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This study investigates the mechanisms driving the acceleration and meandering of the Agulhas Current (AC), focusing on the role of eddy‐mean flow interactions. The analysis revealed that anticyclones originating from the Mozambique Channel and south of Madagascar played pivotal roles in accelerating the AC. Simultaneously, when anticyclones collide with the AC, they undergo processes of rotating and elongating into ellipses. In addition to the previously suggested barotropic instability induced by anticyclones, this study revealed that the merging of cyclones with the AC plays a role in the generation of meanders. Upstream cyclones reduce the horizontal potential vorticity gradient, facilitating eddies to traverse the current. The AC envelops these cyclones and flows in meandering patterns. The places where these meanders form are not exclusive to the Natal Bight. In addition, we further diagnose the kinetic energy conversion to reveal the interaction between eddy anisotropy (i.e., eddy deformation and orientation) and mean flow strain (i.e., stretching and shearing). The results suggest that the anisotropy of anticyclonic and cyclonic eddies prompts downscale KE transfer and the growth of meanders, establishing a positive feedback loop. Contrary to the findings of previous hypotheses, the acceleration of AC in turn leads to a decrease in the mean flow strain rate, exerting negative feedback on energy conversion and inhibiting the development of meanders. These two feedback mechanisms work together to determine the fate of AC meandering. The energetic anisotropy diagnosis holds potential applicability to other western boundary current systems. Plain Language Summary: The Agulhas Current (AC) is the strongest western boundary current in the Southern Hemisphere. The variabilities in its strength and meandering behavior influence the local marine environment and meridional heat transport. This research is devoted to investigating the mechanisms behind the acceleration and formation of meandering. We find that the acceleration in AC is attributed to upstream anticyclones because the velocities of these anticyclones align with the mean flow in their interaction area. Additionally, this study first demonstrates that nonlocal cyclones can reduce the barrier of the horizontal potential vorticity gradient. These cyclones thus cross the current, causing the AC to form a pulse‐like meandering flow. Meandering also occurs locally due to the barotropic instability of the AC, indicating a downscaled conversion of kinetic energy. We employ a diagnosis of the kinetic energy budget, highlighting the significant influence of eddy anisotropy, including the squeezing of anticyclones and the growth of cyclones. However, the acceleration of the AC would reduce its strain, which abates the original barotropic instability. Key Points: Rhythms of the Agulhas Current, acceleration, and meanders on the synoptic scale were studied from a new energetic anisotropy perspectiveAgulhas Current meanders can be generated either by local anticyclone‐mean flow interactions or upstream cyclone mergingBalance between eddy anisotropy and mean flow strain decides meander growth, with broader applications to other western current systems [ABSTRACT FROM AUTHOR]

The Agulhas Return Current (ARC), as a primary component of the Agulhas system, contributes to water exchange and mass transport between the southern portions of the Indian and Atlantic Ocean basins. In this study, satellite altimeter data and reanalysis datasets, and a new set of criteria for the piecewise definition of the jet axis are used to explore the long-term change of the ARC's axis position in recent three decades. It is found that the ARC axis exhibits a significant slanting trend with its western part (35–48°E) migrating northward and the eastern part (48–70°E) migrating southward. The meridional movement of the ARC path could be attributed to large-scale wind forcing. The anomalous surface wind stress curl, by Ekman pumping mechanism, leads to positive–negative–positive sea surface height anomalies in the western section and negative–positive–negative anomalies in the eastern section, thus the ARC axis tilts accordingly, in a northwest–southeast direction. Further analysis suggests that this ARC slanting trend is more dependent on the southward shift of the downstream axis and less on the topographic steering upstream. The downstream axis is more likely to interact with the ACC fronts and its migration could dominate the local EKE pattern by changing the background circulation and energy cascade direction. For the headstream west of 35°E, the ARC axis is more subject to topography, thus the EKE change is more dominated by eddy activity processes, including shedding, propagation and merging. This study provides some new insights into the long-term change of ARC and its interaction with the local EKE variability. [ABSTRACT FROM AUTHOR]

To investigate the expansion mechanism of the temporary cavity produced by high-speed penetrators into ballistic gelatin, a dynamic spherical-cavity-expansion model for gelatin targets was proposed with consideration of the outer boundary size. The theoretical solution of the cavity radial stress was obtained and the energy conversion and conservation relation during the cavity expansion process was established. The influence of the finite boundary to the solutions of the cavity radial stress and the deformation energy in the medium was analyzed. The energy conversion and conservation relation was applied to penetration process of high-speed penetrators into soft targets and regarded as the temporary cavity expansion model. This model is a nonlinear first order differential equation about the cavity radius, which can be solved numerically to obtain the variation of temporary cavity volume with time. Experimental results of high-speed penetrators (bullets and fragment simulating projectile with different shapes) penetrating into ballistic gelatin were analyzed. Temporary cavity results of rhombic fragment simulating projectiles were used to estimate the parameters in the model. Then, model predictions were compared with the temporary cavity results of bullets, spheres and cylinders to verify the reliability of the model. It was found that: (1) if the ratio of the cavity radius to the initial target boundary radius exceeds 0.62, the error caused by ignoring the boundary size effect will exceed 10%; (2) Model predictions for temporary cavity volume of penetration produced by various penetrators are shown to be in good agreement with the corresponding experimental results. [ABSTRACT FROM AUTHOR]

Simple Summary: Fewer than half of ductal carcinoma in situ (DCIS) cases progress to invasive breast cancer (BC); however, most are treated surgically, which raises a concern of overtreatment. Novel approaches to the management of DCIS that do not rely on surgery are warranted. In this study, we assessed the efficacy of heat shock protein 90 (Hsp90)-targeted photodynamic therapy (HS201-PDT) as a novel alternative treatment to target DCIS and prevent progression to invasive BC. The preventive application of HS201-PDT to the mammary glands of spontaneous murine DCIS models significantly improved disease-free survival. Enhancement of immune response with systemically administered anti-PD-L1 antibodies along with repeated HS201-PDT to mammary glands was effective even in a more aggressive DCIS model. Thus, HS201-PDT monotherapy or the combination with anti-PD-L1 antibodies is a promising strategy that could serve as an alternative treatment of DCIS to prevent progression to invasive BC. Ductal carcinoma in situ (DCIS) of the breast is often managed by lumpectomy and radiation or mastectomy, despite its indolent features. Effective non-invasive treatment strategies could reduce the morbidity of DCIS treatment. We have exploited the high heat shock protein 90 (HSP90) activity in premalignant and malignant breast disease to non-invasively detect and selectively ablate tumors using photodynamic therapy (PDT). PDT with the HSP90-targeting photosensitizer, HS201, can not only ablate invasive breast cancers (BCs) while sparing non-tumor tissue, but also induce antitumor immunity. We hypothesized that HS201-PDT would both non-invasively ablate DCIS and prevent progression to invasive BC. We tested in vitro selective uptake and photosensitivity of HS201 in DCIS cell lines compared to the non-selective parental verteporfin, and assessed in vivo antitumor efficacy in mammary fat pad and intraductal implantation models. Selective uptake of HS201 enabled treatment of intraductal lesions while minimizing toxicity to non-tumor tissue. The in vivo activity of HS201-PDT was also tested in female MMTV-neu mice prior to the development of spontaneous invasive BC. Mice aged 5 months were administered HS201, and their mammary glands were exposed to laser light. HS201-PDT delayed the emergence of invasive BC, significantly prolonged disease-free survival (DFS) (p = 0.0328) and tended to improve overall survival compared to the no-treatment control (p = 0.0872). Systemic administration of anti-PD-L1 was combined with HS201-PDT and was tested in a more aggressive spontaneous tumor model, HER2delta16 transgenic mice. A single PDT dose combined with anti-PD-L1 improved DFS compared to the no-treatment control, which was significantly improved with repetitive HS201-PDT given with anti-PD-L1 (p = 0.0319). In conclusion, a non-invasive, skin- and tissue-sparing PDT strategy in combination with anti-PD-L1 antibodies effectively prevented malignant progression of DCIS to invasive BC. This non-invasive treatment strategy of DCIS may be safe and effective, while providing an option to reduce the morbidity of current conventional treatment for patients with DCIS. Clinical testing of HS201 is currently underway. [ABSTRACT FROM AUTHOR]

In this study, we detect and track extratropical cyclones using 6-hourly mean sea level pressure data taken from the Twentieth Century Reanalysis version 3 (20CRv3) over the period 1951–2015 and compare them with those in the Interim and fifth generation of ECMWF reanalyses over the period 1979–2018. Three indices were employed to characterize cyclone activity, including cyclone count, cyclone intensity, and a cyclone activity index (CAI) that combines the count and intensity. The results show that the cyclone indices in the three datasets have comparable annual climatologies and seasonal evolution over the northern extratropical land and ocean in recent decades. Based on the cyclone indices over the period 1951–2010 in 80 ensemble members of 20CRv3, cyclone count and intensity are negatively correlated in winter and tend to be positively and weakly correlated in summer. The interannual CAI variability is dominated by the cyclone count variability. Regional mean cyclone activity can be well represented using the ensemble average cyclone index. We then examined the linkage of the cyclone activity in 20CRv3 and observed cold and warm extremes over Eurasia and North America over the period 1951–2010. In winter, the principal components of interannual cold and warm extreme anomalies are more correlated with the regional mean cyclone count index over Eurasia, while they are more correlated with the cyclone intensity index over North America. The temperature anomalies associated with the regional and ensemble mean cyclone count index explain about 10% (20%) of interannual cold (warm) extreme variances averaged over Eurasia. The temperature anomalies associated with the mean cyclone intensity explain about 10% of interannual cold and warm extreme variances over North America. Large-scale atmospheric circulation anomalies in association with cyclone activity and the induced temperature advection drive temperature anomalies over Eurasia and North America. In summer, circulation and thermal advection anomalies associated with cyclone activity are weak over the two continents. Hence, that season's relationship between cyclone activity and extreme temperature variability is weak. [ABSTRACT FROM AUTHOR]

Impacts of sudden stratospheric warming (SSW) on three severe cold events (C1–C3) over Northern Hemisphere in early 2021 were investigated using subseasonal‐to‐seasonal ensemble forecasts. The SSW was characterized by successive displacement and split of the stratospheric polar vortex (SPV). Ensemble‐based sensitivity analyses showed that C1 over Siberia and C2 over western Canada were more related to SPV variations at a lead time of 1–2 weeks than C3 over central U.S. Within ensemble forecasts, a more elongated SPV with higher geopotential height over northern Eurasia were conducive to C1, whereas a SPV with the more poleward retreat from displacement contributed to C2. The forecast accuracy of stratospheric heights over the sensitive region at 2 weeks lead was significantly correlated with the forecast skill of the tropospheric circulation pattern preceding C1, implying that prediction of specific cold weather events may be improved by a better forecast of key features in SPV variations. Plain Language Summary: Unusually extreme cold events have frequently occurred during the boreal winter in recent decades. These cold air outbreaks at the surface can be profoundly influenced by variations in the stratospheric polar vortex (SPV) with a lead time of weeks. The winter of early 2021 was characterized by successive extreme cold events over Asia and North America, leading to huge societal impacts, such as the unprecedented power outages over central U.S. in mid‐February 2021. These cold events were accompanied by a weak SPV that had been successively displaced and then split. Based on real‐time ensemble forecasts, we show that weakening and stretching of the SPV contributed to the cold event over Siberia. By contrast, the return of the SPV from displacement favored the cold event over western Canada. The subsequent cold surge over central U.S. was more related to mid‐latitude tropospheric processes than stratospheric processes. The prediction of some extremely cold weather events may be significantly improved by more accurate forecasts of the key features of the evolution of the SPV with a lead time of about two weeks. Key Points: Sudden stratospheric warming with a displaced‐to‐split polar vortex in early 2021 had significant influences on surface cold eventsCold event in Siberia (Canada) was related to weakening (poleward retreat between displacement and split) of stratospheric polar vortexAccurate forecasts of stratospheric variations improved forecast of the tropospheric pattern preceding the cold event over Siberia [ABSTRACT FROM AUTHOR]

Purpose: The purpose of this article is to design and make fabrics with colorful melange yarns spun by a three-channel rotor spinning machine. Design/methodology/approach: The three-channel digital rotor-spun machine controls the blending proportion by adjusting the feeding of three-primary color fiber slivers online, so that a piece of colorful yarn presents a variety of colors along the longitudinal direction where constant yarn linear density can be produced flexibly. Various fabric patterns can be produced by three-channel rotor-spun colorful melange yarn with different periods of color. Findings: The fabric, made by the rotor-spun colorful melange yarn, is rich in color, clear in layers, soft in the hand and has a hazy three-dimensional effect. The product is environmentally friendly and saves energy. Originality/value: An innovative idea to develop various colorful fabrics is proposed by combining their pattern with colorful melange yarn produced by a three-channel rotor spinning machine. [ABSTRACT FROM AUTHOR]

The flow and transformation of warm, salty Atlantic‐origin water (AW) in the Arctic Ocean plays an important role in the global overturning circulation that helps regulate Earth's climate. The heat that it transports also impacts ice melt in different parts of the Arctic. This study uses data from a mooring array deployed across the shelf/slope of the Alaskan Beaufort Sea from 2002–2004 to investigate the flow of AW. A short‐lived "rebound jet" of AW on the upper continental slope regularly follows wind‐driven upwelling events. A total of 57 such events, lasting on average 3 days each, occurred over the 2 year period. As the easterly wind subsides, the rebound jet quickly spins up while the isopycnals continue to slump from their upwelled state. The strength of the jet is related to the cross‐slope isopycnal displacement, which in turn is dependent on the magnitude of the wind, in line with previous modeling. Seaward of the rebound jet, the offshore‐most mooring of the array measured the onshore branch of the AW boundary flowing eastward in the Canada Basin. However, the signature of the boundary current was only evident in the second year of the mooring timeseries. We suspect that this is due to the varying influence of the Beaufort Gyre in the two years, associated with a change in pattern of the wind stress curl that helps drive the gyre. Plain Language Summary: The flow and transformation of warm, salty Atlantic‐origin water (AW) in the Arctic Ocean plays an important role in the global overturning circulation that helps regulate Earth's climate. The heat that it transports also impacts ice melt in different parts of the Arctic. This study uses two years of mooring data across the continental shelf and slope of the Alaskan Beaufort Sea to investigate the time‐dependent flow of AW. Short‐lived bursts of AW, known as "rebound jets", occur following easterly wind storms throughout the year. Our measurements support the dynamical explanation for the events previously deduced from numerical modeling. Farther offshore, the mooring array measured one of the branches of the AW boundary current in the Canada Basin. The signature of this flow appears to vary according to the rotation of winds over the basin, which helps drive the Beaufort Gyre. Our results imply a dynamical connection between the gyre and the boundary current, motivating further study. Key Points: A short‐lived "rebound jet" of Atlantic Water (AW) on the upper slope regularly follows wind‐driven upwelling events in the Beaufort SeaA total of 57 such events, lasting on average 3 days each, occurred over the 2 year measurement periodThe onshore branch of the AW boundary current is impacted by local wind stress as well as wind stress curl in the Canada Basin [ABSTRACT FROM AUTHOR]

The content of 1,4-dioxane in narrow-distribution sodium fatty alcohol ether sulfate (narrow- distribution AES) was studied by using n(SO3):n(narrow-distribution fatty alcohol ether), sulfation temperature, volume fraction of SO3, storage time and neutralization temperature as single-factor variables on a laboratory device of sulfur trioxide falling film sulfation. The results showed that, the content of 1,4-dioxane in narrow-distribution AES would increase with the increase of excess SO3, sulfation temperature, volume fraction of SO3, storage time of narrow-distribution fatty alcohol ether, and neutralization temperature. [ABSTRACT FROM AUTHOR]

Two kinds of chitosan surfactants, dodecyl chitosan sulfate (D10CTS) and decyl chitosan sulfate (D12CTS) were synthesized by Schiff base reaction, reduction, sulfation and neutralization reaction. Their structures were identified by infrared spectroscopy (FT-IR), H NMR spectroscopy (¹H NMR), elemental analysis (EA), and thermogravimetric analysis (TGA). The results show that the degrees of alkylation are 0.77 and 0.52, and the degrees of sulfation are 1.35 and 1.79, respectively. Favourable surface activity and spreadability of D10CTS and D12CTS were evidenced by surface tension and contact angle measurements. The critical micelle concentrations (cmc) are 0.69 and 0.49 g/L, and the minimum surface tension γcmc are 39.50 and 35.75 mN/m, respectively. The target products possess certain foaming properties and emulsification performance. The surfactants are low-foaming and are expected to play a potential application in the field of cosmetics. [ABSTRACT FROM AUTHOR]

Synoptic shipboard measurements, together with historical hydrographic data and satellite data, are used to elucidate the detailed structure of the Atlantic Water (AW) boundary current system in the southern Canada Basin and its connection to the upstream source of AW in the Chukchi Borderland. Nine high‐resolution occupations of a transect extending from the Beaufort shelf to the deep basin near 152°W, taken between 2003 and 2018, reveal that there are two branches of the AW boundary current that flow beneath and counter to the Beaufort Gyre. Each branch corresponds to a warm temperature core and transports comparable amounts of Fram Strait Branch Water between roughly 200–700 m depth, although they are characterized by a different temperature/salinity (T/S) structure. The mean volume flux of the combined branches is 0.87 ± 0.13 Sv. Using the historical hydrographic data, the two branches are tracked upstream by their temperature cores and T/S signatures. This sheds new light on how the AW negotiates the Chukchi Borderland and why two branches emerge from this region. Lastly, the propagation of warm temperature anomalies through the region is quantified and shown to be consistent with the deduced circulation scheme. Plain Language Summary: Warm water flows into the Arctic Ocean from the North Atlantic and circulates counterclockwise through the different subbasins of the Arctic. The water is cooled, freshened, and densified as part of the global overturning circulation. The warm water also spreads into the interior Arctic with the potential to melt sea ice. Presently, very little is known about the Atlantic Water (AW) circulation in the Canada Basin, far from the source of the water. In this study, we analyze nine repeat shipboard transects extending from the Beaufort Sea shelf to the deep basin, taken between 2003 and 2018. The transects reveal that there are two branches of the AW boundary current, each characterized by a warm temperature core. The branches transport roughly equal amounts of water. Using an extensive historical database, we demonstrate that the two branches emerge from a region of complex topography known as the Chukchi Borderland. A single AW current entering the Borderland undergoes a series of divisions and merges, which ultimately forms two branches that are further distinguishable by their temperature and salinity structure. Finally, we document the propagation of warm temperature pulses through the region, which is consistent with the deduced circulation scheme. Key Points: The Atlantic Water boundary current has two branches in the southern Canada Basin, flowing beneath and counter to the Beaufort GyreThe two branches emerge from the Chukchi Borderland due to a series of bifurcations of the single branch that enters the BorderlandThe propagation of warm temperature anomalies through the region is consistent with the deduced circulation scheme [ABSTRACT FROM AUTHOR]

Ultra-narrow gap laser welding (ultra-NGLW) is an advanced welding technology for thick bainite steel with a welding gap of only 4 mm. We studied the failure mechanism of the tensile fracture of ultra-NGLW joints of bainitic steel via in situ tensile tests. The tests show that cracks for all micro-zone specimens propagated along the tensile direction at 42°∼45°. Further analysis of the crack tips by Electron Back Scatter Diffraction showed main cracks along directions with high Schmid Factors (SF >0.44), and micro-cracks were found on the grain boundaries of (111) and (101) grains. It was revealed that the wire-filling zone and heat-affected zone were mainly intergranular expansion, whereas in the no filling zone, the crack propagation was transgranular. [ABSTRACT FROM AUTHOR]

Amorphous Ti–Cu–Zr–Ni alloys with minor addition of Sn and Al were prepared by melt spinning technique. The effects of Sn and Al additions on the microstructures and mechanical properties of glassy ribbons were investigated. The amorphous state of ribbons was confirmed by x-ray diffraction and transmission electron microscopy, where those ribbons with Sn addition exhibited a fully amorphous state. The characteristic temperature indicates that Ti45Cu35Zr10Ni5Sn5 alloy has a stronger glass-forming ability, as proven by differential scanning calorimetry. Ti45Cu35Zr10Ni5Al5 alloy showed a better hardness of 9.23 GPa and elastic modulus of 127.15 GPa and good wear resistance. Ti45Cu35Zr10Ni5Sn5 alloy displayed a pop-in event related to discrete plasticity according to nanoindentation. When the temperature is below 560 K, Ti45Cu35Zr10Ni5Sn5 alloy mainly exhibits elasticity. When the temperature rises between 717 K and 743 K, it shows a significant increase in elasticity but decrease in viscoelasticity after the ribbon experiences the main relaxation at 717 K. When the temperature is above 743 K, the ribbon shows viscoplasticity. [ABSTRACT FROM AUTHOR]

Photodynamic therapy (PDT) ablates malignancies by applying focused near-infrared (nIR) light onto a lesion of interest after systemic administration of a photosensitizer (PS); however, the accumulation of existing PS is not tumor-exclusive. We developed a tumor-localizing strategy for PDT, exploiting the high expression of heat shock protein 90 (Hsp90) in cancer cells to retain high concentrations of PS by tethering a small molecule Hsp90 inhibitor to a PS (verteporfin, VP) to create an Hsp90-targeted PS (HS201). HS201 accumulates to a greater extent than VP in breast cancer cells both in vitro and in vivo, resulting in increased treatment efficacy of HS201-PDT in various human breast cancer xenografts regardless of molecular and clinical subtypes. The therapeutic index achieved with Hsp90-targeted PDT would permit treatment not only of localized tumors, but also more diffusely infiltrating processes such as inflammatory breast cancer. Heat shock protein 90 (Hsp90) is highly expressed in cancer cells. Kaneko et al show that targeting Hsp90 on the cancer cell surface with a photosensitizer tethered to an Hsp90 small molecule inhibitor improves the efficacy of photodynamic therapy in various human breast cancer xenografts, suggesting a therapeutic avenue for human disease. [ABSTRACT FROM AUTHOR]

After an unprecedented retreat, the total Arctic sea ice cover for the post-2007 period is characterized by low extent and a remarkable increase in annual cycle amplitude. We have identified the leading role of spring Bering Sea ice in explaining the changes in the amplitude of the annual cycle of total Arctic sea ice. In particular, these changes are related to the recent occurrence of multiyear variability in spring Bering Sea ice extent. This is due to the phase-locking of the North Pacific Gyre Oscillation (NPGO) and the Pacific Decadal Oscillation (PDO) after about 2007, with a correlation coefficient reaching -0.6. Furthermore, there emerge notable changes in the sea level pressure and sea surface temperature patterns associated with the NPGO in the recent decade. After 2007, the NPGO is related to a quadrupole of sea level pressure (SLP) anomalies that is associated with the wind stress curl and Ekman pumping rate anomalies in the Bering deep basin; these account for the change in Bering Sea subsurface variability that contribute to the decadal oscillation of the spring Bering Sea ice extent. [ABSTRACT FROM AUTHOR]

The Arctic sea ice cover has declined at an unprecedented pace since the late 20th century. As a result, the feedback of sea ice anomalies for atmospheric circulation has been increasingly evidenced. While climatic models almost consistently reproduced a decreasing trend of sea ice cover, the reported results show a large distribution. To evaluate the performance of models for simulating Arctic sea ice cover and its potential role in climate change, this study constructed a reasonable metric by synthesizing both linear trends and anomalies of sea ice. This study particularly focused on the Barents Sea and the Kara Sea, where sea ice anomalies have the highest potential to affect the atmosphere. The investigated models can be grouped into three categories according to their normalized skill scores. The strong contrast among the multi-model ensemble means of different groups demonstrates the robustness and rationality of this method. Potential factors that account for the different performances of climate models are further explored. The results show that model performance depends more on the ozone datasets that are prescribed by the model rather than on the chemical representation of ozone. [ABSTRACT FROM AUTHOR]

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Rationale: Alcohol use disorders have become one of the most damaging psychiatric disorders in the world; however, there are no ideal treatments in clinic. Phosphodiesterase-4 (PDE4), an enzyme that specifically hydrolyzes intracellular cyclic AMP (cAMP), has been involved in alcohol use disorders. Roflumilast is the first PDE4 inhibitor approved for treatment of chronic obstructive pulmonary diseases in clinic. It was of particular interest to researchers to determine whether roflumilast altered ethanol consumption. Objectives: The present study tried to determine the effects of roflumilast on ethanol intake and preference. Methods: We used the two-bottle choice paradigm to assess ethanol intake and preference in C57BL/6J mice treated with roflumilast (1, 3, or 10 mg/kg) or rolipram (0.5 mg/kg; positive control). The effect of roflumilast was verified using the ethanol drinking-in-dark (DID) test. Locomotor activity was examined using the open-field test. Intake of sucrose or quinine was also tested to determine whether natural reward preference and aversive stimuli were involved in the effect of PDE4 inhibitors. Results: Similar to rolipram, roflumilast decreased ethanol intake and preference in two-bottle choice and DID tests in a dose-dependent manner, with significant changes at the dose of 10 mg/kg; in contrast, roflumilast did not affect sucrose or quinine drinking, although it decreased locomotor activity at the high dose within 3 h of treatment. Conclusions: These data provide novel demonstration for the effect of roflumilast on ethanol consumption and suggest that roflumilast may be beneficial for treatment of alcoholism. [ABSTRACT FROM AUTHOR]

The CD4CD25 regulatory T cells (Tregs), an innate immunomodulator, suppress cerebral inflammation and maintain immune homeostasis in multiple central nervous system injury, but its role in intracerebral hemorrhage (ICH) has not been fully characterized. This study investigated the effect of Tregs on brain injury using the mouse ICH model, which is established by autologous blood infusion. The results showed that tail intravenous injection of Tregs significantly reduced brain water content and Evans blue dye extravasation of perihematoma at day (1, 3 and 7), and improved short- and long-term neurological deficits following ICH in mouse model. Tregs treatment reduced the content of pro-inflammatory cytokines interleukin (IL)-1β, IL-6, tumor necrosis factor-α, and malondialdehyde, while increasing the superoxide dismutase (SOD) enzymatic activity at day (1, 3 and 7) following ICH. Furthermore, Tregs treatment obviously reduced the number of NF-κB, IL-6, TUNEL and active caspase-3 cells at day 3 after ICH. These results indicate that adoptive transfer of Tregs may provide neuroprotection following ICH in mouse models. [ABSTRACT FROM AUTHOR]

A recent study sequenced the full coding region of SORL1 in 1,255 early-onset Alzheimer's disease (EOAD) cases and 1,938 control individuals, and investigated the contribution of genetic variability in SORL1 to EOAD risk in a European cohort. This study identified six common variants and five low frequency variants in the SORL1 coding sequence. However, none of these 11 variants was significantly associated with EOAD risk after adjusting for multiple testing. We consider whether these 11 SORL1 variants identified in European EOAD contribute to late-onset Alzheimer's disease (LOAD) risk in individuals of European ancestry. Here, we investigated these 11 SORL1 variants identified in European EOAD and LOAD risk in individuals of European ancestry using a large-scale LOAD GWAS. Our results indicate that three genetic variants rs2070045, rs2276412, and rs17125548 as well as their tagged genetic variants contribute to LOAD risk in European population. We further investigate whether these variants could affect SORL1 expression using multiple expression quantitative trait loci (eQTLs) datasets. Our findings suggest that three genetic variants rs2070045, rs1699102, and rs3824968 could significantly regulate SORL1 expression in human brain tissues. We believe that our findings further provide important supplementary information about the involvement of the SORL1 variants in LOAD risk. [ABSTRACT FROM AUTHOR]

Carnosine, an endogenous dipeptide (β-alanyl- l-histidine), exerts multiple neuroprotective properties, but its role in intracerebral hemorrhage (ICH) remains unclear. This study investigates the effect of Carnosine on brain injury using the rat ICH model, which is established by type IV collagenase caudatum infusion. The results indicate that intraperitoneal administration of Carnosine (1000 mg/kg) significantly attenuates brain edema, blood-brain barrier (BBB) disruption, oxidative stress, microglia activation and neuronal apoptosis of perihematoma at 72 h following ICH in rats models, as convinced by preventing the disruption of tight junction protein ZO-1, occludin and claudin-5, followed by the decrease of ROS, MDA, 3-NT, 8-OHDG level and the increase of GSH-Px and SOD activity, then followed by the decline of Iba-1, ED-1, active caspase-3 and TUNEL positive cells and the decrease of IL-1β, IL-6, TNF-α, active caspase-3 and cytochrome c level. Our results suggest that Carnosine may provide neuroprotective effect after experimental ICH in rat models. [ABSTRACT FROM AUTHOR]

The intraseasonal variability of the winter western boundary current (WBC) in the South China Sea (SCS) is investigated using satellite data and mooring observations. The intraseasonal intensification of the northeasterly wind enhances the cross-shelf sea-level gradient, and, thus, causes the basin-scale cyclonic circulation to spin up within around one week. The Southern Cyclonic Gyre in the southwestern SCS further strengthens due to the intensified inertial recirculation of the WBC. Complex empirical orthogonal function analysis reveals that the large sea-level fluctuation around the downstream WBC can mainly be explained by two dominant modes. The first mode is related to intraseasonal variations of the wind field and its spatial field represents the response of the WBC to the westward Rossby waves originated from the interior basin, while the second mode reflects the southward propagation of mesoscale signals along the WBC. Mooring observations recorded the accelerations of the southward WBC three times in winter 2004/2005. While the first two could be linked to the wind intensification, the third one was associated with a cyclonic eddy closely next to the WBC. Initially, this eddy propagated from the Luzon Strait, where active mesoscale processes associated with the Kuroshio intrusion act as important disturbance sources for the SCS. [ABSTRACT FROM PUBLISHER]

Hyperglycemia as the major hallmark of diabetic neuropathy severely limited its therapeutic efficiency. Evidences have revealed that selenium (Se) as an essential trace element could effectively reduce the risk of neurological diseases. In the present study, 3,3′-diselenodipropionic acid (DSePA), a derivative of selenocystine, was employed to investigate its protective effect against high glucose-induced neurotoxicity in PC12 cells and evaluate the underlying mechanism. The results suggested that high glucose showed significant cytotoxicity through launching mitochondria-mediated apoptosis in PC12 cells, accompanied by poly (ADP-ribose) polymerase (PARP) cleavage, caspase activation, and mitochondrial dysfunction. Moreover, high glucose also triggered DNA damage and dysregulation of MAPKs and AKT pathways through reactive oxygen species (ROS) overproduction. p53 RNA interference partially suppressed high glucose-induced cytotoxicity and apoptosis, indicating the role of p53 in high glucose-induced signal. However, DSePA pretreatment effectively attenuated high glucose-induced cytotoxicity, inhibited the mitochondrial dysfunction through regulation of Bcl-2 family, and ultimately reversed high glucose-induced apoptotic cell death in PC12 cells. Attenuation of caspase activation, PARP cleavage, DNA damage, and ROS accumulation all confirmed its protective effects. Moreover, DSePA markedly alleviated the dysregulation of AKT and MAPKs pathways induced by high glucose. Our findings revealed that the strategy of using DSePA to antagonize high glucose-induced neurotoxicity may be a highly effective strategy in combating high glucose-mediated neurological diseases. [ABSTRACT FROM AUTHOR]

The recent accelerated Arctic sea ice decline has been proposed as a possible forcing factor for midlatitude circulation changes, which can be projected onto the Arctic Oscillation (AO) and/or North Atlantic Oscillation (NAO) mode. However, the timing and physical mechanisms linking AO responses to the Arctic sea ice forcing are not entirely understood. In this study, the authors suggest a connection between November sea ice extent in the Barents and Kara Seas and the following winter's atmospheric circulation in terms of the fast sea ice retreat and the subsequent modification of local air-sea heat fluxes. In particular, the dynamical processes that link November sea ice in the Barents and Kara Seas with the development of AO anomalies in February is explored. In response to the lower-tropospheric warming associated with the initial thermal effect of the sea ice loss, the large-scale atmospheric circulation goes through a series of dynamical adjustment processes: The decelerated zonal-mean zonal wind anomalies propagate gradually from the subarctic to midlatitudes in about one month. The equivalent barotropic AO dipole pattern develops in January because of wave-mean flow interaction and firmly establishes itself in February following the weakening and warming of the stratospheric polar vortex. This connection between sea ice loss and the AO mode is robust on time scales ranging from interannual to decadal. Therefore, the recent winter AO weakening and the corresponding midlatitude climate change may be partly associated with the early winter sea ice loss in the Barents and Kara Seas. [ABSTRACT FROM AUTHOR]

Hypothermia treatment is one of the neuroprotective strategies that improve neurological outcomes effectively after brain damage. Minimally invasive surgery (MIS) has been an important treatment of intracerebral hemorrhage (ICH). Herein, we evaluated the neuroprotective effect and mechanism of MIS joint local cooling lavage (LCL) treatment on ICH via detecting the inflammatory responses, oxidative injury, and neuronal apoptosis around the hematoma cavity in rats. ICH model was established by type IV collagenase caudatum infusion. The rats were treated with MIS 6 h after injection, and then were lavaged by normothermic (37 °C) and hypothermic (33 °C) normal saline in brain separately. The results indicated that MIS joint LCL treatment showed enhanced therapeutic effects against ICH-induced inflammation injury and apoptosis in rats, as convinced by the decline of TUNEL-positive cells, followed by the decrease of IL-1β and LDH and increase of IL-10 and SOD. This study demonstrated that the strategy of using MIS joint LCL may achieve enhanced neuroprotection against ICH-induced inflammation injury and apoptosis in rats with potential clinic application. [ABSTRACT FROM AUTHOR]

Granulocyte colony-stimulating factor (G-CSF) is a hematopoietic growth factor with strong neuroprotective properties. However, it has limited capacity to cross the blood-brain barrier and thus potentially limiting its protective capacity. Recent studies demonstrated that intranasal drug administration is a promising way in delivering neuroprotective agents to the central nervous system. The current study therefore aimed at determining whether intranasal administration of G-CSF increases its delivery to the brain and its neuroprotective effect against ischemic brain injury. Transient focal cerebral ischemia in rat was induced with middle cerebral artery occlusion. Our resulted showed that intranasal administration is 8-12 times more effective than subcutaneous injection in delivering G-CSF to cerebrospinal fluid and brain parenchyma. Intranasal delivery enhanced the protective effects of G-CSF against ischemic injury in rats, indicated by decreased infarct volume and increased recovery of neurological function. The neuroprotective mechanisms of G-CSF involved enhanced upregulation of HO-1 and reduced calcium overload following ischemia. Intranasal G-CSF application also promoted angiogenesis and neurogenesis following brain ischemia. Taken together, G-CSF is a legitimate neuroprotective agent and intranasal administration of G-CSF is more effective in delivery and neuroprotection and could be a practical approach in clinic. [ABSTRACT FROM AUTHOR]

Oxidative damage plays a key role in causation and progression of neurodegenerative diseases. Inhibition of oxidative stress represents one of the most effective ways in treating human neurologic diseases. Herein, we evaluated the protective effect of curcumin on PC12 cells against HO-induced neurotoxicity and investigated its underlying mechanism. The results indicated that curcumin pre-treatment significantly suppressed HO-induced cytotoxicity, inhibited the loss of mitochondrial membrane potential (Δ ψm) through regulation of Bcl-2 family expression, and ultimately reversed HO-induced apoptotic cell death in PC12 cells. Attenuation of caspase activation, poly(ADP-ribose) polymerase (PARP) cleavage, DNA damage, and accumulation of reactive oxygen species (ROS) all confirmed its protective effects. Moreover, curcumin markedly alleviated the dysregulation of the MAPK and AKT pathways induced by HO. Taken together, our findings suggest that the strategy of using curcumin could be a highly effective way in combating oxidative damage-mediated human neurodegenerative diseases. [ABSTRACT FROM AUTHOR]

Chemotherapy- or radiotherapy-induced DNA damage activates the Chk1-dependent DNA damage response (DDR) and cell cycle checkpoints to facilitate cell survival. Numerous attempts have been made to identify specific Chk1 inhibitors to enhance the efficiency of chemotherapy or radiotherapy. In this study, we investigated the molecular mechanisms underlying the antitumor activity of LY2603618, a potent and selective small molecule inhibitor of Chk1 protein kinase, in human lung cancer cells. Treatment of cancer cells with LY2603618 caused cell cycle arrest in the G2/M phase. A marked induction of DDR, including the phosphorylation of ATM, Chk2, p53 and histone H2AX, was observed after LY2603618 treatment. LY2603618 inhibited Chk1 autophosphorylation (S296 Chk1) and increased DNA damage-mediated Chk1 phosphorylation (S345 Chk1). In addition, LY2603618-treated lung cancer cells transitioned from LC3-I to LC3-II, a hallmark of autophagy. Blocking autophagy with chloroquine (CQ) further enhanced LY2603618′s inhibitory effect on cell viability/proliferation. LY2603618 also significantly increased p38 and c-Jun N-terminal kinase (JNK) phosphorylation. Pretreatment with the JNK inhibitor reduced cleavage of caspase-3 and PARP levels in LY2603618-treated cells. These results suggest the following: (i) the biological consequences of LY2603618 in lung cancer cells is associated with both inhibition of Chk1 phosphorylation on S296 and activation of the DNA damage response network; and (ii) the anticancer property of LY2603618 might be increased by inhibiting autophagy. [ABSTRACT FROM AUTHOR]

This study reveals that sea ice in the Barents and Kara Seas plays a crucial role in establishing a new Arctic coupled climate system. The early winter sea ice before 1998 shows double dipole patterns over the Arctic peripheral seas. This pattern, referred to as the early winter quadrupole pattern, exhibits the anticlockwise sequential sea ice anomalies propagation from the Greenland Sea to the Barents-Kara Seas and to the Bering Sea from October to December. This early winter in-phase ice variability contrasts to the out-of-phase relationship in late winter. The mean temperature advection and stationary wave heat flux divergence associated with the atmospheric zonal wave-2 pattern are responsible for the early winter in-phase pattern. Since the end of the last century, the early winter quadrupole pattern has broken down because of the rapid decline of sea ice extent in the Barents-Kara Seas. This remarkable ice retreat modifies the local ocean-atmosphere heat exchange, forcing an anomalous low air pressure over the Barents-Kara Seas. The subsequent collapse of the atmospheric zonal wave-2 pattern is likely responsible for the breakdown of the early winter sea ice quadrupole pattern after 1998. Therefore, the sea ice anomalies in the Barents-Kara Seas play a key role in establishing new atmosphere-sea ice coupled relationships in the warming Arctic. [ABSTRACT FROM AUTHOR]

Tyrosine kinase receptor erythropoietin-producing hepatocellular receptor A2 (EphA2) and its predominant ligand EphrinA1 have been studied extensively for their roles of mediating cell adhesion in epithelial cells. However, EphA2 signaling in human fallopian tube epithelial cells is poorly understood. In this study, primary cultured fallopian tube epithelial cells were used as a model treated with EphrinA1-Fc or IgG-Fc (control), to explore the role of EphA2 signal and its network involved in the regulation of cell adhesion of tubal epithelia cells. The activation of EphA2 and focal adhesion kinase (FAK) was evaluated by western blotting assay in the cultured fallopian tube epithelia cells, of which the cell adhesion activity was determined by MTT assay. A significantly negative correlation was found between phosphorylated-EphA2 (Pho-EphA2) and phosphorylated-FAK (Pho-FAK) after exposure to EphrinA1-Fc ( P = 0.000; r = −0.848). EphrinA1-Fc increased Pho-EphA2 and reduced Pho-FAK in seconds, with the apex level of Pho-EphA2 and the nadir level of Pho-FAK detected at the same time (10 min). Cell adhesion of the cultured cells supplemented with EphrinA1-Fc appeared to be weaker than that of the controls at the later time points of the treatment (from 30 to 120 min) ( P < 0.05). Taken together, the EphrinA1 addition directly induces an elevated Pho-EphA2 accompanied by a decreased Pho-FAK in human fallopian tube epithelia cells. Furthermore, activation of EphA2 participates in the regulation of fallopian tube cell adhesion via FAK dephosphorylation. [ABSTRACT FROM AUTHOR]

Subduction, water mass transformation, and transport rates in the Indo-Pacific Ocean are diagnosed in a recent version of the Canadian Centre for Climate Modelling and Analysis coupled model. It is found that the subduction across the base of the winter mixed layer is dominated by the lateral transfer, particularly within the relatively dense water classes corresponding to the densest mode and intermediate waters. However, within lighter densities, including those characterizing the lighter varieties of mode waters, the vertical transfer has a strong positive input to the net subduction. The upper-ocean volume transports across 30°°N and 32°°S are largest within the density classes that correspond to mode waters. In the North Pacific, the buoyancy flux converts the near-surface waters mostly to denser water classes, whereas in the Southern Ocean the surface waters are transformed both to lighter and denser water classes, depending on the density. In response to a doubling of CO2, the subduction, transformation, and transport of mode waters in both hemispheres shift to lighter densities but do not change significantly, whereas the subduction of intermediate waters decreases. The area of large winter mixed layer depths decreases, particularly in the Southern Hemisphere. In the low latitudes, the thermocline water flux that enters the tropical Pacific via the western boundary flows generally increases. However, its anomaly has a complex structure, so that integrated estimates can be sensitive to the isopycnal ranges. The upper part of the Equatorial Undercurrent (EUC) strengthens in the warmer climate, whereas its lower part weakens. The anomaly in the EUC closely follows the anomaly in stratification along the equator. The Indonesian Throughflow transport decreases with part of it being redirected eastward. This part joins with the intensified equatorward thermocline flows at the western boundaries and contributes to the EUC anomaly. [ABSTRACT FROM AUTHOR]

Differentiation of human embryonic stem cells (hESCs) into hematopoietic lineages using various methods has been reported. However, the phenotype that precisely defines the hematopoietic progenitor compartment with clonogenic activities has yet to be determined. Here, we measured and characterized progenitor function of subfractions of cells prospectively isolated from human embryoid bodies (hEBs) during hematopoietic differentiation basing on surface markers CD45, CD34, CD43, and CD38. We report that hematopoietic progenitors predominantly resided in the CD45 subset. CD43 cells lacking CD45 expression were largely devoid of progenitor activity. However, progenitor activity and multipotentiality was more enriched in CD45 cells co-expressing CD43. CD45 subset co-expressing CD34 but lacking CD38 expression (CD45CD34CD38) were further enriched for CFU capacity compared to the CD45CD34CD38 subset. Our study demonstrates a role of CD43 in enriching hematopoietic progenitors derived from hEBs and reveals a hierarchical organization of hESC-derived hematopoietic progenitor compartments defined by phenotypic markers. [ABSTRACT FROM AUTHOR]

Background: Tyrosine kinase receptor erythropoietin-producing hepatocellular receptor A2 (EphA2) is abundant in the endometrium and plays a role in the establishment of eutopic implantation. A similar molecular mechanism may exist between uterine implantation and tubal implantation, therefore EphA2 involvement in tubal pregnancy is suspected. Due to the limited availability of human Fallopian tube specimens, EphA2 expression in human Fallopian tube epithelium remains largely unknown. Methods: A total of 31 women with tubal pregnancy and 41 non-pregnant women with benign uterine diseases were enrolled in this study. Immunohistochemistry was used to investigate the expression pattern of EphA2 in the Fallopian tube epithelium of non-pregnant women (n = 29) and women with tubal pregnancy (n = 17). The changes of EphA2 and its activated form, phosphorylated-EphA2 (Pho-EphA2), in the Fallopian tube epithelium from non-pregnant women (n = 12) and women with tubal pregnancy (n = 14) were compared by quantitative RT-PCR and western blot assay. Results: EphA2 was expressed throughout the Fallopian tube epithelium, including the isthmus, the ampulla and the infundibulum. EphA2 concentration remained unchanged throughout the whole menstrual cycle, irrespective of menstrual phases and tubal regions. EphA2 mRNA in the Fallopian tube epithelium did not differ between normal women and women with tubal pregnancy (P > 0.05). With respect to the protein level, a significantly higher ratio of EphA2 over Pho-EphA2 was shown in women with tubal pregnancy (P < 0.05). Conclusions: EphA2 is widely expressed in human Fallopian tube epithelium in a temporospatial-independent manner. Dysregulated EphA2 and its phosphorylation-dependent regulatory mechanism may unexpectedly enhance the cell adhesion activity of the Fallopian tube epithelial cells, leading to a mis-contact between the Fallopian tube epithelium and the embryo. [ABSTRACT FROM AUTHOR]

Triple-negative breast cancer (TNBC) is an aggressive and molecularly diverse breast cancer subtype typified by the presence of p53 mutations (∼80%), elevated immune gene signatures and neoantigen expression, as well as the presence of tumor infiltrating lymphocytes (TILs). As these factors are hypothesized to be strong immunologic prerequisites for the use of immune checkpoint blockade (ICB) antibodies, multiple clinical trials testing single ICBs have advanced to Phase III, with early indications of heterogeneous response rates of <20% to anti-PD1 and anti-PDL1 ICB. While promising, these modest response rates highlight the need for mechanistic studies to understand how different ICBs function, how their combination impacts functionality and efficacy, as well as what immunologic parameters predict efficacy to different ICBs regimens in TNBC. To address these issues, we tested anti-PD1 and anti-CTLA4 in multiple models of TNBC and found that their combination profoundly enhanced the efficacy of either treatment alone. We demonstrate that this efficacy is due to anti-CTLA4-driven expansion of an individually unique T-cell receptor (TCR) repertoire whose functionality is enhanced by both intratumoral Treg suppression and anti-PD1 blockade of tumor expressed PDL1. Notably, the individuality of the TCR repertoire was observed regardless of whether the tumor cells expressed a nonself antigen (ovalbumin) or if tumor-specific transgenic T-cells were transferred prior to sequencing. However, responsiveness was strongly correlated with systemic measures of tumor-specific T-cell and B-cell responses, which along with systemic assessment of TCR expansion, may serve as the most useful predictors for clinical responsiveness in future clinical trials of TNBC utilizing anti-PD1/anti-CTLA4 ICB. [ABSTRACT FROM AUTHOR]

Expression of human epidermal growth factor family member 3 (HER3), a critical heterodimerization partner with EGFR and HER2, promotes more aggressive biology in breast and other epithelial malignancies. As such, inhibiting HER3 could have broad applicability to the treatment of EGFR- and HER2-driven tumors. Although lack of a functional kinase domain limits the use of receptor tyrosine kinase inhibitors, HER3 contains antigenic targets for T cells and antibodies. Using novel human HER3 transgenic mouse models of breast cancer, we demonstrate that immunization with recombinant adenoviral vectors encoding full length human HER3 (Ad-HER3-FL) induces HER3-specific T cells and antibodies, alters the T cell infiltrate in tumors, and influences responses to immune checkpoint inhibitions. Both preventative and therapeutic Ad-HER3-FL immunization delayed tumor growth but were associated with both intratumoral PD-1 expressing CD8+T cells and regulatory CD4+T cell infiltrates. Immune checkpoint inhibition with either anti-PD-1 or anti-PD-L1 antibodies increased intratumoral CD8+T cell infiltration and eliminated tumor following preventive vaccination with Ad-HER3-FL vaccine. The combination of dual PD-1/PD-L1 and CTLA4 blockade slowed the growth of tumor in response to Ad-HER3-FL in the therapeutic model. We conclude that HER3-targeting vaccines activate HER3-specific T cells and induce anti-HER3 specific antibodies, which alters the intratumoral T cell infiltrate and responses to immune checkpoint inhibition. [ABSTRACT FROM AUTHOR]