Miracle-dz/UniFAR-FTUs huggingface dataset:
High complexity cellular barcoding and clonal tracing reveals stochastic and deterministic parameters of radiation resistance

The impact of functional heterogeneity in response to radiation therapy is poorly understood to the present. It remains elusive whether clonal selection of tumor cells in response to ionizing radiation (IR) is a deterministic or stochastic process. We applied high-resolution lentiviral cellular barcoding for quantitative clonal tracking and deconvolution of clonal dynamics in response to IR. Clonal tracking of over 400.000 HNSCC patient-derived tumor cells and the analyses of over 1500 million sequencing reads in clonogenic survival assays reveals that fractionated IR induced a strong selective pressure for clonal reduction. This significantly exceeded uniform clonal survival probabilities indicative for a strong clone-to clone difference within tumor cell lines. IR induced clonal reduction affected the majority of tumor cells ranging between 96-75% and correlated to the degree of radiation sensitivity. Survival and clonogenicity is characterized by an intensive clonal distortion and dominance of individual tumor cells. Survival to IR is driven by a deterministic clonal selection of a smaller population which commonly survives radiation, while increased clonogenic capacity is a result of clonal competition of cells which have been selected stochastically. A 2-fold increase in radiation resistance results in a 4-fold (p<0.05) higher deterministic clonal selection showing that the ratio of these parameters is amenable to radiation sensitivity which correlates to prognostic biomarkers of HNSCC. Evidence for the existence of a rare subpopulation with an intrinsically radiation resistant phenotype commonly surviving IR was found at a frequency of 0.6-3.3% (p<0.001, FDR 3%). With cellular barcoding we introduce a novel functional heterogeneity associated qualitative readout for tracking dynamics of clonogenic survival in response to radiation. This enables the quantification of intrinsically radiation resistant tumor cells from patient samples and reveals the contribution of stochastic and deterministic clonal selection processes in response to IR.
Antiparasitic Drugs in the United States—Two Roads to High Prices

High prescription drug prices contribute significantly to healthcare spending in the United States and compromise patients' access to quality medical care. A number of factors allow drug manufacturers to set much higher prices in the US than in other comparable high-income nations. Price-control depends primarily on the entry and persistence of generic products following the expiration of the market exclusivity period granted to the manufacturer of the brand name drug. Unfortunately, barriers to generic entry are common, allowing off-patent drugs like albendazole to remain relatively expensive despite having been marketed in the US for decades. By contrast, miltefosine became FDA approved more recently and has maintained a high price tag by way of a novel incentive program—the neglected tropical disease (NTD) priority review voucher (PRV) program. The voucher has a high market value and can be sold or transferred well before the drug for which it was awarded becomes available on the market. While both drugs are used to treat parasitic infections that are uncommon in the US, they differ by market and regulatory conditions—each telling an interesting pricing story.
Effect of GnRH 7 Days Before Presynchronization With Simultaneous PGF2α and GnRH on Reproductive Outcomes in Holstein Dairy Cows

We evaluated if an additional GnRH injection 7 days before pre-synchronization with simultaneous PGF2α and GnRH (PG+G) would improve responses to presynchronization, synchronization, and pregnancy per AI (P/AI). We hypothesized that administering GnRH 7 days before PG+G would increase ovulation and corpus luteum (CL) presence at the PG+G, improve response to OvSynch treatments and P/AI. Holstein cows were blocked by parity and randomly assigned to either a PG+G (Control, n = 205); or to GnRH followed 7 days later by PG+G (ExtG, n = 201). At enrollment, Control was left untreated, whereas ExtG received GnRH. Seven days after enrollment, Control and ExtG received PG+G followed by OvSynch 7 days later (GnRH, 7 days PGF2α, 56 h GnRH, 16 h timed AI). Ovarian dynamics were assessed using ultrasonography in a subset of cows (n = 53 for Control; and n = 50 for ExtG) at each treatment, except the 2nd GnRH of OvSynch. Pregnancy diagnosed at 32- and 67-days post AI. Ovulation at enrollment tended (P = 0.06) to be higher for ExtG, but ovulation was not different at PG+G (P = 0.41) and first GnRH of the OvSynch (P = 0.25). There was a tendency (P = 0.08) for ExtG to have larger CL than Control at PGF2α of the OvSynch. There were no differences in CL and follicle sizes in any other treatment point assessed. There were no differences (P = 0.12) in luteolysis between treatments after PG+G. Overall P/AI was similar between treatments on Day 32 (Control = 33.0% vs. ExtG = 34.6%, P = 0.75) and 67 (Control = 31.8% vs. ExtG = 32.5%, P = 0.29) post AI. There was a tendency for an interaction between treatment and parity (P = 0.09) for P/AI at day 67 post-AI. In multiparous cows, ExtG tended to have greater P/AI than Control, whereas, in primiparous cows Control tended to have greater P/AI than ExtG at day 67 post-AI. In conclusion, the effects of GnRH 7 days before PG+G presynchronization lead to positive and negative tendencies, respectively, in multiparous and primiparous cows for P/AI at day 67 post-AI and needs further investigation.
Chitosan nanoparticle vaccine loaded with crude extracellular proteins of C. perfringens and Salmonella flagella is partially protective against necrotic enteritis in broiler chickens

Necrotic enteritis (NE) causes significant economic losses and food shortages world-wide. There are currently no licensed commercial vaccines against NE in broilers. Chitosan nanoparticles were formulated with extracellular proteins of C. perfringens surface-tagged with Salmonella flagellar proteins. One-day-old male broiler chicks were completely randomized to 3 treatments: Non-vaccinated non-challenged as negative control, Vaccinated-challenged, and non-vaccinated challenge as positive control. On day of hatch, d7, and d14 post-hatch, vaccinated-challenged birds were orally gavage with 50μg vaccine in 0.5ml PBS while positive control birds were gavage with 0.5ml PBS only. Birds in the vaccinated-challenged and positive control groups were orally infected on d14 post-hatch, with 5,000 oocysts/bird of E. maxima, followed by log 8 CFU of a virulent strain of C. perfringens on d19, d20, and d21 post-hatch. From d14 to 21 and d14 to 28 post-hatches, mortality in the vaccinated-challenged group was higher than that in the positive control group, approaching statistical significance (p=0.07). On d21 post-hatch, the mean lesion score of 3 birds/cage in the vaccinated-challenged group was higher than the positive control group, approaching statistical significance (p = 0.05). From d 14 to 28 post-hatch, the feed intake was higher and feed conversion ratio lower in the vaccinated-challenged group compared to the positive control group (p<0.05). On d21 post-hatch, antigen specific recall proliferation in the vaccinated-challenged group was higher than that in the negative and positive control groups (p<0.05). On d21 post-hatch, cecal tonsils CD8+ T lymphocytes expression in the vaccinated-challenged group was similar to the negative control group (p>0.05) but higher than that in the positive control group (p<0.05). Finally, vaccination resulted in an increase in ileal mRNA levels of zonula occluding on d21 post-hatch. In conclusion, there were numerical but not statistically significant decrease in NE lesions and mortality in vaccinated and challenged broilers. Further studies are needed to improve the efficacy of the vaccine and understand the mechanism underlying protection in vaccinated birds.
Slip Flow of a Casson Fluid Flow over an Exponentially Stretching Surface and Heat and Mass Transfer

Numerical solutions for a class of nonlinear differential equations arising in heat and mass transfer of a non-Newtonian fluid towards an exponentially stretching surface are obtained. Casson fluid model is used to characterize the non-Newtonian fluid behaviour. Using the similarity transformations, the governing equations have been transformed into a system of ordinary differential equations. These differential equations are highly nonlinear which cannot be solved analytically. Therefore, bvp4c MATLAB solver has been used for solving it. The flow fields and heat and mass transfer are significantly affected by the physical parameters. The effect of increasing values of the Casson parameter and momentum slip parameter is to suppress the velocity field. But the temperature and concentration is enhanced with increasing Casson parameter and momentum slip parameter.
INTERACCIÓN ACÚSTICA/ESTRUCTURA EN LOS EDIFICIOS DE MADERA ACOUSTIC/STRUCTURE INTERACTION IN TIMBER BUILDINGS

Acoustic and structural performance are closely related in mass timber buildings. The low density of the panels related to their high stiffness are the reasons that made Cross Laminated Timber successful in high-risk seismic areas; nevertheless, these same features are the reasons for the relatively poor sound insulation that they provide as bare structural elements. This paper investigates the aspects of mass timber construction in which the optimization of the one is detrimental to the other. Since in both disciplines a relevant part of the transmission of vibrations (or loads) is carried out by the metallic connections, the work focusses on the acoustic and structural performance of CLT junctions, through the analysis of acoustical and structural tests. First, the influence of the kind and number of screws, hold-downs and angle brackets is analyzed in relation to the structural constraints and their acoustic performance. The results show that different connection systems affect the vibration transmission in a relevant manner and must be compensated through an accurate design of the internal linings. Second, the use of the resilient interlayers at the wall-floor junction is discussed. If on one hand it provides a significant increase of the vibration reduction index, on the other the application of this layer can reduce the ultimate load capacity of the junction up to 38% suggesting that the choice of the soundproofing profile must be accurate.
Multiple time-scales of decision-making in the hippocampus and prefrontal cortex

Neural activity underlying decision making has been reported in many brain regions in the form of choice-specific neuronal sequences that span entire task periods. In contrast to this behavioral-timescale activity, recent work has raised the possibility of fast-timescale decision-making activity in hippocampal and prefrontal regions. Whether these are distinct or complementary mechanisms is unknown. Here, we examined simultaneous hippocampal and prefrontal ensemble activity during learning of a spatial working-memory decision task. We found that both regions formed choice-specific sequences at the behavioral timescale (~seconds), as well as two fast timescales (~100-200 ms), theta cycles during navigation and sharp-wave ripples in inter-trial periods. Behavioral-timescale sequences maintained representations of current goals during navigation. In contrast, at the fast timescales, hippocampal sequences supported deliberation, whereas prefrontal ensembles predicted actual choices. Error trials resulted from impaired interaction between behavioral- and fast-timescale mechanisms. These results establish cooperative interaction at multiple timescales for memory-guided decision making.
AIBP-CAV1-VEGFR3 axis dictates lymphatic cell fate and controls lymphangiogenesis

The lymphatics are essential for the maintenance of tissue fluid homeostasis. Accordingly, lymphatic dysfunction contributes to lymphedema. In development, lymphangiogenesis often requires lymphatic endothelial cell (LEC) lineage specification from the venous ECs and subsequent LEC proliferation and migration, all of which are regulated by the VEGFC/VEGFR3 signaling. Cholesterol is essential for proper cell functions and organ development, yet the molecular mechanism by which cholesterol metabolism controls lymphangiogenesis is unknown. We show that the secreted protein, ApoA1 binding protein (AIBP), dictates lymphatic vessel formation by accelerating cholesterol efflux. Loss of Aibp2, the human paralog in zebrafish, impairs LEC progenitor specification and impedes lymphangiogenesis. Mechanistically, we found that caveolin-1 (CAV-1) suppresses VEGFR3 activation in LECs, and that AIBP-regulated cholesterol efflux disrupts lipid rafts/caveolae and reduces CAV-1 bioavailability, which abolishes the CAV-1 inhibition of VEGFR3 signaling, thereby augmenting VEGFR3 activation and increasing lymphangiogenesis. Enhancement of cholesterol efflux with ApoA1 overexpression or inhibition of cholesterol biosynthesis using atorvastatin restores proper lymphangiogenesis in Aibp2 mutant zebrafish. Loss of Cav-1 increases LEC progenitor specification in zebrafish, and rescues lymphangiogenesis in Aibp2-deficient animals. Recombinant AIBP supplement confers profound LEC fate commitment in the mouse embryonic stem cells (mESC) to LEC differentiation model. Furthermore, enhancement of AIBP-CAV-1-VEGFR3 signaling axis promotes VEGFC-engaged adult lymphangiogenesis in mice. Consistent with these data, AIBP expression is reduced in the epidermis of human lymphedematous skin. These studies identify that AIBP-mediated cholesterol efflux is a critical contributor for lymphangiogenesis. Our studies will provide a new therapeutic avenue for the treatment of lymphatic dysfunctions. One Sentence Summary Our studies identify that AIBP-CAV-1-VEGFR3 axis enhances VEGFC-elicited lymphangiogenesis, which will guide a new therapeutic strategy for the treatment of lymphatic dysfunctions.
Neuronal NOX4 knockdown alleviates pathological tau-related alterations in a humanized mouse model of tauopathy

Approximately 44 million people worldwide live with Alzheimer’s disease (AD) or a related form of dementia. Aggregates of the microtubule-associated protein tau are a common marker of these neurodegenerative diseases collectively termed as tauopathies. However, all therapeutic attempts based on tau have failed, suggesting that tau may only indicate a higher-level causal mechanism. For example, increasing levels of reactive oxygen species (ROS) may trigger protein aggregation or modulate protein degradation. Here we show that type 4 NADPH oxidase (NOX), the most abundant isoform of the only dedicated reactive oxygen producing enzyme family, is upregulated in dementia and AD patients and in a humanized mouse model of tauopathy. Both global knockout and neuronal knockdown of the Nox4 gene in mice, diminished the accumulation of pathological tau and positively modified established tauopathy by a mechanism that implicates modulation of the autophagy-lysosomal pathway (ALP). Moreover, neuronal-targeted NOX4 knockdown was sufficient to reduce neurotoxicity and prevented cognitive decline, suggesting a direct and causal role for neuronal NOX4. Thus, NOX4 is a previously unrecognized causal, mechanism-based target in tauopathies and blood-brain barrier permeable specific NOX4 inhibitors could have therapeutic potential even in established disease. Graphical abstract
The Reproductive Biology of Deep-Sea Elasmobranchs and Batoids from Chatham Rise and the Sub-Antarctic Region of New Zealand

The reproductive biology of thirteen poorly studied deep-sea elasmobranch species, on Chatham Rise and the Sub-Antarctic region of New Zealand, was assessed. The study species are all commonly caught as bycatch in commercial fisheries and include: three viviparous species (Centroselachus crepidater, Centrophorus squamosus, Deania calcea), five deep-sea catsharks (Apristurus spp.), and five deep-sea batoid species. However, due to a lack of knowledge on their general biology, ecology, and taxonomy – the impact of fishing on these species is unknown. A species’ resilience to fishing pressure depends on its biological productivity and susceptibility to capture. Accurate assessment of maturity is critical to understanding productivity and the effects of fishing pressure on fished stocks. Maturity is commonly assessed macroscopically, using a visual assessment that lacks precision and relies on subjective judgement. The wide array of macroscopic maturity assessment keys, used internationally, employ various sets of characteristics to define the same reproductive processes, which can lead to errors and inconsistencies in maturity assessment and parameter estimates (e.g. length-at-maturity), making direct comparisons between studies difficult. Objective reproductive measurements (oviducal gland size, follicle size, uterus width, follicle number and gonad weight) were used to assess the validity and quality of the macroscopic maturity staging key used in New Zealand, towards determining the onset of maturity and accurately distinguishing between macroscopic stages. The results showed that no single measurement gave a clear-cut indicator of maturity and some fish classified as ‘maturing’ were very likely ‘mature’. Uterus width, follicle size and gonadosomatic index values were found to be the most useful attributes in determining the onset of maturity. Uterus width and follicle size were also useful in determining differences between different macroscopic stages, whilst gonadosomatic index values were useful in distinguishing between reproductive strategies. Histological observations, with a particular focus on sperm storage, were also used to inform the quality of macroscopic maturity assignment. Sperm storage was observed for the first time in Centroselachus crepidater, Centrophorus squamosus and Brochiraja asperula. This study successfully highlighted problems in the macroscopic maturity assessment key currently used in New Zealand and proposes an improved, more objective macroscopic staging key. The improved key aims: 1) to assist in distinguishing between maturity stages, particularly between stage 2 (maturing), stage 2 (resting) and stage 6 (post-partum) females, by examining the same key reproductive structures across all macroscopic stages, and 2) to provide more representative maturity data for use in fisheries and demographic models, for more robust assessment of the impacts of fishing pressure on poorly studied deep-sea chondrichthyans.
The Philippine Higher Education Sector in the Time of COVID-19

This paper reports the policy-responses of different Philippine higher education institutions (HEIs) to the novel coronavirus, COVD-19 pandemic. It compares these responses with those made by HEIs in Indonesia, Thailand, and Vietnam. Publicly available data and news reports were used to gauge the general public’s reaction to these policies and how the Philippines’ responses fare with its Southeast Asian neighbors. The paper observes that despite the innovations made by Philippine HEIs in terms of alternative learning modes and technologies for delivering education, there are still gaps and challenges in their responses. It recommends that policy-responses and learning innovations should be grounded on a deeper understanding of distance education and should be sensitive to the call of the times.
Cognitive ability, Socioeconomic Status, and Depressive Symptoms: A Gene-Environment-Trait Correlation

Depression is genetically influenced, but the mechanisms that underlie these influences are largely unknown. Recently, shared genetic influences were found between depression and both cognitive ability and educational attainment (EA). Although genetic influences are often thought to represent direct biological pathways, they can also reflect indirect pathways, including modifiable environmental mediations (gene-environment-trait correlations). Here, I tested whether the genetic correlation between cognitive ability and depressive symptoms partly reflects an environmental mediation involving socioeconomic status (SES). As previously done to increase statistical power, and due to their high phenotypic and genetic correlation, EA was used as a proxy for cognitive ability. Summary statistics from a recent genome-wide association study of EA were used to calculate EA polygenic scores. Two independent samples were used: 522 non-Hispanic Caucasian university students from the Duke Neurogenetics Study (277 women, mean age 19.78±1.24 years) and 5,243 white British volunteers (2,669 women, mean age 62.30±7.41 years) from the UK biobank.Mediation analyses in the two samples indicated that higher proxy-cognitive ability polygenic scores predicted higher SES, which in turn predicted lower depressive symptoms.Current findings suggest that some of the genetic correlates of depressive symptoms depend on an environmental mediation and consequently that modifying the environment, specifically through social and economic policies, can affect the genetic influences on depression. Additionally, these results suggest that findings from genetic association studies of depression may be context-contingent and reflect social, cultural, and economic processes in the examined population.
An Efficient Secure Electronic Payment System for E-Commerce

E-commerce implies an electronic purchasing and marketing process online by using typical Web browsers. As e-commerce is quickly developing on the planet, particularly in recent years, many areas of life are affected, particularly the improvement in how individuals regulate themselves non-financially and financially in different transactions. In electronic payment or e-commerce payment, the gateway is a major component of the structure to assure that such exchanges occur without disputes, while maintaining the common security over such systems. Most Internet payment gateways in e-commerce provide monetary information to customers using trusted third parties directly to a payment gateway. Nonetheless, it is recognized that the cloud Web server is not considered a protected entity. This article aims to develop an efficient and secure electronic payment protocol for e-commerce where consumers can immediately connect with the merchant properly. Interestingly, the proposed system does not require the customer to input his/her identity in the merchant’s website even though the customer can hide his/her identity and make a temporary identity to perform the service. It has been found that our protocol has much improved security effectiveness in terms of confidentiality, integrity, non-repudiation, anonymity availability, authentication, and authorization.