Miracle-dz/UniFAR-FTUs huggingface dataset:
The uptake of metal–organic frameworks: a journey into the cell

The application of metal–organic frameworks (MOFs) in drug delivery has advanced rapidly over the past decade, showing huge progress in the development of novel systems. Although a large number of versatile MOFs that can carry and release multiple compounds have been designed and tested, one of the main limitations to their translation to the clinic is the limited biological understanding of their interaction with cells and the way they penetrate them. This is a crucial aspect of drug delivery, as MOFs need to be able not only to enter into cells but also to release their cargo in the correct intracellular location. While small molecules can enter cells by passive diffusion, nanoparticles (NPs) usually require an energy-dependent process known as endocytosis. Importantly, the fate of NPs after being taken up by cells is dependent on the endocytic pathways they enter through. However, no general guidelines for MOF particle internalization have been established due to the inherent complexity of endocytosis as a mechanism, with several factors affecting cellular uptake, namely NP size and surface chemistry. In this review, we cover recent advances regarding the understanding of the mechanisms of uptake of nano-sized MOFs (nanoMOFs)s, their journey inside the cell, and the importance of biological context in their final fate. We examine critically the impact of MOF physicochemical properties on intracellular trafficking and successful cargo delivery. Finally, we highlight key unanswered questions on the topic and discuss the future of the field and the next steps for nanoMOFs as drug delivery systems.
High Levels of Hyaluronic Acid Synthase-2 Mediate NRF2-Driven Chemoresistance in Breast Cancer Cells

Hyaluronic acid (HA), a ligand of CD44, accumulates in some types of tumors and is responsible for tumor progression. The nuclear factor erythroid 2-like 2 (NRF2) regulates cytoprotective genes and drug transporters, which promotes therapy resistance in tumors. Previously, we showed that high levels of CD44 are associated with NRF2 activation in cancer stem like-cells. Herein, we demonstrate that HA production was increased in doxorubicin-resistant breast cancer MCF7 cells (MCF7-DR) via the upregulation of HA synthase-2 (HAS2). HA incubation increased NRF2, aldo-keto reductase 1C1 (AKR1C1), and multidrug resistance gene 1 (MDR1) levels. Silencing of HAS2 or CD44 suppressed NRF2 signaling in MCF7-DR, which was accompanied by increased doxorubicin sensitivity. The treatment with a HAS2 inhibitor, 4-methylumbelliferone (4-MU), decreased NRF2, AKR1C1, and MDR1 levels in MCF7-DR. Subsequently, 4-MU treatment inhibited sphere formation and doxorubicin resistance in MCF7-DR. The Cancer Genome Atlas (TCGA) data analysis across 32 types of tumors indicates the amplification of HAS2 gene is a common genetic alteration and is negatively correlated with the overall survival rate. In addition, high HAS2 mRNA levels are associated with increased NRF2 signaling and poor clinical outcome in breast cancer patients. Collectively, these indicate that HAS2 elevation contributes to chemoresistance and sphere formation capacity of drug-resistant MCF7 cells by activating CD44/NRF2 signaling, suggesting a potential benefit of HAS2 inhibition.
Developing ACASI questionnaires in Borno State, Nigeria during COVID-19: Using data-informed processes to address complexity, sensitivity, and functionality of family functioning and wellbeing measures

ABSTRACT Audio Computer-Assisted Self-Interview (ACASI) has become increasingly popular for collecting data on sensitive topics among populations with lower levels of literacy. However, the development of an ACASI tool is an involved process that can be further complicated when working in humanitarian contexts during the COVID-19 pandemic. This study describes the development of an ACASI tool to be used in a family-focused intervention evaluation. Participants included adolescent girls aged 10-14, adolescent boys aged 15-19, and caregivers in Borno State, Nigeria. Data to inform the tool’s development were collected using cognitive interviews, ACASI demonstrations, and post-demonstration assessments with adolescent girls, adolescent boys, and caregivers, as well as a focus group discussion with enumerators. Data found high levels of acceptance for the tool and helped identify appropriate visual representations for various answer options to maximize usability. The survey was found to be too long to administer solely through ACASI; the final tool employs a combination of ACASI and computer-assisted personal interview formats. Findings highlight the importance of repeatedly piloting and testing these types of tools to ensure content and language resonate with intended users. However, the steps employed demonstrate that researchers can maintain a commitment to developing high-quality, community-grounded research tools despite challenges germane to humanitarian settings.
General practitioners’ willingness to participate in research networks in Germany

Abstract Objectives To investigate general practitioners’ (GPs’) willingness to participate in long-term medical research and in research networks (RNs). Design and setting Cross-sectional survey among German GPs around Halle-Wittenberg and Leipzig in 2020. Subjects Random sample of 905 GPs. Main outcome measures and results Response rate 37%, 69% female. Overall, 57% were interested in participating in medical research, 34% in an active role in a RN. Interest in RN participation was positively associated with male sex, younger age, previous experiences in medical research, being involved in teaching undergraduates, and having qualification in a further specialty. Main motivators were improving patient care, giving a more realistic picture of GP care, and carrying out research on topics within their own interest areas and a reliable contact person at the leading institution. Most GPs were not afraid of reduced earnings; however, time investment was the main barrier for participation. GPs were willing to dedicate twice as much time to research when remuneration was offered. High rated topics were polypharmacy, chronic diseases, drug safety and adverse drug reactions. Conclusion GPs are interested to participate in practice-based research. The study results providing useful and generalizable insights in barriers and motivators should be considered when building and running GP-RNs. KEY POINTS There is a difference between general practitioners’ (GPs’) overall interest in clinical research and their job and socio-demographic related readiness to participate in research networks (RNs). GPs are interested in RNs when it is a resource of and leading to enhanced patient-oriented care. GPs are willing to dedicate twice as much time to research when remunerated. GPs need a reliable counterpart within the leading institution.
Developmental and evolutionary comparative analysis of a regulatory landscape in mouse and chicken

ABSTRACT Modifications in gene regulation are driving forces in the evolution of organisms. Part of these changes involve cis-regulatory elements (CREs), which contact their target genes through higher-order chromatin structures. However, how such architectures and variations in CREs contribute to transcriptional evolvability remains elusive. We use Hoxd genes as a paradigm for the emergence of regulatory innovations, as many relevant enhancers are located in a regulatory landscape highly conserved in amniotes. Here, we analysed their regulation in murine vibrissae and chicken feather primordia, two skin appendages expressing different Hoxd gene subsets, and compared the regulation of these genes in these appendages with that in the elongation of the posterior trunk. In the two former structures, distinct subsets of Hoxd genes are contacted by different lineage-specific enhancers, probably as a result of using an ancestral chromatin topology as an evolutionary playground, whereas the gene regulation that occurs in the mouse and chicken embryonic trunk partially relies on conserved CREs. A high proportion of these non-coding sequences active in the trunk have functionally diverged between species, suggesting that transcriptional robustness is maintained, despite considerable divergence in enhancer sequences.
Sexual Fluidity in a Malaysian Sample: A Case for the Presence of Facilitative Environments within a Restrictive Sociocultural and Political Landscape

ABSTRACT This study investigated sexual fluidity in attractions and subsequent fluidity in sexual identities, its associations with sexual orientation identity labels, and self-reported likelihood of future change in sexual identity labels in a sample of same-sex attracted Malaysian women and men. Participants completed an online questionnaire measuring sexual fluidity in attractions and sexual identity, sexual orientation identity labels and likelihood of future change in identity labels. Sexual fluidity in attractions was reported by 72% of women and 64% of men, with 44% of women and 38% of men reporting subsequent fluidity in sexual orientation identities. There were no significant gender differences observed in the frequency of sexual fluidity in attractions and change in sexual identity labels. There were also no significant gender differences in the self-reported likelihood of future change in sexual identity labels. Sexual fluidity was found to be associated with sexual identity labels representing non-exclusive sexual attractions for both men and women. Findings provide preliminary support for the presence of facilitative environments within a largely conservative and restrictive sociocultural and political landscape.
Characterization, costs, cues and future perspectives of phenotypic plasticity

Abstract Background Plastic responses of plants to the environment are ubiquitous. Phenotypic plasticity occurs in many forms and at many biological scales, and its adaptive value depends on the specific environment and interactions with other plant traits and organisms. Even though plasticity is the norm rather than the exception, its complex nature has been a challenge in characterizing the expression of plasticity, its adaptive value for fitness and the environmental cues that regulate its expression. Scope This review discusses the characterization and costs of plasticity and approaches, considerations, and promising research directions in studying plasticity. Phenotypic plasticity is genetically controlled and heritable; however, little is known about how organisms perceive, interpret and respond to environmental cues, and the genes and pathways associated with plasticity. Not every genotype is plastic for every trait, and plasticity is not infinite, suggesting trade-offs, costs and limits to expression of plasticity. The timing, specificity and duration of plasticity are critical to their adaptive value for plant fitness. Conclusions There are many research opportunities to advance our understanding of plant phenotypic plasticity. New methodology and technological breakthroughs enable the study of phenotypic responses across biological scales and in multiple environments. Understanding the mechanisms of plasticity and how the expression of specific phenotypes influences fitness in many environmental ranges would benefit many areas of plant science ranging from basic research to applied breeding for crop improvement.
Multi-institutional retrospective study of canine foot pad malignant melanomas: 20 cases.

Melanomas arising from the foot pad are a rare clinical entity in dogs. The biologic behavior of foot pad malignant melanoma is not well understood, and these tumors are infrequently described. The objective of this study was to evaluate the clinical characteristics of primary canine foot pad melanoma in a larger cohort of patients. Eligible cases were solicited from the American College of Veterinary Internal Medicine (ACVIM) Oncology listserv for retrospective review. Included dogs had a cytologic and/or histologic diagnosis of foot pad melanoma evaluated by a board-certified clinical or anatomic pathologist. Dogs with cutaneous, oral, digital, subungual, or interdigital melanomas were excluded. A total of 20 cases were included. Eleven dogs received various adjuvant therapies including chemotherapy, radiation therapy, and/or the ONCEPT canine melanoma vaccine following surgery. At diagnosis, regional lymph node metastasis was observed in four dogs (20%). Seven dogs developed subsequent regional and/or distant metastasis for an overall metastatic rate of 55%. The progression-free interval (PFI) was 101 days (range, 20-960 days). The median survival time (MST) was 240 days (range, 25-479 days). For dogs receiving adjuvant therapy, the MST was 159 days (range, 25-387 days). Canine foot pad melanoma is a rare neoplasm that can exhibit an aggressive behavior.
Routine clinical parameters and laboratory testing predict therapy-related myeloid neoplasms after treatment for breast cancer

We aim to identify predictors of therapy-related myeloid neoplasms (t-MN) in patients with breast cancer (BC) and cytopenias to determine the timing of bone marrow biopsy (BMBx). Patients with BC and cytopenias who were referred for BMBx between 2002-2018 were identified using the Memorial Sloan Kettering Cancer Center institutional database. Characteristics associated with the risk of t-MN were evaluated by multivariable logistic regression and included in a predictive model. The average area under the receiver operating characteristic curve (AUC) was estimated by 5-fold cross-validation. Of the 206 BC patients who underwent BMBx included in our study, 107 had t-MN. By multivariable analysis, white blood cell count 4-11 K/mcL, absolute neutrophil count (ANC) ≥1.5 K/mcL, hemoglobin ≥12.2 g/dL, red cell distribution width 11.5-14.5%, the presence of bone metastasis and a time from BC diagnosis to BMBx <15 months significantly decreased the likelihood of t-MN. The average AUC was 0.88. We stratified our cohort by bone metastasis and by findings on peripheral smear. In both the subset without bone metastasis (n=159) and in the cohort with no blasts or dysplastic cells on peripheral smear (n=96) our variables had similar effects on the risk of t-MN. Among the 47 patients with bone metastasis, an ANC ≥1.5 K/mcL was the only variable associated with a decreased risk of t-MN. Our findings show that in patients with BC and unexplained cytopenias, clinical and laboratory parameters can predict t-MN and assist clinicians in determining the timing of a BMBx.
Noninvasive brain stimulation for cognitive rehabilitation following traumatic brain injury: A systematic review

Abstract Traumatic brain injury (TBI) can cause numerous cognitive deficits. These deficits are associated with disability and reduction in quality of life. Noninvasive brain stimulation (NIBS) provides excitatory or inhibitory stimuli to the cerebral cortex. This review aimed to examine the effectiveness of NIBS (i.e., rTMS and tDCS) on cognitive functions in patients with TBI. PubMed, SCOPUS, PEDro, CINAHL, MEDLINE, REHABDATA, and Web of Science were searched from inception to May 2021. The risk of bias in the randomized controlled trials was assessed using the Cochrane Collaboration’s instrument. The Physiotherapy Evidence Database (PEDro) scale was applied to evaluate the risk of bias in the non-randomized controlled trials. Ten studies met our inclusion criteria. Six studies used repetitive Transcranial Magnetic Stimulation (rTMS), and four used transcranial Direct Current Stimulation (tDCS) as cognitive rehabilitation interventions. The results showed heterogenous evidence for the effects of rTMS and tDCS on cognitive function outcomes in individuals with TBI. The evidence for the effects of NIBS on cognition following TBI was limited. TDCS and rTMS are safe and well-tolerated interventions post-TBI. The optimal stimulation sites and stimulation parameters remain unknown. Combining NIBS with traditional rehabilitation interventions may contribute to greater enhancements in cognitive functions post-TBI.
Finite element simulation of multilayer model to simulate fine needle insertion mechanism into iliac crest for bone marrow biopsy

Abstract The main aim of this work is to use a finite element technique (FEM) to gain understanding about the bone marrow biopsy (BMB) needle insertion process and needle-tissue interactions in the human iliac crest. A multi-layer iliac crest model consists of stratum corneum, dermis, epidermis, hypodermis, cortical, and cancellous bone has been established. This paper proposes a FE model that examines all phases of tissue deformation, including puncture, cutting, needle-tissue interaction, and various stress-strain values for BMB needle during interaction. The results explain the needle-tissue interface and show the potential of this technique to estimate bone damage and tissue deformation for multiple needle dimensions, coefficient of friction, and penetration speeds. The insertion and extraction force of conical-shaped needles in the multi-layered iliac crest model decreased by 18.92% and 37.5%, respectively, as the needle diameter reduced from 11 G to 20 G. It has also been found that the significant insertion motion raises the deformation of the tissue due to the augmented frictional forces but reduces the strain perpendicular to the penetration direction closer to the needle tip. The simulation outcomes are helpful for the optimal design of fine biopsy needles used to perform the bone marrow biopsies.
Climate dictates microbial community composition and diversity in Australian biological soil crusts (biocrusts)

Abstract The soil surface of drylands can typically be colonized by cyanobacteria and other microbes, forming biological soil crusts or ‘biocrusts’. Biocrusts provide critical benefits to ecosystems and are a common component of the largely arid and semi‐arid Australian continent. Yet, their distribution and the parameters that shape their microbial composition have not been investigated. We present here the first detailed description of Australia's biocrust microbiome assessed from 15 sites across the continent using 16S rRNA sequencing. The most abundant bacterial phyla from all sites were Cyanobacteria, Proteobacteria, Actinobacteria, Chloroflexi and Bacteroidetes. Cyanobacterial communities from northern regions were more diverse and unclassified cyanobacteria were a noticeable feature of northern biocrusts. Segregation between northern and southern regions was largely due to the differential abundance of Microcoleus spp. , with M. paludosus dominating in the north and M. vaginatus dominating in the south. The geographical shifts in bacterial composition and diversity were correlated to seasonal temperatures and summer rainfall. Our findings provide an initial reference for sampling strategies to maximize access to bacterial genetic diversity. As hubs for essential ecosystem services, further investigation into biocrusts in arid and semi‐arid regions may yield discoveries of genetic mechanisms that combat increases in warming due to climate change.
Humidity Responsive Reflection Grating Made by Ultrafast Nanoimprinting of a Hydrogel Thin Film.

The response time of state of the art humidity sensors is approximately 8 s. A faster tracking of humidity change is especially required for health care devices. We focused our research on the direct nanostructuring of a humidity-sensitive polymer thin film and combined it with an optical read-out method. Our goal was to improve the response time by changing the surface-to-volume ratio of the thin film and to test a different measurement method compared to state of the art sensors. Large and homogeneous nanostructured areas were fabricated by nanoimprint lithography on poly(2-hydroxyethyl methacrylate) thin films. Those thin films were made by initiated chemical vapor deposition (iCVD). To the author's knowledge, this is the first time nanoimprint lithography was applied on iCVD polymer thin films. With the imprinting process we developed a diffraction grating in the visible wavelength regime. The optical and physicochemical behavior of the nanostructures was modeled with multi-physic simulations. After successful modeling and fabrication a first proof of concept showed that humidity dependency by using an optical detection of the first diffraction order peak is observable. The response time of the structured thin film resulted to be at least three times faster compared to commercial sensors. This article is protected by copyright. All rights reserved.
Identification of repurposing therapeutics toward SARS-CoV-2 main protease by virtual screening

SARS-CoV-2 causes the current global pandemic coronavirus disease 2019. Widely-available effective drugs could be a critical factor in halting the pandemic. The main protease (3CLpro) plays a vital role in viral replication; therefore, it is of great interest to find inhibitors for this enzyme. We applied the combination of virtual screening based on molecular docking derived from the crystal structure of the peptidomimetic inhibitors (N3, 13b, and 11a), and experimental verification revealed FDA-approved drugs that could inhibit the 3CLpro of SARS-CoV-2. Three drugs were selected using the binding energy criteria and subsequently performed the 3CLpro inhibition by enzyme-based assay. In addition, six common drugs were also chosen to study the 3CLpro inhibition. Among these compounds, lapatinib showed high efficiency of 3CLpro inhibition (IC50 value of 35 ± 1 μM and Ki of 23 ± 1 μM). The binding behavior of lapatinib against 3CLpro was elucidated by molecular dynamics simulations. This drug could well bind with 3CLpro residues in the five subsites S1’, S1, S2, S3, and S4. Moreover, lapatinib’s key chemical pharmacophore features toward SAR-CoV-2 3CLpro shared important HBD and HBA with potent peptidomimetic inhibitors. The rational design of lapatinib was subsequently carried out using the obtained results. Our discovery provides an effective repurposed drug and its newly designed analogs to inhibit SARS-CoV-2 3CLpro.
Assessment of screen‐recalled abnormalities for digital breast tomosynthesis versus digital mammography screening in the BreastScreen Maroondah trial

Australia's first population‐based pilot trial comparing digital breast tomosynthesis (DBT) and digital mammography (DM) screening reported detection measures in 2019. This study describes the trial's secondary outcomes pertaining to the assessment process in women screened with DBT or DM, including the type of recalled abnormalities and the procedures performed.
Photoschädigung und Photoalterung – Prävention und Behandlung

Die Belastung der Haut mit natürlicher und künstlicher UV‐Strahlung hat in den letzten Jahren nicht nur durch die verstärkte solare Strahlung als Folge der Ozonabnahme in der Stratosphäre, sondern auch durch ein Freizeitverhalten mit dem Wunsch nach gebräunter Haut deutlich zugenommen. Dieser Wunsch wird nicht nur durch Reisen in die sonnigen Gebiete der Erde, sondern auch durch den häufigen Besuch von Solarien umgesetzt. Hinzu kommt die gestiegene Lebenserwartung in den Industrienationen, die mit einer gesteigerten kumulativen UV‐Belastung korreliert. Konsequenz daraus ist zusätzlich zu Immunsuppression und Hautkarzinogenese auch die Photo‐ oder Lichtalterung der Haut durch den photooxidativen Schaden an Zellen, subzellulären Kompartimenten und Makromolekülen, der durch die Absorption von Photonen in einer sauerstoffreichen Umgebung entsteht. Klinisch manifestiert sich die Photoalterung der Haut in Faltenbildung, Gewebeschlaffheit, ledrigem Erscheinungsbild mit Fragilität, Verletzbarkeit und eingeschränkter Wundheilung. Strategien zur Vermeidung oder Minimierung dieser photooxidativen Langzeitschäden umfassen effektiven UV‐Schutz und das Aufrechterhalten eines oxidativ‐antioxidativen Gleichgewichtes in Zellen und Geweben. Neuere Therapieentwicklungen wie der Einsatz von DNA‐Reparaturenzymen werden ebenfalls diskutiert.