulation demonstrates separation of the exploding wire into a high-density cold core and a low-density hot corona as well as fast rejection of the current from the wire core to the corona during voltage collapse. Important features of the dynamics for the wire core and corona follow from the MHD simulation and are discussed.

Wavelength-dependent measurements of optical-fiber transit time, material dispersion, and attenuation.

A new, to our knowledge, method for measuring the wavelength dependence of the transit time, material dispersion, and attenuation of an optical fiber is described. We inject light from a 4-ns rise-time pulsed broadband flash lamp into fibers of various lengths and record the transmitted signals with a time-resolved spectrograph. Segments of data spanning a range of approximately 3000 A are recorded from a single flash-lamp pulse. Comparison of data acquired with short and long fibers enables the determination of the transit time and the material dispersion as functions of wavelength dependence for the entire recorded spectrum simultaneously. The wavelength-dependent attenuation is also determined from the signal intensities. The method is demonstrated with experiments using a step-index 200-mum-diameter SiO(2) fiber. The results agree with the transit time determined from the bulk glass refractive index to within ?0.035% for the visible (4000-7200-A) spectrum and 0.12% for the UV (2650-4000-A) spectrum and with the attenuation specified by the fiber manufacturer to within ?10%.

Pressor systems involved in the maintenance of arterial pressure after lesions of the rostral ventrolateral medulla.

The current study examined three pressor systems which might support mean arterial pressure (MAP) after lesions of the rostral ventrolateral medulla (RVLM). In two protocols, bilateral electrolytic lesions or sham lesions were placed in the RVLM of rats anesthetized with sodium pentobarbital. In the first protocol, the following drugs were given sequentially after placement of the lesions: captopril (5 mg/kg) and d-pentamethylene methylated tyrosine (30 micrograms/kg), a vascular arginine-vasopressin antagonist (AVPX). A final procedure consisted of spinal-cord transection. The second protocol was identical to the first except that the order of drug administration was reversed. In the first protocol, RVLM lesions caused a slight, but statistically significant, decrease in MAP from 118 +/- 3 mmHg to 103 +/- 5 mmHg. After captopril and AVPX, MAP further decreased to 87 +/- 5 mmHg and 62 +/- 4 mmHg, respectively. The MAP fell to 38 +/- 2 mmHg after spinal-cord transection. In the sham-lesion group, MAP rose slightly from 127 +/- 6 mmHg to 134 +/- 7 mmHg after placement of the sham lesions. A significant reduction in MAP was not seen until after administration of AVPX, which decreased MAP to 103 +/- 6 mmHg. Spinal-cord transection substantially lowered MAP to 36 +/- 4 mmHg. In the second protocol, RVLM lesions had no effect on MAP. Administration of AVPX had little effect on MAP (before: 117 +/- 5 mmHg; after: 102 +/- 7 mmHg). In contrast, sequential administration of captopril substantially decreased MAP to 55 +/- 5 mmHg. Spinal cord transection lowered MAP to 33 +/- 1 mmHg. A decrease in MAP in the companion sham-lesion group was not seen until after administration of captopril (before: 109 +/- 8 mmHg; after: 89 +/- 11 mmHg). The greatest fall in MAP followed spinal cord transection (to 39 +/- 6 mmHg). These results demonstrate normotension after RVLM lesions despite a marked reduction in sympathetic vasomotor activity. They also indicate that, after RVLM lesions, arterial pressure is maintained mainly by activity of the renin-angiotensin system and by AVP secretion.

Skeletal troponin C reduces contractile sensitivity to acidosis in cardiac myocytes from transgenic mice.

Depressed contractile function plays a primary role in the pathophysiology of acute myocardial ischemia. Intracellular acidification is an important factor underlying the inhibition of force production in the ischemic myocardium. The effect of acidosis to depress contractility is markedly greater in cardiac as compared to skeletal muscle; however, the molecular basis of this difference in sensitivity to acidosis is not clearly understood. In this report, we describe transgenic mice that express the fast skeletal isoform of troponin C (sTnC) in cardiac muscle. In permeabilized single cardiac myocytes the shift in the midpoint of the tension-pCa relationship (i.e., pCa50, where pCa is -log[Ca2+]) due to lowering pH from 7.00 to 6.20 was 1.27 +/- 0.03 (n = 7) pCa units in control cardiac TnC (cTnC) expressing myocytes and 0.96 +/- 0.04 (n = 11) pCa unit in transgenic cardiac myocytes (P < 0.001). The effect of pH to alter maximum Ca(2+)-activated tension was unchanged by TnC isoforms in these cardiac myocytes. In a reciprocal experiment, contractile sensitivity to acidosis was increased in fast skeletal muscle fibers following extraction of endogenous sTnC and reconstitution with purified cTnC in vitro. Our findings demonstrate that TnC plays an important role in determining the profound sensitivity of cardiac muscle to acidosis and identify cTnC as a target for therapeutic interventions designed to modify ischemia-induced myocardial contractile dysfunction.

Collision-like interactions between acoustic and electrical signals that produce startle reflexes in reticular formation sites.

A startle-like response can be evoked at low currents by one-pulse electrical stimulation of reticular formation sites from the rostrolateral pons to the caudomedial medulla. To test whether this response is mediated by the same reticular formation neurons as those that mediate the acoustic startle, we delivered a brief, subthreshold acoustic stimulus followed by an 0.1-ms electrical pulse to one side of the reticular formation of rats. The current thresholds for electrical startle were usually powerfully reduced (50-80%) whenever the acoustic stimulation was presented within 5 ms of the electrical pulse. This summation was, however, interrupted by brief (0.2-1.0 ms) spike-like increases in threshold when the electrical pulse was delivered 4.0-4.6 ms after the offset of the acoustic stimulus. The timing of the spike-like increase in threshold shifted to longer intervals in more caudal sites, consistent with the conduction of action potentials in the startle pathway. For example, the increase occurred at an interval of 4.1 ms near the ventral lateral lemniscus (VLL) and at intervals of 4.4-4.6 ms for sites in the pontine or medullary reticular formation. The increases in startle threshold are attributed to collisions between antidromic action potentials evoked by the electrical pulses and orthodromic action potentials evoked by the acoustic stimuli. These results suggest that the neurons in reticular formation that produce the acoustic startle reflex overlap greatly with the neurons that mediate electrically evoked startle-like responses. Also, the acoustic signals mediating the startle reflex must be, in large part, a synchronous volley of action potentials conducted by longitudinal bundles of reticular formation axons.

Cardiovascular effects of lesions of the rostral ventrolateral medulla and the nucleus reticularis parvocellularis in rats.

This study explored the possibility that the nucleus reticularis parvocellularis (NRP) acts in concert with the rostral ventrolateral medulla (RVLM) in the maintenance of mean arterial pressure (MAP). Bilateral electrolytic or chemical lesions (kainic acid) were placed in three groups of rats anesthetized with sodium pentobarbital. In the different groups, lesions were placed only in the NRP or RVLM or in both the NRP and RVLM (NRPRVLM). Captopril (5 mg/kg, i.v.) and an arginine vasopressin antagonist (AVPX), d-pentamethylene methylated tyrosine (30 micrograms/kg, i.v.), were sequentially administered. A final procedure consisted of spinal cord transection. The RVLM lesions did not significantly alter MAP (before: 116 +/- 3 mmHg; after: 106 +/- 5 mmHg). Sequential administration of captopril and AVPX each reduced MAP to 87 +/- 5 mmHg and 62 +/- 4 mmHg, respectively. Spinal-cord transection lowered MAP to 38 +/- 2 mmHg. Lesions of the NRP also did not alter MAP (before: 113 +/- 4 mmHg; after: 118 +/- 5 mmHg). Captopril reduced MAP to 109 +/- 7 mmHg, AVPX had no effect, and spinal-cord transection decreased MAP to 31 +/- 3 mmHg. In contrast to the lack of effect of lesions of the RVLM or NRP on MAP, profound hypotension was observed after NRPRVLM lesions (before: 113 +/- 3 mmHg; after: 51 +/- 3 mmHg). Subsequent administration of captopril decreased MAP to 39 +/- 2 mmHg, and AVPX lowered MAP to 32 +/- 1 mmHg. Spinal-cord transection reduced MAP to 23 +/- 1 mmHg. Several conclusions can be drawn from this study. First, lesions of the RVLM do not decrease MAP because of compensation by the renin-angiotensin system and AVP secretion which is mediated by the NRP. Second, lesions of the NRP do not affect MAP because the intact RVLM can maintain sympathetic tone. Third, the profound hypotension observed after NRPRLVM lesions occurred because of the simultaneous impairment of sympathetic vasomotor activity and the neuroendocrine vasoconstrictor effects of the renin-angiotensin system and AVP secretion.

The dysphoria of heroin addiction.

Levels of dysphoria and opioid dependence were assessed in 54 male patients with heroin addiction applying for drug treatment. During a period of naturalistic heroin use, symptom measures of dysphoria and of spontaneous opioid withdrawal reported by these patients were highly correlated. Upon admission to treatment, levels of dysphoria and opioid withdrawal were assessed before and after a pharmacological challenge with either 0.4 mg naloxone or placebo. Signs and symptoms of opioid withdrawal and symptoms of dysphoria increased in patients following naloxone, but not placebo administration. Naloxone-induced changes in symptoms of dysphoria were correlated with changes in opioid withdrawal as assessed by both subjective and objective measures. These findings suggest that dysphoric mood states in heroin addicts may be, in part, pharmacological sequelae of their drug dependence. Dysphoria due to opioid withdrawal may contribute to the initiation and maintenance of heroin use, and to the high rates of syndromal affective disorders reported in this population.

Clinical characteristics of naloxone-precipitated withdrawal in human opioid-dependent subjects.

Studies were conducted to investigate the clinical characteristics of naloxone-precipitated withdrawal in human opioid-dependent subjects. Each of 20 male patients stabilized on 24 mg of methadone daily received two i.v. pharmacological challenges: one with naloxone (0.05, 0.10, 0.15 and 0.20 mg; five patients each dose), and one with saline placebo. Measures of opioid withdrawal, affective state, cognitive performance and changes in autonomic parameters were assessed after each pharmacological challenge. Naloxone produced dose-dependent increases in opiate withdrawal scale scores and in symptoms of dysphoria as measured by the Profile of Mood States. Differences within subjects between naloxone and placebo infusions in Profile of Mood States scores were highly correlated with differences in opioid withdrawal as assessed by both subjective and objective rating scales. Naloxone also produced substantial increases in pulse, systolic and diastolic blood pressure and respiratory rate, as well as a small decrease in temperature. However, naloxone-induced changes from base-line values in these autonomic parameters correlated only modestly with other measures of opioid withdrawal. No differences between infusions were observed in two measures of cognitive performance (Stroop Color and Word Test, Digit Span Test). The results indicate that dysphoric mood states reflecting a broad range of affective experience must be considered as integral components of the naloxone-precipitated opioid withdrawal syndrome.

Engineering the cardiovascular system. Blood pressure regulation.

We have generated several lineages of transgenic mice that exhibit chronic elevations in the steady-state concentration of atrial natriuretic factor (ANF) in the peripheral circulation. ANF, a peptide hormone synthesized primarily by atrial cardiomyocytes, is a potent natriuretic and diuretic. ANF also reduces blood pressure transiently when acutely administered. To address the potential role of ANF in chronic cardiovascular regulation, we generated transgenic mice that express the ANF gene in the liver. The fusion genes comprised either the mouse transthyretin (TTR) or rat phosphoenolpyruvate carboxykinase (PEPCK) promoters fused to the mouse ANF structural gene and were designed to target to the liver constitutive and inducible expression of pre-pro-ANF, respectively. Transgenic animals harboring the TTR-ANF fusion gene expressed chimeric ANF transcripts exclusively in the liver. In contrast, mice harboring the PEPCK-ANF fusion gene did not express detectable amounts of ANF mRNA in liver even after induction (24-hour fasting). In the TTR-ANF mice, hepatic and plasma immunoreactive ANF concentrations were proportional to the concentration of hepatic ANF transcripts. Moreover, mean arterial blood pressure recorded in conscious transgenic mice was inversely proportional to hepatic ANF expression. These transgenic models demonstrate that chronically elevated ANF concentration can induce sustained hypotension.