Short-lived Activity Research Articles

Twice weekly dosing with Sebelipase alfa (Kanuma®) rescues severely ill infants with Wolman disease

BackgroundSebelipase alfa (Kanuma®) is approved for patients with Wolman disease (WD) at a dosage of 3–5 mg/kg once weekly. Survival rates in the second of two clinical trials was greater, despite recruiting more severely ill patients, probably related to higher initial and maximal doses. We aimed to evaluate the effective pharmacokinetics and pharmacodynamics of Sebelipase alfa when administered to patients with severe WD at 5 mg/kg twice weekly, an intensive regimen which was not assessed in the trials.MethodsWe recruited 3 patients receiving Sebelipase alfa 5 mg/kg twice weekly. We measured LAL activity in leukocytes and plasma oxysterol concentration in two patients and LAL activity in fibroblasts in one patient. Clinical follow up was also assessed.ResultsAnalyses of LAL activity and oxysterols demonstrate that there is short-lived enzyme activity post-dosing which is associated with the release of stored lipids. Clinical data demonstrate that 5 mg/kg twice weekly dosing is well tolerated and effective.Conclusion5 mg/kg twice weekly dosing with Sebelipase alfa rescues severely ill infants with WD by increasing substrate clearance. There is biologically relevant lipid accumulation in the ‘trough’ periods before the next dosing, even with this intensive regimen.

Internal structure of the volcanic island of Surtsey and surroundings: Constraints from a dense aeromagnetic survey

Surtsey, a young basaltic island off the south coast of Iceland, was built by volcanic activity in 1963–1967 from a pre-eruption oceanic seafloor depth of 130 m. An aeromagnetic survey was carried out in October 2021 over a 60 km2 area covering Surtsey and its surroundings. It aimed to explore the internal structure and the possible existence of basaltic intrusions associated with the five vents active at different times over the 3.5 years of eruptive activity. The survey line spacing was 200 m and the flying altitude was generally 90 m a.s.l. The strongest anomalies (amplitude ∼700 nT) are caused by the 30–100 m thick subaerially erupted lava field on the southern part of Surtsey, formed in two episodes of effusive activity:1964–1965 and 1966–1967. 2D spectral analysis and Euler deconvolution indicate that the causative bodies of anomalies outside the island of Surtsey are located within the uppermost 300 m of the seafloor and their horizontal dimensions are similar to or smaller than their depth. 3D forward modeling of the island and its surroundings, constrained by observations during the formation of the island and drill cores extracted in 1979 and 2017, is consistent with an absence, at all vents, of pillow lava and therefore effusive activity in their opening phases. However, the data support the existence of a 10–20 m thick pillow lava field on the seafloor, 2.5–3 km2 in area, extending about ∼1 km to the south of Surtsey. The field is considered to have been fed by magma reaching the seafloor via channelized intrusive flow through the foreset breccia constituting the submarine part of an emerging lava delta during the early stage of effusive eruption in May–July 1964. The general scarcity of significant magnetic bodies within the edifices is consistent with magma fragmentation dominating the submarine eruptions from the onset of activity. A small magnetic anomaly is observed over the submarine edifice of Surtla, built during short-lived activity over ∼10 days in 1963–1964. This anomaly is consistent with observed subaqueous weak or moderate explosive activity that may have allowed a dyke to be preserved within the submarine tephra mound. More violent Surtseyan activity was observed at other vents, however, and may have destroyed any initial dykes that, if preserved, might have been resolved magnetically. Indications of magnetized volcanic rocks of unknown age predating the Surtsey eruption are found beneath the flank of the ephemeral island of Jólnir, the southernmost of the Surtsey vents.

Post-task responses following working memory and movement are driven by transient spectral bursts with similar characteristics.

The post-movement beta rebound has been studied extensively using magnetoencephalography (MEG) and is reliably modulated by various task parameters as well as illness. Our recent study showed that rebounds, which we generalise as "post-task responses" (PTRs), are a ubiquitous phenomenon in the brain, occurring across the cortex in theta, alpha, and beta bands. Currently, it is unknown whether PTRs following working memory are driven by transient bursts, which are moments of short-lived high amplitude activity, similar to those that drive the post-movement beta rebound. Here, we use three-state univariate hidden Markov models (HMMs), which can identify bursts without a priori knowledge of frequency content or response timings, to compare bursts that drive PTRs in working memory and visuomotor MEG datasets. Our results show that PTRs across working memory and visuomotor tasks are driven by pan-spectral transient bursts. These bursts have very similar spectral content variation over the cortex, correlating strongly between the two tasks in the alpha (R2 = .89) and beta (R2 = .53) bands. Bursts also have similar variation in duration over the cortex (e.g., long duration bursts occur in the motor cortex for both tasks), strongly correlating over cortical regions between tasks (R2 = .56), with a mean over all regions of around 300 ms in both datasets. Finally, we demonstrate the ability of HMMs to isolate signals of interest in MEG data, such that the HMM probability timecourse correlates more strongly with reaction times than frequency filtered power envelopes from the same brain regions. Overall, we show that induced PTRs across different tasks are driven by bursts with similar characteristics, which can be identified using HMMs. Given the similarity between bursts across tasks, we suggest that PTRs across the cortex may be driven by a common underlying neural phenomenon.

Engraftment of essential functions through multiple fecal microbiota transplants in chronic antibiotic-resistant pouchitis—a case study using metatranscriptomics

BackgroundIleal pouch-anal anastomosis (IPAA) is the standard of care after total proctocolectomy for ulcerative colitis (UC). Around 50% of patients will experience pouchitis, an idiopathic inflammatory condition. Antibiotics are the backbone of treatment of pouchitis; however, antibiotic-resistant pouchitis develops in 5–10% of those patients. It has been shown that fecal microbiota transplantation (FMT) is an effective treatment for UC, but results for FMT antibiotic-resistant pouchitis are inconsistent.MethodsTo uncover which metabolic activities were transferred to the recipients during FMT and helped the remission, we performed a longitudinal case study of the gut metatranscriptomes from three patients and their donors. The patients were treated by two to three FMTs, and stool samples were analyzed for up to 140 days.ResultsReduced expression in pouchitis patients compared to healthy donors was observed for genes involved in biosynthesis of amino acids, cofactors, and B vitamins. An independent metatranscriptome dataset of UC patients showed a similar result. Other functions including biosynthesis of butyrate, metabolism of bile acids, and tryptophan were also much lower expressed in pouchitis. After FMT, these activities transiently increased, and the overall metatranscriptome profiles closely mirrored those of the respective donors with notable fluctuations during the subsequent weeks. The levels of the clinical marker fecal calprotectin were concordant with the metatranscriptome data. Faecalibacterium prausnitzii represented the most active species contributing to butyrate synthesis via the acetyl-CoA pathway. Remission occurred after the last FMT in all patients and was characterized by a microbiota activity profile distinct from donors in two of the patients.ConclusionsOur study demonstrates the clear but short-lived activity engraftment of donor microbiota, particularly the butyrate biosynthesis after each FMT. The data suggest that FMT triggers shifts in the activity of patient microbiota towards health which need to be repeated to reach critical thresholds. As a case study, these insights warrant cautious interpretation, and validation in larger cohorts is necessary for generalized applications. In the long run, probiotics with high taxonomic diversity consisting of well characterized strains could replace FMT to avoid the costly screening of donors and the risk of transferring unwanted genetic material.1wvY14mjpJT86R5RsB8tdiVideo

Being-in-touch: The (im)possibilities of communicative and tactile connection in online experiences

Amid social distancing and the sole reliance on communication technologies to “keep in touch” precipitated by COVID-19, touch, both communicatively and tactically, emerged in complex ways. This study examines Airbnb Online Experiences as a new media offering possibilities for people to be “in touch” with others around the world through short-lived interactive activities on Zoom. While new media technologies traditionally expand the potential for sustained connection and increasingly replicate elements of “in-person” communication, this emerging digital phenomenon, although enabling wider communicative reach and enhanced somatic experience, exists in fleeting, physically distanced connections. Through ethnography, the article examines how participants navigate circumstances of touch in online experiences, both by ways of communicative contact and physical proximity. The term being-in-touch is proposed, inspired by works on touch from relational ontological perspectives, to capture the multiple meanings and many ways of being in touch, exploring the relational nature and (im)possibilities of connection.

Engineered lentivirus-derived nanoparticles (LVNPs) for delivery of CRISPR/Cas ribonucleoprotein complexes supporting base editing, prime editing and in vivo gene modification.

Implementation of therapeutic in vivo gene editing using CRISPR/Cas relies on potent delivery of gene editing tools. Administration of ribonucleoprotein (RNP) complexes consisting of Cas protein and single guide RNA (sgRNA) offers short-lived editing activity and safety advantages over conventional viral and non-viral gene and RNA delivery approaches. By engineering lentivirus-derived nanoparticles (LVNPs) to facilitate RNP delivery, we demonstrate effective administration of SpCas9 as well as SpCas9-derived base and prime editors (BE/PE) leading to gene editing in recipient cells. Unique Gag/GagPol protein fusion strategies facilitate RNP packaging in LVNPs, and refinement of LVNP stoichiometry supports optimized LVNP yield and incorporation of therapeutic payload. We demonstrate near instantaneous target DNA cleavage and complete RNP turnover within 4 days. As a result, LVNPs provide high on-target DNA cleavage and lower levels of off-target cleavage activity compared to standard RNP nucleofection in cultured cells. LVNPs accommodate BE/sgRNA and PE/epegRNA RNPs leading to base editing with reduced bystander editing and prime editing without detectable indel formation. Notably, in the mouse eye, we provide the first proof-of-concept for LVNP-directed in vivo gene disruption. Our findings establish LVNPs as promising vehicles for delivery of RNPs facilitating donor-free base and prime editing without formation of double-stranded DNA breaks.

Study of atmosphere parameters of the IVV-2M reactor hall

The paper presents the results of a study of radioactive noble gases and from decay products in the atmosphere of the reactor hall of the research nuclear reactor IVV-2M. The distribution of short-lived 88Rb and 138Cs activity by sizes of aerosol particles was measured in the range of 0.5–1000 nm. It is shown that radioactive aerosols are characterized by three main modes with AMTD 2–3 nm, 7–15 nm and 400 nm. About 70% of aerosol activity is due to 88Rb. The equilibrium factor between 88Kr and 88Rb is 0.2 ± 0.1. The total concentration of aerosols particles was measured using an aerosol diffusion spectrometer. The value of unattached fraction of radioactive aerosols in the atmosphere of reactor hall IVV-2M was f = 0.15–0.25 at the average total aerosol particles concentration from 20,000 cm−3 to 53,000 cm−3.

Synchrotron afterglow model for AT 2022cmc: jetted tidal disruption event or engine-powered supernova?

ABSTRACT AT 2022cmc is a luminous optical transient (νLν ≳ 1045 erg s−1) accompanied by decaying non-thermal X-rays (peak duration tX ≲ days and isotropic energy EX,iso ≳ 1053 erg) and a long-lived radio/mm synchrotron afterglow, which has been interpreted as a jetted tidal disruption event (TDE). Both an equipartition analysis and a detailed afterglow model reveal the radio/mm emitting plasma to be expanding mildly relativistically (Lorentz factor $\Gamma \gtrsim \, \mathrm{ few}$ ) with an opening angle θj ≃ 0.1 and roughly fixed energy Ej,iso ≳ few × 1053 erg into an external medium of density profile n ∝ R−k with k ≃ 1.5–2, broadly similar to that of the first jetted TDE candidate Swift J1644+57 and consistent with Bondi accretion at a rate of ∼$10^{-3}\,\dot{M}_{\rm Edd}$ on to a 106 M⊙ black hole before the outburst. The rapidly decaying optical emission over the first days is consistent with fast-cooling synchrotron radiation from the same forward shock as the radio/mm emission, while the bluer slowly decaying phase to follow likely represents a separate thermal emission component. Emission from the reverse shock may have peaked during the first days, but its non-detection in the optical band places an upper bound Γj ≲ 100 on the Lorentz factor of the unshocked jet. Although a TDE origin for AT 2022cmc is indeed supported by some observations, the vast difference between the short-lived jet activity phase tX ≲ days and the months-long thermal optical emission also challenges this scenario. A stellar core-collapse event giving birth to a magnetar or black hole engine of peak duration ∼1 d offers an alternative model also consistent with the circumburst environment, if interpreted as a massive star wind.

Fan-shaped deposits in the northern Hellas region, Mars: Implications for the evolution of water reservoir and climate

Hellas basin is the largest and deepest depositional sink in the southern highlands of Mars. The region to the north of the Hellas basin is characterized by a variety of fan-shaped sedimentary deposits, which record the history of aqueous activities and climate change. We newly identified 20 potential deltas, 134 alluvial fans, 42 debris flows, 137 glacier-related fans, and 121 other fan-shaped landforms including landslides. The accumulation of liquid water-related fans along the northeastern flanks of the Hellas basin is likely controlled by elevation. The focus of this study is the potential deltas and alluvial fans for which detailed geomorphic analysis was carried out. The sediment fans sit mainly within closed basins and their feeder valleys are immature, indicating a short-lived activity of water. We observed two cases of a younger fan system creating an incision through an older sediment fan, indicating a punctuated reduction in the activity of water, in which the duration of the interfluvial period was assessed. We dated the sediment fans and found that they were mainly formed in the Hesperian and Early Amazonian and underwent glacial resurfacing around 700 Myr ago. Only a few fans formed in the Late Noachian were identified. Based on our observations, we submitted snowfall as the main source of water for these sedimentary fans although, as seen in the two cases of alluvial fans, a few of them could also have been fed by small-scale glacial melt. Both water sources supported cold and dry spells. We concluded that the fans record a persistence of water/ice activity until the Middle Amazonian in Martian history.

Immunological effects and activity of multiple doses of zolbetuximab in combination with zoledronic acid and interleukin-2 in a phase 1 study in patients with advanced gastric and gastroesophageal junction cancer

PurposeZolbetuximab (IMAB362) is engineered to induce antibody-dependent cell-mediated cytotoxicity (ADCC) and complement-dependent cytotoxicity. We evaluated ADCC activity and the impact of the immune-modulating drugs zoledronic acid (ZA) and interleukin-2 (IL-2) as co-treatment with zolbetuximab on relevant immune cell populations and ADCC lysis activity.MethodsThis phase 1, multicenter, open-label study investigated the immunological effects and activity, safety, tolerability, and antitumor activity of multiple doses of zolbetuximab alone (n = 5) or in combination with ZA (n = 7) or with ZA plus two different dose levels of IL-2 (low dose: 1 million international units [mIU] [n = 9]; intermediate dose: 3 mIU [n = 7]) in pretreated patients with advanced gastric and gastroesophageal junction (G/GEJ) adenocarcinoma.ResultsTwenty-eight patients with previously treated advanced G/GEJ adenocarcinoma that was CLDN18.2-expressing were enrolled into four treatment arms. Treatment with zolbetuximab + ZA + IL-2 induced short-lived expansion and activation of ADCC-mediating cell populations, namely γ9δ2 T cells and natural killer cells, within 2 days after administration; this effect was more pronounced with intermediate-dose IL-2. Expansion and activation of regulatory T cells treated with either IL2 dose was moderate and short-lived. Strong ADCC activity was observed with zolbetuximab alone. Short-lived ADCC activity was observed in several patients treated with ZA + intermediate-dose IL-2, but not lower-dose IL-2. In the clinical efficacy population, the best confirmed response was stable disease (n = 11/19; 58%).ConclusionsZolbetuximab mediates proficient ADCC in patients with pretreated advanced G/GEJ cancers. Co-treatment with ZA + IL-2 did not further improve this effect.Trial registration: NCT01671774

Ukrainian intellectual Trokhym Zinkivskyi and preservation of historical memory of Taras Shevchenko

The personality of Trochym Zinkivskyi (1861–1891) remains little known and insufficiently developed in modern Ukrainian historiography. The purpose of the article is to study the figure of Trokhym Zinkivskyi in the context of the problem of preserving the historical memory of Taras Shevchenko. Research methods are personalistic, historical-genetic and historical-systemic. Sources: published epistolaries of T. Zinkivskyi and his addressees, memories of contemporaries, biographical articles in the Ukrainian press of the beginning of the 20th century etc. The main results consist in elucidating the peculiarities of the formation of T. Zinkivskyi's worldview under the conditions of the oppression of the Southern Ukrainian lands by the Russian imperial regime, in particular in Berdyansk, Feodosia and Odesa, the establishment of his Ukrainian national-democratic views during his studies and military service in Smila, Shpola and Uman, in Kyiv and St. Petersburg. It is noted that an important factor in the development of his Ukrainian consciousness and identity was his family upbringing, which instilled love for his native language and formed Christian, religious values. A prominent role was played by the reading circle, which included Shevchenkov's «Kobzar» along with other literary works of Ukrainian and foreign writers; as well as Ukrainian folk art. V. Kravchenko, L. Smolenskyi, B. Grinchenko, M. Komarov, and a number of representatives of the Ukrainian colony in St. Petersburg were included in the closest circle of persons who significantly influenced the formation of the worldview of the Ukrainian figure. The article traces the main stages of the intellectual and public activity of the Ukrainian figure in the matter of preserving the historical memory of Kobzar. It is noted that already in the middle and second half of the 80s of the 19th century. T. Zinkivskyi began work in the field of Ukrainian literature, took care of translation activities. In St. Petersburg, he was able to begin wider work for the benefit of Ukrainianism and became an ideological leader of young Ukrainians. The powerful vital energy of the activist was organically combined with consistent and convinced actions in the name of the Ukrainian cause. In the youth group at Shevchenko's anniversary, T. Zinkivskyi read a number of essays, such as «The National Question in Russia», «Shevchenko in the Light of European Criticism», «Young Ukraine» and others. His essay «Taras Shevchenko in the Light of European Criticism», which was read in Ukrainian on the evening of February 25, 1889 in the capital of the empire, was of exceptional importance. This speech, prepared mostly on the basis of French, Austrian, German, and Polish historiographical sources, presented Kobzar as a figure of global poetic scale and destroyed the perception of the Russian metropolitan public about Ukrainians and the Ukrainian language as something provincial and inferior. Conclusions.T. Zinkivskyi became one of the brightest representatives of the «Young Ukraine» generation. The short-lived but important intellectual activity of the ideological leader of young Ukrainians, in particular, speeches at the Shevchenko anniversary, publication of abstracts, epistolaries, drew the attention of contemporaries to the figure of Taras Shevchenko, to his poetic heritage; actualized the issue of preserving the historical memory of Kobzar as a leader of the national values of Ukrainians. It has been proven that during the 1880s and early 1890s, T. Zinkivskyi's intellectual activity contributed to the progress of Ukrainian public affairs and national science, the establishment of Ukrainian national consciousness among the generation of young Ukrainians. The practical significance of the article is that the given material will be of interest to specialists in the context of studying the ethno-national history of Ukraine in the second half of the 19th century. The originality of the article lies in the understanding of insufficiently studied aspects of the activity of the Ukrainian intellectual, who stood at the origins of the idea of «Young Ukraine». Scientific novelty in updating the intellectual activity of T. Zinkivskyi in the matter of preserving Ukrainian national memory and forming national consciousness and identity.

Rheology, shear zone width, microstructural evolution and tectonics of a zippered strike-slip shear zone: The Senador Pompeu shear zone, northern Borborema Province, Brazil

Studies of the Borborema Province have broadly elicited the important role of its abundant strike-slip shear zones in accommodating relative motion of crustal blocks during the Brasiliano orogeny, but seldom quantitatively addressed key aspects of shear zone deformation such as longevity, slip rate, total offset, kinematics and rheology. To provide unprecedented level of detail regarding the dextral Senador Pompeu shear zone of northern Borborema Province, we have conducted a complete structural study using detailed geological mapping, deformation microstructures, Electron Backscatter Diffraction (EBSD), geobarometry, and shear zone width modelling. Our results show that: (i) shear zone width decreases systematically along strike from its northern segment, monotonously composed of high-temperature penetrative mylonitic gneisses, towards the south, made up of low-temperature ultramylonites, cataclasites and pseudotachylytes; (ii) quartz deformation microstructures change consistently from high-T grain boundary migration recrystallization and {m}⟨c⟩ slip in the northern segment, to subgrain rotation/bulging recrystallization, mixed−⟨a⟩ slip and cataclasis in the southern segment; (iii) geobarometry of synkinematic shear zone-bounded plutons indicate a depth difference of c. 10 km over a length of 200 km of the Senador Pompeu shear zone; (iv) shear zone width modelling indicate that slip rates must have been at least 10 mm/yr; (v) geological units show a total offset of 50–75 km; (vi) three dextral closing zipper segments found along the length of the shear zone juxtapose mylonites with opposing kinematics. From the consistent decrease in shear zone width and deformation temperature towards the southwest and the difference in emplacement depth of synkinematic granites we interpret that the northern segment is up-tilted by a few degrees (c. 3°) relative to the southern segment, exposing the strength profile, the brittle-ductile transition and the relation between depth and width of the shear zone. The width simulation carried out on that basis allowed the long-term slip rate to be constrained at >10 mm/yr, from which we interpret that the Senador Pompeu had a short-lived activity of c. 10 Myr (584‒574 Ma).

Neurotrophic Role of the Next-Generation Probiotic Strain L. lactis MG1363-pMG36e-GLP-1 on Parkinson's Disease via Inhibiting Ferroptosis.

Parkinson's disease (PD) is a neurodegenerative disease (NDD) with high and ongoing morbidity, bringing heavy burdens to PD patients seriously. Finding neurotrophic drugs still remains vital due to the limited drug spectrum available currently. Substantial evidence suggests that glucagon-like peptide 1 (GLP-1) exerts neuroprotection on PD, yet the short-lived biological activity markedly hindered its application. Herein, we investigated the neurotrophic role of the next-generation probiotic strain L. lactis MG1363-pMG36e-GLP-1 in 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-induced PD mice and elucidated the mechanisms. Our data suggested that L. lactis MG1363-pMG36e-GLP-1 markedly enhanced motor deficits induced by MPTP via rescuing dopaminergic (DAergic) neurodegeneration in substantia nigra (SN). We found that L. lactis MG1363-pMG36e-GLP-1 exerts neurotrophic effects via activating the Keap1/Nrf2/GPX4 signalling pathway to down-regulate ACSL4 and up-regulate FSP1 to suppress ferroptosis. Additionally, the decreased oxidative stress levels via suppressing generations of ROS and MDA supported our findings. Lastly, we identified that the L. lactis MG1363-pMG36e-GLP-1 administration reversed dysbiosis in PD mice by increasing Akkermansia, Oscillospira, and Sutterella at the genus level. These results indicated that the neurotrophic effects of the next-generation probiotics L. lactis MG1363-pMG36e-GLP-1 against MPTP-induced Parkinsonism are mediated by modulating oxidative stress, inhibiting ferroptosis, and redressing dysbiosis.

Sensory Target Detection at Local and Global Timescales Reveals a Hierarchy of Supramodal Dynamics in the Human Cortex.

To ensure survival in a dynamic environment, the human neocortex monitors input streams from different sensory organs for important sensory events. Which principles govern whether different senses share common or modality-specific brain networks for sensory target detection? We examined whether complex targets evoke sustained supramodal activity while simple targets rely on modality-specific networks with short-lived supramodal contributions. In a series of hierarchical multisensory target detection studies (n = 77, of either sex) using EEG, we applied a temporal cross-decoding approach to dissociate supramodal and modality-specific cortical dynamics elicited by rule-based global and feature-based local sensory deviations within and between the visual, somatosensory, and auditory modality. Our data show that each sense implements a cortical hierarchy orchestrating supramodal target detection responses, which operate at local and global timescales in successive processing stages. Across different sensory modalities, simple feature-based sensory deviations presented in temporal vicinity to a monotonous input stream triggered a mismatch negativity-like local signal which decayed quickly and early, whereas complex rule-based targets tracked across time evoked a P3b-like global neural response which generalized across a late time window. Converging results from temporal cross-modality decoding analyses across different datasets, we reveal that global neural responses are sustained in a supramodal higher-order network, whereas local neural responses canonically thought to rely on modality-specific regions evolve into short-lived supramodal activity. Together, our findings demonstrate that cortical organization largely follows a gradient in which short-lived modality-specific as well as supramodal processes dominate local responses, whereas higher-order processes encode temporally extended abstract supramodal information fed forward from modality-specific cortices.SIGNIFICANCE STATEMENT Each sense supports a cortical hierarchy of processes tracking deviant sensory events at multiple timescales. Conflicting evidence produced a lively debate around which of these processes are supramodal. Here, we manipulated the temporal complexity of auditory, tactile, and visual targets to determine whether cortical local and global ERP responses to sensory targets share cortical dynamics between the senses. Using temporal cross-decoding, we found that temporally complex targets elicit a supramodal sustained response. Conversely, local responses to temporally confined targets typically considered modality-specific rely on early short-lived supramodal activation. Our finding provides evidence for a supramodal gradient supporting sensory target detection in the cortex, with implications for multiple fields in which these responses are studied (e.g., predictive coding, consciousness, and attention).

Chidamide augment sorafenib-derived anti-tumor activities in human osteosarcoma cells lines and xenograft mouse model.

Previous studies have showed promising but short-lived activity of sorafenib in osteosarcoma treatments. Researches have suggested ameliorated sensitivity to standard dose of conventional cancer therapies in combination with histone deacetylase inhibitors (HDACis) through various mechanisms. Herein, for the first time, we exploited the synergism of combination therapies with sorafenib and chidamide, a member of HDACis, in the control of OS using human OS cell lines and OS xenograft mouse model and discussed interactive mechanisms between the two drugs. The combination therapy exerted a strong synergism in the inhibition of OS cell proliferation, meanwhile prominently induced cell apoptosis and cell cycle arrest in G0/G1 phase in OS cells with increased expression of MCL-1, decreased expression of caspase-3 and P21, along with diminished level of the overlapped protein P-ERK1/2. Furthermore, oral administration of the combined treatment led to a more optical therapeutic outcome, including lower degrees of tumoral cell proliferation, greater extent of apoptosis, along with induction of cell cycle arrest in tumor tissues, while exhibiting minimal toxicity. This study shows that the combination of sorafenib and chidamide can combat OS in a synergistic fashion and prompts the promising development of innovative combined therapeutic strategies for OS.

The leaf meristem enigma: The relationship between the plate meristem and the marginal meristem.

Leaf organogenesis is governed by the spatiotemporal activity of the leaf meristem, which has far greater mitotic activity than the shoot apical meristem. The two types of leaf meristems, the plate meristem and the marginal meristem, are distinguished by the location and longevity of their cell proliferative activity. Most leaf lamina outgrowth depends on the plate meristem. The presence of the marginal meristem was a matter of debate in classic anatomy, but recent genetic analyses of leaf growth in Arabidopsis thaliana confirmed its short-lived activity. Several genes key for the regulation of the two meristem types have been identified, and at least superficially, the systems appear to function independently, as they are regulated by different transcription factors and microRNAs. However, many of the details of these regulatory systems, including how the expression of these key factors is spatially regulated, remain unclear. One major unsolved question is the relationship between the plate meristem and the marginal meristem. Here, I present an overview of our current understanding of this topic and discuss questions that remain to be answered.

Apatinib plus ifosfamide and etoposide (IE) versus IE chemotherapy alone for relapsed or refractory osteosarcoma.

e23502 Background: Results of previous study showed promising objective response but short-lived activity of apatinib in the treatment of osteosarcoma refractory to first-line chemotherapy, from which we observed the disease control of musculoskeletal lesions were worse than pulmonary lesions. This treatment failure has partly been overcome by the addition of Ifosfamide and etoposide in OLIE study. We aimed to retrospectively compare the activity of apatinib in combination with IE in relapsed or refractory osteosarcoma with synchronous patients receiving IE chemotherapy alone in two sarcoma centers in China. Methods: We retrospectively analyzed medical files and radiographic materials of patients with osteosarcoma relapsed or refractory to first-line chemotherapy, who had received combination of apatinib and IE regimen or IE chemotherapy alone between June 3rd, 2017 and July 17th, 2020. Seventy-nine patients were included, of whom 33 patients received apatinib in combination with IE and 46 patients received single IE chemotherapy. Results: Patients’ tumor burden and general status were obviously different between these two groups with 16/33 (48.5%) patients receiving apatinib+IE having both Lung and musculoskeletal lesions at baseline and 39/46 (84.8%) patients receiving single IE having just pulmonary lesions at baseline. However at last follow up 16/33 (48.5%) of patients receiving apatinib+IE had all lesions resected while 23/46 (50.0%) of patients receiving IE alone had their lesions resected, which might partly due to down-staging of the diseases. With median follow-up time of 28.4 (IQR, 16.1-38.3) months, 21/33 (63.6%) patients receiving apatinib+IE had objective responses while 13/46 (28.3%) patients receiving single IE chemotherapy had responses. The median event-free survivals (EFS) were respectively 11.4 (IQR, 6.7-18.4) months for apatinib+IE and 11.2 (IQR, 4.4-21.8) months for IE alone without significant statistical differences (P = 0.47). The overall survival (OS) was obviously different because of disease stage and tumor burden according to Kaplan-Meier analysis with median OS time of 30.4 (IQR, 21.8-not reached) months for IE alone and 19.8 (IQR, 13.1-30.6) months (P = 0.019). Conclusions: For osteosarcoma with multiple sites’ metastasis, apatinib plus IE demonstrated clinically meaningful antitumor activity in patients with recurrent or refractory osteosarcoma after failure of MAP/I chemotherapy or even single apatinib or IE treatment alone, with a positive effect on delaying disease progression. This combination deserves further investigation in prospective trials with manageable toxicity.

Wood resource exploitation by Late Holocene occupations in central Argentina: Fire making in rockshelters of the ongamira valley (Córdoba, Argentina)

This paper presents the results of a study of firewood use and management by human groups in the Ongamira valley, Córdoba, Argentina (dated between c. 5700-950 BP). In order to understand firewood gathering practices at different periods in the Late Holocene, samples from 63 combustion events recorded in 9 rockshelters were analysed. From the anthracological analysis (14,976 fragments) 19 woody taxa, and 4 botanically indeterminate taxa, were identified belonging to Chaco Serrano forest vegetation. The identification of abundant small flat fireplaces suggests short-lived activities repeated over time. A detailed analysis of the samples (types of fire pits, alterations during combustion and taphonomic processes) permits inferring firewood gathering in the local vegetation around the sites, as well as some taxa belonging to different environmental settings. Archaeological evidence indicates that groups were mobile, with the establishment of a network of places in the landscape where different activities were carried out (tool production, food consumption and pottery manufacture) with fire making as a central activity. People in the past constantly used different places in the valley, focusing many of their activities in rockshelters.

Mannosylated glycoconjugates on the surface of activated sperm in the giant freshwater prawn are crucial for sperm binding with the egg vitelline envelop.

The unusual morphology and poorlydefined acrosome-like structure in the mature sperm of the giant freshwater prawn Macrobrachium rosenbergii has led to difficulties in identifying the state of sperm activation. Mature distal vas deferens sperm (dVSp) can be activated by the calcium ionophore A23187 to show acrosome reaction-like enzymatic activities that increase their binding and penetration capabilities. However, these short-lived enzymatic activities limit their usefulness as a marker of sperm activation for further qualitative and quantitative analyses, leading to our examining the alterations in the exposureof sperm surface glycoconjugates both as markers of sperm activation and for their role in gamete interaction. Our results showed that after A23187 treatment, there was an increased exposure of mannosylated glycoconjugates on the sperm surface revealed by significant Concanavalin A (Con A) staining. Furthermore, sodium metaperiodate pre-treatment, Con A pre-incubation, or co-incubation with α-mannose monosaccharides all significantly reduced A23187-induced dVSp binding to the egg vitelline envelop, demonstrating the importance of sperm surface mannosylated glycoconjugates in the binding process. These same pre-treatments of sperm also resulted in the inhibition of thebinding of soluble vitelline envelop proteins (MrVE) to both the sperm surface and to mannosylated dVSp protein bands. Therefore, the present study demonstrated the importance of the exposure of mannosylated glycoconjugates on the surface of activated dVSp, both as a reliable marker of sperm activation and as a binding factor in the gamete interaction process. Furthermore, these findings allow for a better understanding of the surface glycoconjugate-mediated interaction process between gametes in this species of prawn.

„To był mastodont” – Mieczysław Szczuka w poszukiwaniu piękna utylitarnego

<p>Artykuł jest próbą biografii Mieczysława Szczuki – polskiego artysty-grafika międzywojnia. Jego krótka działalność jest istotna z uwagi na fascynację radzieckim konstruktywizmem, pionierstwo w zakresie polskiego fotomontażu, działalność teoretyczną oraz zespolenie idei artystycznych<br />z komunistycznym dążeniem do przeprowadzenia rewolucji społeczno-politycznej. Szczuka współtworzył czasopisma artystyczno-literackie (Blok, Dźwignia) oraz angażował się w wydawniczą działalność awangardową. Przywoływane wypowiedzi programowe wpisywały się w artystyczne<br />i literackie dyskusje międzywojenne.</p><p> </p>