Persistent Phase Research Articles

Rate of Prolonged Response after Stopping Thrombopoietin-Receptor Agonists Treatment in Primary Immune Thrombocytopenia (ITP): Results from a Nationwide Prospective Multicenter Interventional Study (STOPAGO)

▪Background: Thrombopoietin receptor agonists(TPO-RAs) have been thought to play only a supporting role in ITP management. Several retrospective studies and a recent prospective study have reported unexpected cases of durable remission after TPO-RAs discontinuation in adult ITP in up to 30%. However, newly diagnosed ITP cases for which spontaneous remission may occur have been included in most of these studies. Thus, the main purpose of this study was to determine the proportion of patients with either persistent or chronic phase and no recent exposure to any potentially curative therapy (i.e., splenectomy or rituximab) achieving long-term remission off-treatment at 24 and 52 months after at least 3 months of TPO-RAs exposure with a complete response (CR).Patients/methods: We conducted a nationwide prospective multicenter interventional study (NCT03119974). Inclusion criteria were: 1) Patients aged > 18 years, with persistent or chronic primary ITP, 2) A stable CR defined by a platelet count > 100 x 10 9/L for more than 2 months on TPO-RA therapy, 3) Treatment with TPO-RA for at least 3 months. Main exclusion criteria were: 1) Anticoagulation or anti-platelet treatment, 2) Previous failure of TPO-RA discontinuation, 3) Concomitant treatment with corticosteroids ± intravenous immunoglobulin 4) Rituximab or splenectomy within the 2 months preceding or after TPO-RA initiation. After inclusion, the decrease and wean of either eltrombopag or romiplostim was initiated according to a standardized protocol (respectively tapering of 25 mg every 2 weeks or tapering of 1 ug/kg every week). In any case TPO-RAs had to be stopped at week 10. In case of relapse after TPO-RA discontinuation, the decision to start a new therapy was left at every investigator discretion. The primary endpoint was the proportion of patients achieving an overall response (CR + R) at week 24 (6 months) after TPO-RAs discontinuation. Secondary outcomes were overall response rate over the study period (W52), bleeding events, and to identify predictive factors, for overall prolonged response (W24 and W52).Results: Forty-nine patients (30 females, 61%), with persistent (n=2) or chronic (n=47, 96%) chronic ITP, with a median age of 58.5 years IQR (41 to 73) fulfilling the eligibility criteria were included over 2 year-period in 22 centers from the French reference network for adult' ITP. Forty patients received eltrombopag and 9 romiplostim at the time of inclusion. One patient was excluded since she was diagnosed pregnant one day after inclusion. In intention to treat 27/48 (56.2%; 95% CI, 29.5 to 58.8) patients achieved the primary-endpoint and maintained an overall response at week 24 after TPO-RAS discontinuation with a complete response for 15/27 (55%). During the full follow-up period of 52 weeks after TPO-RAs discontinuation, overall response was observed in 25/48 (52.1%; 95% CI, 37.2 to 66.2) patients (Figure 1). Bleeding events occurred in 13/21 (61.9%) and 15/23 (65.2%) patients relapsing respectively at 24 and 52 months with a median platelet count of 31´10 9/L(26 to 39) and 31 ´10 9/L(23 to 39). No severe bleeding episode (French bleeding score > 8) occurred. Median time of relapse after tapering initiation was 8 weeks. Among 21 patients with a relapse (<30 x 10 9/L) before week 24, 13 patients were re-challenged with the same TPO-RA with a CR achieved with a median time of 2 weeks (2-4). In univariate analysis, age, ITP duration, TPO-RA duration before discontinuation, platelet count at inclusion and TPO-RAs drug class were not predictive of sustained response.Conclusion: These results showed an unexpectedly high rate of sustained off-treatment remission after TPO-RAs discontinuation in chronic ITP among patients who initially achieve a stable CR. When they occur, relapses are mainly observed within the first weeks after discontinuation, very rarely afterwards and with no severe bleeding. While no predictive factor of lasting remission has been yet identified, our study strongly supports a progressive tapering of the dose of TPO-RAs in patients achieving a stable CR on treatment.Figure 1: Relapse at 52 weeks after TPO-RAs discontinuation [Display omitted] DisclosuresMahevas: GSK: Research Funding; Amgen: Honoraria. Viallard: Novartis: Consultancy; Grifols: Consultancy; LFB: Consultancy; Amgen: Consultancy. Moulis: Amgen: Membership on an entity's Board of Directors or advisory committees, Research Funding; Argenx: Membership on an entity's Board of Directors or advisory committees; Grifols: Membership on an entity's Board of Directors or advisory committees, Research Funding; Novartis: Membership on an entity's Board of Directors or advisory committees, Research Funding; Sobi: Membership on an entity's Board of Directors or advisory committees. Terriou: Sanofi: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding. Michel: Novartis: Consultancy; Amgen: Consultancy; UCB: Honoraria; Argenx: Honoraria; Rigel: Honoraria; Alexion: Honoraria. Godeau: Sobi: Consultancy; Novartis: Consultancy; Amgen: Consultancy; Grifols: Consultancy.

Timing of Health Service Use Among Truck Drivers After a Work-Related Injury or Illness

Purposes Timely delivery of treatment and rehabilitation is generally acknowledged to support injury recovery. This study aimed to describe the timing of health service use by injured truck drivers with work-related injury and to explore the association between demographic and injury factors and the duration of health service use. Methods Retrospective cohort study of injured truck drivers with accepted workers’ compensation claims in the state of Victoria, Australia. Descriptive analyses examined the percentage of injured truck drivers using health services by service type. Logistic regression model examined predictors of any service use versus no service use, and predictors of extended service use (≥ 52 weeks) versus short-term use. Results The timing of health service use by injured truck drivers with accepted workers’ compensation claims varies substantially by service type. General practitioner, specialist physician, and physical therapy service use peaks within the 14 weeks after compensation claim lodgement, whilst the majority of mental health services were accessed in the persistent phase beyond 14 weeks after claim lodgement. Older age, being employed by small companies, and claiming compensation for mental health conditions were associated with greater duration of health service use. Conclusions Injured truck drivers access a wide range of health services during the recovery and return to work process. Delivery of mental health services is delayed, including for those making mental health compensation claims. Health service planning should take into account worker and employer characteristics in addition to injury type.

Real-Time In situ XRD Study of Simvastatin Crystallization in Levitated Droplets

Simvastatin (SV) is an important active pharmaceutical ingredient (API) for treatment of hyperlipidemias, which is known to exist in different crystalline and amorphous phases. It is, therefore, an interesting model to investigate how the outcome of evaporative crystallization in the contactless environment of an acoustically levitated droplet may be influenced by key experimental conditions, such as temperature, solvent properties (e.g., polarity and hygroscopicity), and dynamics of the evaporation process. Here, we describe a real-time and in situ study of simvastatin evaporative crystallization from droplets of three solvents that differ in volatility, polarity, and protic character (acetone, ethanol, and ethyl acetate). The droplet monitorization relied on synchrotron X-ray diffraction (XRD), Raman spectroscopy, imaging, and thermographic analysis. A pronounced solvent-dependent behavior was observed. In ethanol, a simvastatin amorphous gel-like material was produced, which showed no tendency for crystallization over time; in ethyl acetate, a glassy material was formed, which crystallized on storage over a two-week period to yield simvastatin form I; and in acetone, form I crystallized upon solvent evaporation without any evident presence of a stable amorphous intermediate. The XRD and Raman results further suggested that the persistent amorphous phase obtained from ethanol and the amorphous precrystallization intermediate formed in ethyl acetate were similar. Thermographic analysis indicated that the evaporation process was accompanied by a considerable temperature decrease of the droplet surface, whose magnitude and rate correlated with the solvent volatility (acetone > ethyl acetate > ethanol). The combined thermographic and XRD results also suggested that, as the cooling effect increased, so did the amount of residual water (most likely captured from the atmosphere) remaining in the droplet after the organic solvent was lost. Finally, the interpretation of the water fingerprint in the XRD time profiles was aided by molecular dynamics simulations, which also provided insights into the possible role of H2O as an antisolvent that facilitates simvastatin crystallization.

Systematic Review of Antiphospholipid Antibodies in COVID-19 Patients: Culprits or Bystanders?

Purpose of ReviewCOVID-19 patients have a procoagulant state with a high prevalence of thrombotic events. The hypothesis of an involvement of antiphospholipid antibodies (aPL) has been suggested by several reports. Here, we reviewed 48 studies investigating aPL in COVID-19 patients.Recent FindingsPrevalence of Lupus Anticoagulant (LA) ranged from 35% to 92% in ICU patients. Anti-cardiolipin (aCL) IgG and IgM were found in up to 52% and up to 40% of patients respectively. Anti-β2-glycoprotein I (aβ2-GPI) IgG and IgM were found in up to 39% and up to 34% of patients respectively. Between 1% and 12% of patients had a triple positive aPL profile. There was a high prevalence of aβ2-GPI and aCL IgA isotype. Two cohort studies found few persistent LA but more persistent solid phase assay aPL over time.SummaryaPL determination and their potential role is a real challenge for the treatment of this disease.

Changing Spatial Patterns of Deep Convection in the Subpolar North Atlantic

AbstractDeep convection and associated deep water formation are key processes for climate variability, since they impact the oceanic uptake of heat and trace gases and alter the structure and strength of the global overturning circulation. For long, deep convection in the subpolar North Atlantic was thought to be confined to the central Labrador Sea in the western subpolar gyre (SPG). However, there is increasing observational evidence that deep convection also has occurred in the eastern SPG south of Cape Farewell and in the Irminger Sea, in particular, in 2015–2018. Here we assess this recent event in the context of the temporal evolution of spatial deep convection patterns in the SPG since the mid‐twentieth century, using realistic eddy‐rich ocean model simulations. These reveal a large interannual variability with changing contributions of the eastern SPG to the total deep convection volume. Notably, in the late 1980s to early 1990s, the period with highest deep convection intensity in the Labrador Sea related to a persistent positive phase of the North Atlantic Oscillation, the relative contribution of the eastern SPG was small. In contrast, in 2015–2018, deep convection occurred with an unprecedented large relative contribution of the eastern SPG. This is partly linked to a smaller north‐westward extent of deep convection in the Labrador Sea compared to previous periods of intensified deep convection, and may be a first fingerprint of freshening trends in the Labrador Sea potentially associated with enhanced Greenland melting and the oceanic advection of the 2012–2016 eastern North Atlantic fresh anomaly.

Emergence of Self-Sustained Oscillations for SIRS Model on Random Networks

We study the phase transition from the persistence phase to the extinction phase forthe SIRS (susceptible/ infected/ refractory/ susceptible) model of diseases spreading onrandom networks. By studying a temporal evolution and synchronization parameter ofthis model on random networks, we find that, this model on random networks, shows asynchronization phase in a narrow range of very small values of clustering coecient. This ending corroborates the conclusion reached in [Phys. Rev. Lett. 86, 2909 (2001)] that,the clustering coexocient is responsible for the emergence of the synchronization phasein the small world networks. With these results and the result that we had obtainedin [Physica A 535, 122251 (2019)], we give a reasonable justiffcation the reason for theoccurrence of that behavior, at small values of the clustering coeffcient.

Regular swimming exercise prevented the acute and persistent mechanical muscle hyperalgesia by modulation of macrophages phenotypes and inflammatory cytokines via PPARγ receptors

Physically active individuals are less likely to develop chronic pain, and physical exercise is an established strategy to control inflammatory diseases. Here, we hypothesized that 1) peripheral pro-inflammatory macrophages phenotype contribute to predisposition of the musculoskeletal to chronic pain, and that 2) activation of PPARγ receptors, modulation of macrophage phenotypes and cytokines through physical exercise would prevent persistent muscle pain. We tested these hypotheses using swimming exercise, pharmacological and immunochemical techniques in a rodent model of persistent muscle hyperalgesia. Swimming prevented the persistent mechanical muscle hyperalgesia most likely through activation of PPARγ receptors, as well as activation of PPARγ receptors by 15d-PGJ2 and depletion of muscle macrophages in sedentary animals. Acute and persistent muscle hyperalgesia were characterized by an increase in pro-inflammatory macrophages phenotype, and swimming and the 15d-PGJ2 prevented this increase and increased anti-inflammatory macrophages phenotype. Finally, IL-1β concentration in muscle increased in the acute phase, which was also prevented by PPARγ receptors activation through swimming. Besides, swimming increased muscle concentration of IL-10 in both acute and chronic phases, but only in the persistent phase through PPARγ receptors. Our findings suggest physical exercise activates PPARγ receptors and increases anti-inflammatory responses in the muscle tissue by modulating macrophages phenotypes and cytokines, thereby preventing the establishment of persistent muscle hyperalgesia. These results further highlight the potential of physical exercise to prevent chronic muscle pain.

Report of Early Childhood Traumatic Injury Observations & Symptoms: Preliminary Validation of an Observational Measure of Postconcussive Symptoms.

To report preliminary empirical data on a novel, developmentally appropriate, observational postconcussive symptoms inventory for infants, toddlers, and preschoolers. Emergency departments of 2 tertiary, urban pediatric hospitals. Ninety-eight children (0-8 years of age; mean age at injury = 33.00, SD = 24.7 months) with mild traumatic brain injury (concussion) divided into younger (0-2 years) and older (3-8 years) age groups. Observational study. The Report of Early Childhood Traumatic Injury Observations & Symptoms (REACTIONS) documents 17 postconcussive symptoms representing observable manifestations thereof and was completed by parents in the acute (24-48 hours; n = 65), subacute (7-14 days; n = 78), and/or persistent phase (25-35 days; n = 72) post-mild traumatic brain injury. Different patterns of postconcussive symptoms were reported by age group, with behavioral manifestations particularly salient in younger children. More children younger than 2 years had sleep and comfort-seeking symptoms at each of the 3 postinjury time points. Postconcussive symptoms may manifest differently after mild traumatic brain injury sustained during early childhood. To fully understand and address their presence and evolution, developmentally sound measures such as the REACTIONS inventory are required.

Thermal order in large N conformal gauge theories

In this work we explore the possibility of spontaneous breaking of global symmetries at all nonzero temperatures for conformal field theories (CFTs) in D = 4 space-time dimensions. We show that such a symmetry-breaking indeed occurs in certain families of non-supersymmetric large N gauge theories at a planar limit. We also show that this phenomenon is accompanied by the system remaining in a persistent Brout-Englert-Higgs (BEH) phase at any temperature. These analyses are motivated by the work done in [1, 2] where symmetry-breaking was observed in all thermal states for certain CFTs in fractional dimensions.In our case, the theories demonstrating the above features have gauge groups which are specific products of SO(N) in one family and SU(N) in the other. Working in a perturbative regime at the N → ∞ limit, we show that the beta functions in these theories yield circles of fixed points in the space of couplings. We explicitly check this structure up to two loops and then present a proof of its survival under all loop corrections. We show that under certain conditions, an interval on this circle of fixed points demonstrates both the spontaneous breaking of a global symmetry as well as a persistent BEH phase at all nonzero temperatures. The broken global symmetry is ℤ2 in one family of theories and U(1) in the other. The corresponding order parameters are expectation values of the determinants of bifundamental scalar fields in these theories. We characterize these symmetries as baryon-like symmetries in the respective models.

From local resynchronization to global pattern recovery in the zebrafish segmentation clock.

Integrity of rhythmic spatial gene expression patterns in the vertebrate segmentation clock requires local synchronization between neighboring cells by Delta-Notch signaling and its inhibition causes defective segment boundaries. Whether deformation of the oscillating tissue complements local synchronization during patterning and segment formation is not understood. We combine theory and experiment to investigate this question in the zebrafish segmentation clock. We remove a Notch inhibitor, allowing resynchronization, and analyze embryonic segment recovery. We observe unexpected intermingling of normal and defective segments, and capture this with a new model combining coupled oscillators and tissue mechanics. Intermingled segments are explained in the theory by advection of persistent phase vortices of oscillators. Experimentally observed changes in recovery patterns are predicted in the theory by temporal changes in tissue length and cell advection pattern. Thus, segmental pattern recovery occurs at two length and time scales: rapid local synchronization between neighboring cells, and the slower transport of the resulting patterns across the tissue through morphogenesis.

The beneficial activity of curcumin and resveratrol loaded in nanoemulgel for healing of burn-induced wounds

Burns are complicated wounds characterized by prolonged and persistent inflammatory phase. The combination of nutraceuticals in nano-delivery systems is hypothesized to enhance therapeutic efficacy and achieve better healing outcome. In this regard, we investigated the combination of two polyphenols; curcumin and resveratrol, in a nanoemulsion based gel system (nanoemulgel). The ex-vivo skin deposition of the prepared nanoemulgels was measured, and their in-vivo burn healing potential was tested in rat-burn induced model by measurement of inflammatory markers, oxidative stress markers, amino acids and vitamin E levels, in addition to histopathological examination. The particle size of the nanoemulsions ranged from 167 to 180 nm with PDI less than 0.4 and negative zeta potential (−17 to −20 mV). Remarkable retention of the nutraceuticals in the skin when loaded alone or combined in nanoemulgels, reaching ≈60% of the applied dose was shown after 48 h. In vivo results proved the better burn healing outcome of the nanoemulgel formulation combining both curcumin and resveratrol, with histopathological features similar to normal control skin. Findings delineated the augmented burn healing potential of the nutraceuticals combination, and the promising delivery traits of the nanoemulgel dosage form, which can be further exploited with other nutraceuticals combinations.

Summer climate variability over Korea in association with diverse features of ENSO evolution

This study investigates the summer climate variability over Korea that is associated with diverse features of El Nino-Southern Oscillation (ENSO) evolution. Four different ENSO evolution features were analyzed, and the related Korean climate variability during July and August are investigated. The two evolution phases in which El Nino transitions into La Nina and El Nino develops from a neutral state show roughly similar circulation features in affecting the Korean summer climate, but with opposite signs. During the transition of El Nino into La Nina (after El Nino develops from a neutral state), the positive (negative) western North Pacific anticyclonic circulation anomaly directly affects Korea in August, producing a significant warm (cold) surface air temperature (SAT) anomaly in Korea. Notably, the SAT that occurs in July generally exhibits an opposite tendency to that of August in Korea, displaying subseasonal variations. However, the persistent phases of La Nina and El Nino exhibit distinctive features from the two transition phases mentioned. During the persistent La Nina phase, the Pacific-Japan like atmospheric circulation pattern affects Korea, showing a significant warm SAT anomaly over Korea in July, and a roughly similar situation with opposite signs is observed in the persistent El Nino phase. In these cases, the Korean SAT in August exhibits similar anomalies to July. The distinctive variability in the summer climate of Korea during the diverse ENSO evolution phases presented in this study provides a statistical basis for understanding the Korean summer climate in relation to ENSO.

Pseudomonas aeruginosa Elastase Contributes to the Establishment of Chronic Lung Colonization and Modulates the Immune Response in a Murine Model.

Chronic infection by Pseudomonas aeruginosa in cystic fibrosis (CF) patients is a major contributor to progressive lung damage and is poorly treated by available antibiotic therapy. An alternative approach to the development of additional antibiotic treatments is to identify complementary therapies which target bacterial virulence factors necessary for the establishment and/or maintenance of the chronic infection. The P. aeruginosa elastase (LasB) has been suggested as an attractive anti-virulence target due to its extracellular location, its harmful degradative effects on host tissues and the immune system, and the potential to inhibit its activity using small molecule inhibitors. However, while the relevance of LasB in acute P. aeruginosa infection has been demonstrated, it is still unclear whether this elastase might also play a role in the early phase of chronic lung colonization. By analyzing clinical P. aeruginosa clonal isolates from a CF patient, we found that the isolate RP45, collected in the early phase of persistence, produces large amounts of active LasB, while its clonal variant RP73, collected after years of colonization, does not produce it. When a mouse model of persistent pneumonia was used, deletion of the lasB gene in RP45 resulted in a significant reduction in mean bacterial numbers and incidence of chronic lung colonization at Day 7 post-challenge compared to those mice infected with wild-type (wt) RP45. Furthermore, deletion of lasB in strain RP45 also resulted in an increase in immunomodulators associated with innate and adaptive immune responses in infected animals. In contrast, deletion of the lasB gene in RP73 did not affect the establishment of chronic infection. Overall, these results indicate that LasB contributes to the adaptation of P. aeruginosa to a persistent lifestyle. In addition, these findings support pharmacological inhibition of LasB as a potentially useful therapeutic intervention for P. aeruginosa-infected CF patients prior to the establishment of a chronic infection.

The Use of Transient Liquid Phases in Powder Metallurgy

Liquid phase sintering is most widely known in its variant „persistent liquid phase sintering“, in which case the liquid phase is present in constant quantity during the entire isothermal period. There is however also the variant „transient liquid phase“, the melt being present only for a short period in the first stage of sintering and then solidifying through diffusional processes. In this presentation, the preconditions for both variants are presented, in particular with regard to the starting materials. The benefits of transient liquid phases are described, both for sintering – to accelerate material transport, contact formation and microstructural homogenization compared to standard solid state sintering – and for transient liquid phase bonding, a brazing variant which is an attractive method for joining porous powder compacts. Both techniques are highly useful in particular for ferrous powder metallurgy precision components, etc.

Modal synchronization of coupled bistable van der Pol oscillators

The paper revisits recently revealed regimes of the "nonconventional synchronization" in systems of coupled bi-stable Van der Pol oscillators. These regimes are characterized by periodic (or quasiperiodic) almost complete energy exchanges between the coupled oscillators. In the paper it is demonstrated that such responses correspond to synchronization of the modulation amplitudes between symmetric and antisymmetric modes of the system, with persistent phase drift. This observation substantially simplifies the treatment, reduces the dynamics to simple phase cylinder and allows to reveal a rich set of global and local bifurcations of limit cycles and tori in the system. Among other findings, one encounters an unexpected regime of nonstationary asymmetric synchronization.

Immune Response to Persistent Staphyloccocus Aureus Periprosthetic Joint Infection in a Mouse Tibial Implant Model.

Staphyloccocus aureus is one of the major pathogens in orthopedic periprosthetic joint infection (PJI), a devastating complication of total joint arthroplasty that often results in chronic and persistent infections that are refractory to antibiotics and require surgical interventions. Biofilm formation has been extensively investigated as a reason for persistent infection. The cellular composition, activation status, cytokine profile, and role of the immune response during persistent S. aureus PJI are incompletely understood. In this study, we used histology, multiparametric flow cytometry, and gene expression analysis to characterize the immune response in a clinically relevant orthopedic PJI model. We tested the hypothesis that persistent S. aureus infection induces feedback mechanisms that suppress immune cell activation, thereby affecting the course of infection. Surprisingly, persistent infection was characterized by strikingly high cytokine gene expression indicative of robust activation of multiple components of innate and adaptive immunity, along with ongoing severe neutrophil-dominated inflammation, in infected joint and bone tissues. Activation and expansion of draining lymph nodes and a bone marrow stress granulopoiesis reaction were also maintained during late phase infection. In parallel, feedback mechanisms involving T-cell inhibitory receptors and exhaustion markers, suppressive cytokines, and regulatory T cells were activated and associated with decreased T-cell proliferation and tissue infiltration during the persistent phase of infection. These results identify the cellular and molecular components of the mouse immune response to persistent S. aureus PJI and indicate that neutrophil infiltration, inflammatory cytokine responses, and ongoing lymph node and bone marrow reactions are insufficient to clear infection and that immune effector mechanisms are suppressed by feedback inhibitory pathways. These immune-suppressive mechanisms are associated with diminished T-cell proliferation and tissue infiltration and can be targeted as part of adjuvant immunotherapeutic strategies in combination with debridement of biofilm, antibiotics, and other therapeutic modalities to promote eradication of infection. © 2021 American Society for Bone and Mineral Research (ASBMR).

Exogenous abscisic acid coordinating leaf senescence and transport of assimilates into wheat grains under drought stress by regulating hormones homeostasis

Drought at the grain filling stage of wheat will cause premature leaf senescence, thus leading to considerable loss of wheat yield. Therefore, this paper aims to establish a cultivation technology for strong drought resistance, delayed senescence, and yield improvement based on the analysis of hormones homeostasis obtained by applying chemical control substances. Experiments were conducted with two genotypes of wheat. Four water irrigation treatments were applied to impose the water deficit, including well-watered control treatment (WW), mild water deficit (MiWD), moderate water deficit (MoWD), and severe water deficit (SWD). Exogenous abscisic acid (ABA) was sprayed on the plants at the anthesis stage of the wheat. As a result, exogenous ABA reduced initial senescence rate (r0), total duration of chlorophyll (Chltotal), rapid senescence phase (Chlloss), and the accumulated temperature at an inflection point (M) but improved the persistence phase (Chlper) of flag leaves under all of the four treatments. However, exogenous ABA produced inconsistent effects on photoassimilate relocation and grain weight under different treatments. It produced positive regulatory effects on grain weight under WW, MiWD, and MoWD treatments. On the one hand, spraying ABA during the persistence phase of flag leaves reduced the ratios of zeatin to gibberellin (Z/GA3), spermine to spermidine (Spm/Spd), and salicylic acid to ABA (SA/ABA), which prolonged active photosynthesis by stimulating high level of proline (Pro) and increased the activities of antioxidant enzymes, such as superoxide dismutase (SOD), peroxidase (POD), catalase (CAT), and ascorbate peroxidase (APX). Therefore, drought tolerance was enhanced, and more photosynthetic assimilates were accumulated. On the other hand, the rapid senescence phase and the transport rate of assimilates into grains were accelerated, resulting in higher grain weight, yield, and water use efficiency (WUE). However, under SWD treatment, exogenous ABA improved the ratio of SA/ABA, leading to low Pro content and low antioxidant enzyme activity of flag leaves in the rapid loss phase. Meanwhile, drought resistance declined and the transport duration of assimilates into grains was shortened, thus making photosynthetic assimilates redundant. Therefore, exogenous ABA can lead to the reduction in grain weight, yield, and WUE of wheat under SWD treatment.

Phase diagram of the interacting persistent spin-helix state

We study the phase diagram of the interacting two-dimensional electron gas (2DEG) with equal Rashba and Dresselhaus spin-orbit coupling, which for weak coupling gives rise to the well-known persistent spin-helix phase. We construct the full Hartree-Fock phase diagram using a classical Monte-Carlo method analogous to that used in Phys.Rev.B 96, 235425 (2017). For the 2DEG with only Rashba spin-orbit coupling, it was found that at intermediate values of the Wigner-Seitz radius rs the system is characterized by a single Fermi surface with an out-of-plane spin polarization, while at slightly larger values of rs it undergoes a transition to a state with a shifted Fermi surface and an in-plane spin polarization. The various phase transitions are first-order, and this shows up in discontinuities in the conductivity and the appearance of anisotropic resistance in the in-plane polarized phase. In this work, we show that the out-of-plane spin-polarized region shrinks as the strength of the Dresselhaus spin-orbit interaction increases, and entirely vanishes when the Rashba and Dresselhaus spin-orbit coupling strengths are equal. At this point, the system can be mapped onto a 2DEG without spin-orbit coupling, and this transformation reveals the existence of an in-plane spin-polarized phase with a single, displaced Fermi surface beyond rs > 2.01. This is confirmed by classical Monte-Carlo simulations. We discuss experimental observation and useful applications of the novel phase, as well as caveats of using the classical Monte-Carlo method.

Dynamical Phase Modulation and Oscillatory Detuning in Applied Neurostimulation

Neural architectures that are operative in higher order cognition, including consciousness, memory, and motor planning, undergo complex changes in global organization during neurological disease. Increasingly, neurostimulation is therapeutically used for restoring these functions, although the mechanisms of restoration are largely unknown. Extant studies reveal, on the other hand, that non-linear and dynamical principles govern global brain organization, seen in operational features such as persistence, stability, flexibility and non-localization that are likely to be evoked by neurostimulation. These dynamical features are instantiated in neural oscillations, a key mechanism regulating brain function and communication. Due to stochastic influences, oscillator synchronization and desynchronization exhibit limit cycle attractor dynamics, which are characterized by persistent phase modulation rather than fixed point, stationary phase locking. Phase modulation governs information exchange by temporally gating transfer and guiding the trajectory of information distribution. Activation of attractor forces by modest input drive induces dynamic, phase difference detuning that results in phase preference shifts, whereas strong input drive induces low stability phase relations that promote oscillator dissociation and new pair formation. These dynamical features of oscillator behavior are likely to facilitate information transfer to neural networks during neurostimulation of higher order functions.

Cav3.2 overexpression in L4 dorsal root ganglion neurons after L5 spinal nerve cutting involves Egr-1, USP5 and HMGB1 in rats: An emerging signaling pathway for neuropathic pain

Overexpression of Cav3.2 T-type Ca2+ channels in L4 dorsal root ganglion (DRG) participates in neuropathic pain after L5 spinal nerve cutting (L5SNC) in rats. The L5SNC-induced neuropathic pain also involves high mobility group box 1 (HMGB1), a damage-associated molecular pattern protein, and its target, the receptor for advanced glycation end-products (RAGE). We thus studied the molecular mechanisms for the L5SNC-induced Cav3.2 overexpression as well as neuropathic pain in rats by focusing on; 1) possible involvement of early growth response 1 (Egr-1), known to regulate transcriptional expression of Cav3.2, and ubiquitin-specific protease 5 (USP5) that protects Cav3.2 from proteasomal degradation, and 2) possible role of HMGB1/RAGE as an upstream signal. Protein levels of Cav3.2 as well as Egr-1 in L4 DRG significantly increased in the early (day 6) and persistent (day 14) phases of neuropathy after L5SNC, while USP5 protein in L4 DRG did not increase on day 6, but day 14. An anti-HMGB1-neutralizing antibody or a low molecular weight heparin, a RAGE antagonist, prevented the development of neuropathic pain and upregulation of Egr-1 and Cav3.2 in L4 DRG after L5SNC. L5SNC increased macrophages accumulating in the sciatic nerves, and the cytoplasm/nuclear ratio of immunoreactive HMGB1 in those macrophages. Our findings suggest that L5SNC-induced Cav3.2 overexpression in L4 DRG and neuropathic pain involves Egr-1 upregulation downstream of the macrophage-derived HMGB1/RAGE pathway, and that the delayed upregulation of USP5 might contribute to the persistent Cav3.2 overexpression and neuropathy.