Miracle-dz/UniFAR-FTUs huggingface dataset:
Significance of the Pretreatment Neutrophil-to-Lymphocyte and Platelet-to-Lymphocyte Ratios in Predicting the Response to Neoadjuvant Chemotherapy and Survival Rates in Extremity Osteosarcoma: A Multicentre Prospective Study

Abstract Objectives We aimed to assess the effects of pretreatment neutrophil-to-lymphocyte and platelet-to-lymphocyte ratios on the response to neoadjuvant chemotherapy and survival rates in patients with extremity osteosarcoma. Patients and methods Patients with high-grade osteosarcoma admitted to oncologic centers affiliated with Iran University of Medical Sciences, Tehran, Iran from 2015 to 2021 were evaluated retrospectively to assess the impact of complete blood count-related parameters on the pathologic response after neoadjuvant chemotherapy. Then, patients were followed up prospectively to evaluate the survival rates. All patients received at least three cycles of cisplatin/doxorubicin regimen, preoperatively. In this study, the cut-off values for high neutrophil-to-lymphocyte and high platelet-to-lymphocyte ratio were considered 3.28 and 128, respectively. Results One hundred eighty-six patients were enrolled. Patients with high neutrophil-to-lymphocyte ratio and high platelet-to-lymphocyte ratio had a significantly lower overall survival rates (20.7 [95% CI 18–23.5] month vs. 34.6 [95% CI 33.2–36], p = 0.003 and 21.9 [95% CI 20.2–23.6] month versus 35.3 [95% CI 33.9–36.7], p = 0.002; respectively). Moreover, disease-free survival of patients with high platelet-to-lymphocyte ratio was worse than patients with low platelet-to-lymphocyte ratio (20.4 [95% CI 18.4–22.4] month vs. 32.7 [95% CI 30.8–34.7], p = 0.02). Conclusion Our study showed that neutrophil-to-lymphocyte and platelet-to-lymphocyte ratios at the baseline can predict the survival of patients with high-grade osteosarcoma.
Enfortumab vedotin as a salvage option as 5th line therapy for metastatic urothelial bladder cancer

Abstract A 67-year-old female patient with a muscle-invasive, non-metastatic urothelial bladder cancer (UC) (pT2 G3 cN0 cM0) developed metachronous metastases within 6 months after radical cystectomy with ileal conduit urinary diversion. After a good primary response to platinum-based chemotherapy, treatment was switched to the immune checkpoint inhibitor (ICI) pembrolizumab due to progressive disease. Subsequently the patient underwent selective internal radiotherapy (SIRT) of the liver and received vinflunine as well as a re-challenge with pembrolizumab. Two years after the initial diagnosis, rapid disease progression ultimately led to a switch to 5th line therapy with enfortumab vedotin (EV), which had only been approved in the United States at that time. The antibody-drug conjugate was well tolerated by the patient after dose reduction to 1.0 mg/ kg body weight. Simultaneous irradiation of newly occurring precardiac, hepatic and cerebral metastases were necessary. After 10 months of therapy with EV, tumour regression was observed accompanied with good symptom control. The presented case illustrates the efficacy and tolerability of EV in a heavily pre-treated patient with metastatic UC (mUC).
Identification and impact on Pseudomonas aeruginosa virulence of mutations conferring resistance to a phage cocktail for phage therapy

ABSTRACT Phage therapy represents a promising strategy for curing bacterial infections refractory to antibiotics. However, the success rate of phage therapy may be lowered by the emergence of bacterial resistance to the phages used for therapy. In this work, we studied the resistance to the CK4 cocktail, which is a mixture composed of four phages able to cure Pseudomonas aeruginosa infections in animal models. CK4-resistant mutants were easily isolated from cultures grown in either a standard laboratory medium or an artificial sputum medium mimicking the composition of the airway fluid of cystic fibrosis (CF) patients, who are highly susceptible to P. aeruginosa chronic lung infections. In both cases, CK4-resistant mutants resulted in being defective in lipopolysaccharide (LPS) biosynthesis. Accordingly, all CK4 phages were unable to infect wzy mutants lacking the O-antigen polymerase. A survey of the other 15 P. aeruginosa phages isolated from different environmental sources showed that they all needed either wzy or the Type IV-pilus (T4P) biosynthetic gene pilQ for the infection. Overall, our data suggest that 16 out of the 19 analyzed Pseudomonas phages may use either the LPS or the T4P as a receptor. Interestingly, CK4-resistant mutants devoid of the O-antigen had strongly attenuated virulence in a zebrafish embryo infection model, and the lack of T4P also decreased virulence in zebrafish. With respect to isolates from patients with CF, phages not reproducing in the Δwzy mutant had a wider host range than those requiring pilQ, suggesting that phages dependent on PAO1-type T4P may have limited therapeutic value for treating CF-related infections. IMPORTANCE In this work, we identified the putative receptors of 16 Pseudomonas phages and evaluated how resistance to phages recognizing different bacterial receptors may affect the virulence. Our findings are relevant for the implementation of phage therapy of Pseudomonas aeruginosa infections, which are difficult to treat with antibiotics. Overall, our results highlight the need to modify natural phages to enlarge the repertoire of receptors exploited by therapeutic phages and suggest that phages using the PAO1-type T4P as receptor may have limited value for the therapy of the cystic fibrosis infection. In this work, we identified the putative receptors of 16 Pseudomonas phages and evaluated how resistance to phages recognizing different bacterial receptors may affect the virulence. Our findings are relevant for the implementation of phage therapy of Pseudomonas aeruginosa infections, which are difficult to treat with antibiotics. Overall, our results highlight the need to modify natural phages to enlarge the repertoire of receptors exploited by therapeutic phages and suggest that phages using the PAO1-type T4P as receptor may have limited value for the therapy of the cystic fibrosis infection.
Genomics and conservation: Guidance from training to analyses and applications

Environmental change is intensifying the biodiversity crisis and threatening species across the tree of life. Conservation genomics can help inform conservation actions and slow biodiversity loss. However, more training, appropriate use of novel genomic methods and communication with managers are needed. Here, we review practical guidance to improve applied conservation genomics. We share insights aimed at ensuring effectiveness of conservation actions around three themes: (1) improving pedagogy and training in conservation genomics including for online global audiences, (2) conducting rigorous population genomic analyses properly considering theory, marker types and data interpretation and (3) facilitating communication and collaboration between managers and researchers. We aim to update students and professionals and expand their conservation toolkit with genomic principles and recent approaches for conserving and managing biodiversity. The biodiversity crisis is a global problem and, as such, requires international involvement, training, collaboration and frequent reviews of the literature and workshops as we do here.
Update on Current Evidence for the Diagnosis and Management of Nonfunctioning Pituitary Neuroendocrine Tumors

Pituitary neuroendocrine tumors (PitNETs) are the third most frequently diagnosed intracranial tumors, with nonfunctioning PitNETs (nfPitNETs) accounting for 30% of all pituitary tumors and representing the most common type of macroPitNETs. NfPitNETs are usually benign tumors with no evidence of hormone oversecretion except for hyperprolactinemia secondary to pituitary stalk compression. Due to this, they do not typically present with clinical syndromes like acromegaly, Cushing’s disease or hyperthyroidism and instead are identified incidentally on imaging or from symptoms of mass effects (headache, vision changes, apoplexy). With the lack of effective medical interventions, first-line treatment is transsphenoidal surgical resection, however, nfPitNETs often have supra- or parasellar extension, and total resection of the tumor is often not possible, resulting in residual tumor regrowth or reoccurrence. While functional PitNETs can be easily followed for recurrence using hormonal biomarkers, there is no similar parameter to predict recurrence in nfPitNETs, hence delaying early recognition and timely management. Therefore, there is a need to identify prognostic biomarkers that can be used for patient surveillance and as therapeutic targets. This review focuses on summarizing the current evidence on nfPitNETs, with a special focus on potential new biomarkers and therapeutics.
Development of a web application for examining climate data of global lake basins: CGLB

A newly developed web application, Climates of Global Lake Basins (CGLB), combines existing datasets and interactively displays geographical, hydrological, and climatological information for hundreds of lakes around the world. CGLB also provides photographs containing vegetation information as well as quasi-real time monitoring of lake water levels. CGLB can interactively create and animate time series of climatological data in a one-dimensional or two-dimensional (geographical) form. These functions are useful for education, expedition planning, and scientific research. As an example of the application’s use, links between water levels in Kenya’s Lake Turkana and sea surface temperature (SST) and regional precipitation were tested by time-lag correlation analysis. Precipitation showed no significant correlation with the lake water level for time lags of 0, 1, and 2 months. This suggests that variation in land-surface hydrological processes are key to the interannual variability in water levels in the lake. In contrast, SST in the central tropical Pacific was strongly correlated with the lake water level for all time lags. No significant correlation was found between the lake water level and SST in the Indian Ocean adjacent to Kenya, although significant correlations were found between regional precipitation and SST in the Indian Ocean.
Epidemiology of hepatitis D virus infection in Europe: Is it vanishing?

Co‐infection with hepatitis delta virus (HDV) is a challenging health care problem worldwide, estimated to occur in approximately 5%–10% of patients with chronic hepatitis B virus (HBV) infection. While HBV prevalence is decreasing globally, the prevalence of HDV infection is rising in some parts mainly due to injection drug use, sexual transmission and immigration from high endemicity areas. Eastern Europe and the Mediterranean are among the regions with high rates of endemicity for HDV and the immigration from high endemicity areas to Central and Western Europe has changed the HDV epidemiology. We aimed to review the prevalence of HDV infection in Europe. A paucity of publication appears in many European countries. Prevalence studies from some countries are old dated and some other countries did not report any prevalence studies. The studies are accumulated in few countries. Anti‐HDV prevalence is high in Greenland, Norway, Romania, Sweden and Italy. Belgium, France, Germany, Spain, Switzerland, Turkey and United Kingdom reported decreasing prevalences. Among cirrhotic HBV patients, Germany, Italy and Turkey reported higher rates of HDV. The studies including centres across the Europe reported that HIV‐HBV coinfected individuals have higher prevalence of HDV infection. The immigrants contribute the HDV infection burden in Greece, Italy, and Spain in an increasing rate. Previous studies revealed extremely high rates of HDV infection in Germany, Greece, Italy and Sweden. The studies report a remarkably high prevalence of hepatitis delta among HIV/HBV‐coinfected individuals, individuals who inject drugs, immigrants and severe HBV infected patients across Europe. The HDV infection burden still appears to be significant. In the lack of an effective HDV therapy, prevention strategies and active screening of HBV/HDV appear as the most critical interventions for reducing the burden of liver disease related to HDV infection in Europe.
Physical differences in the deep lithosphere of Northern and Central Europe

Abstract A number of large-scale integrated studies, including the TOR and POLONAISE'97 projects, with an emphasis on seismic methods, have been used to elucidate the southwestern boundary (suture zone) between the East European Craton and the Phanerozoic terranes of Western Europe. Results indicate that a thick slab of mantle lithosphere below the craton thins southwestwards beneath the Trans-European Suture Zone and is not seen south of the Variscan front. The thinning is not gradual, but is interrupted by at least two abrupt deep boundaries, the most significant of which corresponds to the surface position of the Tornquist Zone, a major fault. The present geometry of the lithosphere is the result of modification of the margin of the Neoproterozoic continent Baltica by Phanerozoic processes, including the development of the Tornquist Zone and the stretching of the lithosphere in a broad central block SW of this zone. Seismic results and their interpretations from the TOR tomographic project are presented and compared with results from the POLONAISE'97 controlled source project to the SE. Both investigations have shown high-angle, non-symmetrical features extending deep into the mantle.
Exploring Mid-Air Hand Interaction in Data Visualization

Interacting with data visualizations without an instrument or touch surface is typically characterized by the use of mid-air hand gestures. While mid-air expressions can be quite intuitive for interacting with digital content at a distance, they frequently lack precision and necessitate a different way of expressing users' data-related intentions. In this work, we aim to identify new designs for mid-air hand gesture manipulations that can facilitate instrument-free, touch-free, and embedded interactions with visualizations, while utilizing the three-dimensional (3D) interaction space that mid-air gestures afford. We explore mid-air hand gestures for data visualization by searching for natural means to interact with content. We employ three studies-an Elicitation Study, a User Study, and an Expert Study, to provide insight into the users' mental models, explore the design space, and suggest considerations for future mid-air hand gesture design. In addition to forming strong associations with physical manipulations, we discovered that mid-air hand gestures can: promote space-multiplexed interaction, which allows for a greater degree of expression; play a functional role in visual cognition and comprehension; and enhance creativity and engagement. We further highlight the challenges that designers in this field may face to help set the stage for developing effective gestures for a wide range of touchless interactions with visualizations.
Injection drug use and sexually transmitted infections among men who have sex with men: A retrospective cohort study at an HIV/AIDS referral hospital in Tokyo, 2013–2022

Abstract Men who have sex with men (MSM) who use injection drugs (MSM-IDU) are at high risk of sexually transmitted infections (STIs), but the long-term incidence is unclear. We conducted a single-centre retrospective cohort study using the clinical records of non-haemophilia men with human immunodeficiency virus (HIV) who visited the Institute of Medical Science, the University of Tokyo (IMSUT) Hospital, located in Tokyo, Japan, from 2013 to 2022. We analysed 575 patients including 62 heterosexual males and 513 MSM patients, of whom 6.8% (35/513) were injection drug use (IDU). Compared to non-IDU MSM, MSM-IDU had a higher incidence of hepatitis C virus (HCV) (44.8 vs 3.5 /1,000 person-years (PY); incidence rate ratio (IRR) [95% confidence interval (95% CI)], 12.8 [5.5–29.3], p < 0.001) and syphilis (113.8 vs 53.3 /1,000 PY; IRR, 2.1 [1.4–3.1], p < 0.001). The incidence of other symptomatic STIs (amoebiasis, chlamydia, and gonorrhoea infections) was <4/1,000 PY. In multivariable Poisson regression analysis, HCV incidence was associated with MSM (IRR, 1.8 × 106 [9.9 × 105–3.4 × 106], p < 0.001), IDU (IRR, 10.1 [4.0–25.6], p < 0.001), and syphilis infection during the study period (IRR, 25.0 [1.2–518.3]/time/year, p < 0.001). Among men with HIV, the prevalence of IDU in MSM and the long-term incidence of STIs in MSM-IDU were high. IDU and sexual contact are important modes of transmission of HCV among HIV-infected MSM in Tokyo.
Building upon the sugar beverage tax in Mexico: a modelling study of tax alternatives to increase benefits

Introduction In 2014, Mexico implemented a one peso-per-litre tax to sugar-sweetened beverage (SSB). Even though this tax reduced household purchases and predicted population health gains, the magnitude is lower compared with taxes implemented in other settings. In this study, we assessed what would happen if Mexico modified its existing tax to get higher benefits based on currently implemented taxes elsewhere. Methods For each tax scenario, we estimated net benefits as the difference between healthcare savings and lost jobs. We created hypothetical scenarios in which the current tax doubled or would be modified based on existing tax designs around the world including specific taxes (sugar-density or volumetric) and ad-valorem taxes. Results We found that the largest benefits would correspond to a tax increase of 7.4 Mexican pesos (0.45 US dollars (USD)) per SSB litre, following the current tax in Bahrain (the highest tax rate option). This tax is predicted to yield net benefits equivalent to USD 24.7 billion after 10 years of the tax redesign. We also found that sugar-density taxes can result in larger net benefits since, in addition to reductions in consumption associated with responses to prices, they induce product reformulation. Middle-income households are the most benefited group because they reported the highest baseline prevalence of obesity and the largest price elasticity. Conclusion Policymakers should consider pursuing a tax reform adding to the current tax, with significant increases in prices linked to a sugar-density strategy to reach a higher benefit.
Downregulation of ALKBH5 rejuvenates aged human mesenchymal stem cells and enhances their therapeutic efficacy in myocardial infarction

Despite promising results in myocardial infarction (MI), mesenchymal stem cell (MSC)‐based therapy is limited by cell senescence. N6‐methyladenosine (m6A) messenger RNA methylation has been reported to be closely associated with cell senescence. Nonetheless, its role in the regulation of MSC senescence remains unclear. We examined the role of ALKB homolog 5 (ALKBH5) in regulating MSC senescence and determined whether ALKBH5 downregulation could rejuvenate aged MSCs (AMSCs) to improve their therapeutic efficacy for MI. RNA methylation was determined by m6A dot blotting assay. MSC senescence was evaluated by senescence‐associated β‐galactosidase (SA‐β‐gal) staining. A mouse model of acute MI was established by ligation of the left anterior decedent coronary artery (LAD). Compared with young MSCs (YMSCs), m6A level was significantly reduced but ALKBH5 was greatly increased in AMSCs. Overexpression of ALKBH5 reduced m6A modification and accelerated YMSC senescence. Conversely, ALKBH5 knockdown increased m6A modifications and alleviated AMSC senescence. Mechanistically, ALKBH5 regulated the m6A modification and stability of CDKN1C mRNA, which further upregulated CDKN1C expression, leading to MSC senescence. CDKN1C overexpression ameliorated the inhibition of cellular senescence of ALKBH5 siRNA‐treated AMSCs. More importantly, compared with AMSCs, shALKBH5‐AMSCs transplantation provided a superior cardioprotective effect against MI in mice by improving MSC survival and angiogenesis. We determined that ALKBH5 accelerated MSC senescence through m6A modification‐dependent stabilization of the CDKN1C transcript, providing a potential target for MSC rejuvenation. ALKBH5 knockdown rejuvenated AMSCs and enhanced cardiac function when transplanted into the mouse heart following infarction.
Genome-scale analysis of essential gene knockout mutants to identify an antibiotic target process

ABSTRACT We describe a genome-scale approach to identify the essential biological process targeted by a new antibiotic. The procedure is based on the identification of essential genes whose inactivation sensitizes a Gram-negative bacterium (Acinetobacter baylyi) to a drug and employs recently developed transposon mutant screening and single-mutant validation procedures. The approach, based on measuring the rates of loss of newly generated knockout mutants in the presence of antibiotic, provides an alternative to traditional procedures for studying essential functions using conditional expression or activity alleles. As a proof of principle study, we evaluated whether mutations enhancing sensitivity to the β-lactam antibiotic meropenem corresponded to the known essential target process of the antibiotic (septal peptidoglycan synthesis). We found that indeed mutations inactivating most genes needed for peptidoglycan synthesis and cell division strongly sensitized cells to meropenem. Additional classes of sensitizing mutations in essential genes were also identified, including those that inactivated capsule synthesis, DNA replication, or envelope stress response regulation. The essential capsule synthesis mutants appeared to enhance meropenem sensitivity by depleting a precursor needed for both capsule and peptidoglycan synthesis. The replication mutants may sensitize cells by impairing division. Nonessential gene mutations sensitizing cells to meropenem were also identified in the screen and largely corresponded to functions subordinately associated with the essential target process, such as in peptidoglycan recycling. Overall, these results help validate a new approach to identify the essential process targeted by an antibiotic and define the larger functional network determining sensitivity to it.
Determination of progressive stages of type 2 diabetes in a 45% high-fat diet-fed C57BL/6J mouse model is achieved by utilizing both fasting blood glucose levels and a 2-hour oral glucose tolerance test

Type 2 diabetes is considered one of the top ten life-threatening diseases worldwide. Following economic growth, obesity and metabolic syndrome became the most common risk factor for type 2 diabetes. In this regard, high-fat diet-fed C57BL/6J mouse model is widely used for type 2 diabetes pathogenesis and novel therapeutics development. However, criteria for classifying type 2 diabetes progressive stages in this mouse model are yet to be determined, led to the difficulty in experimental end-point decision. In this study, we fed C57BL/6J male mice with 45% high-fat diet, which is physiologically close to human high-fat consumption, and evaluated the progression of type 2 diabetes. After consuming high-fat diet for 4 weeks, mice developed metabolic syndrome, including obesity, significant increase of fasting plasma cholesterol level, elevation of both C-peptide and fasting blood glucose levels. By combining both fasting blood glucose test and 2-hour-oral glucose tolerance test, our results illustrated clear progressive stages from metabolic syndrome into pre-diabetes before onset of type 2 diabetes in C57BL/6J mice given a 45% high-fat diet. Besides, among metabolic measurements, accumulating body weight gain > 16.23 g for 12 weeks could be utilized as a potential parameter to predict type 2 diabetes development in C57BL/6J mice. Thus, these results might support future investigations in term of selecting appropriate disease stage in high-fat diet-fed C57BL/6J mouse model for studying early prevention and treatment of type 2 diabetes.