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BACKGROUND: The present study aimed to validate the accuracy of a tumor-specific antibody to target liver metastases of colorectal cancer. METHODS: A humanized anti-CEA antibody conjugated to a fluorescent dye (M5A-IR800) was tested for targeting human colorectal cancer liver metastases (CRLMs) expressing luciferase in an orthotopic mouse model. Orthotopic mouse models of CRLMs were established by implanting fragments of a luciferase-expressing human colorectal cancer cell line, LS174T, in the liver of nude mice. Mice received 50 µg M5A-IR800 72 h prior to imaging. To test co-localization, bioluminescence imaging was performed using D-luciferin, which was given via intraperitoneal injection just prior to imaging. RESULTS: Tumors were able to be visualized non-invasively through the skin with the luciferase-luciferin signal. Intra-abdominal imaging showed accurate labeling of CRLMs with M5A-IR800, which co-localized with the luciferase-luciferin signal. CONCLUSIONS: The present results validate the accuracy of a tumor-specific anti-CEA antibody in targeting liver metastases of colorectal cancer.

Glioblastoma (GBM) is the most aggressive cancer originating in the brain, but unfortunately combination treatments with resection, radiation, and chemotherapy are relatively ineffective. Therefore, novel methods of adjuvant therapy are critically needed. Cyclotides are plant-derived circular peptides that chemosensitize drug-resistant breast cancer to doxorubicin. We analyzed naturally occurring and synthetic cyclotides (Cycloviolacin O3, Cycloviolacin O19, natural Kalata B1, synthetic Kalata B1, and Vitri E) alone and in co-exposure treatments with the drug temozolomide (TMZ) in human glioblastoma cells. The cyclotides were identified by UPLC-PDA and HPLC-UV. The synthetic Kalata B1 sequence was verified with orbitrap LC-MS, and structural confirmation was provided by NMR spectroscopy. The cyclotides displayed dose-dependent cytotoxicity (IC50 values 2.4-21.1 µM) both alone and as chemosensitizers of U-87 MG and T 98 cells to TMZ. In fact, a 16-fold lower concentration of TMZ (100 µM) was needed for significant cytotoxicity in U-87 MG cells co-exposed to synthetic Kalata B (0.5 µM). Similarly, a 15-fold lower concentration of TMZ (75 µM) was required for a significant reduction in cell viability in T 98 cells co-exposed to synthetic Kalata B1 (0.25 µM). Kalata B1 remained stable in human serum stability assays. The data support the assertion that cyclotides may chemosensitize glioblastoma cells to TMZ.

Measures of attention and memory were evaluated in 6- to 9-month-old infants from two diverse contexts. One sample consisted of African infants residing in rural Malawi (N = 228, 118 girls, 110 boys). The other sample consisted of racially diverse infants residing in suburban California (N = 48, 24 girls, 24 boys). Infants were tested in an eye-tracking version of the visual paired comparison procedure and were shown racially familiar faces. The eye tracking data were parsed into individual looks, revealing that both groups of infants showed significant memory performance. However, how a look was operationally defined impacted some-but not other-measures of infant VPC performance. RESEARCH HIGHLIGHTS: In both the US and Malawi, 6- to 9-month-old infants showed evidence of memory for faces they had previously viewed during a familiarization period. Infant age was associated with peak look duration and memory performance in both contexts. Different operational definitions of a look yielded consistent findings for peak look duration and novelty preference scores-but not shift rate. Operationalization of look-defined measures is an important consideration for studies of infants in different cultural contexts.

BackgroundGastric cancer poses a major diagnostic and therapeutic challenge as surgical resection provides the only opportunity for a cure. Specific labeling of gastric cancer could distinguish resectable and nonresectable disease and facilitate an R0 resection, which could improve survival.MethodsTwo patient-derived gastric cancer lines, KG8 and KG10, were established from surgical specimens of two patients who underwent gastrectomy for gastric adenocarcinoma. Harvested tumor fragments were implanted into the greater curvature of the stomach to establish patient-derived orthotopic xenograft (PDOX) models. M5A (humanized anti-CEA antibody) or IgG control antibodies were conjugated with the near-infrared dye IRDye800CW. Mice received 50 µg of M5A-IR800 or 50 µg of IgG-IR800 intravenously and were imaged after 72 hr. Fluorescence imaging was performed by using the LI-COR Pearl Imaging System. A tumor-to-background ratio (TBR) was calculated by dividing the mean fluorescence intensity of the tumor versus adjacent stomach tissue.ResultsM5A-IR800 administration resulted in bright labeling of both KG8 and K10 tumors. In the KG8 PDOX models, the TBR for M5A-IR800 was 5.85 (SE ± 1.64) compared with IgG-IR800 at 0.70 (SE ± 0.17). The K10 PDOX models had a TBR of 3.71 (SE ± 0.73) for M5A-IR800 compared with 0.66 (SE ± 0.12) for IgG-IR800.ConclusionsHumanized anti-CEA (M5A) antibodies conjugated to fluorescent dyes provide bright and specific labeling of gastric cancer PDOX models. This tumor-specific fluorescent antibody is a promising potential clinical tool to detect the extent of disease for the determination of resectability as well as to visualize tumor margins during gastric cancer resection.

Due to working in static positions and use of repetitive movements over long periods of time, dermatologists are at increased risk of work-related musculoskeletal injury. Historically, studies on procedural ergonomics have focused on dermatologic surgery, however, laser procedures can also have a significant cumulative effect on physician posture. Here, we aim to highlight ergonomic challenges specific to dermatologic laser procedures and suggest areas of improvement in operating room organization, patient positioning, physician mechanics, and instrumentation. For the operating room, it is beneficial to store several devices in the same room, have central placement of electrical outlets, and to position the devices on the same side of the bed as the laser operator. When considering patient positioning, a Trendelenburg bed position can be helpful for vascular lesions on the head, and frequent repositioning of the patient can prevent uncomfortable bending of the operator and laser arm for circumferential lesions. Physicians should maintain a working position with a neutral spine and wrist position, moving the patient and bed as needed to reduce muscle tension. Lastly, laser instrumentation in the future could be improved upon with lightweight consoles and hand pieces, long multi-articulated device arms, and lightweight laser goggles with adjustable head straps. With the use of organizational, ergonomic positioning, and teamwork strategies, we can reduce the risk of musculoskeletal injury for our laser operators.

LUX-ZEPLIN (LZ) is a tonne-scale experiment searching for direct dark matter interactions and other rare events. It is located at the Sanford Underground Research Facility (SURF) in Lead, South Dakota, USA. The core of the LZ detector is a dual-phase xenon time projection chamber (TPC), designed with the primary goal of detecting Weakly Interacting Massive Particles (WIMPs) via their induced low energy nuclear recoils. Surrounding the TPC, two veto detectors immersed in an ultra-pure water tank enable reducing background events to enhance the discovery potential. Intricate calibration systems are purposely designed to precisely understand the responses of these three detector volumes to various types of particle interactions and to demonstrate LZ’s ability to discriminate between signals and backgrounds. In this paper, we present a comprehensive discussion of the key features, requirements, and performance of the LZ calibration systems, which play a crucial role in enabling LZ’s WIMP-search and its broad science program. The thorough description of these calibration systems, with an emphasis on their novel aspects, is valuable for future calibration efforts in direct dark matter and other rare-event search experiments.

The efficacy of ritlecitinib, an oral JAK3/TEC family kinase inhibitor, on active and stable lesions was evaluated in patients with active non-segmental vitiligo in a phase 2b trial (NCT03715829). Patients were randomized to placebo or daily ritlecitinib 50 mg (with or without 4-week 100-mg or 200-mg loading dose), 30 mg, or 10 mg for 24 weeks. Active lesions showed greater baseline expression of inflammatory/immune markers IFNG and CCL5, levels of CD103, and T-cell infiltrates than stable lesions. Patients with more active than stable vitiligo lesions showed higher baseline serum levels of CXCL9 and PD-L1, while patients with more stable than active lesions showed higher baseline serum levels of HO-1. At Week 24, ritlecitinib 50 mg significantly stabilized mean percent change from baseline in depigmentation extent in both active lesions and stable lesions vs. placebo-response, with stable lesions showing greater repigmentation. After 24 weeks of treatment, ritlecitinib 50 mg increased expression of melanocyte markers in stable lesions, while Th1/Th2-related and co-stimulatory molecules decreased significantly in both stable and active lesions. Serum from patients with more active than stable lesions showed decreased levels of ICOS and NK cell activation markers. These data, confirmed at transcription/protein levels, indicate that stable lesion repigmentation occurs early with ritlecitinib, while active lesions require stabilization of inflammation first. ClinicalTrials.gov: NCT03715829.

Correction to: Nature Microbiologyhttps://doi.org/10.1038/s41564-023-01354-6, published online 10 April 2023. In the version of the article initially published, the Acknowledgements section did not include the Host Pathogen Map Initiative grant U19AI135990 to Jeffery S. Cox from the National Institute of Allergy and Infectious Diseases. This has now been updated in the HTML and PDF versions of the article.

Pubertal timing varies considerably and is associated with later health outcomes. We performed multi-ancestry genetic analyses on ~800,000 women, identifying 1,080 signals for age at menarche. Collectively, these explained 11% of trait variance in an independent sample. Women at the top and bottom 1% of polygenic risk exhibited ~11 and ~14-fold higher risks of delayed and precocious puberty, respectively. We identified several genes harboring rare loss-of-function variants in ~200,000 women, including variants in ZNF483, which abolished the impact of polygenic risk. Variant-to-gene mapping approaches and mouse gonadotropin-releasing hormone neuron RNA sequencing implicated 665 genes, including an uncharacterized G-protein-coupled receptor, GPR83, which amplified the signaling of MC3R, a key nutritional sensor. Shared signals with menopause timing at genes involved in DNA damage response suggest that the ovarian reserve might signal centrally to trigger puberty. We also highlight body size-dependent and independent mechanisms that potentially link reproductive timing to later life disease.

Microtremor horizontal-to-vertical spectral ratios (mHVSR) are frequency-dependent ratios of Fourier amplitude spectra of the horizontal to vertical components of a 3-component recording of ambient ground motions from microtremors. Results from mHVSR tests can identify the frequencies associated with site resonances at sites with large impedance contrasts, and hence have potential to provide useful parameters for predicting seismic site response. Site measurements are made by recording ground vibrations either from a temporarily deployed seismometer, typically recording for a relatively short period of time (~1-2 hrs.), or from a permanently-installed broadband seismometer. In this paper, we discuss ongoing work investigating the reliability of low frequency (< ∼0.1 Hz) mHVSR ordinates. Such low frequency ordinates are potentially useful for sites that are known to have deep basins (e.g., LA Basin, Imperial Valley, Great Salt Lake basin), where fundamental frequencies may fall in this range and direct measurements of depth to bedrock are difficult to make. We have found that low-frequency mHVSR ordinates (< ∼0.1-0.2 Hz) are for practical purposes not reliable in most cases, even when measured by high-quality temporary or permanent broadband sensors. In this paper, we discuss sensor drift and its limited impact on the reliability of mHVSR ordinates. We document the low frequency problem for multiple sites, although we do not have a solution as of this writing for how to improve the reliability of low-frequency results.

Word problem solving is the premise for students to generalize their problem solving skills to real world problems. This includes students with autism spectrum disorder (ASD) and intellectual disability (ID). Modified Schema-based Instruction (MSBI) is one strategy that research has shown is effective for teaching students with ASD/ID to acquire and generalize problem solving skills. The key word strategy is an ineffective strategy for teaching students to problem solve, especially since problems in everyday life do not contain key words. This article provided a practitioner friendly 7-step strategy for implementing MSBI with learners who have ASD/ID

Despite the benefits of inclusive education, students with emotional disabilities (EDs), who are disproportionately Black, male, and economically marginalized, continue to be placed in segregated education settings more than students with many other classifications (OSEP Fast Facts: Children Identified With Emotional Disturbance, 2020. Retrieved from https://sites.ed.gov/idea/osep-fast-facts-children-IDed-Emotional-Disturbance-20). In this paper, we describe the functioning of a multiyear university-district research-practice partnership (RPP) and the structures that support the partnership's ability to engage in boundary spanning between researchers, practitioners, and district leaders, toward the ultimate goal of implementing a comprehensive inclusive education model for students with or at risk for EDs. First, we examine survey data from partnership members reflecting on elements of the partnership that we hypothesize to be important for supporting strong communication. Next, we present network data from meetings, one of our partnerships' boundary spanning practices, to illustrate the formal connections between RPP members. We found that the partnership had frequent meetings (N = 389), with high levels of co-attendance between university and district members (33%), although there was some variation based on district members' roles. Overall, members were satisfied with the RPP and perceived the partnership positively in terms of its resources, leadership and members, and effectiveness. This paper contributes to an understanding of both boundary spanning practices in RPPs and some of the key partnership conditions and structures that support the implementation and adaptation of a challenging initiative in school-based mental health.

Previous research evaluating behavior skills training and performance feedback has largely examined factors influencing interventionist performance outcomes. However, to our knowledge, researchers have yet to compile existing literature to specifically explore characteristics associated with improved learner outcomes in the context of interventionist training research. In our meta-analysis, we conducted a regression analysis to examine the relationships between improved interventionist performance, interventionist training approach (behavioral skills training versus performance feedback in isolation), behavior domain (skill acquisition, behavior reduction, or both used in combination), and interventionist type on outcomes for learners. Results suggested that while interventionist performance was significantly correlated with improved learner outcomes, the training approach used was not. Behavior domain was found to reliably predict learner outcomes. Namely, training interventionists on protocols featuring both skill acquisition and behavior reduction were associated with better outcomes for learners than either skill acquisition or behavior reduction in isolation. Finally, interventionist type reliably predicted learner outcomes. That is, behavior therapists were positively correlated with larger learner effect sizes compared to other interventionist type, while post-secondary students as interventionists were correlated with the poorest learner outcomes. We end the paper by discussing potential clinical implications and make recommendations for future research.

In this article, the Education Studies Department (ESD) at Berea College shares lessons learned while becoming an inclusive, justice-focused, and democratic Education Preparation Program (EPP) together with its "Community of Teachers" (CoT). ESD values diversity, equity, inclusion, and belonging (DEI+B) and democratic relationships. These values influence how we do our work. We begin by sharing how the theoretical framework of Community of Practice (CoP) frames our case study. After explaining how a CoP applies to ESD's approach to educator preparation, we give an overview of Berea College. We share some of its history and its eight Great Commitments. We detail how ESD is a unique EPP compared with other more traditional EPPs. Next, we chronicle the story of how ESD "walks its talk" and invests in the teacher profession. We detail the participants of the case study, outline our methodology of the case study, and share the data we analyzed for this article. Data were analyzed and three emergent themes were discovered about the praxis of ESD: (a) community-engaged and justice-focused teacher preparation, (b) community building within teacher preparation programs, and (c) diversity, equity, inclusion, and belonging. The article concludes by sharing implications for EPPs and a conclusion.

The devaluation of women of Color (WoC) by way of gender discrimination and systemic racism is well documented. For WoC in engineering a chief cause is the observable wage gap. Women who identify as Asian, Black/African American, Latina/Chicana, Indigenous/Native American, Native Hawaiian, Pacific Islander, Native Alaskan, and/or multiracial have reported stark wage disparities. In this paper, we offer a phenomenological study of how WoC engineering faculty across U.S. academic institutions describe the challenges and practices associated with wage disparities and how they navigate these disparities. This study, which is based on participant interviews, is guided by three research questions: (1) What do WoC engineering tenure-track faculty perceive about wage disparities based on their race and gender? (2) How do WoC faculty understand the institutional practices that contribute to wage disparities? and (3) How do WoC engineering faculty respond to and address wage disparities? Using structural racism and intersectionality as our guiding conceptual framework, we interviewed 32 self-identified WoC who identified structures and systems of institutional racism related to the maintenance of wage disparities. In terms of findings, we note that WoC have two primary strategies to respond to wage disparity: advocacy and agency. The experiences of WoC engineering faculty in our study highlight unsatisfying institutional responses, and thus WoC often rely on their own agency to advocate for themselves and to advocate for and mentor other WoC faculty. We found a few notable cases where men advocated for women to help close the wage gap. Our work reveals that pay inequity for WoC is often coupled with other forms of exclusion and marginalization. Reducing wage disparities in academia is critical to advancing diversity efforts and ensuring equitable support for WoC faculty. Our findings suggest that institutions can work diligently to rectify wage inequality, including making sustainable structural and salary modifications and sharing the burden of combatting wage inequities. Finally, our findings also highlight the importance of making policy changes to reduce pay inequalities, such as providing transparent pay information and more opportunities to earn merit raises.

Replications provide credibility by demonstrating under what conditions experimental findings can be repeated, the premise behind evidence-based practices. Replications in single-case research also investigate generalization of findings across groups. For groups with high variability, such as individuals with autism, assumptions of generalizability should be based on learners who are similar in critical ways. The purpose of this study was to use Coyne et al.'s framework for replication and the next generation guidelines for single-case research to extend understanding of "for whom" and "under what conditions" modified schema-based instruction (an established evidence-based practice for individuals with autism) is effective. In this distal conceptual replication of Root et al., contextual and instructional variables of theoretical and practical importance were intentionally manipulated or maintained and reported to model transparency and support replicability. Four high school students receiving special education under the Individuals With Disabilities Education Act category of autism were taught mathematical and social problem-solving behaviors within the context of percentage-of-change word problems. Researchers used modified schema-based instruction and augmented reality in a one-on-one setting and assessed generalization to purchasing in the food court of a mall biweekly. We frame our discussion around the recommendations for replication research from Coyne et al. and recommendations for single-case research from Ledford et al., concluding with suggestions for future replications that use single-case research designs.