bluuebunny/crossref_metadata_2025 huggingface dataset:
Recent Developments in PROTAC‐Mediated Protein Degradation: From Bench to Clinic
Authors: Hu Zhenyi , Crews Craig M.
Published: September 2021

Proteolysis‐targeting chimeras (PROTACs), an emerging paradigm‐shifting technology, hijacks the ubiquitin‐proteasome system for targeted protein degradation. PROTACs induce ternary complexes between an E3 ligase and POI, and this induced proximity leads to polyUb chain formation on substrates and eventual proteasomal‐mediated POI degradation. PROTACs have shown great therapeutic potential by degrading many disease‐causing proteins, such as the androgen receptor and BRD4. The PROTAC technology has advanced significantly in the last two decades, with the repertoire of PROTAC targets increased tremendously. Herein, we describe recent developments of PROTAC technology, focusing on mechanistic and kinetic studies, pharmacokinetic study, spatiotemporal control of PROTACs, covalent PROTACs, resistance to PROTACs, and new E3 ligands.
What is the Sugar Code?
Authors: Gabius Hans‐Joachim , Cudic Maré , Diercks Tammo , Kaltner Herbert , Kopitz Jürgen , Mayo Kevin H. , Murphy Paul V. , Oscarson Stefan , Roy René , Schedlbauer Andreas , Toegel Stefan , Romero Antonio
Published: September 2021

A code is defined by the nature of the symbols, which are used to generate information‐storing combinations (e. g. oligo‐ and polymers). Like nucleic acids and proteins, oligo‐ and polysaccharides are ubiquitous, and they are a biochemical platform for establishing molecular messages. Of note, the letters of the sugar code system (third alphabet of life) excel in coding capacity by making an unsurpassed versatility for isomer (code word) formation possible by variability in anomery and linkage position of the glycosidic bond, ring size and branching. The enzymatic machinery for glycan biosynthesis (writers) realizes this enormous potential for building a large vocabulary. It includes possibilities for dynamic editing/erasing as known from nucleic acids and proteins. Matching the glycome diversity, a large panel of sugar receptors (lectins) has developed based on more than a dozen folds. Lectins ‘read’ the glycan‐encoded information. Hydrogen/coordination bonding and ionic pairing together with stacking and C−H/π‐interactions as well as modes of spatial glycan presentation underlie the selectivity and specificity of glycan‐lectin recognition. Modular design of lectins together with glycan display and the nature of the cognate glycoconjugate account for the large number of post‐binding events. They give an entry to the glycan vocabulary its functional, often context‐dependent meaning(s), hereby building the dictionary of the sugar code.
Similarities in Lithium Growth at Vastly Different Rates
Authors: Becherer Julian , Kramer Dominik , Mönig Reiner
Published: September 2021

Lithium electrodeposition is important for lithium metal batteries and is presently a safety and reliability concern for the lithium‐ion technology. In the literature, many models for the growth of dendrites can be found and a strong dependence on deposition rate is expected. To elucidate the process of the lithium deposition, operando light microscopy at the physical resolution limit of light was performed at rates varying by more than three orders of magnitude. The results show different growth regimes depending on the rate, and where needles, bushes, or accelerated bushes dominate the deposition. All these deposits are based on small crystalline needles and flakes. Little evidence for concentration gradient driven deposition was found. At the highest rate, the electrolyte ionically depletes, but the deposition continues by non‐directional bush growth mainly from their insides. An important step at all rates is the insertion into defects in the crystalline lithium.
Altering the microbiome for immunotherapy‐resistant urological tumors—An intriguing but still early concept
Authors: Narayan Vikram M.
Published: September 2021

The intestinal microbiome may play an important role in immunomodulation and affect treatment responses to immune checkpoint inhibitor therapy in genitourinary malignancies. Characterizing this impact will require consensus and standardization of microbiome sample collection, sequencing, and data analytics.
Patient and public involvement in the design and conduct of a large, pragmatic observational trial to investigate recurrent, high‐risk non–muscle‐invasive bladder cancer
Authors: Smith Angela B. , Lee Jenney R. , Lawrence Sarah O. , Ho On , Lavallee Danielle C. , Chisolm Stephanie , MacLean Doug B. , Louwers Renata K. , Wolff Erika M. , Kessler Larry G. , Follmer Kristin M. , Gore John L.
Published: September 2021

Background

Patient‐centered approaches to research design are particularly important for diseases with complex treatment decision‐making, such as recurrent, high‐grade non–muscle‐invasive bladder cancer (NMIBC). The objective of this article is to describe patient and public involvement (PPI) in designing a large, pragmatic observational trial and to articulate barriers, challenges, and lessons learned for future design.

Methods

Through multistakeholder involvement, a large, pragmatic observational trial was designed to investigate the outcomes of high‐risk, recurrent NMIBC, and it was titled Comparison of Intravesical Therapy and Surgery as Treatment Options for Bladder Cancer (CISTO). CISTO's design used the Guidance for Reporting Involvement of Patients and the Public 2 reporting checklist for PPI and built on prior engagement infrastructure in partnership with the Bladder Cancer Advocacy Network.

Results

CISTO's PPI began with research prioritization to identify the highest priority questions facing patients with NMIBC. A pragmatic observational study design was selected and refined through stakeholder input. PPI included patients and caregivers organized into an advocate advisory board and clinicians, researchers, payers, and industry representatives organized into an external advisory board. An engagement plan was created to define the stages of PPI and the level and nature of the involvement of each group. PPI was measured quantitatively and qualitatively through evaluation surveys and iterative feedback from board members, with changes made for continuous improvement.

Conclusions

Through intentional PPI, CISTO aims to produce pragmatic and generalizable results that will allow patients to make informed decisions for recurrent, high‐risk NMIBC based on their personal experiences.

Lay Summary

Involving patients and other stakeholders in research ensures that it reflects the outcomes that matter most to them. This is especially important when research focuses on conditions in which patients face difficult decisions about treatment options.

This article describes the key role that stakeholders played in shaping the Comparison of Intravesical Therapy and Surgery as Treatment Options for Bladder Cancer (CISTO) study. It compares treatments for recurrent noninvasive bladder cancer and describes how stakeholders were engaged to design and develop the study and the practices that supported their involvement.
Associations between neighborhood disinvestment and breast cancer outcomes within a populous state registry
Authors: Plascak Jesse J. , Rundle Andrew G. , Xu Xinyi , Mooney Stephen J. , Schootman Mario , Lu Bo , Roy Jason , Stroup Antoinette M. , Llanos Adana A. M.
Published: September 2021

Background

Breast cancer (BrCa) outcomes vary by social environmental factors, but the role of built‐environment factors is understudied. The authors investigated associations between environmental physical disorder—indicators of residential disrepair and disinvestment—and BrCa tumor prognostic factors (stage at diagnosis, tumor grade, triple‐negative [negative for estrogen receptor, progesterone receptor, and HER2 receptor] BrCa) and survival within a large state cancer registry linkage.

Methods

Data on sociodemographic, tumor, and vital status were derived from adult women who had invasive BrCa diagnosed from 2008 to 2017 ascertained from the New Jersey State Cancer Registry. Physical disorder was assessed through virtual neighborhood audits of 23,276 locations across New Jersey, and a personalized measure for the residential address of each woman with BrCa was estimated using universal kriging. Continuous covariates were z scored (mean ± standard deviation [SD], 0 ± 1) to reduce collinearity. Logistic regression models of tumor factors and accelerated failure time models of survival time to BrCa‐specific death were built to investigate associations with physical disorder adjusted for covariates (with follow‐up through 2019).

Results

There were 3637 BrCa‐specific deaths among 40,963 women with a median follow‐up of 5.3 years. In adjusted models, a 1‐SD increase in physical disorder was associated with higher odds of late‐stage BrCa (odds ratio, 1.09; 95% confidence interval, 1.02‐1.15). Physical disorder was not associated with tumor grade or triple‐negative tumors. A 1‐SD increase in physical disorder was associated with a 10.5% shorter survival time (95% confidence interval, 6.1%‐14.6%) only among women who had early stage BrCa.

Conclusions

Physical disorder is associated with worse tumor prognostic factors and survival among women who have BrCa diagnosed at an early stage.
Expanding Approved Patient Populations for Rare Disease Treatment Using In Vitro Data
Authors: Weaver James L. , Wu Wendy , Hyland Paula L. , Lim Robert , Smpokou Patroula , Pacanowski Michael
Published: September 2021

In vitro cell‐based data can be used to support the extension of pharmaceutical approval to patient subsets with unique genetic variants. A set of conditions should be satisfied to support the extension of approval. The disease mechanism should be well described, and the impact of variants on protein function should be reasonably understood. The incidence data should show that clinical trials for the variants in question are not practical. The overall safety and efficacy of the drug should be clear in adequate and well‐controlled clinical trials. The clinical trial should include patients found to be responders and nonresponders so that both positive and negative predictive power of the in vitro assay may be measured. The mechanism of action of the drug should be clearly defined and should be consistent with the disease mechanism. The assay system should be qualified, including the following points: (i) each variant construct should be confirmed by bidirectional sequencing; (ii) the in vitro assay should directly measure the variant protein function in comparison with the reference protein; (iii) the assay should be formally validated to the extent possible, clearly demonstrating precision, reproducibility, and sensitivity used to support the efficacy claim; and (iv) the primary data should be available for inspection and analytical validation. The overall goal is a robust and validated cell‐based system that can be shown to predict the outcome of targeted therapy.
Risk of Heart Failure in Rheumatoid Arthritis Patients Treated with Tumor Necrosis Factor‐α Inhibitors
Authors: Chen Hung‐Kai , Shao Shih‐Chieh , Weng Meng‐Yu , Lin Swu‐Jane , Hung Ming‐Jui , Chan Yuk‐Ying , Lai Edward Chia‐Cheng
Published: September 2021

This is a retrospective cohort study by analyzing a multi‐institutional electronic medical records database covering 1.3 million individuals (6% of Taiwan’s population) to compare the risk of heart failure (HF) in patients with rheumatoid arthritis (RA) treated with tumor necrosis factor‐α (TNF‐α) inhibitors or conventional synthetic disease‐modifying anti‐rheumatic drugs (csDMARDs). We included patients with RA aged 20 years and older who had treatment failure with at least 2 different csDMARD regimens and newly switched to another csDMARD regimen or TNFis from 2009 to 2019. We followed patients from initiation of the new therapies to the occurrence of hospitalization for heart failure (hHF), death, to the last clinical visit or December 31, 2020. We performed multivariable Cox proportional hazard models to compare TNF‐α inhibitors and csDMARD groups for the risk of hHF, with adjustment for patients’ characteristics. A total of 1,278 TNF‐α inhibitors and 1,932 csDMARDs treated patients were identified, with 78% being women and having an average age of 55 (SD 13.28) years. The incidence rates of hHF for the TNF‐α inhibitors and csDMARD groups were 3.66 and 4.72 per 1,000 person‐years, respectively (adjusted hazard ratio (aHR) 0.59; 95% confidence interval (CI) 0.35–0.97), and the results remained consistent in patients both with an HF history (aHR 0.66; 95% CI 0.03–14.46) and without (aHR 0.49; 95% CI, 0.27–0.89). The findings suggest that those who switched to TNF‐α inhibitors had a reduced risk of hHF, compared with those who switched to another csDMARD regimen.
Development of Keratinocyte Cell Lines Containing Extrachromosomal Human Papillomavirus Genomes
Authors: Coursey Tami L. , McBride Alison A.
Published: September 2021

Human papillomaviruses (HPVs) cause persistent infections in stratified cutaneous and mucosal epithelia. In these infections, the viral DNA replicates as low‐copy‐number, extrachromosomal, double‐stranded‐DNA circular plasmids in the nucleus of the dividing basal cells. When the infected cells begin the process of differentiation, the viral DNA amplifies to a high copy number and virions are assembled in the superficial cells. To study HPV DNA replication, our laboratory generates primary keratinocyte cell lines that contain replicating extrachromosomal HPV genomes. Here, we describe protocols to culture human keratinocytes, to transfect viral DNA into cells using electroporation, to determine the efficiency of genome establishment in cells with a colony‐forming assay, and to measure the copy number and extrachromosomal status of viral genomes using Southern blotting. These methods can be used to study DNA replication of different oncogenic Alphapapillomavirus HPV types. Published 2021. This article is a U.S. Government work and is in the public domain in the USA.

Basic Protocol 1: Electroporation to transfect keratinocytes with recircularized HPV genomes

Alternate Protocol: Use of HPV replicon containing selection marker in keratinocyte transfection

Support Protocol 1: Rheinwald‐Green method of co‐culture of irradiated J2 3T3 feeders and human keratinocytes

Support Protocol 2: Recircularization of HPV genomes

Basic Protocol 2: Quantitative colony formation assay to measure the efficiency of HPV genome establishment

Basic Protocol 3: Southern blot analysis of extrachromosomal viral DNA

Support Protocol 3: Hirt extraction of low‐molecular‐weight DNA

Support Protocol 4: Qiagen DNeasy Blood & Tissue DNA extraction

Support Protocol 5: Generation of a 32P‐labeled HPV DNA probe
Parameter extraction of single‐diode photovoltaic module using experimental current–voltage data
Authors: Sreekantha Reddy S. , Yammani Chandrasekhar
Published: September 2021

Accurate modeling of photovoltaic (PV) module allows proper load scheduling and avoids the uncertainties in grid. This paper uses forward‐backward linear least square error (FB‐LLSE) curve fitting method to estimate the parameters of PV module. The proposed method does not require any data sheet information and initial values of parameters. The proposed method utilizes the experimental data on I–V curve to extract the parameters of PV module. To validate the proposed method, three different PV modules, namely, Mono‐crystalline STM6‐40/36, Poly‐crystalline SMP6‐120/36, PWP‐201, and one Real Time Clock (R.T.C.) France solar cell has been considered. The obtained results are compared with three existing methods in the literature. The performance of the proposed FB‐LLSE method is studied with root mean square error (RMSE), mean absolute error (MAE), normalized root mean square error (NRMSE), and normalized mean absolute error (NMAE). The calculated with proposed FB‐LLSEM is reduced by 10%, 7%, 2.26%, and 1.89%, respectively, for PWP‐201, STMP‐120/36, SMP6‐40/36, and R.T.C France solar cell when compared to the LLSEM method available in the literature. The proposed FB‐LLSE method is found to exhibit low value of RMSE for all three PV modules and one PV cell.
Emergence of the less common cannabinoid Δ8‐Tetrahydrocannabinol in a doping sample
Authors: Rzeppa Sebastian , Große Joachim , Rautenberg Claudia , Thieme Detlef , Lepp Triin , Vallimäe Henn , Keiler Annekathrin M.
Published: September 2021

Δ8‐Tetrahydrocannabinol (Δ8‐THC) as isomer of the well‐known Δ9‐THC has a similar mode of action, and the potency was estimated to be two thirds compared with Δ9‐THC. Content of Δ8‐THC in plant material is low, but formulations containing Δ8‐THC in high concentrations are gaining popularity. Δ8‐THC is to be regarded as prohibited substance according to the Prohibited List of the World Anti‐Doping Agency (WADA). Contradictory results between initial testing procedure and confirmatory quantitation for 11‐Nor‐9‐carboxy‐Δ9‐tetrahydrocannabinol (Δ9‐THC‐COOH) of a doping control sample gave rise for follow‐up testing procedures. After alkaline hydrolysis and liquid–liquid extraction, the sample was analyzed by high‐performance liquid chromatography tandem mass spectrometry (HPLC‐MS/MS) using isocratic elution instead of gradient elution, which is used for standard procedure. Isocratic elution resulted in two peaks instead of one using gradient elution. Both peaks showed same fragmentation. Using certified reference materials, one peak could be assigned to Δ9‐THC‐COOH and the other one with higher intensity to the less common 11‐Nor‐9‐carboxy‐Δ8‐Tetrahydrocannabinol (Δ8‐THC‐COOH) in a concentration of approximately 1200 ng/ml. As complementary method, gas chromatography tandem mass spectrometry (GC‐MS/MS) can also be used for identification. Here Δ8‐ and Δ9‐THC‐COOH can be distinguished by chromatography and by fragmentation. Additional investigations of doping control samples containing Δ9‐THC‐COOH revealed the simultaneous presence of Δ8‐THC‐COOH in low concentrations (0.22–8.91 ng/ml) presumably due to plant origin. Percentage of Δ8‐THC‐COOH varies from 0.05 to 2.83%. In vitro experiments using human liver microsomes showed that Δ8‐THC is metabolized in the same way as Δ9‐THC.
Creating a Research Ethics Consultation Service: Issues to Consider
Authors: Taylor Holly A. , Porter Kathryn M. , Paquette Erin Talati , McCormick Jennifer B. , Tumilty Emma , Arnold Jason F. , Spector‐Bagdady Kayte , Danis Marion , Brandt Debra , Shah Jina , Wilfond Benjamin S. , Lee Lisa M.
Published: September 2021

This article provides pragmatic advice for organizations interested in creating a research ethics consultation service (RECS). A robust RECS has the potential to build capacity among investigators to identify and consider the ethical issues they encounter while conducting their research. Determining whether to establish an RECS should begin with an institutional‐needs assessment that includes three key questions: What are the current resources available to research teams to navigate ethical concerns that arise from their research? Is there a demand or perceived need for more resources? Is there institutional support (financial and otherwise) to establish and maintain an RECS? If this results in the decision to establish the consultation service, relevant institutional stakeholders must be identified and consulted, and personnel with the requisite skills recruited. The next step is to establish an RECS and build the infrastructure to process and respond to requests. The RECS's long‐term sustainability will depend on a stable source of funding and a mechanism to receive constructive feedback to ensure that the service is meeting the institutional needs it set out to address.
A Call for Better, Not Faster, Research Ethics Committee Reviews in the Covid‐19 Era
Authors: Tamariz Leonardo , Hendler Fred J. , Wells John M. , Anderson Annette , Bartlett Stephen
Published: September 2021

With the rapid spread of SARS‐CoV2 has come a rapid proliferation of clinical research studies, resulting in considerable strain on research ethics committees (RECS), which need to review study proposals. RECs are pressured to move through the review process quickly so that studies can get underway to address the pandemic. These committees are also asked to increase efficiency without relaxing the standards for ethical review. RECs are accustomed to external pressure for approval from investigators; however, in the Covid‐19 era, this pressure is coming from not only the sponsors and investigators but also many other stakeholders, including world leaders, the community, the media, and professional organizations. Drawing on the authors' experiences on a central REC reviewing complex multicenter Covid‐19 studies, this commentary describes challenges that are inherent to Covid‐19 research studies, such as the difficulty of obtaining informed consent from patients ill with the highly infectious virus. The commentary recommends several steps that RECs can take to ensure ethical review of research studies during the Covid‐19 pandemic and future infectious disease outbreaks.
The dark side of pseudoscorpion diversity: The German Barcode of Life campaign reveals high levels of undocumented diversity in European false scorpions
Authors: Muster Christoph , Spelda Jörg , Rulik Björn , Thormann Jana , von der Mark Laura , Astrin Jonas J.
Published: September 2021

DNA barcoding is particularly useful for identification and species delimitation in taxa with conserved morphology. Pseudoscorpions are arachnids with high prevalence of morphological crypsis. Here, we present the first comprehensive DNA barcode library for Central European Pseudoscorpiones, covering 70% of the German pseudoscorpion fauna (35 out of 50 species). For 21 species, we provide the first publicly available COI barcodes, including the rare Anthrenochernes stellae Lohmander, a species protected by the FFH Habitats Directive. The pattern of intraspecific COI variation and interspecific COI variation (i.e., presence of a barcode gap) generally allows application of the DNA barcoding approach, but revision of current taxonomic designations is indicated in several taxa. Sequences of 36 morphospecies were assigned to 74 BINs (barcode index numbers). This unusually high number of intraspecific BINs can be explained by the presence of overlooked cryptic species and by the accelerated substitution rate in the mitochondrial genome of pseudoscorpions, as known from previous studies. Therefore, BINs may not be an appropriate proxy for species numbers in pseudoscorpions, while partitions built with the ASAP algorithm (Assemble Species by Automatic Partitioning) correspond well with putative species. ASAP delineated 51 taxonomic units from our data, an increase of 42% compared with the present taxonomy. The Neobisium carcionoides complex, currently considered a polymorphic species, represents an outstanding example of cryptic diversity: 154 sequences from our dataset were allocated to 23 BINs and 12 ASAP units.
Quadrat‐based monitoring of desert grassland vegetation at the Jornada Experimental Range, New Mexico, 1915–2016
Authors: Christensen Erica , James Darren , Maxwell Connie J. , Slaughter Amalia , Adler Peter B. , Havstad Kris , Bestelmeyer Brandon
Published: September 2021

The data set covers a 101‐yr period (1915–2016) of quadrat‐based plant sampling at the Jornada Experimental Range in southern New Mexico. At each sampling event, a pantograph was used to record the location and perimeter of living plants within permanent quadrats. Basal area was recorded for perennial grass species, canopy cover area was recorded for shrub species, and all other perennial species were recorded as point data. The data set includes 122 1 × 1 m permanent quadrats, although not all quadrats were sampled in each year of the study and there is a gap in monitoring from 1980 to 1995. These data provide a unique opportunity to investigate changes in the plant community over 100 yr of variation in precipitation and other environmental conditions. We provide the following data and data formats: (1) the digitized maps in shapefile format; (2) a data table containing coordinates (x, y) of perennial species within quadrats, including cover area for grasses and shrubs; (3) a data table of counts of annual plant individuals per quadrat; (4) a species list indicating growth form and habit of recorded species; (5) a table of dates when each quadrat was sampled; (6) a table of the pasture each quadrat was located within (note that pasture boundaries have changed over time); (7) a table of depth to petrocalcic layer measurements taken at quadrat locations; (8) a table of particle size analysis of soil samples taken at quadrat locations; (9) a table of topographic characteristics of quadrat locations (e.g., concave or convex topography). Pantograph sampling is currently conducted at 5‐yr intervals by USDA‐ARS staff, and new data will be added periodically to the EDI Data Portal Repository (see section V.E.2). This information is released under the Creative Commons license—Attribution—CC BY and the consumer of these data is required to cite it appropriately in any publication that results from its use.
Characteristics and outcome of ambulatory heart failure patients receiving a left ventricular assist device
Authors: Baudry Guillaume , Nesseler Nicolas , Flecher Erwan , Vincentelli André , Goeminne Céline , Delmas Clément , Porterie Jean , Nubret Karine , Pernot Mathieu , Kindo Michel , Hoang Minh Tam , Rouvière Philippe , Gaudard Philippe , Michel Magali , Senage Thomas , Boignard Aude , Chavanon Olivier , Para Marylou , Verdonk Constance , Pelcé Edeline , Gariboldi Vlad , Anselme Frederic , Litzler Pierre‐Yves , Blanchart Katrien , Babatasi Gerard , Bielefeld Marie , Bouchot Olivier , Hamon David , Lellouche Nicolas , Bailleul Xavier , Genet Thibaud , Eschalier Romain , d'Ostrevy Nicolas , Bories Marie‐Cécile , Akar Ramzi Abi , Blangy Hugues , Vanhuyse Fabrice , Obadia Jean François , Galand Vincent , Pozzi Matteo
Published: September 2021

Aims

Despite regularly updated guidelines, there is still a delay in referral of advanced heart failure patients to mechanical circulatory support and transplant centres. We aimed to analyse characteristics and outcome of non‐inotrope‐dependent patients implanted with a left ventricular assist device (LVAD).

Methods and results

The ASSIST‐ICD registry collected LVAD data in 19 centres in France between February 2006 and December 2016. We used data of patients in Interagency Registry for Mechanically Assisted Circulatory Support Classes 4–7. The primary endpoint was survival analysis. Predictors of mortality were searched with multivariable analyses. A total of 303 patients (mean age 61.0 ± 9.9 years, male sex 86.8%) were included in the present analysis. Ischaemic cardiomyopathy was the leading heart failure aetiology (64%), and bridge to transplantation was the main implantation strategy (56.1%). The overall likelihood of being alive while on LVAD support or having a transplant at 1, 2, 3, and 5 years was 66%, 61.7%, 58.7%, and 55.1%, respectively. Age [hazard ratio (HR) 1.03, 95% confidence interval (CI) 1.00–1.05; P = 0.02], a concomitant procedure (HR 2.32, 95% CI 1.52–3.53; P < 0.0001), and temporary mechanical right ventricular support during LVAD implantation (HR 2.94, 95% CI 1.49–5.77; P = 0.002) were the only independent variables associated with mortality. Heart failure medications before or after LVAD implantation were not associated with survival.

Conclusion

Ambulatory heart failure patients displayed unsatisfactory survival rates after LVAD implantation. A better selection of patients who can benefit from LVAD may help improving outcomes.
Emerging Building Blocks for Medicinal Chemistry: Recent Synthetic Advances
Authors: Grygorenko Oleksandr O. , Volochnyuk Dmitriy M. , Vashchenko Bohdan V.
Published: September 2021

Current medicinal chemistry relies heavily on the quality of building blocks, i. e. reagents used to introduce chemical diversity into the target molecules. The last decade witnessed an emergence of many novel (or well‐overlooked old) chemotypes for drug discovery, which is related to adapting new synthetic methodologies, designing new sp3‐enriched bioisosteres, paying attention to previously underrated (or even unwanted) structural motifs, or combination thereof. In this review with 532 references, a survey of selected chemotypes that emerged recently in medicinal chemistry is provided, with a focus on the synthesis of the corresponding building blocks. Thus, saturated (hetero)aliphatic boronates, sulfonyl fluorides, sulfinates, non‐classical sp3‐enriched benzene isosteres, bicyclic morpholine/piperidine/piperazine analogs, as well as gem‐difluorinated cycloalkanes (as an example of emerging fluorinated motifs) are discussed.
Solar Powered Small Unmanned Aerial Vehicles: A Review
Authors: El-Atab Nazek , Mishra Rishabh B. , Alshanbari Reem , Hussain Muhammad M.
Published: September 2021

In recent years, there has been an increasing demand for unmanned aerial vehicles (UAVs) with various capabilities suitable for both military and civilian applications. There is also a substantial interest in the development of novel drones that can fly autonomously in different environments and locations and perform various missions. Nevertheless, current battery‐powered UAVs are limited by their flight range. Consequently, several approaches are being developed to enhance the flight endurance of drones, including augmenting the drone with solar power. In this review, the different classifications of drones that have been developed based on their weight and flight range are identified. Then, the design challenges of the electrical systems embedded in the flying drones are explained. Next, approaches used to increase the flight endurance using various types of solar cells with respect to their materials and mechanical flexibility, in addition to various navigation and control approaches, are discussed in detail. Finally, limitations of existing solar‐powered UAVs are presented in addition to proposed solutions and recommendations for the next generation of drones.
Research methodologies to address clinical unmet needs and challenges in alcohol‐associated liver disease
Authors: Singal Ashwani K. , Kwo Paul , Kwong Allison , Liangpunsakul Suthat , Louvet Alexandre , Mandrekar Pranoti , McClain Craig , Mellinger Jessica , Szabo Gyongyi , Terrault Norah , Thursz Mark , Winder Gerald S. , Kim W. Ray , Shah Vijay H.
Published: September 2021

Alcohol‐associated liver disease (ALD) is emerging worldwide as the leading cause of liver‐related morbidity, mortality, and indication for liver transplantation. The ALD Special Interest Group and the Clinical Research Committee at the digital American Association for the Study of Liver Diseases meeting in November 2020 held the scientific sessions to identify clinical unmet needs in ALD, and addressing these needs using clinical research methodologies. Of several research methodologies, the sessions were focused on (a) studying disease burden of ALD using large administrative databases, (b) developing biomarkers for noninvasive diagnosis of alcohol‐associated hepatitis (AH) and estimation of disease prognosis, (c) identifying therapeutic targets for ALD and AH, (d) deriving accurate models to predict prognosis or posttransplant alcohol relapse as a basis for developing treatment algorithm and a uniform protocol on patient‐selection criteria for liver transplantation, and (e) examining qualitative research methodologies in studying the barriers to implementation of multidisciplinary integrated care model by hepatology and addiction teams for the management of dual pathology of liver disease and of alcohol use disorder. Prospective multicenter studies are required to address many of these clinical unmet needs. Further, multidisciplinary care models are needed to improve long‐term outcomes in patients with ALD.
Magnetic resonance elastography plus Fibrosis‐4 versus FibroScan–aspartate aminotransferase in detection of candidates for pharmacological treatment of NASH‐related fibrosis
Authors: Tamaki Nobuharu , Imajo Kento , Sharpton Suzanne , Jung Jinho , Kawamura Nobuyoshi , Yoneda Masato , Valasek Mark A. , Behling Cynthia , Sirlin Claude B. , Nakajima Atsushi , Loomba Rohit
Published: September 2021

Background and Aims

Patients with NAFLD with significant hepatic fibrosis (Stage ≥ 2) are at increased risk of liver‐related morbidity and are candidates for pharmacologic therapies. In this study, we compared the diagnostic accuracy of MEFIB (the combination of magnetic resonance elastography [MRE] and Fibrosis‐4 [FIB‐4]) and FAST (FibroScan–aspartate aminotransferase; combined liver stiffness measurement by vibration‐controlled transient elastography, controlled attenuation parameter, and aspartate aminotransferase) for detecting significant fibrosis.

Approach and Results

This prospective cohort study included 234 consecutive patients with NAFLD who underwent liver biopsy, MRE, and FibroScan at the University of California San Diego (UCSD cohort) and an independent cohort (N = 314) from Yokohama City University, Japan. The primary outcome was diagnostic accuracy for significant fibrosis (Stage ≥ 2). The proportions of significant fibrosis in the UCSD and Yokohama cohorts were 29.5% and 66.2%, respectively. Area under the receiver operating characteristic curve (95% CI) of MEFIB (0.860 [0.81–0.91]) was significantly higher than that of FAST (0.757 [0.69–0.82]) in the UCSD cohort (p = 0.005), with consistent results in the Yokohama cohort (AUROC, 0.899 [MEFIB] versus 0.724 [FAST]; p < 0.001). When used as the rule‐in criteria (MEFIB, MRE ≥ 3.3 kPa and FIB‐4 ≥ 1.6; FAST ≥ 0.67), the positive predictive value for significant fibrosis was 91.2%–96.0% for MEFIB and 74.2%–89.2% for FAST. When used as the rule‐out criteria (MEFIB, MRE < 3.3 kPa and FIB‐4 < 1.6; FAST ≤ 0.35), the negative predictive value for significant fibrosis was 85.6%–92.8% for MEFIB and 57.8%–88.3% for FAST.

Conclusions

MEFIB has higher diagnostic accuracy than FAST for significant fibrosis in NAFLD, and our results support the utility of a two‐step strategy for detecting significant fibrosis in NAFLD.
Feasibility of an online, mental health‐informed lifestyle program for people aged 60+ years during the COVID‐19 pandemic
Authors: McKeon Grace , Tiedemann Anne , Sherrington Catherine , Teasdale Scott , Mastrogiovanni Chiara , Wells Ruth , Steel Zachary , Rosenbaum Simon
Published: September 2021

Issue addressed

The COVID‐19 pandemic and associated social distancing regulations have disproportionally impacted the health of older adults. Lifestyle interventions targeting physical activity, diet and fostering social connection may help to alleviate the potential negative health consequences. This study aimed to determine the feasibility and preliminary effectiveness of delivering an online group lifestyle intervention for older adults during the COVID‐19 pandemic.

Methods

Adults aged 60+, living in Australia were recruited to a single‐arm feasibility study of a 6‐week program delivered via a private Facebook group between June‐August 2020. Facilitators provided motivation and education on weekly topics including goal setting and reducing sedentary behaviour in the form of Facebook posts and group video calls. Primary outcomes included feasibility and acceptability and secondary outcomes included psychological distress, quality of life (AQoL‐6D), functioning, loneliness and physical activity (PA) with assessments conducted at baseline, post‐intervention and 4‐week follow‐up.

Results

N = 11 participants were recruited and n = 10 (91%) completed the post‐assessment questionnaires. High acceptability was observed and exploratory analysis from pre‐post intervention found evidence of an effect on secondary outcomes.

Conclusions

A mental health informed lifestyle program delivered online via Facebook appears feasible and well‐accepted among older adults and may help to prevent some of the consequences of inactivity and social isolation associated with the pandemic.

So what?

Online lifestyle interventions appear safe and may provide a scalable, cost‐effective strategy for protecting the physical and mental health of older adults during the COVID‐19 pandemic.
Changes in efficiency of tertiary public general hospitals during the reform of public hospitals in Beijing, China
Authors: Zhu Junli , Song Xinrui
Published: September 2021

Background

In March 2009, the Chinese government formally launched a new round of healthcare reform. As the city with the highest concentration of high‐quality medical resources in China, in the past 10 years, Beijing has also been exploring medical reforms. This article studied the performance and development of the 10 tertiary general public hospitals managed by Beijing Municipal Hospital Management Centre to provide policy basis for further deepening Beijing public hospital reform and improving hospital efficiency.

Methods

The 2011, 2015 and 2018 ‘Beijing Health Work Statistics’ were used to evaluate the performance of Beijing's tertiary public general hospitals, based on the Pabon Lasso model and the data envelopment analysis (DEA) model.

Results

Based on the Pabon Lasso model, 60%, 70% and 70% of the hospitals were entirely efficient (zone 3) in 2011, 2015 and 2018. It shows that among the 10 general public hospitals in Beijing, efficient hospitals accounted for the majority and further increased during the reform period. The DEA model further illustrates this point and shows more effective hospitals (80%) than the Pabon Lasso model, showing the efficiency of these hospitals to be improved during the reform period.

Conclusions

The efficiency of the 10 hospitals has gradually improved during the reform period, and the difficulty of seeing a doctor in Beijing at a national medical centre has been relieved to a certain extent. Combining the Pabon Lasso model and the DEA model can analyse hospital efficiency more comprehensively, and can prompt initial information for improving hospital efficiency, but the results also reflect some problems.
Osteoblast‐derived extracellular matrix coated PLLA/silk fibroin composite nanofibers promote osteogenic differentiation of bone mesenchymal stem cells
Authors: Wu Yunliang , Zhou Lei , Li Yuexia , Lou Xiangxin
Published: September 2021

Poly‐L‐lactic acid (PLLA) is one of the most commonly used synthetic materials for regenerative medicine, and silk fibroin (SF) is a natural protein with excellent biocompatibility. Combination of PLLA and SF in a proper proportion by electrospinning may generate composite nanofibers that could meet the requirements of scaffolding in bone tissue engineering. The application of PLLA/SF nanofibrous scaffold for osteogenesis is well established in vitro and in vivo. However, PLLA/SF nanofibrous scaffold does not have an ideal ability to promote cell adhesion, proliferation, and differentiation. Extracellular matrix (ECM) plays a critical role in modulating cellular behavior. However, the role of combination of natural ECM with nanofibrous scaffold in regulating osteogenic differentiation is unclear. In this study, we aimed to develop a novel composite PLLA/SF nanofibrous scaffold coated with osteoblast‐derived extracellular matrix (O‐ECM/PLLA/SF) and analyze the effects of the modified scaffold on osteogenic differentiation of BMSCs. The surface structural features and compositions of the O‐ECM/PLLA/SF scaffold were characterized by SEM and immunofluorescence staining. The capacities of the O‐ECM/PLLA/SF scaffold to induce osteogenic differentiation of BMSCs were investigated by alkaline phosphatase (ALP) and alizarin red staining (ARS). The results showed BMSCs cultured on O‐ECM/PLLA/SF scaffold significantly increased osteogenic differentiation compared with cells cultured individually on a scaffold or O‐ECM. Collectively, these findings indicate that O‐ECM‐coated nanofibrous scaffold can be a promising strategy for osteogenic differentiation of BMSCs, opening a new possibility of utilizing composite scaffolds for bone tissue engineering.
A necessary condition for generic rigidity of bar‐and‐joint frameworks in d‐space
Authors: Guler Hakan , Jackson Bill
Published: September 2021

A graph is ‐sparse if each subset with induces at most edges in . Maxwell showed in 1864 that a necessary condition for a generic bar‐and‐joint framework with at least vertices to be rigid in is that should have a ‐sparse subgraph with edges. This necessary condition is also sufficient when but not when . Cheng and Sitharam strengthened Maxwell's condition by showing thateverymaximal ‐sparse subgraph of should have edges when . We extend their result to all .
Human and animal fertility studies in cystinosis reveal signs of obstructive azoospermia, an altered blood‐testis barrier and a subtherapeutic effect of cysteamine in testis
Authors: Reda Ahmed , Veys Koenraad , Kadam Prashant , Taranta Anna , Rega Laura Rita , Goffredo Bianca M. , Camps Chelsea , Besouw Martine , Cyr Daniel , Albersen Maarten , Spiessens Carl , de Wever Liesbeth , Hamer Robert , Janssen Mirian C.H. , D'Hauwers Kathleen , Wetzels Alex , Monnens Leo , van den Heuvel Lambertus , Goossens Ellen , Levtchenko Elena
Published: September 2021

Cystinosis is an inherited metabolic disorder caused by autosomal recessive mutations in the CTNS gene leading to lysosomal cystine accumulation. The disease primarily affects the kidneys followed by extra‐renal organ involvement later in life. Azoospermia is one of the unclarified complications which are not improved by cysteamine, which is the only available disease‐modifying treatment. We aimed at unraveling the origin of azoospermia in cysteamine‐treated cystinosis by confirming or excluding an obstructive factor, and investigating the effect of cysteamine on fertility in the Ctns−/− mouse model compared with wild type. Azoospermia was present in the vast majority of infantile type cystinosis patients. While spermatogenesis was intact, an enlarged caput epididymis and reduced levels of seminal markers for obstruction neutral α‐glucosidase (NAG) and extracellular matrix protein 1 (ECM1) pointed towards an epididymal obstruction. Histopathological examination in human and mouse testis revealed a disturbed blood‐testis barrier characterized by an altered zonula occludens‐1 (ZO‐1) protein expression. Animal studies ruled out a negative effect of cysteamine on fertility, but showed that cystine accumulation in the testis is irresponsive to regular cysteamine treatment. We conclude that the azoospermia in infantile cystinosis is due to an obstruction related to epididymal dysfunction, irrespective of the severity of an evolving primary hypogonadism. Regular cysteamine treatment does not affect fertility but has subtherapeutic effects on cystine accumulation in testis.
Supply‐controlled calcium carbonate dissolution decouples the seasonal dissolved oxygen andpHminima in Chesapeake Bay
Authors: Su Jianzhong , Cai Wei‐Jun , Testa Jeremy M. , Brodeur Jean R. , Chen Baoshan , Scaboo K. Michael , Li Ming , Shen Chunqi , Dolan Margaret , Xu Yuan‐Yuan , Zhang Yafeng , Hussain Najid
Published: September 2021

Acidification can present a stress on organisms and habitats in estuaries in addition to hypoxia. Although oxygen and pH decreases are generally coupled due to aerobic respiration, pH dynamics may be more complex given the multiple modes of buffering in the carbonate system. We studied the seasonal cycle of dissolved oxygen (DO), pH, dissolved inorganic carbon, total alkalinity, and calcium ion (Ca2+) along the main channel of Chesapeake Bay from May to October in 2016. Contrary to the expected co‐occurrence of seasonal DO and pH declines in subsurface water, we found that the pH decline ended in June while the DO decline continued until August in mid‐Chesapeake Bay. We discovered that aerobic respiration was strong from May to August, but carbonate dissolution was minor in May and June and became substantial in August, which buffered further pH declines and caused the seasonal DO and pH minima mismatch. The rate of calcium carbonate (CaCO3) dissolution was not primarily controlled by the saturation state in bottom water, but was instead likely controlled by the supply of CaCO3particles. The seasonal variability of Ca2+addition in the mid‐bay was connected to Ca2+removal in the upper bay, and the timing of high carbonate dissolution coincided with peak seasonal biomass of upper Bay submerged aquatic vegetation. This study suggests a mechanism for a novel decoupling of DO and pH in estuarine waters associated with CaCO3, but future studies are needed to fully investigate the seasonality of physical transport and cycling of CaCO3.
Fabrication of Robust, Shape Recoverable, Macroporous Bacterial Cellulose Scaffolds for Cartilage Tissue Engineering
Authors: Xun Xiaowei , Li Yaqiang , Zhu Xiangbo , Zhang Quanchao , Lu Ying , Yang Zhiwei , Wan Yizao , Yao Fanglian , Deng Xiaoyan , Luo Honglin
Published: September 2021

Recently, the fabricating of three‐dimensional (3D) macroporous bacterial cellulose (MP‐BC) scaffolds with mechanically disintegrated BC fragments has attracted considerable attention. However, the successful implementation of these materials depends mainly on their mechanical stability and robustness. Here, a non‐toxic crosslinker, 1‐ethyl‐3‐(‐3‐dimethylaminopropyl) carbodiimide hydrochloride/N‐hydroxysuccinimide (EDC/NHS), is employed to induce crosslinking reactions between BC fragments. In addition to their large pore sizes, the EDC/NHS‐crosslinked MP‐BC scaffolds exhibit excellent compression properties and shape recovery ability, owing to the EDC/NHS‐induced crosslinking on the BC nanofibers. The results of in vitro studies reveal that the biocompatibility of MP‐BC scaffolds is better than that of pristine BC scaffolds because the former provided more space for cell proliferation. The results of in vivo studies show that the neocartilage tissue with native cartilage appearance and abundant cartilage‐specific extracellular matrix deposition is successfully regenerated in nude mice. The findings reveal the immense application potential of mechanically robust BC scaffolds with controllable pore sizes and shape‐recoverable properties in tissue engineering.
Factors associated with refeeding hypophosphatemia in adolescents and young adults hospitalized with anorexia nervosa
Authors: Kells Meredith , Gregas Matt , Wolfe Barbara E. , Garber Andrea K. , Kelly‐Weeder Susan
Published: September 2021

Background

Refeeding hypophosphatemia (RH) in individuals with anorexia nervosa (AN) is a potentially fatal complication of nutrition restoration; yet, little is known about risk. This retrospective cohort study examined factors found in hospitalized youth with AN that may contribute to RH.

Methods

We reviewed medical records of 300 individuals diagnosed with AN admitted between the years of 2010 and 2016. Logistic regression examined factors associated with RH. Multivariate regression examined factors associated with phosphorus nadir.

Results

For 300 participants, the mean (SD) age was 15.5 (2.5) years, 88.3% were White, and 88.3% were female. Participants lost an average of 11.3 (9.7) kg of body weight and were 82% (12.1) of median body mass index (BMI). Age (P = .022), nasogastric (NG) tube feeding (P = .054), weight gain (P = .003), potassium level (P = .001), and magnesium level (P = .024) were contributors to RH. Odds of RH were 13.7 times higher for each unit reduction in magnesium, 9.2 times higher for each unit reduction in potassium, three times higher in those who received NG feeding, 1.5 times higher for each kg of weight gain, and 1.2 times higher for each year of age. Regarding phosphorus nadir, serum magnesium level (P < .001) and admission BMI (P = .002) contributed significantly.

Conclusion

The results indicate that age, NG feeding, weight gain, electrolyte abnormalities, and BMI on admission are potential indicators of the development of RH in youth. This study identifies clinical risk factors associated with RH and may guide further investigation.