Miracle-dz/UniFAR-FTUs huggingface dataset:
HSP90 acts as a senomorphic target in senescent retinal pigmental epithelial cells

The senescence of retinal pigment epithelial (RPE) cells is associated with age-related macular degeneration (AMD), a leading cause of blindness in the world. HSP90 is a predominant chaperone that regulates cellular homeostasis under divergent physio-pathological conditions including senescence. However, the role of HSP90 in senescent RPE cells still remains unclear. Here, we reported that HSP90 acts as a senomorphic target of senescent RPE cells in vitro. Using H2O2-induced senescent ARPE-19 cells and replicative senescent primary RPE cells from rhesus monkey, we found that HSP90 upregulates the expression of IKKα, and HIF1α in senescent ARPE-19 cells and subsequently controls the induction of distinct senescence-associated inflammatory factors. Senescent ARPE-19 cells are more resistant to the cytotoxic HSP90 inhibitor IPI504 (IC50 = 36.78 μM) when compared to normal ARPE-19 cells (IC50 = 6.16 μM). Administration of IPI504 at 0.5–5 μM can significantly inhibit the induction of IL-1β, IL-6, IL-8, MCP-1 and VEGFA in senescent ARPE-19 and the senescence-mediated migration of retinal capillary endothelial cells in vitro. In addition, we found that inhibition of HSP90 by IPI504 reduces SA-β-Gal’s protein expression and enzyme activity in a dose-dependent manner. HSP90 interacts with and regulates SA-β-Gal protein stabilization in senescent ARPE-19 cells. Taken together, these results suggest that HSP90 regulates the SASP and SA-β-Gal activity in senescent RPE cells through associating with distinctive mechanism including NF-κB, HIF1α and lysosomal SA-β-Gal. HSP90 inhibitors (e.g. IPI504) could be a promising senomorphic drug candidate for AMD intervention.
Molecular features of exceptional response to neoadjuvant anti-androgen therapy in high-risk localized prostate cancer

High-risk localized prostate cancer (HRLPC) is associated with a substantial risk of recurrence and prostate cancer-specific mortality1. Recent clinical trials have shown that intensifying anti-androgen therapies administered prior to prostatectomy can induce pathologic complete responses (pCR) or minimal residual disease (MRD) (<5 mm), together termed exceptional response, although the molecular determinants of these clinical outcomes are largely unknown. Here, we performed whole exome (WES) and whole transcriptome sequencing (RNA-seq) on pre-treatment multi-regional tumor biopsies from exceptional responders (ER: pCR and MRD patients) and non-responders (NR: pathologic T3 or lymph node positive disease) treated with intensive anti-androgen therapies prior to prostatectomy. SPOP mutation and SPOPL copy number loss were exclusively observed in ER, while TP53 mutation and PTEN copy number loss were exclusively observed in NR. These alterations were clonal in all tumor phylogenies per patient. Additionally, transcriptional programs involving androgen signaling and TGFβ signaling were enriched in ER and NR, respectively. The presence of these alterations in routine biopsies from patients with HRLPC may inform the prospective identification of responders to neoadjuvant anti-androgen therapies to improve clinical outcomes and stratify other patients to alternative biologically informed treatment strategies.
An objective function for order preserving hierarchical clustering

We present an objective function for similarity based hierarchical clustering of partially ordered data that preserves the partial order. That is, if $x \le y$, and if $[x]$ and $[y]$ are the respective clusters of $x$ and $y$, then there is an order relation $\le'$ on the clusters for which $[x] \le' |y]$. The theory distinguishes itself from existing theories for clustering of ordered data in that the order relation and the similarity are combined into a bi-objective optimisation problem to obtain a hierarchical clustering seeking to satisfy both. In particular, the order relation is weighted in the range $[0,1]$, and if the similarity and the order relation are not aligned, then order preservation may have to yield in favor of clustering. Finding an optimal solution is NP-hard, so we provide a polynomial time approximation algorithm, with a relative performance guarantee of $O\! \left(\log^{3/2} \! \! \, n \right)$, based on successive applications of directed sparsest cut. We provide a demonstration on a benchmark dataset, showing that our method outperforms existing methods for order preserving hierarchical clustering with significant margin. The theory is an extension of the Dasgupta cost function for divisive hierarchical clustering.
Clinical Outcomes of Meniscal Allograft Transplantation With Respect to the Minimal Clinically Important Difference

Background: Arthroscopic-assisted meniscal allograft transplantation (MAT) has become a viable and effective treatment option for young active patients with postmeniscectomy pain. The minimal clinically important difference (MCID) of patient-reported outcome measures (PROMs) is imperative to evaluate the clinical significance of surgical interventions and inform clinical practice guidelines in orthopaedic surgery. Purpose: To perform a systematic review of clinical outcome studies of patients undergoing MAT and compare postoperative improvement with established MCID thresholds. Study Design: Systematic review and meta-analysis; Level of evidence, 4. Methods: A systematic review was performed using the PubMed, Web of Science, and Cochrane Library databases. A meta-analysis was performed using data obtained from studies reporting patient-reported outcomes. Subgroup analysis was performed on patients undergoing isolated lateral MAT using fresh-frozen grafts. Weighted mean postoperative improvements in the International Knee Documentation Committee (IKDC), Lysholm, and visual analog scale for pain (VAS pain) were calculated and compared with MCID values to determine if they met the MCID threshold. Results: A total of 35 studies were identified, including 1658 unique patients. Weighted mean postoperative score improvements exceeded MCID thresholds for the VAS pain, IKDC, and Lysholm. Subgroup analysis of patients undergoing isolated lateral fresh-frozen MAT demonstrated postoperative improvements exceeding the MCID for the Lysholm and VAS pain. Conclusion: Evaluating postoperative PROMs with respect to the MCID is crucial to evaluate the effect of MAT on functional improvement. The results of the present meta-analysis suggest that postoperative improvements after MAT are clinically meaningful as reflected by PROMs exceeding the MCID threshold for the IKDC, Lysholm, and VAS pain.
Malware Sight-Seeing: Accelerating Reverse-Engineering via Point-of-Interest-Beacons

New types of malware are emerging at concerning rates. However, analyzing malware via reverse engineering is still a time-consuming and mostly manual task. For this reason, it is necessary to develop techniques that automate parts of the reverse engineering process and that can evade the built-in countermeasures of modern malware. The main contribution of this paper is a novel method to automatically find so-called Points-of-Interest (POIs) in executed programs. POIs are instructions that interact with data that is known to an analyst. They can be used as beacons in the analysis of malware and can help to guide the analyst to the interesting parts of the malware. Furthermore, we propose a metric for POIs , the so-called confidence score that estimates how exclusively a POI will process data relevant to the malware. With the goal of automatically extract peers in P2P botnet malware, we demonstrate and evaluate our approach by applying it on four botnets (ZeroAccess, Sality, Nugache, and Kelihos). We looked into the identified POIs for known IPs and ports and, by using this information, leverage it to successfully monitor the botnets. Furthermore, using our scoring system, we show that we can extract peers for each botnet with high accuracy.
Degrees of randomized computability: decomposition into atoms

In this paper we study structural properties of LV-degrees of the algebra of collections of sequences that are non-negligible in the sense that they can be computed by a probabilistic algorithm with positive probability. We construct atoms and infinitely divisible elements of this algebra generated by sequences, which cannot be Martin-L\"of random and, moreover, these sequences cannot be Turing equivalent to random sequences. The constructions are based on the corresponding templates which can be used for defining the special LV-degrees. In particular, we present the template for defining atoms of the algebra of LV-degrees and obtain the decomposition of the maximal LV-degree into a countable sequence of atoms and their non-zero complement -- infinitely divisible LV-degree. We apply the templates to establish new facts about specific LV-degrees, such as the LV-degree of the collection of sequences of hyperimmune degree. We construct atoms defined by collections of hyperimmune sequences, moreover, a representation of LV-degree of the collection of all hyperimmune sequences will be obtained in the form of a union of an infinite sequence of atoms and an infinitely divisible element.
Mining points of interest via address embeddings: an unsupervised approach

Digital maps are commonly used across the globe for exploring places that users are interested in, commonly referred to as points of interest (PoI). In online food delivery platforms, PoIs could represent any major private compounds where customers could order from such as hospitals, residential complexes, office complexes, educational institutes and hostels. In this work, we propose an end-to-end unsupervised system design for obtaining polygon representations of PoIs (PoI polygons) from address locations and address texts. We preprocess the address texts using locality names and generate embeddings for the address texts using a deep learning-based architecture, viz. RoBERTa, trained on our internal address dataset. The PoI candidates are identified by jointly clustering the anonymised customer phone GPS locations (obtained during address onboarding) and the embeddings of the address texts. The final list of PoI polygons is obtained from these PoI candidates using novel post-processing steps that involve density-based cluster refinement and graph-based technique for cluster merging. This algorithm identified 74.8 % more PoIs than those obtained using the Mummidi-Krumm baseline algorithm run on our internal dataset. We use area-based precision and recall metrics to evaluate the performance of the algorithm. The proposed algorithm achieves a median area precision of 98 %, a median recall of 8 %, and a median F-score of 0.15. In order to improve the recall of the algorithmic polygons, we post-process them using building footprint polygons from the OpenStreetMap (OSM) database. The post-processing algorithm involves reshaping the algorithmic polygon using intersecting polygons and closed private roads from the OSM database, and accounting for intersection with public roads on the OSM database. We achieve a median area recall of 70 %, a median area precision of 69 %, and a median F-score of 0.69 on these post-processed polygons. The ground truth polygons for the evaluation of the metrics were obtained using manual validation of the algorithmic polygons obtained from the Mummidi-Krumm baseline approach. These polygons are not used to train the proposed algorithm pipeline, and hence, the algorithm is unsupervised.
Feasibility of an online, mental health-informed lifestyle program for people aged 60+ years during the COVID-19 pandemic.

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.
A sick plot–based protocol for dry root rot disease assessment in field‐grown chickpea plants

Abstract Premise A comprehensive field‐based screening protocol is lacking for dry root rot (DRR) disease in chickpea, which is caused by Macrophomina phaseolina (formerly referred to as Rhizoctonia bataticola). Here, we describe a protocol for establishing a sick plot for DRR to enable disease assessment of a large number of chickpea plants during the natural growing season. Methods and Results We used a chickpea plot with >30% DRR incidence, and enriched the inoculum by cultivating highly susceptible chickpea plant genotypes and incorporating infected plant material into the soil. The chickpea plants were then subjected to infection in developed sick plots with various levels of soil moisture under natural field conditions. Conclusions Our protocol provides a robust way to impose M. phaseolina infection on chickpea plants under natural field conditions and to investigate plant responses to the infection at morphological, physiological, and molecular levels. This method can also be used to screen for other soil‐borne diseases in a variety of plants.
Predictors of asthma‐related quality of life in a large cohort of asthmatics: A cross‐sectional study in a secondary care center

Abstract Background In recent decades, asthma‐related quality of life questionnaires have joined objective clinical indicators as important outcome measures. In this study, we sought to investigate the predictors of asthma‐related quality of life in a large cohort of patients recruited from a secondary care center. Methods We conducted a cross‐sectional study on asthmatics (N = 1301) recruited from the Liège University Hospital asthma clinic (Belgium). After performing a descriptive analysis highlighting the distribution of scores from the Mini Asthma Quality of Life Questionnaire (Mini AQLQ) and its four dimensions (symptoms, activity limitation, emotional function, and environmental stimuli), we did multiple regression analysis to identify the independent predictors of AQLQ. Results Multiple regression beta analysis showed that AQLQ and its four dimensions were primarily associated with asthma control (p < 0.0001 in all instances). Female gender was associated with a lower score for the AQLQ's activity and environmental dimensions (p < 0.05 for both), while current smokers had a higher score on the AQLQ's environmental dimension (p < 0.0001). The burden of asthma treatment was associated with a lower score for the AQLQ's emotional (p < 0.05) and environmental (p < 0.05) dimensions. BMI was associated with a lower score in the AQLQ's activity dimension (p < 0.0001), while the opposite was true for the FeNO test (p < 0.0001). Sputum neutrophils were inversely related to the score for the AQLQ's symptom dimension (p < 0.05), whereas post‐bronchodilator FEV1 showed a positive relationship for that same dimension (p < 0.05). Conclusion Asthma control is the main predictor of AQLQ score and impacts all its dimensions, but demographic, functional, and airway inflammatory parameters may also influence some dimensions of the AQLQ.
Late diagnosis of HIV infection and its associated factors in Shiraz, Southern Iran: a retrospective study

ABSTRACT Late diagnosis (LD) of HIV infection can give rise to suboptimal responses to antiretroviral treatment. The current study aimed to determine the prevalence and associated factors of HIV LD in Shiraz, Southern Iran. This retrospective cohort study was conducted from August 1997 to May 2018. Medical records were examined to extract required data. Individuals with time period less than three months from HIV diagnosis to an advanced phase of AIDS on CD4 < 350 were considered as LD. Multivariable logistic regression used to investigate the associated factors of late HIV diagnosis and adjusted odds ratios were reported. Of 1385 individuals, 1043 (75.3%) were considered as LD. The following factors were identified as the associated factors of LD: age at diagnosis (OR = 1.72, 95% CI: 1.22, 2.41), HCV co-infection (OR = 1.65, 95% CI: 1.23, 2.21), not living in Shiraz (OR = 1.36, 95% CI: 1.02, 1.82), increased likelihood of LD and being housewife (OR = 0.67, 95% CI: 0.47, 0.95) which decreased the likelihood of LD. Our results showed delayed diagnosis of a large proportion of individuals with HIV. It is critical to improve the HIV testing guidelines in Iran to identify individuals with HIV without delays in order to provide them with timely HIV medical care and treatment.
Optimization of the Formulation of Rice Biscuits Supplemented with D. Edulis (L.) Powder Using Response Surface Methodology

Trends in the food industry are nowadays directed towards the reduction of the level of trans fatty acids in food intended for human consumption. The present study was designed and aimed at valorizing Dacryodes edulis (L.) powder as a substitute for margarine in the production of functional rice biscuits. The effect of substituting margarine and refined wheat flour with D. edulis powder locally called safou and rice flour, respectively, at different proportions was assessed for the sensory and physicochemical properties of the formulated biscuits. For this, statistical models were developed, validated, and optimized using the response surface methodology with the Doehlert design as a tool. The results showed that an increase in the substitution rate of margarine with of D. edulis powder enhanced the aroma while the substitution of refined wheat flour with rice flour led to an improvement of the overall quality of the biscuits. The optimal composition of dough for the production of biscuits with satisfying sensory properties was 20.24% of wheat flour, 24.51% of rice flour, 19.09% of margarine, and 2.47% of D. edulis powder. The optimized biscuit which scored the highest overall acceptability contained proteins (10.33 g/100 g DM), fat (27.66 g/100 g DM), crude fibers (2.5 g/100 g DM), ash (3.55 g/100 g DM), and carbohydrates (54.01 g/100 g DM). It has an energy density of 506.3 ± 0.1 kcal/g and could therefore be suitable for the management of malnutrition. Mineral analysis revealed that the biscuit contained sodium (0.200 mg/100 g), potassium (0.192 mg/100 g), phosphorus (0.123 mg/100 g), iron (33.60 ppm), and zinc (26.81 ppm) at levels satisfying the recommended daily intakes. The results of this study demonstrated the suitability of safou as substitute of margarine in the rice biscuit formulation and suggests the potential of the formulated biscuits in the management of malnutrition and noncommunicable diseases such as hypertension, obesity, and cardiovascular diseases.
Role of C5a and C5aR in doxorubicin-induced cardiomyocyte senescence

Doxorubicin (DOX) is an efficacious antineoplastic drug; however, its use is limited due to its cardiotoxicity. Cardiomyocyte senescence is considered to be a key factor in the development of DOX-related cardiomyopathy. Complement component 5a (C5a) and the C5a receptor (C5aR) have been reported to play a key role in the process of cellular senescence. However, to the best of our knowledge, the exact role of C5a and C5aR in cellular senescence in the heart remains largely unknown. Reverse transcription-quantitative (RT-q)PCR and western blot assays were used to analyze the expression levels of C5a and C5aR in H9c2 embryonic rat cardiomyocytes and AC16 human cardiomyocyte-like cells. The cells were treated with DOX and a C5aR antagonist (C5aRA). The expression of TNF-α and IFN-γ was determined using ELISA and western blotting. The levels of reactive oxygen species (ROS) were also measured using ELISA. Cellular senescence was determined using senescence-associated β-galactosidase (SA-β-gal) staining and by analyzing the protein expression levels of p53, p16, p21 and insulin-like growth factor-binding protein 3 (IGFBP3). The expression levels of C5a and C5aR were found to be upregulated during the DOX-induced senescence of H9c2 and AC16 cardiomyocytes. Treatment with C5aRA downregulated TNF-α and IFN-γ expression, in addition to ROS levels. Furthermore, C5aRA prevented DOX-induced cellular senescence and decreased the levels of positive SA-β-gal staining in H9c2 and AC16 cardiomyocytes, in addition to downregulating the expression levels of p53, p16, p21 and IGFBP3. C5aRA also increased the telomere length and telomerase activity in H9c2 and AC16 cardiomyocytes following DOX stimulation. In conclusion, the findings of the present study indicated that C5a and C5aR may play a key role in cardiomyocyte senescence, and treatment with C5aRA may be an effective method for preventing DOX-induced cardiomyocyte aging.
The complete chloroplast genome sequence of Arundo formosana Hack. (Poaceae)

Abstract Arundo formosana Hack. belongs to the Arundionideae subfamily of Poaceae. In this study, we sequenced and assembled the complete chloroplast genome of A. formosana. The complete chloroplast genome was 136,919 bp in size, including a large single copy region of 82,039 bp, a small single-copy region of 12,108 bp and a pair of reverse repeats of 21,386 bp in size. The annotation of A. formosana indicates that it contained 81 protein-coding genes, 47 tRNA and 8 rRNA. Our phylogenetic analysis of the 36 grass complete chroloplast genomes of protein-coding genes using Cyperus rotundus as outgroup showed that A. formosana is closely related to Crinipes species to form the Arundionideae lineage of the grass family.
Improved Synthesis of a Cyclic Glutamine Analogue Used in Antiviral Agents Targeting 3C and 3CL Proteases Including SARS-CoV-2 Mpro

An intermediate in the synthesis of numerous antiviral protease inhibitors is the glutamine analogue, (3S)-pyrrolid-2-one-3-yl-l-alanine. Preparations of compounds based on this pharmacophore are hindered by the lack of a reliably high yielding synthesis of protected forms of this amino acid. We describe an improved scalable route with readily available reagents and facile purification. This methodology employs γ-allylation of dimethyl N-BocGlu, further Boc N-protection, OsO4-periodate oxidation, O-Me oxime formation, and RaNi-catalyzed hydrogenolysis with concomitant cyclization under basic conditions.