Miracle-dz/UniFAR-FTUs huggingface dataset:
Two-Dimensional Pickup and Delivery Routing Problem with Loading Constraints

In this paper, a special case of the vehicle routing problem in which the demands consist in a set of rectangular two-dimensional weighted items is considered. The vehicles have a two-dimensional loading surface and a maximum weight capacity. These problems have a routing and a packing component. A framework to handle the loading of a vehicle is proposed. A Constraint Programming loading model based on a scheduling approach is developed. It is also shown that the non-overlapping rectangle constraint can be extended to handle a practical constraint called sequential loading constraint.
Adrenal gland plasticity in lactating rats and mice is sufficient to maintain basal hypersecretion of corticosterone

Abstract Increased basal glucocorticoid secretion and a reduced glucocorticoid response during acute stress, despite only minor changes in the secretion of the major secretagogue adrenocorticotropic hormone (ACTH), have been documented in the peripartum period in several species. We recently showed that the adrenal gland, the site of glucocorticoid synthesis, undergoes substantial postpartum-associated plasticity in the rat at mid-lactation. Here, we asked the question whether adrenal changes already take place around parturition in the rat and in another species, namely the mouse. After demonstrating that several components of the adrenal machinery mediating cholesterol supply for steroidogenesis, including protein levels of hormone-sensitive lipase, low-density lipoprotein receptor (LDLR) and scavenger receptor class-B type-1 (SRB1), are upregulated, while hydroxymethylglutaryl coenzyme A reductase (HMGCR) is downregulated in the lactating rat one day after delivery, as previously observed at mid-lactation, we demonstrated profound changes in the mouse. In detail, protein expression of LDLR, SRB1, HMGCR and adrenal lipid store density were increased in the mouse adrenal one day after parturition as tested via western blot analysis and oil-red lipid staining, respectively. Moreover, using in vitro culture techniques, we observed that isolated adrenal explants from lactating mice secreted higher levels of corticosterone under basal conditions, but showed impaired responsiveness to ACTH, mimicking the in vivo scenario. These results suggest that mechanisms of adaptation in the maternal adrenal after delivery, namely increased cholesterol availability and decreased ACTH sensitivity, are crucial for the basal increase in circulating glucocorticoids and maternal stress hyporesponsiveness that are typical of this period.
Computer-aided diagnosis of lung carcinoma using deep learning - a pilot study

Aim: Early detection and correct diagnosis of lung cancer are the most important steps in improving patient outcome. This study aims to assess which deep learning models perform best in lung cancer diagnosis. Methods: Non-small cell lung carcinoma and small cell lung carcinoma biopsy specimens were consecutively obtained and stained. The specimen slides were diagnosed by two experienced pathologists (over 20 years). Several deep learning models were trained to discriminate cancer and non-cancer biopsies. Result: Deep learning models give reasonable AUC from 0.8810 to 0.9119. Conclusion: The deep learning analysis could help to speed up the detection process for the whole-slide image (WSI) and keep the comparable detection rate with human observer.
Serine protease inhibitors serpina1 and serpina3 are down-regulated in bone marrow during hematopoietic progenitor mobilization

Mobilization of hematopoietic progenitor cells into the blood involves a massive release of neutrophil serine proteases in the bone marrow. We hypothesize that the activity of these neutrophil serine proteases is regulated by the expression of naturally occurring inhibitors (serpina1 and serpina3) produced locally within the bone marrow. We found that serpina1 and serpina3 were transcribed in the bone marrow by many different hematopoietic cell populations and that a strong reduction in expression occurred both at the protein and mRNA levels during mobilization induced by granulocyte colony-stimulating factor or chemotherapy. This decreased expression was restricted to the bone marrow as serpina1 expression was maintained in the liver, leading to no change in plasma concentrations during mobilization. The down-regulation of serpina1 and serpina3 during mobilization may contribute to a shift in the balance between serine proteases and their inhibitors, and an accumulation of active neutrophil serine proteases in bone marrow extravascular fluids that cleave and inactivate molecules essential to the retention of hematopoietic progenitor cells within the bone marrow. These data suggest an unexpected role for serpina1 and serpina3 in regulating the bone marrow hematopoietic microenvironment as well as influencing the migratory behavior of hematopoietic precursors.
Presence of a Phytoplasma Associated with Witches-Broom Disease in Ugni molinae Turcz. and Gaultheria phillyreifolia (Pers.) Sleumer Determined by DAPI, PCR, and DNA Sequencing

Murta (Ugni molinae Turcz.) and common chaura (Gaultheria phillyreifolia (Pers.) Sleumer) are native species of Chile. Plants of both species have shown over-branching like witches’ broom. The causal agents of these symptoms in many plants are phytoplasma. To verify the presence of these microorganisms, DAPI (4’,6-diamidino2-phenylindole) staining analysis and polymerase chain reaction (PCR) were performed in symptomatic and asymptomatic plants. Positive PCR samples were sequenced to identify the pathogens involved. In individuals of both species with witches’ broom symptoms, DAPI staining showed fluorescent bodies in the phloem tissues, but not in asymptomatic plants. Verification by nested-PCR, phytoplasmatic DNA was amplified from diseased murta and chaura, but not in apparently healthy plants. Sequencing of amplified products allowed locating phytoplasma within the ash yellows group (16SrVII) and related to Candidatus phytoplasma fraxini. This is the first report of phytoplasma in Chilean native species. Considering the diversity of plant species infected by the ash yellows group suggests that G. phillyreifolia and U. molinae could be a phytoplasma reservoir for other economically important agricultural crops.
Systemic Treatment Strategies for Patients with Hereditary Breast Cancer Syndromes.

Hereditary breast cancer syndromes are associated with an increased risk of breast cancer and constitute a unique patient population, making up approximately 5%-10% of breast cancer cases in the United States. By virtue of the germline mutations that define these syndromes, invasive breast cancers in these patients have unique mechanisms that can be rationally targeted for therapeutic opportunities distinct from standard of care treatments in nongermline mutation associated breast cancers. This review intends to describe existing data on several of the most common hereditary breast cancer syndromes, including BRCA-related breast cancer syndrome, Li-Fraumeni syndrome, Cowden syndrome, Peutz-Jeghers syndrome, and hereditary diffuse gastric cancer syndrome, specifically focusing on rational therapeutics utilized in these distinct patient subgroups and completed or ongoing clinical trials evaluating their efficacy. By exploiting the distinct biologic features associated with these syndromes, tailored treatment strategies have the potential for improved efficacy and lower toxicity. Knowledge of the emergence of these targeted cancer therapies is critical for appropriate management in these patients, extending beyond treatment to highlight the need for appropriate genetic screening to allow for early recognition of these patients and therefore appropriate treatment. IMPLICATIONS FOR PRACTICE Molecular testing allows for identification of germline mutations that place individuals at high risk for breast cancer and that are associated with distinct histopathology and molecular characteristics that define the invasive breast cancer cases that these patients develop. These unique characteristics may ultimately provide rational targets for systemic treatments with improvements in both morbidity and efficacy. Identification of patients with these germline mutations is important for not only appropriate screening and prophylaxis, but knowledge of therapies specifically targeting several of the most common hereditary breast cancer syndromes is essential to ensure appropriate treatment of invasive breast cancers in these patients.
Is minimally invasive colon resection better than traditional approaches?: First comprehensive national examination with propensity score matching.

IMPORTANCE Minimally invasive colectomies are increasingly popular options for colon resection. OBJECTIVE To compare the perioperative outcomes and costs of robot-assisted colectomy (RC), laparoscopic colectomy (LC), and open colectomy (OC). DESIGN, SETTING, AND PARTICIPANTS The US Nationwide Inpatient Sample database was used to examine outcomes and costs before and after propensity score matching across the 3 surgical approaches. This study involved a sample of US hospital discharges from 2008 to 2010 and all patients 21 years of age or older who underwent elective colectomy. MAIN OUTCOMES AND MEASURES In-hospital mortality, complications, ostomy rates, conversion to open procedure, length of stay, discharge disposition, and cost. RESULTS Of the 244129 colectomies performed during the study period, 126284 (51.7%) were OCs, 116261 (47.6%) were LCs, and 1584 (0.6%) were RCs. In comparison with OC, LC was associated with a lower mortality rate (0.4% vs 2.0%), lower complication rate (19.8% vs 33.2%), lower ostomy rate (3.5 vs 13.0%), shorter median length of stay (4 vs 6 days), a higher routine discharge rate (86.1% vs 68.4%), and lower overall cost than OC ($11742 vs $13666) (all P<.05). Comparison between RC and LC showed no significant differences with respect to in-hospital mortality (0.0% vs 0.7%), complication rates (14.7% vs 18.5%), ostomy rates (3.0% vs 5.1%), conversions to open procedure (5.7% vs 9.9%), and routine discharge rates (88.7% vs 88.5%) (all P>.05). However, RC incurred a higher overall hospitalization cost than LC ($14847 vs $11966, P<.001). CONCLUSIONS AND RELEVANCE In this nationwide comparison of minimally invasive approaches for colon resection, LC demonstrated favorable clinical outcomes and lower cost than OC. Robot-assisted colectomy was equivalent in most clinical outcomes to LC but incurred a higher cost.
An automated pipeline for mitochondrial segmentation on ATUM-SEM stacks

It is possible now to look more closely into mitochondrial physical structures due to the rapid development of electron microscope (EM). Mitochondrial physical structures play important roles in both cellular physiology and neuronal functions. Unfortunately, the segmentation of mitochondria from EM images has proven to be a difficult and challenging task, due to the presence of various subcellular structures, as well as image distortions in the sophisticated background. Although the current state-of-the-art algorithms have achieved some promising results, they have demonstrated poor performances on these mitochondria which are in close proximity to vesicles or various membranes. In order to overcome these limitations, this study proposes explicitly modelling the mitochondrial double membrane structures, and acquiring the image edges by way of ridge detection rather than by image gradient. In addition, this study also utilizes group-similarity in context to further optimize the local misleading segmentation. Then, the experimental results determined from the images acquired by automated tape-collecting ultramicrotome scanning electron microscopy (ATUM-SEM) demonstrate the effectiveness of this study's proposed algorithm.
Diagnosis and Treatment of Urticaria and Angioedema: A Worldwide Perspective

Urticaria and angioedema are common clinical conditions representing a major concern for physicians and patients alike. The World Allergy Organization (WAO), recognizing the importance of these diseases, has contributed to previous guidelines for the diagnosis and management of urticaria. The Scientific and Clinical Issues Council of WAO proposed the development of this global Position Paper to further enhance the clinical management of these disorders through the participation of renowned experts from all WAO regions of the world. Sections on definition and classification, prevalence, etiology and pathogenesis, diagnosis, treatment, and prognosis are based on the best scientific evidence presently available. Additional sections devoted to urticaria and angioedema in children and pregnant women, quality of life and patient-reported outcomes, and physical urticarias have been incorporated into this document. It is expected that this article will supplement recent international guidelines with the contribution of an expert panel designated by the WAO, increasing awareness of the importance of urticaria and angioedema in medical practice and will become a useful source of information for optimum patient management worldwide.
Detecting Remote Sequence Homology in Disordered Proteins: Discovery of Conserved Motifs in the N-Termini of Mononegavirales phosphoproteins

Paramyxovirinae are a large group of viruses that includes measles virus and parainfluenza viruses. The viral Phosphoprotein (P) plays a central role in viral replication. It is composed of a highly variable, disordered N-terminus and a conserved C-terminus. A second viral protein alternatively expressed, the V protein, also contains the N-terminus of P, fused to a zinc finger. We suspected that, despite their high variability, the N-termini of P/V might all be homologous; however, using standard approaches, we could previously identify sequence conservation only in some Paramyxovirinae. We now compared the N-termini using sensitive sequence similarity search programs, able to detect residual similarities unnoticeable by conventional approaches. We discovered that all Paramyxovirinae share a short sequence motif in their first 40 amino acids, which we called soyuz1. Despite its short length (11–16aa), several arguments allow us to conclude that soyuz1 probably evolved by homologous descent, unlike linear motifs. Conservation across such evolutionary distances suggests that soyuz1 plays a crucial role and experimental data suggest that it binds the viral nucleoprotein to prevent its illegitimate self-assembly. In some Paramyxovirinae, the N-terminus of P/V contains a second motif, soyuz2, which might play a role in blocking interferon signaling. Finally, we discovered that the P of related Mononegavirales contain similarly overlooked motifs in their N-termini, and that their C-termini share a previously unnoticed structural similarity suggesting a common origin. Our results suggest several testable hypotheses regarding the replication of Mononegavirales and suggest that disordered regions with little overall sequence similarity, common in viral and eukaryotic proteins, might contain currently overlooked motifs (intermediate in length between linear motifs and disordered domains) that could be detected simply by comparing orthologous proteins.
ACID/BASE CHEMISTRY FOR ASPHALT MODIFICATION (WITH DISCUSSION)

The advent of Superpave heightened the need for asphalts with an extended range between the temperature at which the asphalt has sufficient modulus to resist rutting (T sub h) and the temperature limit for critical stiffness to prevent thermal cracking (T sub l). Acidic and basic modifiers have been shown to improve asphalt stiffness, elevating T sub h without unduly harming T sub l. The low cost of these materials relative to polymers and other modifiers that improve asphalt temperature susceptibility makes their use compelling in a competitive environment focused upon manufacturing Performance-Graded (PG) asphalt binders. Amine antistripping agents (ASAs) have long been added to asphalt mixtures to reduce deleterious effects of moisture. The antistripping activity of the amine is typically attributed to the nitrogen lone pair of electrons, which show strong affinity for the aggregate surface in the presence of water. What happens, then, when such basic compounds are added to mixtures containing acid-modified asphalt? Fundamental laws of chemistry would dictate that the acid modifier and the basic ASA may react with each other to form an amine salt. This raises several questions: Will T sub h drop if the acid modifier is neutralized? Can the ASA continue to resist moisture if the active electron pairs have been blocked by the acidic protons (H+)? Will the product salt contribute to moisture damage in the pavement, either by leaving the asphalt film more permeable to water, or by emulsifying the asphalt in the presence of heat, moisture, and traffic? To address these questions, a research study was initiated by the Kansas Department of Transportation (KDOT). Phase 1 was a binder study, with dynamic shear rheometry (DSR) measurements of T sub h on asphalt binders modified with varying concentrations of phosphoric acid, two different modified fatty imidazoline antistripping agents, and blends of acid and imidazoline. These same binders were then dissolved in toluene and extracted with water to determine extracted pH and to monitor for possible emulsification of asphalt into the aqueous phase. Phase 2 was a mixture stripping study. A moisture sensitive aggregate was blended with PG 58-22 that had been modified with various acid/base combinations. The resulting mixtures were evaluated for moisture damage. Hamburg and Asphalt Pavement Analyzer wheel-tracking tests were run alongside KDOT's retained tensile strength test (KT-56), since it was theorized that mechanical loading might be necessary to simulate damage from in-situ asphalt emulsification. Key findings were: phosphoric acid additives significantly increased asphalt stiffness at high temperatures and moisture damage may occur if acid is used at elevated concentrations; ASAs consistently reduced moisture damage in both KT-56 and wheel-tracking tests; phosphoric acid reacts with ASA, resulting in significant moisture damage; and binder T sub h should be specified or confirmed following amine addition when a mix requires ASA.
See No Spanish: Implicit Cues, Personal Experience, and Attitudes toward Immigration

Are Americans’ responses to immigration cues similar to their responses to racial cues? This paper explores how implicit and explicit cues influence immigration attitudes. To explain explicit cues’ varying impacts, it conceives of the implicit/explicit distinction using continuous variables. The paper hypothesizes that the effect of cues will be moderated by personal experience with immigrants. It tests these claims using four survey experiments with more than 2,500 respondents. Seeing Spanish text acts as a potent implicit cue. Even brief exposures to written Spanish can undermine support for immigration among key subgroups, including Democratic voters and those who hear Spanish frequently. Yet explicit anti-immigration appeals backfire, particularly among those who frequently interact with Latino immigrants. Thus the distinction between implicit and explicit attitudes proves critical in understanding attitudes on immigration. Casual contact with immigrants can increase the effect of cues, suggesting that they are most influential when they resonate with personal experience.
Synergistic Targeting of the Regulatory and Catalytic Subunits of PI3Kδ in Mature B-cell Malignancies

Purpose: Aberrant activation of the B-cell receptor (BCR) is implicated in the pathogenesis of mature B-cell tumors, a concept validated in part by the clinical success of inhibitors of the BCR-related kinases BTK (Bruton's tyrosine kinase) and PI3Kδ. These inhibitors have limitations, including the paucity of complete responses, acquired resistance, and toxicity. Here, we examined the mechanism by which the cyclic-AMP/PDE4 signaling axis suppresses PI3K, toward identifying a novel mechanism-based combinatorial strategy to attack BCR-dependency in mature B-cell malignancies. Experimental Design: We used in vitro and in vivo diffuse large B-cell lymphoma (DLBCL) cell lines and primary chronic lymphocytic leukemia (CLL) samples to preclinically evaluate the effects of the combination of the FDA-approved phosphodiesterase 4 (PDE4) inhibitor roflumilast and idelalisib on cell survival and tumor growth. Genetic models of gain- and loss-of-function were used to map multiple signaling intermediaries downstream of the BCR. Results: Roflumilast elevates the intracellular levels of cyclic-AMP and synergizes with idelalisib in suppressing tumor growth and PI3K activity. Mechanistically, we show that roflumilast suppresses PI3K by inhibiting BCR-mediated activation of the P85 regulatory subunit, distinguishing itself from idelalisib, an ATP-competitive inhibitor of the catalytic P110 subunit. Using genetic models, we linked the PDE4-regulated modulation of P85 activation to the oncogenic kinase SYK. Conclusions: These data demonstrate that roflumilast and idelalisib suppress PI3K by distinct mechanisms, explaining the basis for their synergism, and suggest that the repurposing of PDE4 inhibitors to treat BCR-dependent malignancies is warranted. Clin Cancer Res; 24(5); 1103–13. ©2017 AACR.
Transcranial Magnetic Stimulation of Medial Prefrontal and Cingulate Cortices Reduces Cocaine Self-Administration: A Pilot Study

Background Previous studies have shown that repetitive transcranial magnetic stimulation (rTMS) to the dorsolateral prefrontal cortex may serve as a potential treatment for cocaine use disorder (CUD), which remains a public health problem that is refractory to treatment. The goal of this pilot study was to investigate the effect of rTMS on cocaine self-administration in the laboratory. In the self-administration sessions, CUD participants chose between cocaine and an alternative reinforcer (money) in order to directly measure cocaine-seeking behavior. The rTMS was delivered with the H7 coil, which provides stimulation to the medial prefrontal cortex (mPFC) and anterior cingulate cortex (ACC). These brain regions were targeted based on previous imaging studies demonstrating alterations in their activation and connectivity in CUD. Methods Volunteers with CUD were admitted to an inpatient unit for the entire study and assigned to one of three rTMS groups: high frequency (10 Hz), low frequency (1 Hz), and sham. Six participants were included in each group and the rTMS was delivered on weekdays for 3 weeks. The cocaine self-administration sessions were performed at three time points: at baseline (pre-TMS, session 1), after 4 days of rTMS (session 2), and after 13 days of rTMS (session 3). During each self-administration session, the outcome measure was the number of choices for cocaine. Results The results showed a significant group by time effect (p = 0.02), where the choices for cocaine decreased between sessions 2 and 3 in the high frequency group. There was no effect of rTMS on cocaine self-administration in the low frequency or sham groups. Conclusion Taken in the context of the existing literature, these results contribute to the data showing that high frequency rTMS to the prefrontal cortex may serve as a potential treatment for CUD.