bluuebunny/crossref_metadata_2025 huggingface dataset:
Simulation of Pregnancy-Related Abdominal Mass Results in Nonimmediate Changes in Postural Control: An Exploratory Study
Authors: Danna-dos-Santos Alessander , Cardoso Vinicius Saura , Magalhaes Alessandra Tanuri , Driusso Patricia , Degani Adriana Menezes
Published: July 2022

Background:

Changes to segmental inertial properties, abdominal growth, and increased circulating relaxin are some of the numerous contributing factors to higher risks of falling during pregnancy. These factors emerge in different phases of pregnancy, have a cumulative effect, and vary across women. For these reasons, determining each factor's role in the development of higher fall risk is challenging and yet crucial in uncovering their clinical importance.

Objectives:

To investigate the independent effect of additional abdominal weight on balance control in nonpregnant women.

Study Design:

A longitudinal study.

Methods:

Ten healthy women were submitted to computerized posturography while an additional abdominal weight (7% of body mass) was applied for 24 hours. Postural behavior was recorded from 4 experimental conditions: before placement of the additional weight (Baseline), immediately after placement of the abdominal weight (T1), 24 hours after continuous application of the abdominal weight (T2), and immediately after abdominal weight removal (T3). Variables of interest were extracted from the participant's body sway dynamics and included the center of pressure (COP) migration area, range, root mean square (RMS), mean velocity, median frequency (F50), and signal sample entropy (SEnt).

Results:

At T3, significant increases were found for the COP migration area, mediolateral range, and mediolateral RMS (P values range: .005-.013). Also at T3, significant decreases were found for mediolateral F50 and SEnt (P values range: .001-.038).

Conclusion:

Modifications in balance behavior were observed when the abdominal weight was removed after 24 hours of application. Significant changes occurred in the mediolateral body sway amplitude and regularity suggesting the presence of mediolateral instability.
Recovery of Unaided Hearing After Cochlear Implantation in Patient With Bilateral Menière's Disease
Authors: Raymond Mallory , Strange Christine , Rizk Habib
Published: July 2022

Objective

To report a novel occurrence of unaided hearing recovery after cochlear implantation in a patient with Menière's disease.

Patients

A 49-year-old woman with bilateral Menière's disease and vestibular migraine.

Intervention(s)

Cochlear implantation

Main Outcome Measure(s)

Postoperative unaided and aided pure tone thresholds and speech recognition measures.

Results

Six-month postoperative unaided hearing in the implanted ear was in the moderate sensorineural hearing loss range with a speech reception threshold of 45 dB and word recognition score of 95%, representing a significant improvement from preoperative hearing, which was in the profound sensorineural hearing loss range with an unaided speech awareness threshold of 75 dB and inability to perform speech recognition testing. Aided testing also demonstrated an expected postoperative improvement after 6 months with a CNC word and AzBio in quiet score of 96% and 93%, respectively, from 0% and 9% preoperatively.

Conclusion

Unaided hearing improvement after cochlear implantation in a patient with Menière's disease is unexpected, but possible and might lend insight into the poorly understood underlying mechanisms of sensorineural hearing loss in patients with Menière's disease.
Implementation of Interprofessional Meetings Preparing Caregivers of Patients With Brain Injury for Discharge
Authors: Lutz Andrea M. , Warehime Kathleen M. , Woods Anne B. , Ruth Lauren E. , Burnside Amy , Bell Theodore D. , Buchko Barbara L.
Published: July 2022

Purpose of Study:

Caregivers are often unprepared to care for patients discharged with brain injury. Interprofessional team meetings with the caregiver used in some specialties improve discharge planning. The purpose of this study was to evaluate the effect of a standardized interprofessional caregiver meeting on caregiver readiness for caregiving.

Primary Practice Setting:

The study was implemented on an eight-bed brain injury unit within a 73-bed Magnet-designated surgery and rehabilitation hospital in south central Pennsylvania.

Methodology and Sample:

This study used a pre-/post-quasi-experimental retrospective design. Caregivers of patients admitted to the brain injury unit completed the Preparedness for Caregiving Scale at admission and discharge. The intervention group received an interprofessional team meeting focused on the needs of the caregiver in preparation for caregiving within 3–4 days of admission compared with unscheduled meetings as needed.

Results:

Scores improved significantly from admission to discharge in usual care and intervention groups. Sample size was insufficient to detect differences between groups. Health care providers and caregivers expressed improvement in communication and readiness for discharge.

Implications for Case Management Practice:

Early interprofessional meetings with the purpose of getting to know and understanding the needs of caregivers of patients with brain injury could guide us to better prepare the caregiver for caregiving at home. The Preparedness for Caregiving Scale can be useful to assess multiple domains of caregiving. This proactive approach may improve communication and discharge readiness for patients with brain injury.
Integrating Spiritual Care in Population Health and Care Management
Authors: Valenti-Hein Charles
Published: July 2022

Purpose/Objectives:

The purpose of this case study is to describe the movement of spiritual care into outpatient, managed care and population health settings, as it has evolved in a major not-for-profit health care system in the United States. The objective is to begin to establish the effectiveness of integrating spiritual care as a part of the interdisciplinary team (IDT) in these contexts.

Primary Practice Setting(s):

The case study presents two practice settings: a remote patient monitoring program for patients with complex medical conditions, and integration into population health as a part of a Medicare Advantage Insurance program that is a cooperative venture between the health care system (Ascension) and an established insurance program (Centene).

Findings/Conclusions:

The cases presented suggest that the integration of spiritual care into the outpatient, managed care and population health contexts has a threefold benefit: enhancing patient care, increasing the effectiveness of the IDT, and providing for the care and support of the members of the IDTs themselves.

Implications for Case Management Practice:

The cases presented suggest inclusion of spiritual care in the care management/population health approach to patient care is viable and valuable both for the benefit of the patient and the functioning of the care team.
Hospital Case Management
Authors: McLaughlin Davis Mary , Morley Colleen
Published: July 2022

Purpose/Objectives:

In June 2019, a Case Management Society of America (CMSA) task force published “The Practice of Hospital Case Management: A White Paper.” This was an important first step to outline the value of hospital case managers (HCMs) and to put forward recommendations for how to operationalize a major change in most hospitals for how case managers can practice.

The SARS-CoV2 (COVID-19) pandemic drastically changed the practice of all interdisciplinary work within hospitals. The White Paper recommended that HCMs follow a select patient population through the hospital. Hospital case manager leaders realized that HCMs can work remotely and communicate with patients because meeting them in person was not an option. Hospital case managers are still resistant to leaving the hospital unit–based model, even after they experienced the value of this concept during the height of the pandemic.

Primary Practice Setting:

Acute care hospitals.

Findings/Conclusions:

The White Paper recommended separating HCMs from utilization management. One unintended consequence is the loss of necessary knowledge and competencies. These are related to compliance with the Centers for Medicare & Medicaid Services Conditions of Participation and regulatory mandates that can affect patient care and financial well-being. Hospital case manager leaders must stay current with these government requirements for hospitals and for all levels of care and keep the case managers informed, proficient, and fluent when coordinating the care of patients.

Implications for Case Management Practice:

Hospital case manager practice is evolving; change is the single constant in health care. This review of the CMSA Hospital Case Management Whitepaper demonstrates that in just three short years, the landscape of health care can change dramatically.

Today's HCM leader must proactively address a multigenerational workforce, lack of title protection, and the COVID-19–induced “Great Resignation.” The value of the HCM has never been more apparent as during the pandemic as the need to “empty beds” is critical, and the HCM is the professional who has the skill to provide efficient and patient-centered care coordination. The HCM leader practices positive leadership techniques that benefit the leader, the HCM, and most importantly the patient.
Aligning Nursing Ethics With Critical and Open Pedagogy in Nursing Education
Authors: Petrovic Kristin , Perry Beth , Walsh Pamela
Published: July 2022

Background:

There is a need to increase access to nursing education that is meaningful and socially just.

Purpose:

To investigate the alignment of critical and open pedagogy in nursing education with nursing principles of ethics.

Method:

Narrative thematic synthesis literature review of Canadian and American sources related to nursing education.

Results:

Thematic analysis of 29 full-text sources that align nursing ethical principles with critical and open pedagogy in nursing education.

Conclusion:

Critical and open pedagogy aligns with nursing practice ethics and facilitates meaningful and socially just nursing education experiences.
Perceptual warping exposes categorical representations for speech in human brainstem responses
Authors: Carter Jared A. , Bidelman Gavin M.
Published: July 2022

The brain transforms continuous acoustic events into discrete category representations to downsample the speech signal for our perceptual-cognitive systems. Such phonetic categories are highly malleable and heir percepts can change depending on surrounding stimulus context. Previous work suggests these acoustic-phonetic mapping and perceptual warping of speech emerge in the brain no earlier than auditory cortex. Here, we examined whether these auditory-category phenomena inherent to speech perception occur even earlier in the human brain, at the level of auditory brainstem. We recorded speech-evoked frequency following responses (FFRs) during a task designed to induce more/less warping of listeners’ perceptual categories depending on stimulus presentation order of a speech continuum (random, forward, backward directions). We used a novel clustered stimulus paradigm to rapidly record the high trial counts needed for FFRs concurrent with active behavioral tasks. We found serial stimulus order caused perceptual shifts (hysteresis) near listeners’ category boundary confirming identical speech tokens are perceived differentially depending on stimulus context. Critically, we further show neural FFRs during active (but not passive) listening are enhanced for prototypical vs. category-ambiguous tokens and are biased in the direction of listeners’ phonetic label even for acoustically-identical speech stimuli. Our data expose FFRs carry category-level information and suggest top-down processing actively shapes the neural encoding and categorization of speech at subcortical levels. These findings suggest the acoustic-phonetic mapping and perceptual warping in speech perception occur surprisingly early along the auditory neuroaxis, which might aid understanding by reducing ambiguity inherent to the speech signal.
Potential adverse effects of an educational intervention: Development of a framework
Authors: Oxman Matt , Chesire Faith Chelagat , Mugisha Michael , Ssenyonga Ronald , Ngatia Benson , Nsangi Allen , Lewin Simon , Moberg Jenny , Sewankambo Nelson , Kaseje Margaret , Melby-Lervåg Monica , Fretheim Atle , Oxman Andrew David , Rosenbaum Sarah
Published: July 2022

Background

Researchers often overlook potential adverse effects of educational and public health interventions (increases in adverse outcomes, or decreases in beneficial outcomes, attributed to the intervention). To help us identify potential adverse effects of an educational intervention intended to improve critical thinking about health choices, we developed a framework. We also did a preliminary prioritisation of outcomes in the framework for randomised trials of the intervention, and associated process evaluations.

Methods

Based on relevant evidence and theory, we developed an initial framework. For feedback on the initial framework, we sent a survey to 70 external experts. We conducted a thematic analysis of the qualitative survey data. After revising the framework based on the survey findings, we interviewed teachers in the context where we are evaluating the intervention, to help identify any effects still missing from the framework, and preliminarily prioritise potential outcomes for the evaluation.

Results

We received responses from 38 of the 70 external experts (54%), including researchers and others with a variety of expertise within health, education, and design. Overall, the responses were positive. However, they also included critical feedback that led to substantial revisions of the framework’s content and presentation. The revised framework has six categories of potential adverse effects: decision-making harms, psychological harms, equity harms, group and social harms, waste, and other harms. We interviewed three teachers, who did not suggest any missing outcomes. Based on the interview findings, we prioritised three outcomes for the evaluation of the intervention: work-related stress; wasted time or resources; and conflict, in particular between students and family.

Discussion

As far as we are aware, the framework presented in this article is the first tool of its kind in education research. The framework is a “living” tool, which can be improved upon, as well as adapted. We have used it to inform the development of interview and observation guides, and we are using it to inform the development of outcome measures. Important limitations of the framework include limits to its comprehensiveness, and the use of terminology with different meanings or interpretations depending on the context. Our approach to identifying and evaluating potential adverse effects of an educational intervention can have value to other researchers.

Conclusion

Rigorous evaluations of potential adverse effects of educational and public health interventions can be time and resource-intensive. However, that cost might be small compared to the cost of implementing harmful interventions.
The macroevolutionary impact of recent and imminent mammal extinctions on Madagascar
Authors: Michielsen Nathan M. , Goodman Steven M. , Soarimalala Voahangy , van der Geer Alexandra A.E. , Dávalos Liliana M. , Saville Grace I. , Upham Nathan , Valente Luis
Published: July 2022

Madagascar’s biota has suffered recent extinctions and many of its unique species are threatened. However, the severity of recent and potential extinctions in a global evolutionary context is unquantified. We compiled a phylogenetic dataset for the complete non-marine mammalian biota of Madagascar and estimated natural rates of extinction, colonization, and speciation. We measured how long it would take to restore Madagascar’s mammalian biodiversity under these rates, the “evolutionary return time” (ERT). We show the loss of currently threatened Malagasy mammal species would have a much deeper long-term impact than all the extinctions since human arrival to the island. A return from current to pre-human diversity would take 1.6 million years (Myr) for bats, and 2.9 Myr for non-volant mammals. However, if species currently classified as threatened go extinct, the ERT rises to 2.9 Myr for bats and 23 Myr for non-volant mammals. The evolutionary history currently under threat on Madagascar is much greater than on other islands, suggesting an extinction wave with deep evolutionary impact is imminent unless immediate conservation actions are taken.
Possible Functional Proximity of Various Organisms Based on Taste Receptors Genomics
Authors: Hassan Sk. Sarif , Sil Moumita , Chakraborty Subhajit , Goswami Arunava , Basu Pallab , Nawn Debaleena , Uversky Vladimir N.
Published: July 2022

Taste is one of the essential senses in providing the organism a faithful representation of the external world. Taste perception is responsible for basic food and drink appraisal and bestows the organism with valuable discriminatory power. Umami and sweet are “good” tastes that promote consumption of nutritive food, whereas bitter and sour are “bad” tastes that alert the organism to toxins and low pH, promoting rejection of foods containing harmful substances. Not every animal has the same sense of taste as humans. Variation in the taste receptor genes contributes to inter and intra organism differences of taste (sweet/bitter) sensation and preferences. Therefore a deeper understanding was needed to comprehend taste perception by various vertebrates and accordingly elucidate a possible proximity among them. In this study, a total 20 Type-1 (sweet) and 189 Type-2 (bitter) taste receptor complete-amino acid sequences were taken from the 20 vertebrate organisms (18 mammalian, 1 aves, and 1 amphibian). Among 10 primates, 8 including humans were very close based on genomics of taste receptors and rodent organisms viz. the rat and mouse were away from them. This investigation throws light on the similitude and dissimilitude of perception of sweet and bitter taste among 20 different organisms, steered by quantitative analysis of their genomic data. Furthermore, it enlightened that ligand binding affinity of sweet/bitter taste molecules in the taste receptors of any proximal pair of organisms would be similar.
Distance-dependent distribution thresholding in probabilistic tractography
Authors: Chang Ya-Ning , Halai Ajay D. , Lambon Ralph Matthew A.
Published: July 2022

Tractography is widely used in human studies of connectivity with respect to every brain region, function, and is explored developmentally, in adulthood, aging, and in disease. However, the core issue of how to systematically threshold, taking into account the inherent differences in connectivity values for different track lengths, and to do this in a comparable way across studies has not been solved. The study adopted Monte Carlo derived distance-dependent distributions (DDDs) to generate distance-dependent thresholds with various levels of alpha for connections of varying lengths. As a test case, we applied the DDD approach to generate a language connectome. The resulting connectome showed expected short- and long-distance structural connectivity in the close and distant regions within the language network. The finding demonstrates that the DDD approach can be used for both individual and group thresholding. Critically, it offers a standard method that can be applied to various probabilistic tracking datasets.
CTCF, BEAF-32 and CP190 are not required for the initial establishment of TADs in early Drosophila embryos, but have locus specific roles
Authors: Cavalheiro Gabriel R. , Girardot Charles , Viales Rebecca R. , Feng Songjie , Pollex Tim , Cao T. B. Ngoc , Lacour Perrine , Rabinowitz Adam , Furlong Eileen E.M.
Published: July 2022

The boundaries of Topologically-Associating Domains (TADs) are delimited by insulators and active promoters, however how they are initially established during embryogenesis remains unclear. Here, we examined this during the first hours of Drosophila embryogenesis. DNA-FISH on individual embryos indicates that domains form during zygotic genome activation (ZGA), but have extensive cell-to-cell heterogeneity compared to later stages. Most newly formed boundaries are occupied by combinations of CTCF, BEAF- 32 and/or CP190. Depleting each insulator from chromatin revealed that TADs can still establish during ZGA, although with lower insulation, with particular boundaries being more sensitive. Some weakened boundaries have aberrant gene expression, however the majority of mis-expressed genes have no obvious relationship to changes in domain-boundary insulation. Deletion of an active promoter (thereby blocking transcription) at one boundary had a greater impact compared to deleting the insulator-bound region itself. These results suggest cross-talk between insulators and transcription might reinforce domain formation during embryogenesis.
Long-term Christmas Bird Counts describe Neotropical urban bird diversity
Authors: Angela Echeverry-Galvis María , Ramírez Pabla Lozano , Amaya-Espinel Juan David
Published: July 2022

A significant gap in understanding the response of biodiversity to urban areas is the lack of long-term studies. Most of the information on urban birds comes from studies carried out in the northern hemisphere, and they include data that don’t exceed three years. Although short-term studies contribute to knowledge about bird community diversity and their spatial distribution in urban areas, they could be biased towards more conspicuous and abundant species. One of the few multi-temporal datasets available for birds in urban areas is the Christmas Bird Count (CBC). Using annual CBC data available between 2001 and 2018 from 21 urban and peri-urban sample sites assessed from the main cities of Colombia, we identified and analyzed long-term trends on the cumulative diversity of bird communities as well as on their spatial distribution. We estimated comparative trends in richness, abundance, similarity, and complementarity of avifauna for each city and sample site based on their responses to urbanization and dietary guilds. We identified almost a quarter of the species registered in Colombia (464 of 1954). The representativeness of the community obtained during 18 years exceeds 84%, showing richness that ranges between 214 and 278 species in the three cities. Bird species and individuals registered showed wide variation of the sample sites. We found more dwellers, insectivorous and granivorous species in urban areas, with frugivores relegated to peri-urban sites, usually coinciding with avoider species. Natural peri-urban areas and intra-urban wetlands and urban parks were the most important refuges for birds and maintained the highest avoider and utilizer species richness. Long-term inventories are fundamental for determining consolidated bird diversity and distributional patterns. This information established a baseline for decision-making and applying recommendations that allow reconciling the growing demand for urban areas with the need to preserve the native avifauna in megadiverse Neotropical countries such as Colombia.
Spatial consistency of cell growth direction during organ morphogenesis requires CELLULOSE-SYNTHASE INTERACTIVE1
Authors: Mollier Corentin , Skrzydeł Joanna , Borowska-Wykręt Dorota , Majda Mateusz , Bayle Vincent , Battu Virginie , Totozafy Jean-Chrisologue , Dulski Mateusz , Fruleux Antoine , Wrzalik Roman , Mouille Grégory , Smith Richard S. , Monéger Françoise , Kwiatkowska Dorota , Boudaoud Arezki
Published: July 2022

Extracellular matrices generally contain fibril-like polymers that may be organized in parallel arrays. Although their role in morphogenesis has been long recognized, it is still unclear how the subcellular control of fibril synthesis translates into well-defined organ shape. Here, we addressed this question using the Arabidopsis sepal as a model organ. In plants, cell growth is driven by turgor pressure and restrained by the extracellular matrix known as the cell wall. Cellulose is the main load-bearing component of the plant cell wall and cellulose microfibrils are thought to channel growth perpendicularly to their main orientation. Given the key function of CELLULOSE SYNTHASE INTERACTIVE 1 (CSI1) in guidance of cellulose synthesis, we investigated the role of CSI1 in sepal morphogenesis. We observed that sepals fromcsi1mutants are shorter, although their newest cellulose microfibrils are more aligned compared to wild type. Surprisingly, cell growth anisotropy was similar incsi1and wild-type plants. We resolved this apparent paradox using polarized Raman microspectroscopy, live imaging of growing sepals, and bespoke mechanical assays. We found that CSI1 is required for spatial consistency of growth direction across the sepal and for the maintenance of overall organ elongation. Our work illustrates how the subcellular regulation of the extracellular matrix may control morphogenesis at multiple scales.
Biophysical ordering transitions underlie genome 3D re-organization during cricket spermiogenesis
Authors: Orsi Guillermo A. , Tortora Maxime M.C. , Horard Béatrice , Baas Dominique , Kleman Jean-Philippe , Bucevičius Jonas , Lukinavičius Gražvydas , Jost Daniel , Loppin Benjamin
Published: July 2022

Spermiogenesis is a radical process of differentiation whereby sperm cells acquire a compact and specialized morphology to cope with the constraints of sexual reproduction while preserving their main cargo, an intact copy of the paternal genome. In animals, this often involves the replacement of most histones by sperm-specific nuclear basic proteins (SNBPs). Yet, how the SNBP-structured genome achieves compaction and accommodates shaping remain largely unknown. Here, we exploited confocal, electron and super-resolution microscopy observations, coupled with polymer modeling simulations to identify the higher-order architecture of sperm chromatin in the needle-shaped nucleus of the emerging model cricket Gryllus bimaculatus. Accompanying spermatid differentiation and shaping, the SNBP-based genome was strikingly reorganized as ~25nm-thick fibers orderly coiled along the elongated nucleus axis. This chromatin spool was further found to achieve large-scale helical twisting in the final stages of spermiogenesis, favoring its ultracompaction. Through a combination of microscopy observations and polymer simulations, we revealed that these dramatic transitions may be recapitulated by a surprisingly simple biophysical principle based on a nucleated rigidification of chromatin linked to the histone-to-SNBP transition within a confined nuclear space. Our work highlights a unique, liquid crystal-like mode of higher-order genome organization in ultracompact cricket sperm completely distinct from nucleosomal chromatin, and establishes a multidisciplinary methodological framework to explore the diversity of non-canonical modes of DNA organization.

SIGNIFICANCE STATEMENT

Animal sperm cells are highly compact and atypically shaped compared to other cell types. How DNA is packaged and organized in the 3D space of sperm cell nuclei to cope with these constraints is poorly understood. In this work, we identified an original and elegant solution to this problem in crickets, whereby DNA fibers orderly spool and twist to fit into ultracompact, needle-shaped sperm cells. To understand this reorganization, we modeled DNA fibers in the nucleus as polymers and found that a relatively simple mechanism through which fibers become more rigid bit by bit can largely recapitulate our observations. Our multidisciplinary work highlights a simple solution to compact DNA to extreme levels in specialized nuclei.
TROP2 represents a negative prognostic factor in colorectal adenocarcinoma and its expression is associated with features of epithelial-mesenchymal transition and invasiveness
Authors: Švec Jiří , Šťastná Monika , Janečková Lucie , Hrčkulák Dušan , Vojtěchová Martina , Onhajzer Jakub , Kříž Vítězslav , Galušková Kateřina , Šloncová Eva , Kubovčiak Jan , Pfeiferová Lucie , Hrudka Jan , Matěj Radoslav , Waldauf Petr , Havlůj Lukáš , Kolář Michal , Kořínek Vladimír
Published: July 2022

Trophoblastic cell surface antigen 2 (TROP2) is a membrane glycoprotein overexpressed in many solid tumors with poor prognosis, including intestinal neoplasms. In our study, we show that TROP2 is expressed in preneoplastic lesions and its expression is maintained in most colorectal cancer (CRC). High TROP2 positivity correlated with lymph node metastases and poor tumor differentiation and was a negative prognostic factor. To investigate the role of TROP2 in intestinal tumors, we analyzed two mouse models with conditional disruption of the adenomatous polyposis coli (Apc) tumor suppressor gene, human adenocarcinoma samples, patient-derived organoids, and TROP2-deficient tumor cells. We found that Trop2 is produced early after Apc inactivation and its expression is associated with transcription of genes involved in epithelial-mesenchymal transition, regulation of migration, invasiveness, and extracellular matrix remodeling. A functionally similar group of genes was also enriched in TROP2-positive cells from human CRC samples. To decipher the driving mechanism of TROP2 expression, we analyzed its promoter. In human cells, this promoter was activated by β-catenin and additionally by Yes1-associated transcriptional regulator (YAP). The regulation of TROP2 expression by active YAP was verified by YAP knockdown in CRC cells. Our results suggest a possible link between aberrantly activated Wnt/β-catenin signaling, YAP, and TROP2 expression.

Simple Summary

Colorectal cancer (CRC) is one of the most common cancers worldwide. While systemic treatment of CRC is based on chemotherapy, subsequent therapeutic options are far less effective. Trophoblast cell surface antigen 2 (TROP2) is highly expressed in many carcinomas, including CRC, where its expression correlates with poor prognosis. Anti-TROP2-targeted therapy was approved for the treatment of breast and urothelial carcinomas. We aimed to determine whether TROP2 is a suitable target for the treatment of CRC. We demonstrated that TROP2 expression in CRC correlates with lymph node metastasis and poor tumor differentiation. Analysis of mouse tumor models, patient-derived organoids, and tumor cells revealed that TROP2 expression is associated with features related to epithelial-mesenchymal transition and invasiveness. Our results suggest that TROP2 targeting may be a promising approach, especially in the early phase of treatment.
Antibody recognition of CD4-induced open HIV-1 Env trimers
Authors: Yang Zhi , Dam Kim-Marie A. , Gershoni Jonathan M. , Zolla-Pazner Susan , Bjorkman Pamela J.
Published: July 2022

HIV-1 envelope (Env), a heterotrimer of gp120-gp41 subunits, mediates fusion of the viral and host cell membranes after interactions with the host receptor CD4 and a coreceptor. CD4 binding induces rearrangements in Env trimer, resulting in a CD4-induced (CD4i) open Env conformation. Structural studies of antibodies isolated from infected donors have defined antibody-Env interactions, with one class of antibodies specifically recognizing the CD4i open Env conformation. Here, we characterize a group of monoclonal antibodies isolated from HIV-1 infected donors (V2i mAbs) that display characteristics of CD4i antibodies. Binding experiments demonstrate that the V2i mAbs preferentially recognize CD4-bound open Env trimers. Structural characterizations of V2i mAb-Env-CD4 trimer complexes using single-particle cryo-electron microscopy show recognition by V2i mAbs using different angles of approach to the gp120 V1V2 domain and the β2/β3 strands on a CD4i open conformation Env with no direct interactions of the mAbs with CD4. We also characterize CG10, a CD4i antibody that was raised in mice immunized with a gp120-CD4 complex, complexed with Env trimer and CD4. CG10 exhibits similar characteristics to the V2i antibodies: i.e., recognition of the open Env conformation, but shows direct contacts to both CD4 and gp120. Structural comparisons of these and previously characterized CD4i antibody interactions with Env provide a suggested mechanism for how these antibodies are elicited during HIV-1 infection.

Importance

The RV144 HIV-1 clinical vaccination trial showed mild protection against viral infection. Antibody responses to the V1V2 region of HIV-1 Env gp120 were correlated inversely with the risk of infection. In addition, antibodies targeting V1V2 have been correlated with protections from SIV and SHIV infections in non-human primates. We structurally characterized V2i antibodies directed against V1V2 isolated from HIV-1 infected humans in complex with open Env trimers bound to the host receptor CD4. We also characterized a CD4i antibody that interacts with CD4 as well as the gp120 subunit of an open Env trimer. Our study suggests how V2i and CD4i antibodies were elicited during HIV-1 infection.
Ethnic disparities in medication adherence? A systematic review examining the association between ethnicity and antidiabetic medication adherence
Authors: Asiri Rayah , Todd Adam , Robinson Anna , Husband Andy
Published: July 2022

Objectives

Adherence to prescribed medication is an essential component of diabetes management to obtain optimal outcomes. Understanding the relationship between medication adherence and ethnicity is key in optimising treatment for all people with different chronic illnesses, including those with diabetes. The aim of this review is to examine whether the adherence to antidiabetic medications differed by ethnicity among people with diabetes.

Methods

A systematic review was conducted of studies reporting adherence to antidiabetic medication amongst people from different ethnic groups. MEDLINE, Embase, CINAHL, and PsycINFO were searched from their inception to June 2021 for quantitative studies with a specific focus on studies assessing adherence to antidiabetic medications (PROSPERO: CRD42021278392). The Joanna Briggs Institute critical appraisal checklist and a second checklist designed for studies using retrospective databases were used to assess study quality. A narrative synthesis approach was used to summarize the results based on the medication adherence measures.

Results

Of 15,685 citations screened, 39 studies that included observational retrospective database research and cross-sectional studies were selected, each of which involved diverse ethnic groups from different settings. This review identified a difference in the adherence to antidiabetic medications by ethnicity in 37 studies, despite adjustment for several confounding variables that may otherwise explain these differences.

Conclusion

This review revealed that adherence to antidiabetic medication differed by ethnicity. Further research is needed to explore the ethnicity-related factors that may provide an explanation for these disparities.
Engineering human Mucosal Associated Invariant T (MAIT) cells with chimeric antigen receptors for cancer immunotherapy1
Authors: Dogan Mikail , Karhan Ece , Kozhaya Lina , Placek Lindsey , Chen Xin , Yigit Mesut , Unutmaz Derya
Published: July 2022

Engineering immune cells with chimeric antigen receptors (CAR) is a promising technology in cancer immunotherapy. Besides classical cytotoxic CD8+ T cells, innate cell types such as NK cells have also been used to generate CAR-T or CAR-NK cells. Here we devised an approach to program a non-classical cytotoxic T cell subset called Mucosal Associated Invariant T (MAIT) cells into effective CAR-T cells against B cell lymphoma and breast cancer cells. Accordingly, we expressed anti-CD19 and anti-Her2 CARs in activated primary human MAIT cells and CD8+ T cells, expanded them in vitro and compared their cytotoxicity against tumor cell targets. We show upon activation through CARs, CAR-MAIT cells exhibit high levels of cytotoxicity towards target cells, comparable to CD8+ CAR-T cells, but interestingly expressed lower levels of IFN-γ than conventional CAR CD8+ T cells. Additionally, in the presence of vitamin B2 metabolite 5-ARU, which is a conserved compound that activates MAIT cells through MHC-I related (MR1) protein, MAIT cells killed MR1-expressing target breast cancer and B cell lymphoma cell lines in a dose dependent manner. Thus, MAIT cells can be genetically edited as CAR-T cells or mobilized and expanded by MR1 ligands as an off-the-shelf novel approach to cell-based cancer immunotherapy strategies while being comparable to conventional methods in effectivity.

Key Points

MAIT cells expressing CARs effectively kill CD19 and Her2 expressing targets

CAR-MAITs display strong cytotoxicity with lower TNF-γ compared to CD8+ CAR-T cells
Assembly mechanism and cryoEM structure of RecA recombination nucleofilaments from Streptococcus pneumoniae
Authors: Maud Hertzog , Noé Perry Thomas , Pauline Dupaigne , Sandra Serres , Violette Morales , Anne-Lise Soulet , Bell Jason C , Emmanuel Margeat , Stephen Kowalczykowski , Le Cam Eric , Rémi Fronzes , Patrice Polard
Published: July 2022

RecA-mediated Homologous Recombination (HR) is a key mechanism for genome maintenance and plasticity in bacteria. It proceeds through RecA assembly into a dynamic filament on ssDNA, the presynaptic filament, which mediates DNA homology search and ordered DNA strand exchange. Here, we combined structural, single molecule and biochemical approaches to characterize the ATP-dependent assembly mechanism of the presynaptic filament of RecA from Streptococcus pneumoniae (SpRecA), in comparison to the Escherichia coli RecA (EcRecA) paradigm. EcRecA polymerization on ssDNA is assisted by the Single-Stranded DNA Binding (SSB) protein, which unwinds ssDNA secondary structures that block EcRecA nucleofilament growth. We report that neither of the two paralogous pneumococcal SSBs could assist SpRecA polymerization on ssDNA. Instead, we found that the conserved RadA helicase promotes this SpRecA nucleofilamentation in an ATP-dependent manner. This allowed us to solve the atomic structure of such a long native SpRecA nucleopolymer by cryoEM stabilized with ATPγS. It was found to be equivalent to the crystal structure of the EcRecA filament with a marked difference in how RecA mediates nucleotide orientation in the stretched ssDNA. Then, our results show that SpRecA and EcRecA HR activities are different, in correlation with their distinct ATP-dependent ssDNA binding modes.
Infection cycle and phylogeny of the Polinton-like virus Phaeocystis globosa virus virophage-14T
Authors: Roitman Sheila , Rozenberg Andrey , Lavy Tali , Brussaard Corina P. D. , Kleifeld Oded , Béjà Oded
Published: July 2022

Virophages are small dsDNA viruses dependent on a nucleocytoplasmic large-DNA virus infection of a cellular host for replication. Putative virophages infecting algal hosts are classified together with polinton-like viruses, transposable elements widely found in algal genomes, yet the lack of isolated strains raises questions about their existence as independent entities. In this work we isolated and characterized a virophage (PgVV-14T) co-infecting Phaeocystis globosa with the Phaeocystis globosa virus-14T (PgV-14T). PgVV-14T decreases the fitness of its PgV-14T viral host, yet it does not salvage the cellular host population. We found viral-like elements resembling PgVV-14T in Phaeocystis genomes, suggesting that these virophages are capable of integrating to the cellular host genome, bridging the gap between Polinton-like viruses and virophages. This system, with a giant virus, a virophage and endogenous viral elements preying on an algal host, presents an opportunity to gain a better understanding on the evolution of eukaryotes and their viruses.
P2G3 human monoclonal antibody neutralizes SARS-CoV-2 Omicron subvariants including BA.4 and BA.5 and Bebtelovimab escape mutants
Authors: Turelli Priscilla , Fenwick Craig , Raclot Charlène , Genet Vanessa , Pantaleo Giuseppe , Trono Didier
Published: July 2022

The rapid evolution of SARS-CoV-2 has led to a severe attrition of the pool of monoclonal antibodies still available for COVID-19 prophylaxis or treatment. Omicron subvariants notably escape most antibodies developed so far, with Bebtelovimab last amongst clinically approved therapeutic antibodies to display still good activity against all of them including the currently dominant BA.4/BA.5. We recently described P2G3, a broadly active SARS-CoV-2 monoclonal antibody, which targets a region of Spike partly overlapping with the site recognized by Bebtelovimab. Here, we reveal that P2G3 efficiently neutralizes SARS-CoV-2 omicron subvariants including BA.4/BA.5. We further demonstrate that P2G3 neutralizes Omicron BA.2 and BA.4 mutants escaping Bebtelovimab blockade, whereas the converse is not true.

Funding

EU COVICIS program; private foundation advised by CARIGEST SA.
Chaperone-Directed Ribosome Repair after Oxidative Damage
Authors: Yang Yoon-Mo , Jung Youngeun , Abegg Daniel , Adibekian Alexander , Carroll Kate , Karbstein Katrin
Published: July 2022

Reactive oxygen species are ubiquitous in cells, where they damage RNA and protein. While relief mechanisms, including effects on translation, have been described, whether ribosomes are functionally compromised by oxidation, and how this damage is mitigated, remains unknown. Here we show that cysteines in ribosomal proteins, including Rps26, are readily oxidized and rendered non-functional, which is exacerbated when yeast are exposed to H2O2. Oxidized Rps26 is released from ribosomes by its chaperone Tsr2, which allows for repair of the damaged ribosomes with newly made Rps26. Ribosomes containing damaged Rpl10 or Rpl23 are similarly repaired by their chaperones, Sqt1 and Bcp1. Ablation of this pathway impairs growth, which is exacerbated under oxidative stress. These findings reveal a novel mechanism for chaperone-mediated ribosome repair with implications for aging and health.

One-Sentence Summary

Chaperones repair thiol-oxidized ribosomes by release of damaged components and incorporation of newly made ribosomal proteins.
Disruption of theAspergillus fumigatusRNA interference machinery alters the conidial transcriptome
Authors: Kelani Abdulrahman A. , Bruch Alexander , Rivieccio Flora , Visser Corissa , Krüger Thomas , Weaver Danielle , Pan Xiaoqing , Schäuble Sascha , Panagiotou Gianni , Kniemeyer Olaf , Bromley Michael J. , Bowyer Paul , Barber Amelia E. , Brakhage Axel A. , Blango Matthew G.
Published: July 2022

The RNA interference (RNAi) pathway has evolved numerous functionalities in eukaryotes, with many on display in Kingdom Fungi. RNAi can regulate gene expression, facilitate drug resistance, or even be altogether lost to improve growth potential in some fungal pathogens. In the WHO fungal priority pathogen,Aspergillus fumigatus, the RNAi system is known to be intact and functional. To extend our limited understanding ofA. fumigatusRNAi, we first investigated the genetic variation in RNAi-associated genes in a collection of 217 environmental and 83 clinical genomes, where we found that RNAi components are conserved even in clinical strains. Using endogenously expressed inverted-repeat transgenes complementary to a conditionally essential gene (pabA) or a nonessential gene (pksP), we determined that a subset of the RNAi componentry is active in inverted-repeat transgene silencing in conidia and mycelium. Analysis of mRNA-seq data from RNAi double-knockout strains linked theA. fumigatusdicer-like enzymes (DclA/B) and RNA-dependent RNA polymerases (RrpA/B) to regulation of conidial ribosome biogenesis genes; however, surprisingly few endogenous small RNAs were identified in conidia that could explain this broad change. Although RNAi was not clearly linked to growth or stress response defects in the RNAi knockouts, serial passaging of RNAi knockout strains for six generations resulted in lineages with diminished spore production over time, indicating that loss of RNAi can exert a fitness cost on the fungus. Cumulatively,A. fumigatusRNAi appears to play an active role in defense against double-stranded RNA species alongside a previously unappreciated housekeeping function in regulation of conidial ribosomal biogenesis genes.
iPHoP: an integrated machine-learning framework to maximize host prediction for metagenome-assembled virus genomes
Authors: Roux Simon , Camargo Antonio Pedro , Coutinho Felipe H. , Dabdoub Shareef M. , Dutilh Bas E. , Nayfach Stephen , Tritt Andrew
Published: July 2022

The extraordinary diversity of viruses infecting bacteria and archaea is now primarily studied through metagenomics. While metagenomes enable high-throughput exploration of the viral sequence space, metagenome-derived genomes lack key information compared to isolated viruses, in particular host association. Different computational approaches are available to predict the host(s) of uncultivated viruses based on their genome sequences, but thus far individual approaches are limited either in precision or in recall, i.e. for a number of viruses they yield erroneous predictions or no prediction at all. Here we describe iPHoP, a two-step framework that integrates multiple methods to provide host predictions for a broad range of viruses while retaining a low (<10%) false-discovery rate. Based on a large database of metagenome-derived virus genomes, we illustrate how iPHoP can provide extensive host prediction and guide further characterization of uncultivated viruses. iPHoP is available at https://bitbucket.org/srouxjgi/iphop, through a Bioconda recipe, and a Docker container.
CryoEM single particle reconstruction with a complex-valued particle stack
Authors: Bromberg Raquel , Guo Yirui , Borek Dominika , Otwinowski Zbyszek
Published: July 2022

Single particle reconstruction (SPR) in cryoEM is an image processing task with an elaborate hierarchy that starts with a large number of very noisy multi-frame images. Efficient representation of the intermediary image structures is critical for keeping the calculations manageable. One such intermediary structure is called a particle stack and contains cut-out images of particles in square boxes of predefined size. The micrograph that is the source of the boxed images is usually corrected for motion between frames prior to particle stack creation. However, the contrast transfer function (CTF) or its Fourier Transform point spread function (PSF) are not considered at this step. Historically, the particle stack was intended for large particles and for a tighter PSF, which is characteristic of lower resolution data. The field now performs analyses of smaller particles and to higher resolution, and these conditions result in a broader PSF that requires larger padding and slower calculations to integrate information for each particle. Consequently, the approach to handling structures such as the particle stack should be reexamined to optimize data processing.

Here we propose to use as a source image for the particle stack an exit-wave-reconstruction-based image, in which CTF correction is implicitly applied as a real component of the image. The final CTF correction that we later refine and apply has a very narrow PSF, and so cutting out particles from micrographs that were approximately corrected for CTF does not require extended buffering, i.e. the boxes during the analysis only have to be large enough to encompass the particle. The Fourier Transform of an exit-wave reconstruction creates an image that has complex values. This is a complex value image considered in real space, opposed to standard SPR data processing where complex numbers appear only in Fourier space. This extension of the micrograph concept provides multiple advantages because the particle box size can be small while calculations crucial for high resolution reconstruction such as Ewald sphere correction, aberration refinement, and particlespecific defocus refinement can be performed on the small box data.

Highlights

▪ A complex-valued particle stack facilitates flexible and fast data processing

▪ A real-valued, compact particle stack can be used at intermediate steps

▪ Whole micrograph padding is used from the beginning of data analysis