Parallel Activation Research Articles

Stability and Change in the C-Domain in American Swedish

This article introduces American Swedish (AmSw) into the discussion of the C-domain in heritage Scandinavian. The study is based on spontaneous speech data from the Swedish part of the Corpus of American Nordic Speech (CANS), compared to a baseline of homeland Swedish dialect speakers. We show that the C-domain in AmSw is primarily characterized by stability; this is evidenced by a relatively robust V2 syntax and left dislocation patterns that resemble the homeland baseline. However, we also show that AmSw diverges in some respects: there are some V2 violations and a stronger preference for SV clauses (subject-initial main clauses) at the expense of XVS clauses (non-subject-initial main clauses). These results are similar to previous findings from American Norwegian. We argue that the diverging patterns exhibited by AmSw speakers are not indicative of any fundamental change in their Swedish grammar. The occasional V2 violations are attributed to parallel activation of English and Swedish, and speakers sometimes failing to inhibit English, which is their dominant language. The increase of SV clauses is analyzed as a preference for the canonical word order of the dominant language, but within the limits of what the heritage grammar permits. The patterns in AmSw can be described as cases of attrition and cross-linguistic influence; however, we argue for a nuanced use of these terms.

FakeNewsLab: Experimental Study on Biases and Pitfalls Preventing Us from Distinguishing True from False News

Misinformation posting and spreading in social media is ignited by personal decisions on the truthfulness of news that may cause wide and deep cascades at a large scale in a fraction of minutes. When individuals are exposed to information, they usually take a few seconds to decide if the content (or the source) is reliable and whether to share it. Although the opportunity to verify the rumour is often just one click away, many users fail to make a correct evaluation. We studied this phenomenon with a web-based questionnaire that was compiled by 7298 different volunteers, where the participants were asked to mark 20 news items as true or false. Interestingly, false news is correctly identified more frequently than true news, but showing the full article instead of just the title, surprisingly, does not increase general accuracy. Additionally, displaying the original source of the news may contribute to misleading the user in some cases, while the genuine wisdom of the crowd can positively assist individuals’ ability to classify news correctly. Finally, participants whose browsing activity suggests a parallel fact-checking activity show better performance and declare themselves as young adults. This work highlights a series of pitfalls that can influence human annotators when building false news datasets, which in turn can fuel the research on the automated fake news detection; furthermore, these findings challenge the common rationale of AI that suggest users read the full article before re-sharing.

Molecular foundations of the etiology and pathogenesis of Legg-Calve-Perthes disease and prospects for targeted therapy: A literature review

BACKGROUND: The etiology and pathogenesis of the development of LeggCalvePerthes disease, despite intensive research, remains not fully understood. Most studies have concluded about the multifactorial genesis of the development of hip osteochondropathy. Moreover, a complete understanding of all elements of pathogenesis leading to the manifestation and the progressive development of aseptic necrosis make it possible to develop targeted antiresorptive therapy. At present, several studies have investigated impaired functioning of signaling pathways that influence bone homeostasis during the development of LeggCalvePerthes disease. In addition, impaired metabolism in avascular necrosis is characterized by significant complexity and heterogeneity, which is based on aseptic inflammation associated with ischemic stress. Concepts of antiresorptive therapy were developed based on the results of studies on the pathogenesis of LeggCalvePerthes disease. Nevertheless, these treatment algorithms have not achieved wide practical application and require further investigation.
 AIM: This study aimed to conduct a literary analysis of the molecular basis of the etiology and pathogenesis of LeggCalvePerthes disease and assess the prospects of therapy aimed at correcting bone homeostasis disorders.
 MATERIALS AND METHODS: Data sources were PubMed, Medline, Scopus, Web of Science, and RSCI databases, without language restrictions.
 RESULTS: The relationship between ischemic stress and the induction of a cytokine cascade with a predominance of the biological actions of proinflammatory cytokines, with parallel activation of intracellular regulatory networks that determine osteoresorptive processes, including due to pyroptosis, is shown. Data on the possibility of various variants of targeted antiresorptive therapy with the use of genetically engineered drugs are presented.
 CONCLUSIONS: The pathogenesis of LeggCalvePerthes disease is characterized by significant genetic heterogeneity with the induction of various mediators of inflammation, angiogenesis, and osteogenesis, depending on the disease stage. Investigating features of impaired bone homeostasis regulation in the case of LeggCalvePerthes disease at the molecular and cellular level opens up opportunities for the development and clinical application of personalized therapy.

Linking networking capability and ambidextrous innovation strategies: the mediating roles of knowledge assimilation application and knowledge transformation application

PurposeFrom the perspective of social networks and knowledge networks, this study aims to empirically examine an updated four-dimension networking capability (NC) construct and test the relationships between it and innovation strategies through knowledge application activities in the context of Chinese manufacturing firms.Design/methodology/approachData analysis is conducted on a quantitative survey of 219 manufacturing firms in China with a mixed method of partial least squares structural equation modeling and fuzzy-set qualitative comparative analysis.FindingsThe results indicate that knowledge assimilation application (KAA) and knowledge transformation application (KTA) fully mediate the relationships between NC and ambidextrous innovation strategies. KAA has a stronger association with exploitative innovation (EL) than with exploratory innovation (ER), and KTA has a stronger association with ER than with EL.Research limitations/implicationsThe authors develop the conceptualization of NC and examine its role in knowledge application activities within a firm. Further, the authors adopt an alternative perspective to highlight the importance of KAA and KTA in mediating the relationships between NC and exploratory and exploitative innovation strategies.Practical implicationsThe findings indicate that firms should build NC based on their knowledge requirements and knowledge network structure. Additionally, managers should possess in-depth insights regarding an effective knowledge application toward different types of external knowledge from partners. More specific, firms are more likely to conduct KAA for a high degree of knowledge relatedness, while for a low degree of knowledge relatedness, firms are more likely to conduct KTA.Originality/valueThe authors provide a novel alternative insight into knowledge application activities. From the perspective of knowledge networks, the authors argue that there are two distinct and parallel activities (i.e. KAA and KTA). The authors empirically examined the mediating roles of KAA and KTA in the NC–ambidextrous innovation strategies relationships as well as enriched the literature on their relationships.

The structure of social anxiety in Russian society: gender emphasis

The article presents the structure of Russian citizens' anxiety in the gender context, focusing on the attitude of Russian women to the economic and social policy conducted by the authorities, self-assessment of their financial situation, expectations and vision of the future. The material is based on the data of the 52nd stage of the All-Russian monitoring "How are you, Russia?", conducted with the participation of the authors in May 2022 by the Institute of Socio-Political Research of FCTAS RAS. It shows the convergence of men's and women's value judgments due to the increased social and economic activity of women. At the same time, there is still a traditional difference in the level of income, as well as in the distribution of gender roles according to the archetypes "woman = keeper of the family home" and "man = strategist, thinking globally. Respondents of both sexes expressed equally minimal concern about the topic of the special military operation in Ukraine, with women showing serious concern about the economic consequences of the current foreign policy. In the structure of their anxiety, problems of rising prices, economic sanctions, deteriorating relations with the U.S. and Europe, and, as a consequence, fear of an uncertain future lead the way. Lack of stability and uncertainty decrease the loyalty to the power structures among female respondents, who are the most vulnerable in the current situation, slightly increasing the level of protest activity in parallel.

P17.16.B Additional antitumoral activity of TTFields stimulation and Chloride Intracellular Channel 1 inhibition in human glioblastoma primary culture

Abstract Background Glioblastoma relapse inevitably occurs in the majority of patients after surgery. Chemo- and radiotherapy are in most cases ineffective, while Tumor Treating Fields (TTFields) therapy delays average tumor recurrence by a few months. It is widely accepted that tumor reappearance is a result of the proliferation of residual glioblastoma stem cell (GSC) subpopulation, which escaped surgery. Previous experiments demonstrated that inhibition of the membrane form of Chloride Intracellular Channel 1 (tmCLIC1) is particularly efficient to hit GSCs in glioblastoma human primary cultures. tmCLIC1 is an ideal target as it is express only in the tumor cell membranes. tmCLIC1 blockage slowdown GSC cell cycle at G1/S transition. On the contrary, TTFields act mainly during G2/M progression. The objective of our study is to test the therapeutic potential of combining TTFields exposure with the inhibition of the protein transmembrane Chloride Intracellular Channel 1 (tmCLIC1), which is crucial for GSCs proliferation. Material and Methods Cell preparation: human primary culture from patients’ biopsies. Stimulation device: NOVOCURE Inovitro system®. Stimulation procedure: long-term TTFields stimulation in in-vitro experiments mimics glioblastoma cells’ recrudescence. Analysis: cytofluorimetry for stem cell recognition, cell-cycle progression, and cell count. Results Cell growth is inhibited after the first three days of TTFields exposure. However, despite the chronic presence of TTFields stimulation in prolonged experiments, glioblastoma cells reestablish the ability to proliferate. At the end of twelve days, exponentially growing cells show an increase in stemness markers, a drop in the membrane resistance with a related increase of membrane current, and an average depolarized membrane potential. Twelve days of TTFields treatment resulted in a progressive increase in GSCs in the tumor cell population from 10% to more than 30%. Thus, experiments have been designed to combine TTFields stimulation with tmCLIC1 inhibition. This would include in the treatment of the vast majority of the glioblastoma cell population. After twelve days, the parallel antiproliferative activities show a complete impairment in cell proliferation. Conclusion The additive effect of TTFields stimulation and tmCLIC1 ion channel inhibition could represent an efficacious step forward to optimize an antitumoral therapy against glioblastoma expansion.

Uncertainty Aware T2SS Based Dyna-Q-Learning Framework for Task Scheduling in Grid Computing

Abstract Task scheduling is an important activity in parallel and distributed computing environment like grid because the performance depends on it. Task scheduling gets affected by behavioral and primary uncertainties. Behavioral uncertainty arises due to variability in the workload characteristics, size of data and dynamic partitioning of applications. Primary uncertainty arises due to variability in data handling capabilities, processor context switching and interplay between the computation intensive applications. In this paper behavioral uncertainty and primary uncertainty with respect to tasks and resources parameters are managed using Type-2-Soft-Set (T2SS) theory. Dyna-Q-Learning task scheduling technique is designed over the uncertainty free tasks and resource parameters. The results obtained are further validated through simulation using GridSim simulator. The performance is good based on metrics such as learning rate, accuracy, execution time and resource utilization rate.

A general theory of consciousness II: The language problem

ABSTRACT It is generally assumed that what we hear in our head is what we think and that, when we tell a thought to somebody else, the other person understands what our thought has been. This paper analyzes how we think and what happens when we communicate our thoughts verbally to others and to ourselves. The assumption that we become conscious in language is erroneous: verbal communication is only an intermediary. The conscious experience of verbal communication is a sensory phenomenon. We think through sensory images (see Part I). This natural way of thinking, is a very refined and accurate method of translating thought into consciousness. It expresses our essentially unconscious neural cognitive activity in conscious sensory images: visual thinkers ‘see’ what they have thought. Why humans use verbal communication to express their thoughts to themselves is difficult to understand as the verbal way is extremely limited. The complex parallel cognitive activity has to be encoded into language tokens which are positioned sequentially as a string of symbols which somehow must express something comparable. Talking to oneself is directed to an imaginary person who is assumed to be the talking person himself. This imaginary person develops with the inner voice in infants and when the child grows up, that imaginary person remains there, somebody he talks to when he thinks and to which he attributes his feelings and his actions. The imaginary person is experienced as the human Self, but actually verbalizes the thoughts of the natural – animal – Self.

Human Blood Serum Inhibits Ductal Carcinoma Cells BT474 Growth and Modulates Effect of HER2 Inhibition.

Trastuzumab, a HER2-targeted antibody, is widely used for targeted therapy of HER2-positive breast cancer (BC) patients; yet, not all of them respond to this treatment. We investigated here whether trastuzumab activity on the growth of HER2-overexpressing BT474 cells may interfere with human peripheral blood endogenous factors. Among 33 individual BC patient blood samples supplemented to the media, BT474 sensitivity to trastuzumab varied up to 14 times. In the absence of trastuzumab, human peripheral blood serum samples could inhibit growth of BT474, and this effect varied ~10 times for 50 individual samples. In turn, the epidermal growth factor (EGF) suppressed the trastuzumab effect on BT474 cell growth. Trastuzumab treatment increased the proportion of BT474 cells in the G0/G1 phases of cell cycle, while simultaneous addition of EGF decreased it, yet not to the control level. We used RNA sequencing profiling of gene expression to elucidate the molecular mechanisms involved in EGF- and human-sera-mediated attenuation of the trastuzumab effect on BT474 cell growth. Bioinformatic analysis of the molecular profiles suggested that trastuzumab acts similarly to the inhibition of PI3K/Akt/mTOR signaling axis, and the mechanism of EGF suppression of trastuzumab activity may be associated with parallel activation of PKC and transcriptional factors ETV1-ETV5.

Too Many Moving Pieces: Parallel Acquisitions and Forecasting Bias in Acquisition Integration

Although firms often conduct multiple acquisitions simultaneously with overlapping procedures running in parallel, little is known about the consequences of parallel acquisitions on a focal acquisition’s integration planning. Drawing on information overload research and the attention-based view of the firm, we propose that parallel acquisitions may result in information overload in which managers with bounded rationality have constrained capacity to proceed the amount, the characteristics, and the flow of information. Leveraging a novel measure of integration decision quality – the underestimation of integration costs, we find that parallel acquisitions are associated with significantly higher likelihood of integration cost underestimation. Our paper advances acquisition research by introducing the effect of activity load on integration and by illuminating the cognitive challenges in managing parallel activities.

Reconceptualizing breaks in translation: Breaking down or breaking through?

Various observable on-screen translator behaviors, such as extended pauses in activity, mouse hovering, cycling through tabs/windows, and different kinds of scrolling, all common occurrences during task completion, have been regarded as potential problem indicators (cf. Angelone, 2018). Their presence is often attributed to a breakdown in declarative and/or procedural knowledge at a concrete problem nexus (Angelone and Shreve, 2011). Inspired by recent translation process research on aspects of cognitive ergonomics, pause-related cognitive rhythms (Muñoz and Cardona, 2018), and Kussmaul’s notion of parallel activity in the translation process (1995), we re-examine such phenomena through a different lens. We propose these phenomena may represent the loci of volitional, potentially strategic breaks rather than problem indicators per se. That is, the breaks observed are not necessarily linked to specific problems, but rather to subjects’ cognitive resource management. Our findings suggest that apparently random behaviors, seemingly unrelated to the task, generally have a positive impact on performance from both process and product perspectives. We refer to these breaks as instances of cognitive suspension, and, based on our findings, propose that translators engage in them as a refresh mechanism when performance has either waned or runs the risk of doing so. We start by examining cognitive suspension in terms of types and scope. This is followed by an empirical analysis of its direct impact on translation performance, as established by number of errors, number of generated characters, and number of typos within established windows (areas of interest) that precede and follow its occurrence.

Process mining based on patient waiting time: an application in health processes

Purpose Similar to many business processes, waiting times are also essential for health care processes, especially in obstetrics and gynecology outpatient department (GOD), because pregnant women may be affected by long waiting times. Since creating process models manually presents subjective and nonrealistic flows, this study aims to meet the need of an objective and realistic method. Design/methodology/approach In this study, the authors investigate time-related bottlenecks in both departments for different doctors by process mining. Process mining is a pragmatic analysis to obtain meaningful insights through event logs. It applies data mining techniques to business process management with more comprehensive perspectives. Process mining in this study enables to automatically create patient flows to compare considering each department and doctor. Findings The study concludes that average waiting times in the GOD are higher than obstetrics outpatient department. However, waiting times in departments can change inversely for different doctors. Research limitations/implications The event log was created by expert opinions because activities in the processes had just starting timestamp. The ending time of activity was computed by considering the average duration of the corresponding activity under a normal distribution. Originality/value This study focuses on administrative (nonclinical) health processes in obstetrics and GOD. It uses a parallel activity log inference algorithm (PALIA) to produce process trees by handling duplicate activities. Infrequent information in health processes can have critical information about the patient. PALIA considers infrequent activities in the event log to extract meaningful information, in contrast to many discovery algorithms.

The Time Course of Language Production as Revealed by Pattern Classification of MEG Sensor Data.

Language production involves a complex set of computations, from conceptualization to articulation, which are thought to engage cascading neural events in the language network. However, recent neuromagnetic evidence suggests simultaneous meaning-to-speech mapping in picture naming tasks, as indexed by early parallel activation of frontotemporal regions to lexical semantic, phonological, and articulatory information. Here we investigate the time course of word production, asking to what extent such “earliness” is a distinctive property of the associated spatiotemporal dynamics. Using MEG, we recorded the neural signals of 34 human subjects (26 males) overtly naming 134 images from four semantic object categories (animals, foods, tools, clothes). Within each category, we covaried word length, as quantified by the number of syllables contained in a word, and phonological neighborhood density to target lexical and post-lexical phonological/phonetic processes. Multivariate pattern analyses searchlights in sensor space distinguished the stimulus-locked spatiotemporal responses to object categories early on, from 150 to 250 ms after picture onset, whereas word length was decoded in left frontotemporal sensors at 250-350 ms, followed by the latency of phonological neighborhood density (350-450 ms). Our results suggest a progression of neural activity from posterior to anterior language regions for the semantic and phonological/phonetic computations preparing overt speech, thus supporting serial cascading models of word production.SIGNIFICANCE STATEMENT Current psycholinguistic models make divergent predictions on how a preverbal message is mapped onto articulatory output during the language planning. Serial models predict a cascading sequence of hierarchically organized neural computations from conceptualization to articulation. In contrast, parallel models posit early simultaneous activation of multiple conceptual, phonological, and articulatory information in the language system. Here we asked whether such earliness is a distinctive property of the neural dynamics of word production. The combination of the millisecond precision of MEG with multivariate pattern analyses revealed subsequent onset times for the neural events supporting semantic and phonological/phonetic operations, progressing from posterior occipitotemporal to frontal sensor areas. The findings bring new insights for refining current theories of language production.

Capacity limits in sentence comprehension: Evidence from dual-task judgements and event-related potentials

There is an ongoing controversy over whether readers can access the meaning of multiple words, simultaneously. To date, different experimental methods have generated seemingly contradictory evidence in support of serial or parallel processing accounts. For example, dual-task studies suggest that readers can process a maximum of one word at a time (White, Palmer & Boynton, 2018), while ERP studies have demonstrated neural priming effects that are more consistent with parallel activation (Wen, Snell & Grainger, 2019). To help reconcile these views, I measured neural responses and behavioral accuracy in a dual-task sentence comprehension paradigm. Participants saw masked sentences and two-word phrases and had to judge whether or not they were grammatical. Grammatically correct sentences (This girl is neat) produced smaller N400 responses compared to scrambled sentences (Those girl is fled): an N400 sentence superiority effect. Critically, participants' grammaticality judgements on the same trials showed striking capacity limitations, with dual-task deficits closely matching the predictions of a serial, all-or-none processing account. Together, these findings suggest that the N400 sentence superiority effect is fully compatible with serial word recognition, and that readers are unable to process multiple sentence positions simultaneously.

The Features of the Shadow Economy Impact’ on Biomass Energy Sector

The shadow economy is a significant factor in impoverishing the economies of countries and unequal operating and competitive conditions distort the market economy system, as opaque parallel activities impoverish socially responsible business units. The biomass energy sector faces this risk because the biomass supply chain is not yet fully secure and balanced. The study conducted by the authors showed that the manifestations of the shadow economy in the biomass energy sector are possible in the biomass production and transportation sub-sectors. Lack of digitization and poor resource management can lead to the problem of misuse of resources, which has non-transparent economic activities. The evaluation methodology developed by the authors allows to investigate the directions of shadow economy in the biomass energy sector and to measure the possible extent of such activities. The measurements were made in order to compare the official activities of enterprises with the factors attributable to the shadow economy. This is also due to the lack of innovation and digital solutions. The application of innovative solutions would help to reduce the size of the shadow economy, which would increase the income of regions and the state, and reduce the level of poverty.

Ultra-rapid and automatic interplay between L1 and L2 semantics in late bilinguals: EEG evidence

Converging behavioral and neuroimaging evidence suggests parallel activation of native (L1) and second (L2) language codes in bilinguals, with the modulation of the N400 as the most likely neural correlate of such L1-L2 interplay at lexico-semantic level. However, this relatively late effect may reflect secondary controlled processes, in contrast to earlier modulations found in monolinguals (<200 msec) indicative of fast and automatic lexico-semantic L1 access, which has so far not been documented for bilingualism. To address this, we investigated early neurophysiological crosslinguistic activation during bilingual word access. EEG signals were recorded from a group of late bilinguals during a masked-priming crosslinguistic task in which L1 (Russian) words were presented as subliminal primes for 50 msec before L2 (English) target words. Prime-target pairs matched either phonologically only, semantically only, both phonologically and semantically, or did not match. Cluster-based random permutation analyses revealed a main effect of semantic similarity at 40–60 msec over centro-posterior scalp sites, reflecting a negative-going shift of ERP amplitudes for semantically similar prime-target pairs. Importantly, neural source reconstruction showed activations within a left-hemispheric network comprising the middle and superior temporal cortex and the angular gyrus as the most likely neural substrate of this early semantic effect. Furthermore, analyses also revealed significant differences over frontocentral sites for the main effect of semantic and phonological similarity, ranging from 312 to 356 and 380–444 msec respectively, thus confirming previously described N400 crosslinguistic effects. Our findings confirm the existence of an integrated brain network for the bilingual lexicon and reveal the earliest (∼50 msec) crosslinguistic effect reported so far, suggesting fast and automatic L1–L2 interplay, followed by later (possibly top-down controlled) processing stages.

Exploring Educational Designs by Schematic Models: Visualizing Educational Value and Critical Issues of Recognition and Socio-Material Frames

Drawing on experiences from a large-scale Nordic co-design research project, this paper explores the development of cross-border blended education with the aim to strengthen students’ Nordic identity and knowledge of neighboring Nordic languages illuminating the flow of didactical designs students were offered to engage in, i.e. the knowledge content, activities, spaces and resources. The iterative, three-year educational development of designing for learning proved to provide space for shared and collaborative knowledge development involving students in rich, authentic, and goal-oriented inter-Nordic comprehension practices on multiple levels, addressing content-related as well as contextual frames in teaching situations. Schematic models of the didactical designs revealed initial dis-alignment and diverse appropriation of modes and media in parallel cooperative activities combined with collaborative cross-border face-to-face talk promoting students to take perspective, compare, and contrast. Addressing the socio-material frames of teaching gave an opportunity to discover new learning goals and design activities in new adequate arrangements of the physical classroom and the digital space. The analysis demonstrates that students developed linguistic, cultural, critical, and digital competences of varied educational value based on the teams’ divergent approaches to knowledge processes to incorporate digital technologies in teaching practice. The study highlights the critical factors of recognizing digital, multimodal meaning-making and informal skills as means to promote learning and schools’ remaining insufficient provision of digital infrastructure for learning activities in blended learning environments.

Deep-Sea: A Reconfigurable Accelerator for Classic CNN

To meet the changing real-time edge engineering application requirements of CNN, aiming at the lack of universality and flexibility of CNN hardware acceleration architecture based on ARM+FPGA, a general low-power all pipelined CNN hardware acceleration architecture is proposed to cope with the continuously updated CNN algorithm and accelerate in hardware platforms with different resource constraints. In the framework of the general hardware architecture, a basic instruction set belonging to the architecture is proposed, which can be used to calculate and configure different versions of CNN algorithms. Based on the instruction set, the configurable computing subsystem, memory management subsystem, on-chip cache subsystem, and instruction execution subsystem are designed and implemented. In addition, in the processing of convolution results, the on-chip storage unit is used to preprocess the convolution results, to speed up the activation and pooling calculation process in parallel. Finally, the accelerator is modeled at the RTL level and deployed on the XC7Z100 heterogeneous device. The lightweight networks YOLOv2-tiny and YOLOv3-tiny commonly used in engineering applications are verified on the accelerator. The results show that the peak performance of the accelerator reaches 198.37 GOP/s, the clock frequency reaches 210 MHz, and the power consumption is 4.52 w under 16-bit width.

Plasma-Derived Hemopexin as a Candidate Therapeutic Agent for Acute Vaso-Occlusion in Sickle Cell Disease: Preclinical Evidence.

People living with sickle cell disease (SCD) face intermittent acute pain episodes due to vaso-occlusion primarily treated palliatively with opioids. Hemolysis of sickle erythrocytes promotes release of heme, which activates inflammatory cell adhesion proteins on endothelial cells and circulating cells, promoting vaso-occlusion. In this study, plasma-derived hemopexin inhibited heme-mediated cellular externalization of P-selectin and von Willebrand factor, and expression of IL-8, VCAM-1, and heme oxygenase-1 in cultured endothelial cells in a dose-responsive manner. In the Townes SCD mouse model, intravenous injection of free hemoglobin induced vascular stasis (vaso-occlusion) in nearly 40% of subcutaneous blood vessels visualized in a dorsal skin-fold chamber. Hemopexin administered intravenously prevented or relieved stasis in a dose-dependent manner. Hemopexin showed parallel activity in relieving vascular stasis induced by hypoxia-reoxygenation. Repeated IV administration of hemopexin was well tolerated in rats and non-human primates with no adverse findings that could be attributed to human hemopexin. Hemopexin had a half-life in wild-type mice, rats, and non-human primates of 80–102 h, whereas a reduced half-life of hemopexin in Townes SCD mice was observed due to ongoing hemolysis. These data have led to a Phase 1 clinical trial of hemopexin in adults with SCD, which is currently ongoing.

Global organization of neuronal activity only requires unstructured local connectivity.

Modern electrophysiological recordings simultaneously capture single-unit spiking activities of hundreds of neurons spread across large cortical distances. Yet, this parallel activity is often confined to relatively low-dimensional manifolds. This implies strong coordination also among neurons that are most likely not even connected. Here, we combine in vivo recordings with network models and theory to characterize the nature of mesoscopic coordination patterns in macaque motor cortex and to expose their origin: We find that heterogeneity in local connectivity supports network states with complex long-range cooperation between neurons that arises from multi-synaptic, short-range connections. Our theory explains the experimentally observed spatial organization of covariances in resting state recordings as well as the behaviorally related modulation of covariance patterns during a reach-to-grasp task. The ubiquity of heterogeneity in local cortical circuits suggests that the brain uses the described mechanism to flexibly adapt neuronal coordination to momentary demands.