BRAVO self-confined expression through WOX5 in the Arabidopsis root stem-cell niche.

In animals and plants, stem-cell niches are local microenvironments that are tightly regulated to preserve their unique identity while communicating with adjacent cells that will give rise to specialized cell types. In the primary root of Arabidopsis thaliana, two transcription factors, BRAVO and WOX5, among others, are expressed in the stem-cell niche. Intriguingly, BRAVO, a repressor of quiescent center divisions, confines its own gene expression to the stem-cell niche, as evidenced in a bravo mutant background. Here, we propose through mathematical modeling that BRAVO confines its own expression domain to the stem-cell niche by attenuating a WOX5-dependent diffusible activator of BRAVO. This negative feedback drives WOX5 activity to be spatially restricted as well. The results show that WOX5 diffusion and sequestration by binding to BRAVO are sufficient to drive the experimentally observed confined BRAVO expression at the stem-cell niche. We propose that the attenuation of a diffusible activator can be a general mechanism acting at other stem-cell niches to spatially confine genetic activity to a small region while maintaining signaling within them and with the surrounding cells.

The impact of cancer metastases on COVID-19 outcomes: A COVID-19 and Cancer Consortium registry-based retrospective cohort study.

BACKGROUND: COVID-19 can have a particularly detrimental effect on patients with cancer, but no studies to date have examined if the presence, or site, of metastatic cancer is related to COVID-19 outcomes. METHODS: Using the COVID-19 and Cancer Consortium (CCC19) registry, the authors identified 10,065 patients with COVID-19 and cancer (2325 with and 7740 without metastasis at the time of COVID-19 diagnosis). The primary ordinal outcome was COVID-19 severity: not hospitalized, hospitalized but did not receive supplemental O2, hospitalized and received supplemental O2, admitted to an intensive care unit, received mechanical ventilation, or died from any cause. The authors used ordinal logistic regression models to compare COVID-19 severity by presence and specific site of metastatic cancer. They used logistic regression models to assess 30-day all-cause mortality. RESULTS: Compared to patients without metastasis, patients with metastases have increased hospitalization rates (59% vs. 49%) and higher 30 day mortality (18% vs. 9%). Patients with metastasis to bone, lung, liver, lymph nodes, and brain have significantly higher COVID-19 severity (adjusted odds ratios [ORs], 1.38, 1.59, 1.38, 1.00, and 2.21) compared to patients without metastases at those sites. Patients with metastasis to the lung have significantly higher odds of 30-day mortality (adjusted OR, 1.53; 95% confidence interval, 1.17-2.00) when adjusting for COVID-19 severity. CONCLUSIONS: Patients with metastatic cancer, especially with metastasis to the brain, are more likely to have severe outcomes after COVID-19 whereas patients with metastasis to the lung, compared to patients with cancer metastasis to other sites, have the highest 30-day mortality after COVID-19.

Regulatory mechanisms for specification and patterning of plant vascular tissues.

Plant vascular tissues, the conduits of water, nutrients, and small molecules, play important roles in plant growth and development. Vascular tissues have allowed plants to successfully adapt to various environmental conditions since they evolved 450 Mya. The majority of plant biomass, an important source of renewable energy, comes from the xylem of the vascular tissues. Efforts have been made to identify the underlying mechanisms of cell specification and patterning of plant vascular tissues and their proliferation. The formation of the plant vascular system is a complex process that integrates signaling and gene regulation at transcriptional and posttranscriptional levels. Recently, a wealth of molecular genetic studies and the advent of cell biology and genomic tools have enabled important progress toward understanding its underlying mechanisms. Here, we provide a comprehensive review of the cell and developmental processes of plant vascular tissue and resources recently available for studying them that will enable the discovery of new ways to develop sustainable energy using plant biomass.

A Novel Photopharmacological Tool: Dual-Step Luminescence for Biological Tissue Penetration of Light and the Selective Activation of Photodrugs.

Conventional pharmacology lacks spatial and temporal selectivity in terms of drug action. This leads to unwanted side effects, such as damage to healthy cells, as well as other less obvious effects, such as environmental toxicity and the acquisition of resistance to drugs, especially antibiotics, by pathogenic microorganisms. Photopharmacology, based on the selective activation of drugs by light, can contribute to alleviating this serious problem. However, many of these photodrugs are activated by light in the UV-visible spectral range, which does not propagate through biological tissues. In this article, to overcome this problem, we propose a dual-spectral conversion technique, which simultaneously makes use of up-conversion (using rare earth elements) and down-shifting (using organic materials) techniques in order to modify the spectrum of light. Near-infrared light (980 nm), which penetrates tissue fairly well, can provide a "remote control" for drug activation. Once near-IR light is inside the body, it is up-converted to the UV-visible spectral range. Subsequently, this radiation is down-shifted in order to accurately adjust to the excitation wavelengths of light which can selectively activate hypothetical and specific photodrugs. In summary, this article presents, for the first time, a "dual tunable light source" which can penetrate into the human body and deliver light of specific wavelengths; thus, it can overcome one of the main limitations of photopharmacology. It opens up promising possibilities for the moving of photodrugs from the laboratory to the clinic.

Human-Centric Lighting: Rare-Earth-Free Photoluminescent Materials for Correlated Color Temperature Tunable White LEDs.

Artificial lighting is ubiquitous in modern society, with detrimental effects on sleep and health. The reason for this is that light is responsible not only for vision but also for non-visual functions, such as the regulation of the circadian system. To avoid circadian disruption, artificial lighting should be dynamic, changing throughout the day in a manner comparable to natural light in terms of both light intensity and associated color temperature. This is one of the main goals of human-centric lighting. Regarding the type of materials, the majority of white light-emitting diodes (WLEDs) make use of rare-earth photoluminescent materials; therefore, WLED development is at serious risk due to the explosive growth in demand for these materials and a monopoly on sources of supply. Photoluminescent organic compounds are a considerable and promising alternative. In this article, we present several WLEDs that were manufactured using a blue LED chip as the excitation source and two photoluminescent organic dyes (Coumarin 6 and Nile Red) embedded in flexible layers, which function as spectral converters in a multilayer remote phosphor arrangement. The correlated color temperature (CCT) values range from 2975 K to 6261 K, while light quality is preserved with chromatic reproduction index (CRI) values superior to 80. Our findings illustrate for the first time the enormous potential of organic materials for supporting human-centric lighting.

Objective measurement of Spanish emotion vocabulary.

Current research on emotion knowledge and competence emphasises the role of language. Emotion vocabulary is one of the indicators of emotion knowledge that can be objectively measured; however, the metric properties of the scores obtained in tests and tasks to measure it have seldom been adequate. In this study we designed and validated a Spanish emotion vocabulary test (MOVE) employing a corpus approach to construct cloze multiple-choice items, administered the test to a Spanish-speaking sample from two countries, Spain and Argentina, and analysed structural validity of the test items with the Rasch model measurement approach. Eighty-eight items showed adequate fit. Overall, a substantial percentage of variance was explained by a latent variable. Reliability indexes at the test, item, and person level were also adequate. As a vocabulary test, the MOVE can be used in psychological and neurological investigation, as well as in language learning research.

Evidence of Age Estimation Procedures in Forensic Dentistry: Results from an Umbrella Review.

Background and objective: Age estimation is an important tool when dealing with human remains or undocumented minors. Although the skull, the skeleton or the hand-wrist are used in age estimation as maturity indicators, they often present a lack of good conditions for a correct identification or estimation. Few systematic reviews (SRs) have been recently published; therefore, this umbrella review critically assesses their level of evidence and provides a general, comprehensive view. Materials and methods: Considering the review question "What is the current evidence on age determination approaches in Forensic Dentistry?" an electronic database search was conducted in four databases (PubMed, Cochrane, WoS, LILACS) up to December 2022, focusing on SRs of age estimation through forensic dentistry procedures. The methodological quality was analyzed using the measurement tool to assess SRs criteria (AMSTAR2). Results: Eighteen SRs were included: five of critically low quality, six of low quality, three of moderate quality and four of high quality. The SRs posited that Willems' method is more accurate and less prone to overestimation; most methods seem to be geographically sensitive; and 3D-imaging and artificial intelligence tools demonstrate high potential. Conclusions: The quality of evidence on age estimation using dental approaches was rated as low to moderate. Well-designed clinical trials and high-standard systematic reviews are essential to corroborate the accuracy of the different procedures for age estimation in forensic dentistry.

Brassinosteroid signaling in plant development and adaptation to stress.

Brassinosteroids (BRs) are steroid hormones that are essential for plant growth and development. These hormones control the division, elongation and differentiation of various cell types throughout the entire plant life cycle. Our current understanding of the BR signaling pathway has mostly been obtained from studies using Arabidopsis thaliana as a model. In this context, the membrane steroid receptor BRI1 (BRASSINOSTEROID INSENSITIVE 1) binds directly to the BR ligand, triggering a signal cascade in the cytoplasm that leads to the transcription of BR-responsive genes that drive cellular growth. However, recent studies of the primary root have revealed distinct BR signaling pathways in different cell types and have highlighted cell-specific roles for BR signaling in controlling adaptation to stress. In this Review, we summarize our current knowledge of the spatiotemporal control of BR action in plant growth and development, focusing on BR functions in primary root development and growth, in stem cell self-renewal and death, and in plant adaption to environmental stress.

Impact of a Nurse-Driven Patient Empowerment Intervention on the Reduction in Patients' Anxiety and Depression During ICU Discharge: A Randomized Clinical Trial.

OBJECTIVES: To assess the impact of a nurse-driven patient empowerment intervention on anxiety and depression of patients during ICU discharge. DESIGN: A prospective, multicenter, randomized clinical trial. SETTING: Three ICUs (1 medical, 1 medical and surgical, and 1 coronary) of three tertiary hospitals. PATIENTS: Adults admitted to the ICU greater than 18 years old for greater than or equal to 48 hours with preserved consciousness, the ability to communicate and without delirium, who were randomized to receive the nurse-driven patient empowerment intervention (NEI) (intervention group [IG] or standard of care [control group (CG)]) before ICU discharge. INTERVENTION: The NEI consisted of an individualized intervention with written information booklets, combined with verbal information, mainly about the ICU process and transition to the ward, aimed at empowering patients in the transition process from the ICU to the general ward. MEASUREMENTS AND RESULTS: Patients completed the Hospital Anxiety and Depression Scale before and after (up to 1 wk) ICU discharge. IG ( n = 91) and CG ( n = 87) patients had similar baseline characteristics. The NEI was associated with a significant reduction in anxiety and depression ( p < 0.001) and the presence of depression ( p = 0.006). Patients with comorbidities and those without family or friends had greater reductions in anxiety and depression after the NEI. After the intervention, women and persons with higher education levels had lower negative outcomes. CONCLUSIONS: We found that a NEI before ICU discharge can decrease anxiety and depression in critically ill survivors. The long-term effect of this intervention should be assessed in future trials. TRIAL REGISTRATION: NCT04527627 ( https://clinicaltrials.gov/ct2/show/NCT04527627 ).

Precise transcriptional control of cellular quiescence by BRAVO/WOX5 complex in Arabidopsis roots.

Understanding stem cell regulatory circuits is the next challenge in plant biology, as these cells are essential for tissue growth and organ regeneration in response to stress. In the Arabidopsis primary root apex, stem cell-specific transcription factors BRAVO and WOX5 co-localize in the quiescent centre (QC) cells, where they commonly repress cell division so that these cells can act as a reservoir to replenish surrounding stem cells, yet their molecular connection remains unknown. Genetic and biochemical analysis indicates that BRAVO and WOX5 form a transcription factor complex that modulates gene expression in the QC cells to preserve overall root growth and architecture. Furthermore, by using mathematical modelling we establish that BRAVO uses the WOX5/BRAVO complex to promote WOX5 activity in the stem cells. Our results unveil the importance of transcriptional regulatory circuits in plant stem cell development.

Base-Mediated Nitrophenyl Reductive Cyclization for the Synthesis of Hexahydro-2,6-methano-1-benzazocines.

A Diels-Alder reaction leading to 4-nitrophenylcyclohexanones followed by a newly developed base-mediated reductive cyclization of the resulting ketone tethered to the nitrobenzene moiety gives access to the hexahydro-2,6-methano-1-benzazocine ring system present in several biologically interesting natural products such as aspernomine. The scope of the reaction was explored with eight substituted nitrobenzenes, obtaining yields of up to 87%. The highest cytotoxicity was observed in benzazocine 4h, bearing an enone moiety, which was active against eight cancer cell lines.

Connecting Aortic Stiffness to Vascular Contraction: Does Sex Matter?

This study was designed to connect aortic stiffness to vascular contraction in young male and female Wistar rats. We hypothesized that female animals display reduced intrinsic media-layer stiffness, which associates with improved vascular function. Atomic force microscopy (AFM)-based nanoindentation analysis was used to derive stiffness (Young's modulus) in biaxially (i.e., longitudinal and circumferential) unloaded aortic rings. Reactivity studies compatible with uniaxial loading (i.e., circumferential) were used to assess vascular responses to a selective α1 adrenergic receptor agonist in the presence or absence of extracellular calcium. Elastin and collagen levels were indirectly evaluated with fluorescence microscopy and a picrosirius red staining kit, respectively. We report that male and female Wistar rats display similar AFM-derived aortic media-layer stiffness, even though female animals withstand higher aortic intima-media thickness-to-diameter ratio than males. Female animals also present reduced phenylephrine-induced aortic force development in concentration-response and time-force curves. Specifically, we observed impaired force displacement in both parts of the contraction curve (Aphasic and Atonic) in experiments conducted with and without extracellular calcium. Additionally, collagen levels were lower in female animals without significant elastin content and fragmentation changes. In summary, sex-related functional differences in isolated aortas appear to be related to dissimilarities in the dynamics of vascular reactivity and extracellular matrix composition rather than a direct response to a shift in intrinsic media-layer stiffness.

Chronological age range estimation of cervical vertebral maturation using Baccetti method: a systematic review and meta-analysis.

BACKGROUND: The timing of growth is a key factor for correct orthodontic treatment planning. Cervical vertebrae maturation (CVM) is no exception, although the reported chronological ages vary in the literature. OBJECTIVE: We aimed to estimate the average chronological age for each Baccetti's CVM staging. SEARCH METHODS: Search on MEDLINE-PubMed, Scopus, LILACS, Google Scholar, Cochrane Central Register of Controlled Trials (CENTRAL) was conducted until July 2021. The review was performed according to Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines. SELECTION CRITERIA: Observational or interventional studies reporting chronological age classified through Baccetti's CVM method were included. DATA COLLECTION AND ANALYSIS: Methodological quality was assessed, and pooled estimates were carried out through random-effects meta-analysis of single means. The impact of sex and continent were also investigated through subgroup analyses. RESULTS: Forty-one studies were included (9867 participants, 4151 men, and 5716 women). The average chronological age was 9.7 years old (95% confidence interval [CI]: 9.4 to 10.1) in CS1, 10.8 years old (95% CI: 10.5 to 11.1) in CS2, 12.0 years old (95% CI: 11.7 to 12.2) in CS3, 13.4 years old (95% CI: 13.2 to 13.6) in CS4, 14.7 years old (95% CI: 14.4 to 15.1) in CS5, and 15.8 years old (95% CI: 15.3 to 16.3) in CS6. A significant difference was found between the sexes in all CVM stages. We also found significant differences across continents. CONCLUSIONS: For each CVM staging a chronological age range was successfully estimated. Girls presented an earlier skeletal maturation compared to boys. The skeletal maturation differs also according to continents, except for CMV stage 1, pointing to the need for personalized ranges according to each region. REGISTRATION: Registration number: PROSPERO: CRD42021225422.

Is Re-introducing Major Open and Minimally Invasive Surgery during COVID-19 Safe for Patients and Healthcare Workers? An International, Multi-centre Cohort Study in the Field of Oesophago-gastric Surgery.

INTRODUCTION: The COVID-19 pandemic has resulted in unparalleled changes to patient care, including the suspension of cancer surgery. Concerns regarding COVID-19-related risks to patients and healthcare workers with the re-introduction of major complex minimally invasive and open surgery have been raised. This study examines the COVID-19 related risks to patients and healthcare workers following the re-introduction of major oesophago-gastric (EG) surgery. PATIENTS AND METHODS: This was an international, multi-centre, observational study of consecutive patients treated by open and minimally invasive oesophagectomy and gastrectomy for malignant or benign disease. Patients were recruited from nine European centres serving regions with a high population incidence of COVID-19 between 1 May and 1 July 2020. The primary endpoint was 30-day COVID-19-related mortality. All staff involved in the operative care of patients were invited to complete a health-related survey to assess the incidence of COVID-19 in this group. RESULTS: In total, 158 patients were included in the study (71 oesophagectomy, 82 gastrectomy). Overall, 87 patients (57%) underwent MIS (59 oesophagectomy, 28 gastrectomy). A total of 403 staff were eligible for inclusion, of whom 313 (78%) completed the health survey. Approaches to mitigate against the risks of COVID-19 for patients and staff varied amongst centres. No patients developed COVID-19 in the post-operative period. Two healthcare workers developed self-limiting COVID-19. CONCLUSIONS: Precautions to minimise the risk of COVID-19 infection have enabled the safe re-introduction of minimally invasive and open EG surgery for both patients and staff. Further studies are necessary to determine the minimum requirements for mitigations against COVID-19.

Experiments in interdisciplinarity: Responsible research and innovation and the public good.

In Europe, responsible research and innovation (RRI) has emerged as a science policy measure that demands the early integration of a broad range of social actors and perspectives into research and development (R&D). More collaboration of the social sciences and humanities (SSH) with science and engineering appears within this policy framework as a crucial element that will enable better technological development. However, RRI is new to both natural scientists and SSH scholars, and interdisciplinary collaborations are challenging for many reasons. In this paper, we discuss these challenges while suggesting that what RRI can be in a particular project is not a given but remains an empirical question. Natural scientists and SSH scholars need to coresearch RRI in an experimental mode.

MyROOT: a method and software for the semiautomatic measurement of primary root length in Arabidopsis seedlings.

Root analysis is essential for both academic and agricultural research. Despite the great advances in root phenotyping and imaging, calculating root length is still performed manually and involves considerable amounts of labor and time. To overcome these limitations, we developed MyROOT, a software for the semiautomatic quantification of root growth of seedlings growing directly on agar plates. Our method automatically determines the scale from the image of the plate, and subsequently measures the root length of the individual plants. To this aim, MyROOT combines a bottom-up root tracking approach with a hypocotyl detection algorithm. At the same time as providing accurate root measurements, MyROOT also significantly minimizes the user intervention required during the process. Using Arabidopsis, we tested MyROOT with seedlings from different growth stages and experimental conditions. When comparing the data obtained from this software with that of manual root measurements, we found a high correlation between both methods (R2  = 0.997). When compared with previous developed software with similar features (BRAT and EZ-Rhizo), MyROOT offered an improved accuracy for root length measurements. Therefore, MyROOT will be of great use to the plant science community by permitting high-throughput root length measurements while saving both labor and time.

Paracrine brassinosteroid signaling at the stem cell niche controls cellular regeneration.

Stem cell regeneration is crucial for both cell turnover and tissue healing in multicellular organisms. In Arabidopsis roots, a reduced group of cells known as the quiescent center (QC) act as a cell reservoir for surrounding stem cells during both normal growth and in response to external damage. Although cells of the QC have a very low mitotic activity, plant hormones such as brassinosteroids (BRs) can promote QC divisions. Here, we used a tissue-specific strategy to investigate the spatial signaling requirements of BR-mediated QC divisions. We generated stem cell niche-specific receptor knockout lines by placing an artificial microRNA against BRI1 (BRASSINOSTEROID INSENSITIVE 1) under the control of the QC-specific promoter WOX5. Additionally, QC-specific knock-in lines for BRI1 and its downstream transcription factor BES1 (BRI1-EMS-SUPPRESOR1) were also created using the WOX5 promoter. By analyzing the roots of these lines, we show that BES1-mediated signaling cell-autonomously promotes QC divisions, that BRI1 is essential for sensing nearby inputs and triggering QC divisions and that DNA damage promotes BR-dependent paracrine signaling in the stem cell niche as a prerequisite to stem cell replenishment.

TOPLESS mediates brassinosteroid control of shoot boundaries and root meristem development in Arabidopsis thaliana.

The transcription factor BRI1-EMS-SUPRESSOR 1 (BES1) is a master regulator of brassinosteroid (BR)-regulated gene expression. BES1 together with BRASSINAZOLE-RESISTANT 1 (BZR1) drive activated or repressed expression of several genes, and have a prominent role in negative regulation of BR synthesis. Here, we report that BES1 interaction with TOPLESS (TPL), via its ERF-associated amphiphilic repression (EAR) motif, is essential for BES1-mediated control of organ boundary formation in the shoot apical meristem and the regulation of quiescent center (QC) cell division in roots. We show that TPL binds via BES1 to the promoters of the CUC3 and BRAVO targets and suppresses their expression. Ectopic expression of TPL leads to similar organ boundary defects and alterations in QC cell division rate to the bes1-d mutation, while bes1-d defects are suppressed by the dominant interfering protein encoded by tpl-1, with these effects respectively correlating with changes in CUC3 and BRAVO expression. Together, our data unveil a pivotal role of the co-repressor TPL in the shoot and root meristems, which relies on its interaction with BES1 and regulation of BES1 target gene expression.

SOLTI-1503 PROMETEO TRIAL: combination of talimogene laherparepvec with atezolizumab in early breast cancer.

New treatment strategies such as immune checkpoint inhibitors and oncolytic viruses are opening new possibilities in cancer therapy. Preliminary results in melanoma and other tumors showed that the combination of talimogene laherparepvec with an anti-PD-1/PD-L1 or anti-CTLA4 has greater efficacy than either therapy alone, without additional safety concerns beyond those expected for each agent. The presence of residual cancer after neoadjuvant chemotherapy in early breast cancer patients is an unmet medical need. SOLTI-1503 PROMETEO is a window of opportunity trial, which evaluates the combination of talimogene laherparepvec in combination with atezolizumab in women with operable HER2-negative breast cancer who present residual disease after neoadjuvant chemotherapy. The primary end point is the rate of residual cancer burden 0/1. Clinical Trial Registration: NCT03802604.