Discovery of Potent, Selective, and Orally Available IRE1α Inhibitors Demonstrating Comparable PD Modulation to IRE1 Knockdown in a Multiple Myeloma Model.

The lack of selective and safe in vivo IRE1α tool molecules has limited the evaluation of IRE1α as a viable target to treat multiple myeloma. Focus on improving the physicochemical properties of a literature compound by decreasing lipophilicity, molecular weight, and basicity allowed the discovery of a novel series with a favorable in vitro safety profile and good oral exposure. These efforts culminated in the identification of a potent and selective in vivo tool compound, G-5758, that was well tolerated following multiday oral administration of doses up to 500 mg/kg. G-5758 demonstrated comparable pharmacodynamic effects to induced IRE1 knockdown as measured by XBP1s levels in a multiple myeloma model (KMS-11).

Unconventional human CD61 pairing with CD103 promotes TCR signaling and antigen-specific T cell cytotoxicity.

Cancer remains one of the leading causes of mortality worldwide, leading to increased interest in utilizing immunotherapy strategies for better cancer treatments. In the past decade, CD103+ T cells have been associated with better clinical prognosis in patients with cancer. However, the specific immune mechanisms contributing toward CD103-mediated protective immunity remain unclear. Here, we show an unexpected and transient CD61 expression, which is paired with CD103 at the synaptic microclusters of T cells. CD61 colocalization with the T cell antigen receptor further modulates downstream T cell antigen receptor signaling, improving antitumor cytotoxicity and promoting physiological control of tumor growth. Clinically, the presence of CD61+ tumor-infiltrating T lymphocytes is associated with improved clinical outcomes, mediated through enhanced effector functions and phenotype with limited evidence of cellular exhaustion. In conclusion, this study identified an unconventional and transient CD61 expression and pairing with CD103 on human immune cells, which potentiates a new target for immune-based cellular therapies.

Biochemical characterization of rice xylan biosynthetic enzymes in determining xylan chain elongation and substitutions.

Grass xylan consists of a linear chain of ß-1,4-linked xylosyl residues that often form domains substituted only with either arabinofuranose (Araf) or (methyl)glucuronic acid [(Me)GlcA] residues and it lacks the unique reducing end tetrasaccharide sequence found in dicot xylan. The mechanism of how grass xylan backbone elongation is initiated and how its distinctive substitution pattern is determined remain elusive. Here, we performed biochemical characterization of rice xylan biosynthetic enzymes, including xylan synthases, glucuronyltransferases and methyltransferases. Activity assays of rice xylan synthases demonstrated that they required short xylooligomers as acceptors for their activities. While rice xylan glucuronyltransferases effectively glucuronidated unsubstituted xylohexaose acceptors, they transferred little GlcA residues onto Araf-substituted xylohexaoses and rice xylan 3-O-arabinosyltransferase could not arabinosylate GlcA-substituted xylohexaoses, indicating that their intrinsic biochemical properties may contribute to the distinctive substitution pattern of rice xylan. In addition, we found that rice xylan methyltransferase exhibited a low substrate binding affinity, which may explain the partial GlcA methylation in rice xylan. Furthermore, immunolocalization of xylan in xylem cells of both rice and Arabidopsis showed that it was deposited together with cellulose in secondary walls without forming xylan-rich nanodomains. Together, our findings provide new insights into the biochemical mechanisms underlying xylan backbone elongation and substitutions in grass species.

Factors Affecting Gonadal Shielding Use Among Technologists in California.

PURPOSE: To assess the patient gonadal shielding practices of radiologic technologists in the state of California. METHODS: A survey invitation was sent via email to registered radiologic technologists in California to collect data to determine whether there were significant associations between gonadal shielding practices and various categorical variables, including patient sex, patient age, body part, availability of gonadal shielding protocols, availability of gonadal shields, and supervisor encouragement. RESULTS: There was a significant association between gonadal shielding protocol availability and supervisor encouragement of using gonadal shielding (P = .005) and between gonadal shielding availability and supervisor encouragement of using gonadal shielding (P < .001). Contrary to other studies in the literature, there was a significant difference between patient sex and the likelihood of gonadal shielding use, with participants indicating that they shield girls and women more often than they shield boys and men (P < .001). DISCUSSION: There was a sex-based difference in the frequency of gonadal shielding usage among the sample in this study. Also, supervisors providing accessible protocols and encouraging gonadal shielding can increase technologists' use of gonadal shielding. CONCLUSION: Gonadal shielding is the current Code of Federal Regulations standard, although most professional and scientific organizations support discontinuing shielding during abdominal and pelvic radiography examinations. Shielding of these areas is more likely to occur with the availability of gonadal shielding, supervisory encouragement, protocols mandating shielding, and state regulations.

Phenotype of Parathyroid-targeted Cdc73 Deletion in Mice Is Strain-dependent.

Hyperparathyroidism jaw-tumor syndrome is an autosomal dominant disorder caused by mutations in the CDC73/HRPT2 tumor suppressor gene, encoding parafibromin, and manifesting benign or malignant parathyroid tumors, ossifying jaw fibromas, uterine tumors, and kidney lesions. Sporadic parathyroid carcinomas also frequently exhibit inactivating CDC73 mutations and loss of parafibromin. To study the role of CDC73 in parathyroid cell proliferation in vivo, we generated mice with a parathyroid-specific deletion of Cdc73. Homozygous knockout mice on a mixed B6/129/CD1 background had decreased serum calcium and PTH and smaller parathyroid glands compared with heterozygous or wild-type littermates, whereas homozygous Cdc73-null mice on other backgrounds exhibited no abnormalities in parathyroid gland function or development. No hypercalcemia or parathyroid hypercellularity was observed in mice of any background examined at any age. Thus, although postnatally acquired complete loss of CDC73 causes parathyroid cell proliferation and hyperparathyroidism, such as seen in human hyperparathyroidism jaw-tumor syndrome, our results suggest that earlier, developmentally imposed complete loss of Cdc73 can cause a primary defect in parathyroid gland structure/function in a strain-dependent manner. This striking disparity in parathyroid phenotype related to genetic background offers a unique opportunity in an in vivo model system to precisely dissect and identify the responsible molecular mechanisms.

A comprehensive SARS-CoV-2 and COVID-19 review, Part 2: host extracellular to systemic effects of SARS-CoV-2 infection.

COVID-19, the disease caused by SARS-CoV-2, has caused significant morbidity and mortality worldwide. The betacoronavirus continues to evolve with global health implications as we race to learn more to curb its transmission, evolution, and sequelae. The focus of this review, the second of a three-part series, is on the biological effects of the SARS-CoV-2 virus on post-acute disease in the context of tissue and organ adaptations and damage. We highlight the current knowledge and describe how virological, animal, and clinical studies have shed light on the mechanisms driving the varied clinical diagnoses and observations of COVID-19 patients. Moreover, we describe how investigations into SARS-CoV-2 effects have informed the understanding of viral pathogenesis and provide innovative pathways for future research on the mechanisms of viral diseases.

Communication consistency, completeness, and complexity of digital ideography in trustworthy mobile extended reality.

Communication barriers long-associated with ideographs, including combinatorial grapholinguistic complexity, computational encoding-decoding complexity, and technological rendering and deployment, become trivialized through advancements in interoperable smart mobile digital devices. Such technologies impart unprecedented extended-reality user hazards only mitigated by unprecedented colloquial and bureaucratic societal norms. Digital age norms thus influence natural ideographic language origins and evolution in ways novel to human history.

Ownership psychology as a "cognitive cell" adaptation: A minimalist model of microbial goods theory.

Microbes perfect social interactions with intuitive logics and goal-directed reciprocity. These multilevel, cognition-resembling adaptations in Dictyostelid cellular molds enable individual-to-group viability through public/private bacterial farming and dynamic marketspaces. Like humans and animals, Dictyostelid livestock-ownership depends on environmental sensing, cooperation, and competition. Moreover, social-norm policing of cosmopolitan colonies coordinates farmer decisions, phenotypes, and ownership identities with bacteria herding, privatization, and consumption.

Trauma-Informed Care in Medical Imaging and Radiation Therapy to Reduce Retraumatization.

PURPOSE: To provide an overview of trauma-informed care, including the neurobiology of trauma, interventions to reduce retraumatizing patients who have experienced trauma, and implications of trauma-informed care in medical imaging and radiation therapy. METHODS: A comprehensive search of electronic databases related to the purpose of this project resulted in the collection of 12 peer-reviewed journal articles. Two conference papers, 1 behavioral science textbook, 1 trauma neurobiology textbook, 1 professional conference presentation, and 1 governmental report also were reviewed to complement the journal articles. A thematic analysis was performed to identify commonalities among the selected sources. RESULTS: Four themes identified in the literature included definitions of trauma-informed care, neurobiology of trauma, pillars of trauma-informed care for intervention, and implications in medical imaging and radiation therapy. DISCUSSION: A trauma-informed health care professional realizes the prevalence of trauma, recognizes the signs and symptoms of trauma, responds by integrating knowledge about trauma into practice, and actively resists retraumatizing the patient (ie, avoids creating an environment that inadvertently reminds patients of their traumatic experiences and causes them to experience emotional and biological stress). The pillars of trauma-informed care include safety, trustworthiness or transparency, peer support, collaboration, empowerment, and responsiveness or cultural considerations. Delivery of health care often involves assessment and interventions in locations on the patient's body where trauma has previously occurred, increasing the probability of retraumatization and manifestation of signs and symptoms of trauma. Radiologic technologists and radiation therapists should be trauma-informed when they are interacting with and caring for patients to reduce retraumatization. A hypothetical case study also is presented to show how radiologic technologists can use the pillars of trauma-informed care in the clinic. CONCLUSION: Because many aspects of care, including routine care in medical imaging and radiation therapy, can be an unintentional reminder of a traumatic experience, health care professionals should be trauma-informed when they are interacting with and caring for patients.

GTAC enables parallel genotyping of multiple genomic loci with chromatin accessibility profiling in single cells.

Understanding clonal evolution and cancer development requires experimental approaches for characterizing the consequences of somatic mutations on gene regulation. However, no methods currently exist that efficiently link high-content chromatin accessibility with high-confidence genotyping in single cells. To address this, we developed Genotyping with the Assay for Transposase-Accessible Chromatin (GTAC), enabling accurate mutation detection at multiple amplified loci, coupled with robust chromatin accessibility readout. We applied GTAC to primary acute myeloid leukemia, obtaining high-quality chromatin accessibility profiles and clonal identities for multiple mutations in 88% of cells. We traced chromatin variation throughout clonal evolution, showing the restriction of different clones to distinct differentiation stages. Furthermore, we identified switches in transcription factor motif accessibility associated with a specific combination of driver mutations, which biased transformed progenitors toward a leukemia stem cell-like chromatin state. GTAC is a powerful tool to study clonal heterogeneity across a wide spectrum of pre-malignant and neoplastic conditions.

Analysis of Peer-Reviewed Articles in ASRT Scholarly Journals.

PURPOSE: To analyze peer-reviewed articles in the American Society of Radiologic Technologists (ASRT) scholarly journals, Radiologic Technology and Radiation Therapist, and identify types of research and collaborative efforts among top producers. METHODS: A retrospective analysis was conducted by searching the Radiologic Technology and Radiation Therapist archives on the ASRT website to evaluate peer-reviewed articles from 2011 to 2021. A Microsoft Excel spreadsheet was created to document the types of research being published in the ASRT journals, as well as the number of authors for each peer-reviewed article, education levels of authors, collaborative efforts of top producers of scholarship, and mean authorship index of top producers. RESULTS: During this 11-year period, 217 peer-reviewed articles were published in the ASRT journals with most being original research studies (152, 70.0%). Most of the articles were written by 2 authors (68, 31.3%) or 4 or more authors (65, 30.0%). Of the 635 total authors, most held a doctoral degree (247, 38.9%) or a master's degree (212, 33.4%). Five top producers of research were identified as having published 5 or more peer-reviewed articles, and their mean authorship index was 95.5. Four top producers routinely collaborated on research articles. DISCUSSION: Initiatives, such as mentorships, to promote continued publication of original research studies and increase standalone literature reviews and case studies specific to the ASRT journals might be warranted. Medical imaging and radiation therapy educators can capitalize on collaboration by mentoring undergraduate and graduate students in various research opportunities to prepare future scholars in the profession. Further, medical imaging and radiation therapy authors should consider rotating author responsibilities on a collaborative team. Because the ASRT is the premier professional association for the medical imaging and radiation therapy community, authors should consider publishing in their 2 journals to advance and add to the profession's body of knowledge. CONCLUSION: Research articles in the ASRT journals demonstrate high collaborative authorship efforts. This study provides a foundation for future research to improve advancement of knowledge in the medical imaging and radiation therapy profession.

Evaluation of T cell responses to naturally processed variant SARS-CoV-2 spike antigens in individuals following infection or vaccination.

Most existing studies characterizing severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2)-specific T cell responses are peptide based. This does not allow evaluation of whether tested peptides are processed and presented canonically. In this study, we use recombinant vaccinia virus (rVACV)-mediated expression of SARS-CoV-2 spike protein and SARS-CoV-2 infection of angiotensin-converting enzyme (ACE)-2-transduced B cell lines to evaluate overall T cell responses in a small cohort of recovered COVID-19 patients and uninfected donors vaccinated with ChAdOx1 nCoV-19. We show that rVACV expression of SARS-CoV-2 antigen can be used as an alternative to SARS-CoV-2 infection to evaluate T cell responses to naturally processed spike antigens. In addition, the rVACV system can be used to evaluate the cross-reactivity of memory T cells to variants of concern (VOCs) and to identify epitope escape mutants. Finally, our data show that both natural infection and vaccination could induce multi-functional T cell responses with overall T cell responses remaining despite the identification of escape mutations.

Leading past COVID-19: An analysis of remote work now and beyond.

In response to the coronavirus disease 2019 (COVID-19) pandemic, many cancer centers and clinics deployed remote work options for their employees. Due to the rapid response needed during this crisis, little to no feedback was obtained from dosimetrists. This study aimed to assess the productivity level and job satisfaction of medical dosimetrists in response to changes in working conditions due to the COVID-19 pandemic. With the assistance from the medical dosimetrists certification board (MDCB), critical data was gathered via an original instrument conducted and distributed by The University of Texas MD Anderson Cancer Center-School of Health Professions to all current practicing certified medical dosimetrists registered with the MDCB. Data were collected using Qualtrics and analyzed with IBM's SPSS. Most (326, 77.7%) participants indicated they transitioned to a version of remote work due to COVID-19. Almost half of the participants (208, 49.5%) reported increased job satisfaction due to the option to work remotely. The participants reported being extremely satisfied with the individual (247, 58.8%) and department (201, 47.9%) productivity levels even after implementing remote work options. Most participants (225, 53.6%), independent of age and years of experience, would prefer to stay in a hybrid role even after COVID-19 abates. These findings suggest that most dosimetrists prefer to perform their job remotely or asynchronously. A one size fits all job model design may make it difficult for organizations to attract, retain, and grow top dosimetrists. Industry leaders and employers may benefit by embracing this change as dosimetrists may value work-set-up flexibility over other employer-based benefits. Further research is needed to assess the unintended consequences of remote work environments in this profession.

Microbial biomanufacturing for space-exploration-what to take and when to make.

As renewed interest in human space-exploration intensifies, a coherent and modernized strategy for mission design and planning has become increasingly crucial. Biotechnology has emerged as a promising approach to increase resilience, flexibility, and efficiency of missions, by virtue of its ability to effectively utilize in situ resources and reclaim resources from waste streams. Here we outline four primary mission-classes on Moon and Mars that drive a staged and accretive biomanufacturing strategy. Each class requires a unique approach to integrate biomanufacturing into the existing mission-architecture and so faces unique challenges in technology development. These challenges stem directly from the resources available in a given mission-class-the degree to which feedstocks are derived from cargo and in situ resources-and the degree to which loop-closure is necessary. As mission duration and distance from Earth increase, the benefits of specialized, sustainable biomanufacturing processes also increase. Consequentially, we define specific design-scenarios and quantify the usefulness of in-space biomanufacturing, to guide techno-economics of space-missions. Especially materials emerged as a potentially pivotal target for biomanufacturing with large impact on up-mass cost. Subsequently, we outline the processes needed for development, testing, and deployment of requisite technologies. As space-related technology development often does, these advancements are likely to have profound implications for the creation of a resilient circular bioeconomy on Earth.

Neural Field Continuum Limits and the Structure-Function Partitioning of Cognitive-Emotional Brain Networks.

In The cognitive-emotional brain, Pessoa overlooks continuum effects on nonlinear brain network connectivity by eschewing neural field theories and physiologically derived constructs representative of neuronal plasticity. The absence of this content, which is so very important for understanding the dynamic structure-function embedding and partitioning of brains, diminishes the rich competitive and cooperative nature of neural networks and trivializes Pessoa's arguments, and similar arguments by other authors, on the phylogenetic and operational significance of an optimally integrated brain filled with variable-strength neural connections. Riemannian neuromanifolds, containing limit-imposing metaplastic Hebbian- and antiHebbian-type control variables, simulate scalable network behavior that is difficult to capture from the simpler graph-theoretic analysis preferred by Pessoa and other neuroscientists. Field theories suggest the partitioning and performance benefits of embedded cognitive-emotional networks that optimally evolve between exotic classical and quantum computational phases, where matrix singularities and condensations produce degenerate structure-function homogeneities unrealistic of healthy brains. Some network partitioning, as opposed to unconstrained embeddedness, is thus required for effective execution of cognitive-emotional network functions and, in our new era of neuroscience, should be considered a critical aspect of proper brain organization and operation.

COVID-19 Contingency Planning Among Radiologic Science Programs.

PURPOSE: To examine radiologic science programs' contingency planning related to the COVID-19 pandemic. METHODS: Using a mixed-methods approach, educators in magnetic resonance, medical dosimetry, radiation therapy, and radiography programs were surveyed to identify curricular changes, policy implementation, and financial implications related to pandemic recovery efforts. Quantitative data were summarized using descriptive statistics and percentages. Thematic analyses were performed on the qualitative responses. RESULTS: Continued curricular changes involved using technology to teach in the online environment and ensuring the safety and protection of students during clinical rotations. Institutional policies implemented because of the pandemic included social distancing guidelines, mask requirements, and availability of vaccine. The greatest financial implication witnessed among the sample of educators at their respective institutions was the halting of employer-related travel. Faced with the spontaneous shift to online learning while not being equipped with the appropriate training, most of the educator participants experienced COVID-19 fatigue and burnout related to teaching online. DISCUSSION: Social distancing guidelines make it difficult for large classes to meet in person, so virtual lectures using video conferencing platforms were an essential part of teaching during the pandemic. Most educators in this study selected recording technology for lectures as the most useful educational technology tool integrated into the didactic portion of their program. For many educators, having administration realize the adoption of technology is integral to and viable for radiologic science programs was a positive outcome of COVID-19. The pandemic caused educators in the study to experience fatigue and burnout related to online learning; however, the educators also expressed a high degree of comfort with using technology in the online learning environment. This implies that the source of fatigue and burnout was likely not associated with the technology, but with the focused and swift transition to predominately online learning. CONCLUSION: Although educators in this sample felt moderately prepared to handle future viral outbreaks and extremely comfortable using technology in the virtual classroom, additional research is needed to develop viable contingency plans and explore pedagogical approaches to content delivery beyond the traditional, in-person structure.