CDK9 phosphorylates RUNX1 to promote megakaryocytic fate in megakaryocytic-erythroid progenitors.

The specification of megakaryocytic (Mk) or erythroid (E) lineages from primary human megakaryocytic-erythroid progenitors (MEP) is crucial for hematopoietic homeostasis, yet the underlying mechanisms regulating fate specification remain elusive. In this study, we identify RUNX1 as a key modulator of gene expression during MEP fate specification. Overexpression of RUNX1 in primary human MEP promotes Mk specification, while pan-RUNX inhibition favors E specification. Although total RUNX1 levels do not differ between Mk progenitors (MkP) and E progenitors (ErP), there are higher levels of serine-phosphorylated RUNX1 in MkP than ErP, and mutant RUNX1 with phospho-serine/threonine mimetic mutations (RUNX1-4D) significantly enhances the functional efficacy of RUNX1. To model the effects of RUNX1 variants, we employ human erythroleukemia (HEL) cell lines expressing wild-type (WT), phosphomimetic (RUNX1-4D), and non-phosphorylatable (RUNX1-4A) mutants showing that the three forms of RUNX1 differentially regulate expression of 2,625 genes. Both WT and RUNX1-4D variants increase expression in 40%, and decrease expression in another 40%, with lesser effects of RUNX1-4A. We find a significant overlap between the upregulated genes in WT and RUNX1-4D-expressing HEL cells and those upregulated in primary human MkP versus MEP. While inhibition of known RUNX1 serine/threonine kinases does not affect phosphoserine RUNX1 levels in primary MEP, specific inhibition of CDK9 in MEP leads to both decreased RUNX1 phosphorylation and increased erythroid commitment. Collectively, our findings show that serine/threonine phosphorylation of RUNX1 promotes Mk fate specification and introduce a novel kinase for RUNX1 linking the fundamental transcriptional machinery with activation of a cell-type specific transcription factor.

Implementing a resilience coach program to support first year housestaff during the COVID-19 pandemic: early pilot results and comparison with non-housestaff sessions.

BACKGROUND: In response to the COVID-19 pandemic, we launched the Penn Medicine Coping First Aid program to provide psychosocial supports to our health system community. Our approach leveraged lay health worker volunteers trained in principles of Psychological First Aid to deliver coaching services through a centralized virtual platform. METHODS: We emailed all (n = 408) first year housestaff (i.e., residents and fellows) with an invitation to schedule a session with a resilience coach. We compared the mental health concerns, symptoms, and Psychological First Aid techniques recorded in (n = 67) first year housestaff sessions with (n = 91) sessions of other employees in the health system. RESULTS: Between June and November 2020, forty-six first year housestaff attended at least one resilience coaching session. First year housestaff most commonly presented with feelings of anxiety and sadness and shared concerns related to the availability of social support. Resilience coaches most frequently provided practical assistance and ensured safety and comfort to first year housestaff. First year housestaff reported fewer physical or mental health symptoms and held shorter sessions with resilience coaches than non-housestaff. CONCLUSIONS: This work offers insights on how to address psychosocial functioning through low-intensity interventions delivered by lay personnel. More research is needed to understand the efficacy of this program and how best to engage housestaff in wellness and resilience programs throughout training, both during and beyond COVID-19.

Building an Integrated Data Infrastructure to Examine the Spectrum of Suicide Risk Factors in Philadelphia Medicaid.

While there are many data-driven approaches to identifying individuals at risk of suicide, they tend to focus on clinical risk factors, such as previous psychiatric hospitalizations, and rarely include risk factors that occur in nonclinical settings, such as jails or emergency shelters. A better understanding of system-level encounters by individuals at risk of suicide could help inform suicide prevention efforts. In Philadelphia, we built a community-level data infrastructure that encompassed suicide death records, behavioral health claims, incarceration episodes, emergency housing episodes, and involuntary commitment petitions to examine a broader spectrum of suicide risk factors. Here, we describe the development of the data infrastructure, present key trends in suicide deaths in Philadelphia, and, for the Medicaid-eligible population, determine whether suicide decedents were more likely to interact with the behavioral health, carceral, and housing service systems compared to Medicaid-eligible Philadelphians who did not die by suicide. Between 2003 and 2018, there was an increase in the number of annual suicide deaths among Medicaid-eligible individuals, in part due to changes in Medicaid eligibility. There were disproportionately more suicide deaths among Black and Hispanic individuals who were Medicaid-eligible, who were younger on average, compared to suicide decedents who were never Medicaid-eligible. However, when we accounted for the racial and ethnic composition of the Medicaid population at large, we found that White individuals were four times as likely to die by suicide, while Asian, Black, Hispanic, and individuals of other races were less likely to die by suicide. Overall, 58% of individuals who were Medicaid-eligible and died by suicide had at least one Medicaid-funded behavioral health claim, 10% had at least one emergency housing episode, 25% had at least one incarceration episode, and 22% had at least one involuntary commitment. By developing a data infrastructure that can incorporate a broader spectrum of risk factors for suicide, we demonstrate how communities can harness administrative data to inform suicide prevention efforts. Our findings point to the need for suicide prevention in nonclinical settings such as jails and emergency shelters, and demonstrate important trends in suicide deaths in the Medicaid population.

Biophysical properties of human body louse nit related proteins: LNSP1, Agp9 and Agp22.

The human parasitic head and body lice lay their eggs on either hair or clothing. Attachments of the eggs are possible because the female lice secret a glue substance from the accessory gland along with the egg, which hardens into a nit sheath that secures and protects the egg (The "nit" commonly refers to either the louse egg with an embryo or the empty hatched egg). Proteins called the louse nit sheath protein (LNSP) are suggested to be the major proteins of the nit sheath, but transcriptome profiling of the accessory glands indicated other proteins such as Agp9 and Agp22 are also expressed in the glands. In this study, human body louse LNSP1 (partial), Agp9, and Agp22 are recombinantly produced using the E. coli expression system, and the biophysical properties characterized. Circular dichroism analysis indicated that the secondary structure elements of LNSP1 N-terminal and middle-domains, Agp9, and Agp22 are prominently random coiled with up to 10-30% anti-parallel ß-sheet element present. Size-exclusion chromatography profiles of LNSP1 proteins further suggested that the ß-sheets made of the smaller N-terminal domain stacks onto the ß-sheets of the larger middle-domain.

Structure-function analysis of the role of megakaryoblastic leukemia 1 in megakaryocyte polyploidization.

Not available.

Expanding horizons of cross-linguistic research on reading: The Multilingual Eye-movement Corpus (MECO).

Scientific studies of language behavior need to grapple with a large diversity of languages in the world and, for reading, a further variability in writing systems. Yet, the ability to form meaningful theories of reading is contingent on the availability of cross-linguistic behavioral data. This paper offers new insights into aspects of reading behavior that are shared and those that vary systematically across languages through an investigation of eye-tracking data from 13 languages recorded during text reading. We begin with reporting a bibliometric analysis of eye-tracking studies showing that the current empirical base is insufficient for cross-linguistic comparisons. We respond to this empirical lacuna by presenting the Multilingual Eye-Movement Corpus (MECO), the product of an international multi-lab collaboration. We examine which behavioral indices differentiate between reading in written languages, and which measures are stable across languages. One of the findings is that readers of different languages vary considerably in their skipping rate (i.e., the likelihood of not fixating on a word even once) and that this variability is explained by cross-linguistic differences in word length distributions. In contrast, if readers do not skip a word, they tend to spend a similar average time viewing it. We outline the implications of these findings for theories of reading. We also describe prospective uses of the publicly available MECO data, and its further development plans.

Current understanding of human megakaryocytic-erythroid progenitors and their fate determinants.

PURPOSE OF REVIEW: This review focuses on our current understanding of fate decisions in bipotent megakaryocyte-erythroid progenitors (MEPs). Although extensive research has been carried out over decades, our understanding of how MEP commit to the erythroid versus megakaryocyte fate remains unclear. RECENT FINDINGS: We discuss the isolation of primary human MEP, and focus on gene expression patterns, epigenetics, transcription factors and extrinsic factors that have been implicated in MEP fate determination. We conclude with an overview of the open debates in the field of MEP biology. SUMMARY: Understanding MEP fate is important because defects in megakaryocyte and erythrocyte development lead to disease states such as anaemia, thrombocytopenia and leukaemia. MEP also represent a model system for studying fundamental principles underlying cell fate decisions of bipotent and pluripotent progenitors, such that discoveries in MEP are broadly applicable to stem/progenitor cell biology.

High-Efficiency Anion-Exchange Membrane Water Electrolyzer Enabled by Ternary Layered Double Hydroxide Anode.

Developing high-efficiency and low-cost oxygen-evolving electrodes in anion exchange membrane (AEM) water electrolysis technology is one of the major challenges. Herein, it is demonstrated that the surface corrosion of a conventional Ni foam electrode in the presence of Fe3+ and V3+ cations can transform it into an electrode with a high catalytic performance for oxygen evolution reaction (OER). The corroded electrode consists of a ternary NiFeV layered double hydroxide (LDH) nanosheet array supported on the Ni foam surface. This NiFeV LDH electrode achieves an OER current density of 100 mA cm-2 at an overpotential of 272 mV in 1 m KOH, outperforming the IrO2 catalyst by 180 mV. Density functional theory calculations reveal that the unique structure and the presence of vanadium in NiFeV LDH play a key role in achieving improved OER activity. When coupled with a commercial Pt/C cathode catalyst, the resulting AEM water electrolyzer achieves a cell current density as high as 2.1 A cm-2 at a voltage of only 1.8 Vcell in 1 m KOH, which is similar to the performance of the proton exchange membrane water electrolyzer obtained from the IrO2 and Pt/C catalysts pair.

The peptidyl prolyl isomerase, PIN1 induces angiogenesis through direct interaction with HIF-2α.

PIN1, the peptidyl-prolyl isomerase (PPIase), is an enzyme that changes the conformation of phosphoproteins. The conformational change induced by PIN1 alters the function and stability of the target proteins. PIN1 is overexpressed in many different types of malignancies, including breast, lung, cervical, brain and colorectal tumors. PIN1 overexpression has been associated with activation of multiple oncogenic signaling pathways during tumor development. Hypoxia-inducible factor 2α (HIF-2α), a transcription factor activated in hypoxia, plays a role in erythropoiesis, glycolysis, tissue invasion, metastasis and angiogenesis. In this study, we found the direct interaction between HIF-2α and PIN1 in colorectal cancer HCT116 cells. Notably, serine 16 and lysine 63 residues of PIN1 were critical for its interaction with HIF-2α. When PIN1 protein was silenced by transient transfection of PIN1 short interfering RNA, the expression of HIF-2α was attenuated under a hypoxic condition. Moreover, genetic and pharmacologic inhibition of PIN1 abrogated the expression of vascular endothelial growth factor and angiogenesis. The cycloheximide chase experiment revealed the stabilization of HIF-2α by PIN1. Both WW and PPIase domains of PIN1 appear to be critical for its interaction with HIF-2α.

Structural diversity and flexibility of diabodies.

Diabodies are bispecific antibody fragments that have two antigen binding Fv domains. They are unique among hundreds of different formats of bispecific antibodies because they are small and rigid enough to be crystallized. Diabodies are generated by connecting variable regions of heavy and light chains by a peptide linker. Because of the short length of the linker, intramolecular association of the variable regions is not allowed. Instead, the variable regions from the different peptide chains associate together, forming a dimeric complex with two antigen binding sites. Previous crystallographic studies of diabodies demonstrate the extraordinary structural diversity of diabodies. They have also shown that the relative orientation and interaction of the two Fv domains in diabodies have substantial flexibility due to instability of the Fv interface. Introduction of site specific mutations and disulfide bridges can reduce flexibility and therefore increase rigidity and predictability of the diabody structures. These stabilized diabodies will be useful for future application to structural biology and protein nanotechnology.

Direct Chemical Synthesis of Plasmonic Black Colloidal Gold Superparticles with Broadband Absorption Properties.

Self-assembly of plasmonic metal nanoparticles can provide an opportunity of creating colloidal superparticles with fascinating optical properties arising from interparticle plasmonic coupling, but typically requires multiple steps involving solvent and/or ligand exchange. We developed a direct, one-step chemical synthesis of plasmonic black colloidal Au superparticles with broadband absorption in visible and near-infrared regions. During the synthesis, the Au superparticles were formed through self-assembly of in-situ-formed Au nanoparticles driven by solvophobic interactions between nanoparticles and solvent. These superparticles could be solution-processed to fabricate a thin film, which exhibited near-perfect absorption over a broad range from 400 nm to 2.5 µm as well as the excellent antireflective property. Thanks to their broadband absorption property, the Au superparticles showed good performances for near-infrared surface-enhanced Raman spectroscopy and light-to-heat conversion.

On the nature of structure in structural priming.

Like Branigan & Pickering (B&P), we agree that processing evidence is important for linguistic theorization; however, without much evidence of priming of hierarchical argument structure independent of linear ordering, the nature of "structure" in structural priming remains unclear. Consequently, it is an empirical question whether structural priming and acceptability judgments tap into cognitive processes of a similar nature.

Processing Control Information in a Nominal Control Construction: An Eye-Tracking Study.

In an eye-tracking experiment, we examined the processing of the nominal control construction. Participants' eye-movements were monitored while they read sentences that included either giver control nominals (e.g. promise in Luke's promise to Sophia to photograph himself) or recipient control nominals (e.g. plea in Luke's plea to Sophia to photograph herself). In order to examine both the initial access of control information, and its later use in on-line processing, we combined a manipulation of nominal control with a gender match/mismatch paradigm. Results showed that there was evidence of processing difficulty for giver control sentences (relative to recipient control sentences) at the point where the control dependency was initially created, suggesting that control information was accessed during the early parsing stages. This effect is attributed to a recency preference in the formation of control dependencies; the parser prefers to assign a recent antecedent to PRO. In addition, readers slowed down after reading a reflexive pronoun that mismatched with the gender of the antecedent indicated by the control nominal (e.g. Luke's promise to Sophia to photograph herself). The mismatch cost suggests that control information of the nominal control construction was used to constrain dependency formation involving a controller, PRO and a reflexive, confirming the use of control information in on-line interpretation.

Effects of inference demands and structural complexity on transitive inference processing: comment on Lee and Kwon (2013) (.).

In a recent study that investigated the processing of transitive inferences, Lee and Kwon (2013 ) concluded that only informational complexity leads to processing difficulty, that structural complexity affects earlier stages of processing than informational complexity, and that working memory resources are shared between sentence processing and other cognitive processes. Here, the evidence for these findings is scrutinized, and it is argued that there exist significant difficulties in drawing such conclusions based on the methodology and presented data.

When social hierarchy matters grammatically: Investigation of the processing of honorifics in Korean.

Korean grammar encodes relative social hierarchies among interlocutors in various ways. This study utilized honorific subject-verb agreement in Korean to investigate how social hierarchies are processed during sentence comprehension. The experimental results showed that honorific violations elicited processing difficulties. The use of an honorific verb with an unhonorifiable subject resulted in lower naturalness ratings, longer reading times, and elicited a P600, similar to effects observed with number, person, and gender agreement in Spanish or English. These findings suggest that social hierarchies have become integrated into grammar, constraining how native Korean speakers process sentences. However, the agreement between honorific subjects and verbs seems asymmetrical; the mismatch effect was smaller or absent when an honorifiable subject was not accompanied by an honorific verb, suggesting that while an honorific verb requires an honorifiable subject, the reverse is not necessarily true. The results indicate that the -si agreement in Korean is a form of morpho-syntactic agreement, despite its asymmetrical nature.

Facile generation of biepitopic antibodies with intrinsic agonism for activating tumor necrosis factor receptors.

Agonist antibodies are being pursued for therapeutic applications ranging from neurodegenerative diseases to cancer. For the tumor necrosis factor (TNF) receptor superfamily, higher-order clustering of three or more receptors is key to their activation, which can be achieved using antibodies that recognize two unique epitopes. However, the generation of biepitopic (i.e., biparatopic) antibodies typically requires animal immunization and is laborious and unpredictable. Here, we report a simple method for identifying biepitopic antibodies that potently activate TNF receptors without the need for additional animal immunization. Our approach uses existing, receptor-specific IgGs, which lack intrinsic agonist activity, to block their corresponding epitopes, then selects single-chain antibodies that bind accessible epitopes. The selected antibodies are fused to the light chains of IgGs to generate human tetravalent antibodies. We highlight the broad utility of this approach by converting several clinical-stage antibodies against OX40 and CD137 (4-1BB) into biepitopic antibodies with potent agonist activity.

M-Finder: Uncovering functionally associated proteins from interactome data integrated with GO annotations.

BACKGROUND: Protein-protein interactions (PPIs) play a key role in understanding the mechanisms of cellular processes. The availability of interactome data has catalyzed the development of computational approaches to elucidate functional behaviors of proteins on a system level. Gene Ontology (GO) and its annotations are a significant resource for functional characterization of proteins. Because of wide coverage, GO data have often been adopted as a benchmark for protein function prediction on the genomic scale. RESULTS: We propose a computational approach, called M-Finder, for functional association pattern mining. This method employs semantic analytics to integrate the genome-wide PPIs with GO data. We also introduce an interactive web application tool that visualizes a functional association network linked to a protein specified by a user. The proposed approach comprises two major components. First, the PPIs that have been generated by high-throughput methods are weighted in terms of their functional consistency using GO and its annotations. We assess two advanced semantic similarity metrics which quantify the functional association level of each interacting protein pair. We demonstrate that these measures outperform the other existing methods by evaluating their agreement to other biological features, such as sequence similarity, the presence of common Pfam domains, and core PPIs. Second, the information flow-based algorithm is employed to discover a set of proteins functionally associated with the protein in a query and their links efficiently. This algorithm reconstructs a functional association network of the query protein. The output network size can be flexibly determined by parameters. CONCLUSIONS: M-Finder provides a useful framework to investigate functional association patterns with any protein. This software will also allow users to perform further systematic analysis of a set of proteins for any specific function. It is available online at http://bionet.ecs.baylor.edu/mfinder.

Not in my treatment center: Leadership's perception of barriers to MOUD adoption.

INTRODUCTION: Despite their well-established effectiveness, medications for opioid use disorder (MOUD) are widely underutilized across the United States. In the context of a large publicly funded behavioral health system, we examined the relationship between a range of implementation barriers and a substance use disorder treatment agency's level of adoption of MOUD. METHODS: We surveyed leadership of publicly funded substance use disorder treatment centers in Philadelphia about the significance of barriers to implementing MOUD related to their workforce, organization, funding, regulations, and beliefs about MOUD's efficacy and safety. We queried leaders on the percentage of their patients with opioid use disorder who receive MOUD and examined associations between implementation barriers and MOUD adoption. RESULTS: Ratings of regulatory, organizational, or funding barriers of respondents who led high MOUD adopting agencies (N = 20) were indistinguishable from those who led agencies that were low adopting of MOUD (N = 23). In contrast, agency leaders who denied MOUD-belief or workforce barriers were significantly more likely to lead high-MOUD-adopting organizations. CONCLUSIONS: These findings suggest that leadership beliefs about MOUD may be a key factor of the organizational decision to adopt and should be a target of implementation efforts to increase direct provision of these medications.

Where do psychologists turn to inform clinical decisions? Audience segmentation to guide dissemination strategies.

Background: Audience segmentation is an analysis technique that can identify meaningful subgroups within a population to inform the tailoring of dissemination strategies. We have conducted an empirical clustering audience segmentation study of licensed psychologists using survey data about the sources of knowledge they report most often consulting to guide their clinical decision-making. We identify meaningful subgroups within the population and inform the tailoring of dissemination strategies for evidence-based practice (EBP) materials. Method: Data come from a 2018-2019 web-based survey of licensed psychologists who were members of the American Psychological Association (APA; N = 518, response rate = 29.8%). Ten dichotomous variables assessed sources that psychologists regularly consult to inform clinical decision-making (e.g., colleagues, academic literature, and practice guidelines). We used latent class analysis to identify segments of psychologists who turn to similar sources and named each segment based on the segment's most salient characteristics. Results: Four audience segments were identified: the No-guidelines (45% of psychologists), Research-driven (16%), Thirsty-for-knowledge (9%), and No-reviews (30%). The four segments differed not only in their preferred sources of knowledge, but also in the types of evidence-based posttraumatic stress disorder (PTSD) treatments they provide, their awareness and usage intention of the APA PTSD clinical practice guideline, and attitudes toward clinical practice guidelines. Conclusion: The results demonstrate that licensed psychologists are heterogeneous in terms of their knowledge-seeking behaviors and preferences for knowledge sources. The distinctive characteristics of these segments could guide the tailoring of dissemination materials and strategies to subsequently enhance the implementation of EBP among psychologists.

Audience segmentation is a dissemination strategy that categorizes a group of intended users or audience into meaningful subgroups based on their beliefs, behaviors, and/or other characteristics. Like many other scientific or medical fields, clinical psychology also struggles to use clinically tested psychological treatments (or EBPs) in everyday practice due to practical challenges. To help address such barriers, professional organizations like the American Psychological Association (APA) publish clinical practice guidelines that practitioners can use to learn more about EBPs. However, even these clinical practice guidelines are not often used, so this study employed the audience segmentation analysis to better understand psychologists' diverse attitudes, behaviors, and preferences regarding clinical practice guidelines and other clinical information sources. Our study found four distinct subgroups within approximately 600 APA-registered psychologists based on their preferred source of knowledge: the no-guidelines (45% of psychologists), research-driven (16%), thirsty-for-knowledge (9%), and no-reviews (30%). Each subgroup also varied in the types of evidence-based treatments they provide, as well as their awareness, willingness to use, and attitudes toward clinical practice guidelines. This result shows that licensed psychologists are not a uniform group and that dissemination strategies should be adjusted to each subgroup's characteristics to maximize the effort to increase the use of EBPs among psychologists.