Miracle-dz/UniFAR-FTUs huggingface dataset:
Mammalian display to secretion switchable libraries for antibody preselection and high throughput functional screening

ABSTRACT Recently, there has been a co-evolution of mammalian libraries and diverse microfluidic approaches for therapeutic antibody hit discovery. Mammalian libraries enable the preservation of full immune repertoires, produce hit candidates in final format and facilitate broad combinatorial bispecific antibody screening, while several available microfluidic methodologies offer opportunities for rapid high-content screens. Here, we report proof-of-concept studies exploring the potential of combining microfluidic technologies with mammalian libraries for antibody discovery. First, antibody secretion, target co-expression and integration of appropriate reporter cell lines enabled the selection of in-trans acting agonistic bispecific antibodies. Second, a functional screen for internalization was established and comparison of autocrine versus co-encapsulation setups highlighted the advantages of an autocrine one cell approach. Third, synchronization of antibody-secreting cells prior to microfluidic screens reduced assay variability. Furthermore, a display to secretion switchable system was developed and applied for pre-enrichment of antibody clones with high manufacturability in conjunction with subsequent screening for functional properties. These case studies demonstrate the system’s feasibility and may serve as basis for further development of integrated workflows combining manufacturability sorting and functional screens for the identification of optimal therapeutic antibody candidates.
Physician Perceptions of the Clinical, Economic and Humanistic Burden of Disease and Unmet Needs in Myelofibrosis: Preliminary Findings from the MPN Landmark Survey in Indonesia

Background/ Objective: Myelofibrosis (MF) is a severe form of Myeloproliferative Neoplasms (MPNs). It is a rare disease in Indonesia and is reportedly associated with symptoms resulting in poor quality-of-life, pre-mature mortality, disability, and loss of productivity. As the disease is rare, there are limited published information around MF, particularly in Indonesia. Methods: A cross-sectional survey was designed and administered between November and December 2021 among practicing Haematologists-Medical Oncologists who are experienced in treating patients with MF. The objectives of the survey were to assess physician’s understanding of the overall diagnosis of MF, the disease burden, current treatment practices and remaining unmet needs. Outcomes were analysed descriptively. Result: The survey was completed by 30 respondents. The findings suggest that symptom burden is high and has a significant negative impact on quality-of-life. Treatment burden is also high which can result in high healthcare resource utilisation. Physicians expressed need for novel therapeutic options and improved access and coverage for such options. There is also a need to improve access and coverage for JAK V617F testing locally and local hospital infrastructures should be upgraded to ensure MF is accurately diagnosed. Patient may benefit from information on MPN, which may result in earlier presentation, diagnosis and treatment which can improve outcomes. Conclusion: The findings align with previous international research reporting that symptoms and treatment burden are high, and that novel therapeutic options are needed. Additional patient research might be required to better understand the patient experience of MF and how this can be improved.
Socio-Economic Differences in Mortality: Implications for Pensions Policy

The analyses included in the report show that there are big socio-economic differences in mortality, especially for men, and they appear to have become bigger over time. The report discusses implications of mortality differentials for five major areas of pension policy: the progressivity of the pension system, the pension eligibility age, the retirement incentives, future pension expenditures and private pensions. The empirical work shows that the mortality differentials reduce progressivity in pension systems. Moreover, there is empirical evidence that raising retirement age is not more unfair to socio-economic groups with lower life expectancy. Les analyses presentees ici montrent qu’il existe de fortes differences socioeconomiques en termes de mortalite, surtout chez les hommes, et qu’elles se sont apparemment accentuees au fil du temps. Ce document examine les consequences des ecarts de mortalite pour cinq grands aspects de la politique de retraite : la progressivite du systeme de retraite, l’âge d’ouverture des droits a pension, les incitations a la retraite, les depenses de retraite futures et les pensions privees. Les travaux empiriques font apparaitre que les ecarts de mortalite reduisent la progressivite des regimes de retraite. De plus, des donnees d’observation montrent que le relevement de l’âge de la retraite n’est pas plus penalisant pour les categories socioeconomiques ayant une esperance de vie plus courte.
Histological and immunohistochemical characterization of mucosa‐associated lymphoid tissue and antigen‐presenting cells in trachea and lung of cattle

The presence of bronchus‐associated lymphoid tissue (BALT) and its structural components has been described in different healthy animal species and in animals with diseases of the respiratory tract. In contrast to normal mammals, BALT is absent in healthy human adult lungs, but has been found in the lungs of children. The histological characteristics of organized mucosa‐associated lymphoid tissue (MALT), its subsets of immune cells and their in situ distribution in the lung of healthy subadult and adult cattle shows close similarities with BALT in humans and other animal species such as sheep, horses and pigs. This study clearly demonstrates that organized MALT also occurs in the tracheal mucosa of cattle. The absence of tracheal MALT and BALT in calves suggest that these structures are not constitutive. In the mucosa of bovine trachea, bronchi and bronchioli, MHC II+ and CD11c+ dendritic cells (DCs) are located in the epithelium and in the lamina propria mucosae. These DCs are already present in calves soon after birth. Examination of tangential epithelial sheets shows that in the bovine tracheal epithelium, like in man and rat, a dense network of MHC II+ and CD11c+ DCs exists and that their number is considerably higher than in conventional transverse sections. In the bovine tracheal and bronchial epithelium, MHC II+ DCs are extending their dendrites towards the lumen indicating that these DCs possibly are involved in sampling of luminal antigens. The presence of significantly higher numbers of MHC II+ DCs in the tracheal and bronchial/bronchiolar mucosa of older cattle in than in calves possibly results from local stimulation with exogenous antigens during postnatal life. Detection of DCs expressing the costimulatory molecules CD80 and CD86 in calves and cattle suggests maturation of DCs, which is most likely induced by stimulation with exogenous antigens.
Growth Faults of South Louisiana

ABSTRACT A detailed summary of the physical characteristics of over 1452 fault cuts representing 312 faults is given. As a preface to the origin of South Louisiana faulting a pre-Cenozoic history of the Gulf Coast is constructed. In this respect it is suggested that the basement rocks of the South Louisiana area were an extension of the continental area of North America and were not oceanic in origin. The area was positive through all of the Paleozoic and was not submerged by marine waters until after salt deposition. The first stages of geosynclinal development, the geology of the domeless area of central Louisiana, the Eocene fault trend and the Oligocene domal trend are discussed. Growth faults are defined as those faults which have a substantial increase in throw with depth and across which, from the upthrown to the downthrown block, there is a great thickening of correlative section. Trend growth faults are regionally sustained growth faults. A theory of origin and development of these trend growth faults is made in which it is maintained that the faults originated as a result of folding and later developed their growth characteristics along an inner to middle shelf area (similar to our present continental shelf) in an environment of rapid, fairly shallow water deposition. Evidence for this concept is given in detail in which it is shown that growth faulting could have developed contemporaneously with sedimentation only in an environment where the sea floor was undergoing vigorous, nearly constant agitation by shallow water disturbing agents. A reference area is shown in which the theoretical concepts are evaluated with respect to known phenomena. The economic implications of the paper with respect to the entrapment of gas and oil are given.
Regularized Machine Learning Models for Prediction of Metabolic Syndrome Using GCKR, APOA5, and BUD13 Gene Variants: Tehran Cardiometabolic Genetic Study

Objective: Metabolic syndrome (MetS) is a complex multifactorial disorder that considerably burdens healthcare systems. We aim to classify MetS using regularized machine learning models in the presence of the risk variants of GCKR, BUD13 and APOA5, and environmental risk factors. Materials and Methods: A cohort study was conducted on 2,346 cases and 2,203 controls from eligible Tehran Cardiometabolic Genetic Study (TCGS) participants whose data were collected from 1999 to 2017. We used different regularization approaches [least absolute shrinkage and selection operator (LASSO), ridge regression (RR), elasticnet (ENET), adaptive LASSO (aLASSO), and adaptive ENET (aENET)] and a classical logistic regression (LR) model to classify MetS and select influential variables that predict MetS. Demographics, clinical features, and common polymorphisms in the GCKR, BUD13, and APOA5 genes of eligible participants were assessed to classify TCGS participant status in MetS development. The models’ performance was evaluated by 10-repeated 10-fold crossvalidation. Various assessment measures of sensitivity, specificity, classification accuracy, and area under the receiver operating characteristic curve (AUC-ROC) and AUC-precision-recall (AUC-PR) curves were used to compare the models. Results: During the follow-up period, 50.38% of participants developed MetS. The groups were not similar in terms of baseline characteristics and risk variants. MetS was significantly associated with age, gender, schooling years, body mass index (BMI), and alternate alleles in all the risk variants, as indicated by LR. A comparison of accuracy, AUCROC, and AUC-PR metrics indicated that the regularization models outperformed LR. Regularized machine learning models provided comparable classification performances, whereas the aLASSO model was more parsimonious and selected fewer predictors. Conclusion: Regularized machine learning models provided more accurate and parsimonious MetS classifying models. These high-performing diagnostic models can lay the foundation for clinical decision support tools that use genetic and demographical variables to locate individuals at high risk for MetS.
Acrolein increases the concentration of intracellular Zn2⁺ by producing mitochondrial reactive oxygen species in A549 cells

Smoking or occupational exposure leads to low concentrations of acrolein on the surface of the airways. Acrolein is involved in the pathophysiological processes of various respiratory diseases. Reports showed that acrolein induced an increase in mitochondrial reactive oxygen species (mROS). Furthermore, exogenous H₂O₂ was found to increase intracellular Zn2⁺ concentration ([Zn2⁺]ᵢ). However, the specific impact of acrolein on changes in intracellular Zn2⁺ levels has not been fully investigated. Therefore, this study aimed to investigate the effects of acrolein on mROS and [Zn2⁺]ᵢ in A549 cells. We used Mito Tracker Red CM-H2Xros (MitoROS) and Fluozin-3 fluorescent probes to observe changes in mROS and intracellular Zn2⁺. The results revealed that acrolein increased [Zn2⁺]ᵢ in a time- and dose-dependent manner. Additionally, the production of mROS was observed in response to acrolein treatment. Subsequent experiments showed that the intracellular Zn2⁺ chelator TPEN could inhibit the acrolein-induced elevation of [Zn2⁺]ᵢ but did not affect the acrolein-induced mROS production. Conversely, the acrolein-induced elevation of mROS and [Zn2⁺]ᵢ were significantly decreased by the inhibitors of ROS formation (NaHSO₃, NAC). Furthermore, external oxygen free radicals increased both [Zn2⁺]ᵢ levels and mROS production. These results demonstrated that acrolein-induced elevation of [Zn2⁺]ᵢ in A549 cells was mediated by mROS generation, rather than through a pathway where [Zn2⁺]ᵢ elevation leads to mROS production.
Total and Regional Fat/Muscle Mass Ratio and Risks of Incident Cardiovascular Disease and Mortality

Background To evaluate the sex‐specific associations of total and regional fat/muscle mass ratio (FMR) with cardiovascular disease (CVD) incidence and mortality, and to explore the underlying mechanisms driven by cardiometabolites and inflammatory cells. We compared the predictive value of FMRs to body mass index. Methods and Results This population‐based, prospective cohort study included 468 885 UK Biobank participants free of CVD at baseline. Fat mass and muscle mass were estimated using a bioelectrical impedance assessment device. FMR was calculated as fat mass divided by muscle mass in corresponding body parts (total body, trunk, arm, and leg). Multivariable Cox proportional hazards models and mediation analyses were used. During 12.5 years of follow‐up, we documented 49 936 CVD cases and 4158 CVD deaths. Higher total FMR was associated with an increased risk of incident CVD (hazard ratios [HRs] were 1.63 and 1.83 for men and women, respectively), ischemic heart disease (men: HR, 1.61; women: HR, 1.81), myocardial infarction (men: HR, 1.72; women: HR, 1.49), and congestive heart failure (men: HR, 2.25; women: HR, 2.57). The positive associations of FMRs with mortality from total CVD or its subtypes were significant mainly in trunk and arm for male patients (P for trend <0.05). We also identified 8 cardiometabolites and 5 inflammatory cells that partially mediated FMR‐CVD associations. FMRs were modestly better at discriminating cardiovascular mortality risk. Conclusions Higher total and regional FMRs were associated with an increased risk of CVD and mortality, partly mediated through cardiometabolites and inflammatory cells. Early monitoring of FMR should be considered to alleviate CVD risk. FMRs were superior to body mass index in predicting CVD mortality.
Ultrasound/MRI-targeted biopsy versus saturated trans-rectal ultrasound guided biopsy of prostate in patients with primary negative conventional biopsy and still elevated PSA: a prospective randomized clinical trial.

INTRODUCTION To evaluate and compare the rate of cancer detection by two methods Saturated TRUS guided biopsy and ultrasound/magnetic resonance imaging (US/MRI)-targeted biopsy in patients with primary negative prostate cancer in standard 12 cores biopsy evaluation but still have elevated prostate specific antigen (PSA). MATERIALS AND METHODS From 105 patients who met our inclusion criteria, 53 patients underwent US/MRI-targeted biopsy and 52 remaining patients underwent Saturated 20 core TRUS guided biopsy in a prospective randomized clinical trial. RESULTS The mean age (±SD) was 62.2 (±8.2) year. The mean PSA (±SD) was 11.8 (±7.5) ng/ml. The mean prostate volume was 56.1 (±24.8) ml. Adenocarcinoma of prostate was detected in 9/52 (17.3%) patients in groups saturated biopsy and 14/53 (26.4%) patients in US/MRI-targeted biopsy group and there was no difference in cancer detection rate between 2 groups (P=0.252). except four patients with fever (two in each group), there was no other serious complication (Clavien grade 3 or higher) occurred in the patients. In the multivariate analysis, higher pre-procedure PSA, lower size of the prostate, pathology of ASAP and presence of nodule in DRE were independent predictors for cancer detection in second biopsy (P=0.036, P<0.001, P=0.013 and P=0.031, respectively). CONCLUSION We didn't find any superiority in cancer detection rate and any different in complication rate between these two methods saturated TRUS guided biopsy and US/MRI-targeted biopsy.
Impact of Physician Dual Practices on a Pediatric-Oncology Outreach-Program

Objective: Physician dual practices (PDP) can be defined as ‘doctors combining clinical work in public and private health-sector. ’ This study explores the impact of PDP on a long-term pediatric-oncology outreach-program between large referral hospitals in the Netherlands, Indonesia and Kenya. Methods: This cross-sectional descriptive study used a self-administered semi-structured survey. The most senior doctor from each partner site was interviewed in June 2022. The survey contained 70 closed-ended and 7 open-ended questions and took 30-45 minutes to complete. Closed-ended questions were evaluated on 2-5 point rating scales. Informed consent was acquired and respondents endorsed the final report. Results: In the Netherlands an estimated 0-20% of senior doctors combine work in public and private-sector, while 60-80% do so in Indonesia and Kenya according to the respondents. In Indonesia and Kenya, most of doctors are involved in PDP to augment low government salaries. Impact of PDP on pediatric-oncology care is minimal in the Netherlands, but detrimental in Indonesia and Kenya: shortage of experienced doctors, limited supervision of junior staff, slow diagnostics and delays in chemotherapy administration ultimately lead to undermining of the quality of care and adverse patient outcomes. Conclusions: PDP adversely impact patient care at the Indonesian and Kenyan partner sites of a pediatric-oncology outreach-program. Strategies addressing PDP in resource-poor settings are required to improve treatment outcomes and survival of children with cancer.
A Numerical Simulation of Horizontal Axis Hydrokinetic Turbine with and without Augmented Diffuser

The hydrodynamic analysis of a horizontal axis hydrokinetic turbine is carried out, using a third-generation diffuser. The turbine constituted of three blades and a radius of 0.75 m, using the hydrodynamic profile NREL S822 for the design of both the blades and the housing of the 3rd generation diffuser. Both models were meshed and subsequently hydrodynamically simulated using the ANSYS CFX 18.2® program in a transient state. For analysis, it was used the k-e turbulence model, with a water input speed of 1.5 m/s and a variation of the angular velocity from 0 to 160 RPM, with steps of 10 RPM. As a result, the power coefficient (Cp) of the turbine was obtained with and without a diffuser, in addition to the velocity profile of each model. The maximum power coefficient (Cpmax) reached by the turbine with and without diffuser is 0.487 at a TSR of 95, and 0.285 at a TSR of 100, respectively, equivalent to an increase of 41.5% of Cp with respect to the turbine without diffuser, and 82.1% with relation to the Betz limit. Speeds are reached between 1.5 to 2.1 m/s and 1.5 to 1.8 m/s, upstream of the turbine with and without diffuser, respectively, and from 2.3 to 2.6 m/s and 1.8 to 2.1 m/s downstream of it, in the same order
Emerging Treatment Options for the Treatment of Metastatic Urothelial Cancer: Therapeutic Potential of Enfortumab Vedotin

: Enfortumab vedotin (EV) is an antibody–drug conjugate with humanized anti-Nectin-4 antibody linked with a microtubule-disrupting agent called monomethyl auristatin E. Nectin-4 is a cellular adhesion protein that is overexpressed in urothelial cancer. EV was approved in December 2019 for patients with locally advanced or metastatic urothelial cancer who previously received platinum-based chemotherapy and immune checkpoint inhibitors. Here, we reviewed the clinical efficacy and safety data that led to the accelerated approval of EV for treating patients with metastatic urothelial cancer. Emerging clinical data on EV-based combinational therapeutic trials for metastatic urothelial cancer were also reviewed.
Treatment outcomes of secukinumab in adult patients with moderate‐to‐severe plaque psoriasis in China: A real‐world multicenter retrospective study

Secukinumab is effective in treating patients with moderate‐to‐severe plaque psoriasis. However, most studies assessing its effectiveness in routine clinical settings in China are mostly single‐center studies with a limited sample size. The objective of this study was to assess secukinumab's efficacy, treatment patterns, and characteristics in patients with moderate‐to‐severe plaque psoriasis. This 24‐week, multicenter (n = 5) retrospective study analyzed the data of Chinese adult patients with moderate‐to‐severe plaque psoriasis who initiated secukinumab treatment between May 2019 and March 2020. The Psoriasis Area and Severity Index (PASI), body surface area (BSA), Investigator's Global Assessment Modified 2011 (IGA mod 2011), and Dermatology Life Quality Index (DLQI) were assessed. Dermatologists documented the treatment dosage and modification reasons. Of the 244 secukinumab‐naïve patients, most were men (73.4%, 179/244) and weighed 60–90 kg (72.8%, 177/243). The mean (SD) age at secukinumab initiation was 38.1 (11.6) years, and the disease duration was 13.5 (7.9) years. Most patients (97.1%, 237/244) received secukinumab 300 mg. At weeks 4, 12, 16, and 24, the proportion of patients achieving PASI 75 (≥75% reduction from baseline) was 40.0%, 92.1%, 88.4%, and 88.9%, respectively; PASI 90 was 15.0%, 73.7%, 81.4%, and 68.3%, respectively; and PASI 100 was 8.7%, 40.8%, 58.1%, and 41.3%, respectively. During the same periods, BSA and IGA mod 2011 showed similar improvement trends. An increasing proportion of patients achieved DLQI of 0–1 (21.6%, 65.7%, 75.0%, and 80.3%, respectively). Treatment modification was highest at week 12. The average interval between two administrations after week 4 was 62.95 days. Secukinumab was highly effective in improving the PASI, IGA, BSA, and DLQI in Chinese patients with moderate‐to‐severe plaque psoriasis throughout the first 24 weeks. The treatment pattern for Chinese patients differs from that in the clinical guidelines.