A toolkit for a modern gynecologic oncology tissue bank.

OBJECTIVES: Tissue banking procedures have evolved to keep pace with precision medicine, technology, emerging understanding of racial disparities, and regulatory requirements. However, there is little published guidance regarding strategies to create and maintain a successful biorepository. Our objective is to describe the infrastructure and protocols used by our Gynecologic Oncology Tissue Bank. METHODS: Our Tissue Bank was founded in 1992. In August 2022, internal funding was used to modernize the Tissue Bank. We hired three full-time employees, implemented universal screening of patients treated by gynecologic oncology faculty, updated consenting protocols, and standardized communication with providers. Tumor tissue, blood derivatives, ascites, and pleural fluid were collected from eligible, consenting patients and processed. Patient-derived cell lines and organoids were generated. For quality control purposes, one formalin-fixed, paraffin-embedded (FFPE) sample per tissue site was analyzed by a board-certified pathologist. All samples were labeled and tracked in an OpenSpecimen collection protocol and clinically annotated in a secure database. RESULTS: From August 2022 to October 2023, 227 patients (83% white, 15% Black, 1% Asian) were enrolled and 4249 specimens were collected. Adherent cell lines were generated from 15 patients with ovarian cancer and cell suspensions for organoid generation were collected from 46 patients with ovarian cancer. A recharge center was established to self-sustain the Tissue Bank. Samples have been shared with academic and commercial collaborators. CONCLUSIONS: Our Tissue Bank has enrolled a large number of diverse patients, collected numerous specimen types, and collaborated widely. The procedures described here provide guidance for other institutions establishing similar resources.

A Proline-Squaraine Ligand Framework (Pro-SqEB) for Stereoselective Rhodium(II)-Catalyzed Cyclopropanations.

A proline-squaraine ligand (Pro-SqEB) that demonstrates high levels of stereoselectivity in olefin cyclopropanations when anchored to a Rh2II scaffold is introduced. High yields and enantioselectivities were achieved in the cyclopropanation of alkenes with diazo compounds in the presence of Rh2(Pro-SqEB)4. Notably, the unique electronic and steric design of this catalyst enabled the use of polar solvents that are otherwise incompatible with most RhII complexes.

Role of turgor-pressure induced boundary tension in the maintenance of the shoot apical meristem of Arabidopsis thaliana.

In plants, the robust maintenance of tissue structure is crucial to supporting its functionality. The multi-layered shoot apical meristem (SAM) of Arabidopsis, containing stem cells, is an approximately radially symmetric tissue whose shape and structure is maintained throughout the life of the plant. In this paper, a new biologically calibrated pseudo-three-dimensional (P3D) computational model of a longitudinal section of the SAM is developed. It includes anisotropic expansion and division of cells out of the cross-section plane, as well as representation of tension experienced by the SAM epidermis. Results from the experimentally calibrated P3D model provide new insights into maintenance of the structure of the SAM epidermal cell monolayer under tension and quantify dependence of epidermal and subepidermal cell anisotropy on the amount of tension. Moreover, the model simulations revealed that out-of-plane cell growth is important in offsetting cell crowding and regulating mechanical stresses experienced by tunica cells. Predictive model simulations show that tension-determined cell division plane orientation in the apical corpus may be regulating cell and tissue shape distributions needed for maintaining structure of the wild-type SAM. This suggests that cells' responses to local mechanical cues may serve as a mechanism to regulate cell- and tissue-scale patterning.

Harnessing the omics revolution to address the global biodiversity crisis.

Human disturbances are altering global biodiversity in unprecedented ways. We identify three fundamental challenges underpinning our understanding of global biodiversity (namely discovery, loss, and preservation), and discuss how the omics revolution (e.g. genomics, transcriptomics, proteomics, metabolomics, and meta-omics) can help address these challenges. We also discuss how omics tools can illuminate the major drivers of biodiversity loss, including invasive species, pollution, urbanization, overexploitation, and climate change, with a special focus on highly diverse tropical environments. Although omics tools are transforming the traditional toolkit of biodiversity research, their application to addressing the current biodiversity crisis remains limited and may not suffice to offset current rates of biodiversity loss. Despite technical and logistical challenges, omics tools need to be fully integrated into global biodiversity research, and better strategies are needed to improve their translation into biodiversity policy and practice. It is also important to recognize that although the omics revolution can be considered the biologist's dream, socioeconomic disparity limits their application in biodiversity research.

Moving past the challenges and misconceptions in urban adaptation research.

Although the field of urban evolutionary ecology has recently expanded, much progress has been made in identifying adaptations that arise as a result of selective pressures within these unique environments. However, as studies within urban environments have rapidly increased, researchers have recognized that there are challenges and opportunities in characterizing urban adaptation. Some of these challenges are a consequence of increased direct and indirect human influence, which compounds long-recognized issues with research on adaptive evolution more generally. In this perspective, we discuss several common research challenges to urban adaptation related to (1) methodological approaches, (2) trait-environment relationships and the natural history of organisms, (3) agents and targets of selection, and (4) habitat heterogeneity. Ignoring these challenges may lead to misconceptions and further impede our ability to draw conclusions regarding evolutionary and ecological processes in urban environments. Our goal is to first shed light on the conceptual challenges of conducting urban adaptation research to help avoid the propagation of these misconceptions. We further summarize potential strategies to move forward productively to construct a more comprehensive picture of urban adaptation, and discuss how urban environments also offer unique opportunities and applications for adaptation research.

Concentration-dependent transcriptional switching through a collective action of cis-elements.

Gene expression specificity of homeobox transcription factors has remained paradoxical. WUSCHEL activates and represses CLAVATA3 transcription at lower and higher concentrations, respectively. We use computational modeling and experimental analysis to investigate the properties of the cis-regulatory module. We find that intrinsically each cis-element can only activate CLAVATA3 at a higher WUSCHEL concentration. However, together, they repress CLAVATA3 at higher WUSCHEL and activate only at lower WUSCHEL, showing that the concentration-dependent interactions among cis-elements regulate both activation and repression. Biochemical experiments show that two adjacent functional cis-elements bind WUSCHEL with higher affinity and dimerize at relatively lower levels. Moreover, increasing the distance between cis-elements prolongs WUSCHEL monomer binding window, resulting in higher CLAVATA3 activation. Our work showing a constellation of optimally spaced cis-elements of defined affinities determining activation and repression thresholds in regulating CLAVATA3 transcription provides a previously unknown mechanism of cofactor-independent regulation of transcription factor binding in mediating gene expression specificity.

Combined computational modeling and experimental analysis integrating chemical and mechanical signals suggests possible mechanism of shoot meristem maintenance.

Stem cell maintenance in multilayered shoot apical meristems (SAMs) of plants requires strict regulation of cell growth and division. Exactly how the complex milieu of chemical and mechanical signals interact in the central region of the SAM to regulate cell division plane orientation is not well understood. In this paper, simulations using a newly developed multiscale computational model are combined with experimental studies to suggest and test three hypothesized mechanisms for the regulation of cell division plane orientation and the direction of anisotropic cell expansion in the corpus. Simulations predict that in the Apical corpus, WUSCHEL and cytokinin regulate the direction of anisotropic cell expansion, and cells divide according to tensile stress on the cell wall. In the Basal corpus, model simulations suggest dual roles for WUSCHEL and cytokinin in regulating both the direction of anisotropic cell expansion and cell division plane orientation. Simulation results are followed by a detailed analysis of changes in cell characteristics upon manipulation of WUSCHEL and cytokinin in experiments that support model predictions. Moreover, simulations predict that this layer-specific mechanism maintains both the experimentally observed shape and structure of the SAM as well as the distribution of WUSCHEL in the tissue. This provides an additional link between the roles of WUSCHEL, cytokinin, and mechanical stress in regulating SAM growth and proper stem cell maintenance in the SAM.

Convergent total synthesis of (+)-calcipotriol: A scalable, modular approach to vitamin D analogs.

A convergent approach for the total synthesis of calcipotriol (brand name: Dovonex), a proven vitamin D analog used for the treatment of psoriasis, and medicinally relevant synthetic analogs is described. A complete approach, not wedded to semisynthesis, toward both the A-ring and CD-ring is reported. From a retrosynthetic standpoint, hidden symmetry within the decorated A-ring is disclosed, which allowed for scalable quantities of this advanced intermediate. In addition, a radical retrosynthetic approach is described, which highlights an electrochemical reductive coupling as well as an intramolecular hydrogen atom transfer Giese addition to establish the 6,5-transcarbon skeleton found in the vitamin D family. Finally, a late-stage decarboxylative cross-coupling approach allowed for the facile preparation of various C20-arylated derivatives that show promising biological activity in an initial bioassay.

Ni-electrocatalytic Csp3-Csp3 doubly decarboxylative coupling.

Cross-coupling between two similar or identical functional groups to form a new C-C bond is a powerful tool to rapidly assemble complex molecules from readily available building units, as seen with olefin cross-metathesis or various types of cross-electrophile coupling1,2. The Kolbe electrolysis involves the oxidative electrochemical decarboxylation of alkyl carboxylic acids to their corresponding radical species followed by recombination to generate a new C-C bond3-12. As one of the oldest known Csp3-Csp3 bond-forming reactions, it holds incredible promise for organic synthesis, yet its use has been almost non-existent. From the perspective of synthesis design, this transformation could allow one to agnostically execute syntheses without regard to polarity or neighbouring functionality just by coupling ubiquitous carboxylates13. In practice, this promise is undermined by the strongly oxidative electrolytic protocol used traditionally since the nineteenth century5, thereby severely limiting its scope. Here, we show how a mildly reductive Ni-electrocatalytic system can couple two different carboxylates by means of in situ generated redox-active esters, termed doubly decarboxylative cross-coupling. This operationally simple method can be used to heterocouple primary, secondary and even certain tertiary redox-active esters, thereby opening up a powerful new approach for synthesis. The reaction, which cannot be mimicked using stoichiometric metal reductants or photochemical conditions, tolerates a range of functional groups, is scalable and is used for the synthesis of 32 known compounds, reducing overall step counts by 73%.

Generation of Functionalized Azepinone Derivatives via a (4 + 3)-Cycloaddition of Vinyl Ketenes and α-Imino Carbenes Derived from N-Sulfonyl-triazoles.

An intermolecular RhII-catalyzed, formal (4 + 3)-cycloaddition between vinyl ketenes and N-sulfonyl-1,2,3-triazoles for the construction of azepinone products is described. Employing vinyl ketenes as a 1,4-dipolar surrogate, instead of the more commonly used dienyl moieties, allows for the intermolecular and selective formation of azepinone products over a potential (3 + 2)-cycloadduct under mild reaction conditions allows for the generation of azepinone products in up to 98% yield.

Rational Design and Identification of Harmine-Inspired, N-Heterocyclic DYRK1A Inhibitors Employing a Functional Genomic In Vivo Drosophila Model System.

Deregulation of dual-specificity tyrosine phosphorylation-regulated kinase 1A (DYRK1A) plays a significant role in developmental brain defects, early-onset neurodegeneration, neuronal cell loss, dementia, and several types of cancer. Herein, we report the discovery of three new classes of N-heterocyclic DYRK1A inhibitors based on the potent, yet toxic kinase inhibitors, harmine and harmol. An initial in vitro evaluation of the small molecule library assembled revealed that the core heterocyclic motifs benzofuranones, oxindoles, and pyrrolones, showed statistically significant DYRK1A inhibition. Further, the utilization of a low cost, high-throughput functional genomic in vivo model system to identify small molecule inhibitors that normalize DYRK1A overexpression phenotypes is described. This in vivo assay substantiated the in vitro results, and the resulting correspondence validates generated classes as architectural motifs that serve as potential DYRK1A inhibitors. Further expansion and analysis of these core compound structures will allow discovery of safe, more effective chemical inhibitors of DYRK1A to ameliorate phenotypes caused by DYRK1A overexpression.

Analyzing the Quality of Twitter Data Streams.

There is a general belief that the quality of Twitter data streams is generally low and unpredictable, making, in some way, unreliable to take decisions based on such data. The work presented here addresses this problem from a Data Quality (DQ) perspective, adapting the traditional methods used in relational databases, based on quality dimensions and metrics, to capture the characteristics of Twitter data streams in particular, and of Big Data in a more general sense. Therefore, as a first contribution, this paper re-defines the classic DQ dimensions and metrics for the scenario under study. Second, the paper introduces a software tool that allows capturing Twitter data streams in real time, computing their DQ and displaying the results through a wide variety of graphics. As a third contribution of this paper, using the aforementioned machinery, a thorough analysis of the DQ of Twitter streams is performed, based on four dimensions: Readability, Completeness, Usefulness, and Trustworthiness. These dimensions are studied for several different cases, namely unfiltered data streams, data streams filtered using a collection of keywords, and classifying tweets referring to different topics, studying the DQ for each topic. Further, although it is well known that the number of geolocalized tweets is very low, the paper studies the DQ of tweets with respect to the place from where they are posted. Last but not least, the tool allows changing the weights of each quality dimension considered in the computation of the overall data quality of a tweet. This allows defining weights that fit different analysis contexts and/or different user profiles. Interestingly, this study reveals that the quality of Twitter streams is higher than what would have been expected.

Myelodysplastic Syndromes and Modalities of Treatment: An Updated Literature Review.

Myelodysplastic syndromes (MDS) represent a large group of rare and diverse clonal stem cell disorders. These are classified into several different phenotypes and typically arise following a multistep genetic process, whereby genetic mutations alter the DNA damage and cellular stress responses, impacting transcription, RNA splicing, epigenetics, and cytokine signaling. However, despite the advances made regarding molecular pathophysiology and prognostic criteria and the influx of new treatment modalities, management is primarily based on prognostic scores, such as the Revised International Prognostic Scoring System. This poses a significant challenge to current healthcare professionals due to poor comprehension of the underlying pathophysiology. Hence, this review integrates the latest research and treatment modalities for MDS and discusses the different genetic mutations outlined in the revised World Health Organization 2016 MDS classification system and the associated treatment modalities. Additionally, future directions of research and clinical management of MDS are discussed.

CLAVATA3 mediated simultaneous control of transcriptional and post-translational processes provides robustness to the WUSCHEL gradient.

Regulation of the homeodomain transcription factor WUSCHEL concentration is critical for stem cell homeostasis in Arabidopsis shoot apical meristems. WUSCHEL regulates the transcription of CLAVATA3 through a concentration-dependent activation-repression switch. CLAVATA3, a secreted peptide, activates receptor kinase signaling to repress WUSCHEL transcription. Considering the revised regulation, CLAVATA3 mediated repression of WUSCHEL transcription alone will lead to an unstable system. Here we show that CLAVATA3 signaling regulates nuclear-cytoplasmic partitioning of WUSCHEL to control nuclear levels and its diffusion into adjacent cells. Our work also reveals that WUSCHEL directly interacts with EXPORTINS via EAR-like domain which is also required for destabilizing WUSCHEL in the cytoplasm. We develop a combined experimental and computational modeling approach that integrates CLAVATA3-mediated transcriptional repression of WUSCHEL and post-translational control of nuclear levels with the WUSCHEL concentration-dependent regulation of CLAVATA3. We show that the dual control by the same signal forms a seamless connection between de novo WUSCHEL synthesis and sub-cellular partitioning in providing robustness to the WUSCHEL gradient.

Compact Bandwidth Enhanced Cavity-Backed Magneto-Electric Dipole Antenna with Outer Γ-Shaped Probe for GNSS Bands.

In this paper, a wideband small cavity-backed magneto-electric (ME) antenna is proposed. This antenna is linearly polarized and designed to cover all the Global Navigation Satellite System (GNSS) bands. It exhibits small external dimensions of 90 × 90 × 40 mm3 (0.34 × 0.34 × 0.15 λ3 at lowest frequency) and achieves a wide impedance bandwidth of 40.5% (from 1.14 to 1.72 GHz) due to the excitation of a third resonance of the ME structure. It also provides a regular broadside gain of 5.2 dBi and stable radiation pattern in both E and H planes of the antenna.

Oxyphosphonium Enolate Equilibria in a (4+1)-Cycloaddition Approach toward Quaternary C3-Spirooxindole Assembly.

An efficient and convergent (4+1)-cycloaddition strategy toward the construction of spirooxindole benzofurans that involves the intermediacy of an isatin-derived oxyphosphonium enolate is presented. Mechanistic investigations employing in situ NMR analysis of the reaction mixture revealed a correlation between phosphonium enolate structure and product distribution that was heavily influenced by the solvent and reaction temperature.

Coronary Artery Calcium Score - A Reliable Indicator of Coronary Artery Disease?

Coronary artery disease (CAD) is caused by atheromatous blockage of coronary vessels leading to acute coronary events that usually occur when a plaque ruptures and a thrombus forms. CAD is a known cause of significant cardiovascular events, accounting for more than 50% of the deaths in western countries, and most of the patients with CAD remain asymptomatic. The coronary artery calcium (CAC) score has been created as a measure of coronary atherosclerosis. This article has compiled various studies that conclude the clinical relationship between coronary artery calcium and the development of cardiovascular (CV) events by using the CAC score as a reliable indicator of CAD. This article has reviewed the pathophysiology and risk factors of CAD, along with various methods of CAC scoring. It also underlined the reliability of CAC scoring for early detection of CAD in asymptomatic individuals. We emphasized the importance of age-dependent risk factor analysis combined with practical screening tools like CAC scoring for early diagnosis of CAD can help direct the treatment and prevent deaths in asymptomatic individuals.

Anterior Cruciate Ligament Injury: Conservative Versus Surgical Treatment.

The most frequent type of ligament injury is an anterior cruciate ligament (ACL). The mechanisms of an ACL injury are classified as direct contact, indirect contact, and non-contact. Physical examination for the assessment of the ACL is commonly used in routine care in the evaluation of the knee and is part of the diagnostic process. Due to the high degree of variability in their presentation and outcomes, treatment must be tailored according to factors such as patient demographics, the severity of the damage, and long-term improvement profile. When it comes to ACL injuries, low-quality data have been produced that reveals no difference in patient-reported knee function results between surgical ACL restoration and conservative therapy. However, these results must be evaluated in the perspective of the fact that many individuals with an ACL rupture remained symptomatic after rehabilitation and eventually underwent ACL reconstruction surgery. This article has reviewed the risk factors and the mechanisms that commonly lead to ACL injuries. This article has also discussed the clinical significance of conservative and surgical management and has highlighted the implications of both approaches.

Stroke and Pneumonia: Mechanisms, Risk Factors, Management, and Prevention.

A stroke is a cerebrovascular medical emergency characterized by the sudden loss of neurological function due to interruption to the blood supply. A serious and common complication of stroke is pneumonia. This review article outlined various studies in order to understand the pathogenesis pathways that lead to the development of stroke-associated pneumonia, as well as therapeutic and preventive options to reduce pneumonia. The article looked for risk factors that increase the risk of developing pneumonia among stroke patients. In addition, it has reviewed various therapeutic modalities, such as postural modifications, pharmacological treatment, and other unique treatments, in an attempt to find which of them are efficient to decrease the occurrence of pneumonia and which of them are not. The article also attempts to emphasize the importance of early screening for dysphagia among stroke patients and demonstrates the importance of preventive strategies that can be easily implemented, such as routine oral care and behavioral modifications.

Celiac Disease, Beyond the Bowel: A Review of Its Neurological Manifestations.

Celiac disease (CD) is a multi-systemic autoimmune condition that causes a hyperinflammatory response when gluten is ingested. There has been a shift in the clinical presentation of CD from a mere malabsorption disorder to an autoimmune condition that affects multiple organ systems, which could increase the rate of hospitalizations and a decreased quality of life. This article has compiled various studies that have explored the neurological manifestations of celiac disease, their epidemiology, possible pathogenic mechanisms, diagnosis, and treatment. The most common neurological conditions include gluten ataxia (GA), gluten neuropathy, gluten encephalopathy, and epilepsy which usually present as sporadic diseases which are difficult to diagnose in the absence of gastrointestinal (GI) symptoms. The treatment for most of these conditions is a gluten-free diet (GFD) regardless of GI involvement.