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In 2020, the United States experienced twin pandemics disproportionately impacting BIPOC communities and their schools and school systems--one new, COVID-19, and one longstanding, that of white supremacy and anti-Black racism. This phenomenological study of 20 Black female principals in two states provides insights into how these leaders, who so often center racial justice and caring for BIPOC children and communities in their leadership practice, grappled with these pandemics and how doing so impacted their leadership and work. Findings suggest that leading through these twin pandemics further cemented these women's commitments to engage in advocacy and justice work on behalf of their communities and students. They also reported, regarding racial inequity and white supremacy, feeling both a cautious optimism stemming from seeing the work they had long engaged in being taken up at scale, and by white colleagues in particular, and frustration, experiencing this engagement often as "performative" and thus unlikely to lead to real change. And yet they also spoke of their deep commitment to advocacy and social justice moving forward and their role in ensuring that all their students receive the education, opportunities, and outcomes they deserve.

Microcombs-optical frequency combs generated in microresonators-have advanced tremendously in the past decade, and are advantageous for applications in frequency metrology, navigation, spectroscopy, telecommunications, and microwave photonics. Crucially, microcombs promise fully integrated miniaturized optical systems with unprecedented reductions in cost, size, weight, and power. However, the use of bulk free-space and fiber-optic components to process microcombs has restricted form factors to the table-top. Taking microcomb-based optical frequency synthesis around 1550 nm as our target application, here, we address this challenge by proposing an integrated photonics interposer architecture to replace discrete components by collecting, routing, and interfacing octave-wide microcomb-based optical signals between photonic chiplets and heterogeneously integrated devices. Experimentally, we confirm the requisite performance of the individual passive elements of the proposed interposer-octave-wide dichroics, multimode interferometers, and tunable ring filters, and implement the octave-spanning spectral filtering of a microcomb, central to the interposer, using silicon nitride photonics. Moreover, we show that the thick silicon nitride needed for bright dissipative Kerr soliton generation can be integrated with the comparatively thin silicon nitride interposer layer through octave-bandwidth adiabatic evanescent coupling, indicating a path towards future system-level consolidation. Finally, we numerically confirm the feasibility of operating the proposed interposer synthesizer as a fully assembled system. Our interposer architecture addresses the immediate need for on-chip microcomb processing to successfully miniaturize microcomb systems and can be readily adapted to other metrology-grade applications based on optical atomic clocks and high-precision navigation and spectroscopy.

The history of English language education is punctuated with teaching and learning theories and approaches advocated by different communities of practice. One of such recent trend is the support for the integration of intercultural communicative competence (ICC) in the English language classroom. To date, minimal studies have examined this extension of the English language classroom. Hence, to determine the teaching practice of ICC this study looked at the identity-in-practice and -in-discourse, as well as sources of pedagogical knowledge of four English teachers teaching at private institutions in Bangkok. This study employed a discourse analysis approach to first identify the participants' emergent trajectories and funds of knowledge, and subsequently compared the findings with the fundamental principles of intercultural education, or the community of practice that support ICC. The findings indicated that while some participants' trajectories paralleled the tenets of ICC, there were also divergent ones. This reflected the contextualization of intercultural education, as well as the teachers' (lack of) knowledge regarding ICC. More than this, the findings also indicated the viability of a community of practice, especially for intercultural education, in a disparate educational sector.

While reflection has been a common tool for examining the development of teaching and learning practices in the classroom, its use in a language learning setting is still peripheral and minimal. To understand the potential of reflection in supporting language learning, this study presents a qualitative meta-synthesis on selected studies. These studies consider students' reflection as the main object of inquiry. Ten studies from various disciplines in higher education were analyzed through iterative reading and review. Three categories emerged, which dealt with the research underpinnings of the studies, the participants and context, and the benefits of reflection. These categories were then discussed to provide practical implications for the integration of reflection as a primary learning tool in a language classroom, whilst being cognizant of known issues, such as language learners experiencing difficulties when having to express thought.

This study examines Thai English majors' perceptions towards engagement. The aim of this study is to be better informed of the English language learning experience of students in an international environment where English is used as a foreign language. A mixed methods approach was employed. A modified version of the National Survey of Student Engagement (NSSE) was used to collect quantitative data, while qualitative data was collected through a focus group interview. Correlation scores and one-way ANOVA were calculated to examine the survey data. Results indicated that almost all the categories of engagement were significantly correlated, except for the correlation between supportive learning environment and faculty interaction. The one-way ANOVA test, on the other hand, revealed that students' year of study had a significant effect on at least three components of engagement. The quantitative results were further informed by data collected from a focus group interview. From the interview, students were able to describe the classroom atmosphere, teachers' pedagogical strategies, as well as challenges they faced in their studies. From the findings, it was evident that the Thai students were open to different pedagogical approaches, and that they were not culturally constrained. This may be the hallmark of international education, wherein students take on a contextualized approach to learning, aside from being in a context where a foreign language is used.

Macroautophagy/autophagy is a cellular degradation and recycling process that supports cellular homeostasis. Since an autophagosome marker, microtubule-associated protein 1A/1B-light chain 3 (LC3)-II, was found in cell-derived extracellular vesicles (EVs), autophagy may cooperate with EV secretion pathways to control unconventional secretion of intracellular molecules. Several studies have demonstrated that pharmacological inhibition of autophagic turnover and pathogen-induced endolysosomal dysfunction enhanced the secretion of autophagosome-like EVs (ALVs). However, whether external stimulation induces ALV secretion is unclear. Here we showed that co-stimulation with IL-4 and anti-CD40 antibody (IL-4:CD40) enhanced the secretion of LC3-II+ALVs compared to co-stimulation by IL-4 and lipopolysaccharide (IL-4:LPS) or by IL4 and anti-IgM antibody in B cells. While IL-4:LPS stimulation accelerated autophagic flux, IL-4:CD40 stimulation reduced autophagosome-lysosome fusion without affecting lysosomal function. Although both IL-4:LPS and IL-4:CD40 induced the expression of similar genes involved in vesicle fusion or transportation, IL-4:CD40 preferentially enhanced the expression of the small GTPase RAB27a compared to IL-4:LPS. Genetic disruption by the CRISPR-Cas9 system revealed that loss of RAB27a membrane-binding ability impaired LC3-II+ALV secretion but not ALIX+EV secretion in B-lymphoma A20 cells. Additionally, reconstitution of human wild-type RAB27A in RAB27a mutant A20 cells restored LC3-II+ALV secretion, indicating that RAB27a controls autophagosome secretion. Furthermore, LC3-II+ALVs were found in the sera of tumor-bearing mice and the plasma of healthy human donors. Our findings may provide a role for B-cell secretory autophagy in regulating intercellular communication under various physiological conditions, such as vaccination, pathogen infection, and B-cell lymphoma progression. Abbreviations: ALVs: autophagosome-like vesicles; ATG: autophagy-related; Baf A1: bafilomycin A1; CNX: calnexin; EVs: extracellular vesicles; Ig: immunoglobulin; IL: Interleukin; LC3: microtubule-associated protein 1A/1B-light; LPS: Lipopolysaccharides; MVs: microvesicles; RAB: member RAS oncogene family; TLR: toll-like receptor

ABSTRACT Recent advances in adaptive immune receptor repertoire sequencing have provided abundant B cell receptor (BCR) sequences under various conditions, including vaccination and disease. However, determining target antigen and epitope specificity of the corresponding antibodies is a major challenge due to their exceptional sequence diversity. Here, we introduce a novel method to cluster antibodies sharing antigenic targets based on their complementarity determining region (CDR) sequences. Using the proposed method, we demonstrate that SARS-CoV-2 spike protein receptor-binding domain (RBD) binders and non-RBD binders from publicly available BCR data were classified correctly, with a cluster purity of 95%. These clusters were then leveraged for annotating unlabeled COVID-19 patient BCR data, enabling the discovery of novel anti-RBD antibodies. We further validated the method by clustering BCR repertoires obtained from single-cell immune profiling of diphtheria-tetanus-pertussis (DTP)-vaccinated donors. Antibody expression and antigen-binding assays demonstrated that the clusters exhibited 96% antigen purity, surpassing the apparent 82% purity achieved by assigning antigens to the same B cells using fluorescently labeled DTP antigen probes. Moreover, antibodies within certain clusters were found to possess neutralizing activity, suggesting that CDR clusters contain epitope-level information. Together, this study offers a simple approach for antigen- and epitope-specific BCR discovery that is reproducible, inexpensive, and applicable to a wide range of antigen targets.IMPORTANCEDetermining antigen and epitope specificity is an essential step in the discovery of therapeutic antibodies as well as in the analysis adaptive immune responses to disease or vaccination. Despite extensive efforts, deciphering antigen specificity solely from BCR amino acid sequence remains a challenging task, requiring a combination of experimental and computational approaches. Here, we describe and experimentally validate a simple and straightforward approach for grouping antibodies that share antigen and epitope specificities based on their CDR sequence similarity. This approach allows us to identify the specificities of a large number of antibodies whose antigen targets are unknown, using a small fraction of antibodies with well-annotated binding specificities.

BACKGROUND: Adult-onset inflammatory syndromes often manifest with overlapping clinical features. Variants in ubiquitin-related genes, previously implicated in autoinflammatory disease, may define new disorders. METHODS: We analyzed peripheral-blood exome sequence data independent of clinical phenotype and inheritance pattern to identify deleterious mutations in ubiquitin-related genes. Sanger sequencing, immunoblotting, immunohistochemical testing, flow cytometry, and transcriptome and cytokine profiling were performed. CRISPR-Cas9-edited zebrafish were used as an in vivo model to assess gene function. RESULTS: We identified 25 men with somatic mutations affecting methionine-41 (p.Met41) in UBA1, the major E1 enzyme that initiates ubiquitylation. (The gene UBA1 lies on the X chromosome.) In such patients, an often fatal, treatment-refractory inflammatory syndrome develops in late adulthood, with fevers, cytopenias, characteristic vacuoles in myeloid and erythroid precursor cells, dysplastic bone marrow, neutrophilic cutaneous and pulmonary inflammation, chondritis, and vasculitis. Most of these 25 patients met clinical criteria for an inflammatory syndrome (relapsing polychondritis, Sweets syndrome, polyarteritis nodosa, or giant-cell arteritis) or a hematologic condition (myelodysplastic syndrome or multiple myeloma) or both. Mutations were found in more than half the hematopoietic stem cells, including peripheral-blood myeloid cells but not lymphocytes or fibroblasts. Mutations affecting p.Met41 resulted in loss of the canonical cytoplasmic isoform of UBA1 and in expression of a novel, catalytically impaired isoform initiated at p.Met67. Mutant peripheral-blood cells showed decreased ubiquitylation and activated innate immune pathways. Knockout of the cytoplasmic UBA1 isoform homologue in zebrafish caused systemic inflammation. CONCLUSIONS: Using a genotype-driven approach, we identified a disorder that connects seemingly unrelated adult-onset inflammatory syndromes. We named this disorder the VEXAS (vacuoles, E1 enzyme, X-linked, autoinflammatory, somatic) syndrome. (Funded by the NIH Intramural Research Programs and the EU Horizon 2020 Research and Innovation Program.).

Does being disagreeable-that is, behaving in aggressive, selfish, and manipulative ways-help people attain power? This question has long captivated philosophers, scholars, and laypeople alike, and yet prior empirical findings have been inconclusive. In the current research, we conducted two preregistered prospective longitudinal studies in which we measured participants' disagreeableness prior to entering the labor market and then assessed the power they attained in the context of their work organization ∼14 y later when their professional careers had unfolded. Both studies found disagreeable individuals did not attain higher power as opposed to extraverted individuals who did gain higher power in their organizations. Furthermore, the null relationship between disagreeableness and power was not moderated by individual differences, such as gender or ethnicity, or by contextual variables, such as organizational culture. What can account for this null relationship? A close examination of behavior patterns in the workplace found that disagreeable individuals engaged in two distinct patterns of behavior that offset each other's effects on power attainment: They engaged in more dominant-aggressive behavior, which positively predicted attaining higher power, but also engaged in less communal and generous behavior, which predicted attaining less power. These two effects, when combined, appeared to cancel each other out and led to a null correlation between disagreeableness and power.

Plant NLR-type receptors serve as sensitive triggers of host immunity. Their expression has to be well-balanced, due to their interference with various cellular processes and dose-dependency of their defense-inducing activity. A genetic arms race with fast-evolving pathogenic microbes requires plants to constantly innovate their NLR repertoires. We previously showed that insertion of the COPIA-R7 retrotransposon into RPP7 co-opted the epigenetic transposon silencing signal H3K9me2 to a new function promoting expression of this Arabidopsis thaliana NLR gene. Recruitment of the histone binding protein EDM2 to COPIA-R7-associated H3K9me2 is required for optimal expression of RPP7. By profiling of genome-wide effects of EDM2, we now uncovered additional examples illustrating effects of transposons on NLR gene expression, strongly suggesting that these mobile elements can play critical roles in the rapid evolution of plant NLR genes by providing the raw material for gene expression mechanisms. We further found EDM2 to have a global role in NLR expression control. Besides serving as a positive regulator of RPP7 and a small number of other NLR genes, EDM2 acts as a suppressor of a multitude of additional NLR genes. We speculate that the dual functionality of EDM2 in NLR expression control arose from the need to compensate for fitness penalties caused by high expression of some NLR genes by suppression of others. Moreover, we are providing new insights into functional relationships of EDM2 with its interaction partner, the RNA binding protein EDM3/AIPP1, and its target gene IBM1, encoding an H3K9-demethylase.

Background: Complex ureteric strictures and injuries occurring during major abdominal and pelvic operations may cause significant morbidity and distress to patients. A rendezvous procedure is an endoscopic technique used in case of such injuries. Objective: To evaluate perioperative and long-term outcomes of rendezvous procedures to treat complex ureteric strictures and injuries. Design, setting, and participants: We retrospectively reviewed patients undergoing a rendezvous procedure for ureteric discontinuity including strictures and injuries, treated between 2003 and 2017 at our Institution and completing at least 12 mo of follow-up. We divided patients into two groups: early postsurgical obstruction, leakage, or detachment (group A) and late strictures (oncological/postsurgical; group B). Outcome measurements and statistical analysis: If appropriate, we performed a retrograde study ± rigid ureteroscopy to assess the stricture 3 mo after the rendezvous procedure, followed by a MAG3 renogram at 6 wk, 6 mo, and 12 mo, and annually thereafter for 5 yr. Results and limitations: Forty-three patients underwent a rendezvous procedure, 17 in group A (median age 50 yr, range 30–78) and 26 in group B (median age 60 yr, range: 28–83). Ureteric strictures and ureteric discontinuities were stented successfully in 15 out of 17 patients in group A (88.2%) and 22 out of 26 patients (84.6%) in group B. For both groups, the median follow-up was 6 yr. In group A, of 17 patients, 11 (64.7%) were stent free with no further interventions, two (11.7%) had a subsequent Memokath stent insertion (38%), and two (11.7%) required reconstruction. Of 26 patients in group B, eight (30.7%) required no further interventions and were stent free, ten (38.4%) were maintained with long-term stenting, and one was managed with a Memokath stent (3.8%). Of the 26 patients, only three (11.5%) required major reconstruction, while four patients with malignancy (15%) died during follow-up. Conclusions: With a combined antegrade and retrograde approach, the majority of complex ureteric strictures/injuries can be bridged and stented with an overall immediate technical success rate of above 80%, avoiding major surgery in unfavourable circumstances and allowing time for stabilisation and recovery of the patient. Additionally, in case of technical success, further interventions may be unnecessary in up to 64% of patients with acute injury and about 31% of patients with late stricture. Patient summary: The majority of complex ureteric strictures and injuries can be resolved using a rendezvous approach, avoiding major surgery in unfavourable circumstances. Moreover, this approach can help avoid further interventions in 64% of such patients.

This case study blends the accounts of 10 Black women who engaged in a research study on their experiences of microaggressions when serving as school leaders, to tell the story of one Black female principal in a mostly White suburban district. We describe the ways the environment enabled and perpetuated gendered racist incidents at multiple levels and detail some of the microaggressions affecting her career path, leadership, and community interactions, as well as the ways she overcomes these obstacles and persists. We contextualize this narrative in the literature around gender, race, and school leadership, in studies of gendered racism, and finally in White allyship scholarship. We conclude by posing questions around whose responsibility it is to address these issues, and the structural changes necessary to do so.

Background: Assessment of residual fragments (RFs) is a key step after treatment of kidney stones. Objective: To evaluate differences in RFs estimation based on unenhanced computerized tomography (CT) versus X-rays/ultrasound after retrograde intrarenal surgery (RIRS) for kidney stones. Design: A retrospective analysis of data from 20 centers of adult patients who had RIRS was done (January 2018–August 2021). Methods: Exclusion criteria: ureteric stones, anomalous kidneys, bilateral renal stones. Patients were divided into two groups (group 1: CT; group 2: plain X-rays or combination of X-rays/ultrasound within 3 months after RIRS). Clinically significant RFs (CSRFs) were considered RFs ⩾ 4 mm. One-to-one propensity score matching for age, gender, and stone characteristics was performed. Multivariable logistic regression analysis was performed to evaluate independent predictors of CSRFs. Results: A total of 5395 patients were included (1748 in group 1; 3647 in group 2). After matching, 608 patients from each group with comparable baseline and stone characteristics were included. CSRFs were diagnosed in 1132 patients in the overall cohort (21.0%). Post-operative CT reported a significantly higher number of patients with RFs ⩾ 4 mm, before (35.7% versus 13.9%, p

In recent decades, there has been a dramatic rise in the rates of children being born after in utero exposure to drugs of abuse, particularly opioids. Opioids have been shown to have detrimental effects on neurons and glia in the central nervous system (CNS), but the impact of prenatal opioid exposure (POE) on still-developing synaptic circuitry is largely unknown. Astrocytes exert a powerful influence on synaptic development, secreting factors to either promote or inhibit synapse formation and neuronal maturation in the developing CNS. Here, we investigated the effects of the partial µ-opioid receptor agonist buprenorphine on astrocyte synaptogenic signaling and morphological development in cortical cell culture. Acute buprenorphine treatment had no effect on the excitatory synapse number in astrocyte-free neuron cultures. In conditions where neurons shared culture media with astrocytes, buprenorphine attenuated the synaptogenic capabilities of astrocyte-secreted factors. Neurons cultured from drug-naïve mice showed no change in synapses when treated with factors secreted by astrocytes from POE mice. However, this same treatment was synaptogenic when applied to neurons from POE mice, indicating a complex neuroadaptive response in the event of impaired astrocyte signaling. In addition to promoting morphological and connectivity changes in neurons, POE exerted a strong influence on astrocyte development, disrupting their structural maturation and promoting the accumulation of lipid droplets (LDs), suggestive of a maladaptive stress response in the developing CNS.