Miracle-dz/UniFAR-FTUs huggingface dataset:
Low Energy Pathways and Non-native Interactions

Four versions of a β-sheet protein (CD2.d1) have been made, each with a single artificial disulfide bond inserted into hairpin structures. Folding kinetics of reduced and oxidized forms shows bridge position strongly influences its effect on the folding reaction. Bridging residues 58 and 62 does not affect the rapidly formed intermediate (I) or rate-limiting transition (t) state, whereas bridging 33 and 38, or 31 and 41, lowers the t-state energy, with the latter having the stronger influence. Bridging residues 79 and 90 stabilizes both I- and t-states. To assess additivity in the energetic effects of these bridges, four double-bridge variants have also been made. All show precise additivity of overall stability, with two showing additivity when ground states and the rate-limiting t-state are assessed, i.e. no measurable change in the folding mechanism occurs. However, combining 31-41 and 79-90 bridges produces a molecule that folds through a different pathway, with a much more stable intermediate than expected and a much higher t-state barrier. This is explained by the artificial introduction of stabilizing, non-native contacts in the I-state. More surprisingly, for another double-bridge version (58-62 and 79-90) both I- and t-states are less stable than expected, showing that conformational constraints introduced by the two bridges prevent formation of non-native contacts that would otherwise stabilize the I- and t-states, thereby lowering the energy of the folding landscape in the wild-type (unbridged) molecule. We conclude that the lowest energy path for folding has I- and t-state structures that are stabilized by non-native interactions.
Low temperature inhibits RNA silencing‐mediated defence by the control of siRNA generation

Temperature dramatically affects plant–virus interactions. Outbreaks of virus diseases are frequently associated with low temperature, while at high temperature viral symptoms are often attenuated (heat masking) and plants rapidly recover from virus diseases. However, the underlying mechanisms of these well‐known observations are not yet understood. RNA silencing is a conserved defence system of eukaryotic cells, which operates against molecular parasites including viruses and transgenes. Here we show that at low temperature both virus and transgene triggered RNA silencing are inhibited. Therefore, in cold, plants become more susceptible to viruses, and RNA silencing‐based phenotypes of transgenic plants are lost. Consistently, the levels of virus‐ and transgene‐derived small (21–26 nucleotide) interfering (si) RNAs—the central molecules of RNA silencing‐mediated defence pathways—are dramatically reduced at low temperature. In contrast, RNA silencing was activated and the amount of siRNAs gradually increased with rising temperature. However, temperature does not influence the accumulation of micro (mi) RNAs, which play a role in developmental regulation, suggesting that the two classes of small (si and mi) RNAs are generated by different nuclease complexes.
MEDIATION OF ANTIGEN‐INDUCED SUPPRESSION OF RENAL ALLOGRAFT REJECTION BY A CD4 (W3/25+) T CELL

The mechanism of induction of specific immunosuppression by preoperative donor-specific blood transfusion in the rodent remains unclear. In a previous study we demonstrated that a single LEW blood transfusion in a DA rat results in the generation of donor-specific suppressor cells in the lymph node and thoracic duct lymph, detectable both in vivo and in vitro 7 days after DST. In contrast, no such activity was found in the splenic compartment. In this study lymphoid cells were harvested from either untreated DA rats or DA rats transfused 7 days previously with LEW blood and purified by rosette depletion using appropriate monoclonal antibodies. The purified lymphocyte subpopulation from transfused rats, of splenic or TDL origin, was adoptively transferred into syngeneic, lightly irradiated (200 rads) DA rats, where the adoptive transfer of 4.25 x 10(7) T (OX12-negative) cells (98.9% pure) or 2.5 x 10(7) CD4 (i.e., W3/25-positive, OX8 and OX12-negative) cells (97.9% pure), both of TDL origin, resulted in the indefinite survival of a LEW kidney (median survival time [MST]greater than 100 days), but not a PVG kidney (MST = 11 days). In contrast lymphocytes of splenic origin, regardless of the phenotype, did not prolong graft survival. Thus we have phenotypically characterized a CD4 (W3/25+) T suppressor cell that is generated after a single DST and is detectable 7 days later in the TDL but not the splenic compartment. Although there was no significant difference in the lymphocyte subset composition of lymphoid organs from transfused and untreated hosts, as determined by flow cytometry, the mean channel fluorescence of the lymphocyte population markers of cells harvested from transfused animals was significantly less than that observed with untreated controls, a finding which remains unexplained.
Introduction to the Symposium on ‘Geoengineering: Governing Solar Radiation Management'

The term solar radiation management (SRM) describes a set of speculative technologies that might help humanity respond to climate change. SRM technologies would operate, if ever developed and deployed at scale, by reflecting a small amount of solar energy back into space before that energy warms the planet. For at least a decade, SRM has been grouped together under the umbrella of climate engineering or geoengineering with a second suite of climate change response options, referred to as carbon dioxide removal (CDR) technologies, with geoengineering typically defined as the ‘deliberate large-scale manipulation of the planetary environment to counteract anthropogenic climate change’ Shepherd (2009, p. 1). This loose alignment between SRM and CDR approaches is, though, changing. Article 4(1) of the Paris Agreement calls for a balancing of ‘anthropogenic emissions by sources and removals by sinks of greenhouse gases’ by the latter half of the century. Those interested in the development of carbon dioxide removal technologies have picked up on the Paris Agreement’s highlighting of sinks to suggest that CDR should more properly be seen as part of the climate change mitigation agenda, preferring to leave the controversial climate engineering label to apply solely to SRM (De Coninck 2018). We support this drawing of a sharper line between proposed SRM and CDR activities, largely because the governance and other challenges associated with SRM tend to be markedly different from those associated with CDR, and in the following we focus strictly on SRM technologies. SRM as an enterprise could, conceivably, offer great benefits, but the risks to the environment, human wellbeing, and international order are not yet fully understood. For these and other reasons, any talk of SRM is contentious. In fact, SRM was long excluded from any serious discussion of climate change politics because many see it as generating a moral hazard. These voices argue that any consideration of SRM draws attention or could
Muscle discretization affects the loading transferred to bones in lower-limb musculoskeletal models

Modelling the mechanical effect of muscles is important in several research and clinical contexts. However, few studies have investigated the effect of different muscle discretizations from a mechanical standpoint. The present study evaluated the errors of a reduced discretization of the lower-limb muscles in reproducing the muscle loading transferred to bones. Skeletal geometries and a muscle data collection were derived from clinical images and dissection studies of two cadaver specimens. The guidelines of a general method previously proposed for a different anatomical district were followed. The data collection was used to calculate the mechanical effect of muscles, i.e. the generalized force vectors, and the errors between a large and a reduced discretization, in a reference skeletal pose and in the extreme poses of the range of motion of joints. The results showed that the errors committed using a reduced representation of muscles could be significant and higher than those reported for a different anatomical region. In particular, the calculated errors were found to be dependent on the individual anatomy and on the skeletal pose. Since different biomechanical applications may require different discretization levels, care is suggested in identifying the number of muscle lines of action to be used in musculoskeletal models.
Proteolytic Cleavage of Versican and Involvement of ADAMTS-1 in VEGF-A/VPF-Induced Pathological Angiogenesis

Malignant tumors and chronic inflammatory diseases induce angiogenesis by overexpressing vascular endothelial growth factor A (VEGF-A/VPF). VEGF-A-induced pathological angiogenesis can be mimicked in immunoincompetent mice with an adenoviral vector expressing VEGF-A164 (Ad-VEGF-A164). The initial step is generation of greatly enlarged “mother” vessels (MV) from preexisting normal venules by a process involving degradation of their rigid basement membranes. Immunohistochemical and Western blot analyses revealed that versican, an extracellular matrix component in the basement membranes of venules, is degraded early in the course of MV formation, resulting in the appearance of a versican N-terminal DPEAAE fragment associated with MV endothelial cells. The protease ADAMTS-1, known to cleave versican near its N terminus to generate DPEAAE, is also upregulated by VEGF-A in parallel with MV formation and localizes to the endothelium of the developing MV. The authors also show that MMP-15 (MT-2 MMP), a protease that activates ADAMTS-1, is upregulated by VEGF-A in endothelial cells in vitro and in vivo. These data suggest VEGF-A initiates MV formation, in part, by inducing the expression of endothelial cell proteases such as ADAMTS-1 and MMP-15 that act in concert to degrade venular basement membrane versican. Thus, versican is actively processed during the early course of VEGF-A-induced pathological angiogenesis.
Effect of early antibiotic treatment on the formation of sperm antibodies in experimentally induced epididymitis.

This investigation was conducted to evaluate whether or not experimentally produced epididymitis could induce the development of cytotoxic sperm antibodies and if effective antibiotic therapy could reverse the development of immunity to sperm. Escherichia coli was injected into the tail of the epididymis in adult Lewis rats to induce epididymitis and was allowed to incubate for 24 h, 72 h, 8 days, or 15 days. Serum titers of cytotoxic sperm antibodies at these time intervals were determined. Sperm antibody titers began to rise 3 days after inoculation, peaked, and plateaued at 8 days. The titers were negligible in the control rats. Two other groups of rats were inoculated with E. coli in a similar manner and were treated with tetracycline 25 mg/kg/day starting at either 24 h or 8 days after inoculation, for 7 days. The antibody titers became negligible in these two treated groups, the results being statistically significant when contrasted with the infected but untreated groups (p < .001 and < .05, respectively, for the 24-h and 8-day groups). However, histological examination of the antibiotic-treated and untreated specimens revealed significant inflammation and infection of the epididymis in both treated groups. Testicular alterations were consistent in both groups. It is concluded that epididymitis consequent to infection with E. coli can induce cytotoxic antibody formation in Lewis rats. Treatment with appropriate antibiotics may suppress the antibody response either through a direct immunosuppressive effect of the antibiotic or through a decrease in the antigenic load of killed sperm secondary to eradication of the infection.
Clusterin Overexpression and Its Possible Protective Role in Transthyretin Deposition in Familial Amyloidotic Polyneuropathy

Abstract Extracellular chaperones such as clusterin may contribute to extracellular protein homeostasis in neurodegenerative disorders. It has been implicated in fibrillogenesis and extracellular misfolded protein clearance in Alzheimer disease. We investigated the localization and potential functions of clusterin in familial amyloidotic polyneuropathy (FAP), a neurodegenerative disorder characterized by extracellular deposition of mutant transthyretin (TTR) in the peripheral nervous system. We observed increased clusterin expression in human FAP nerves, in the dorsal root ganglia of mutant TTR transgenic mice with TTR deposition, and in human neuroblastoma cells incubated with oligomeric TTR. Clusterin colocalized with extracellular TTR aggregates in human FAP nerves and was detected in aggregates extracted from FAP tissues. Abolition of clusterin expression using small interfering RNA in a HEK293 cell line that secretes wild-type TTR resulted in increased TTR aggregation in the medium, thus suggesting a protective role for clusterin in inhibition of TTR aggregation. However, under the conditions examined, toxicity of oligomeric TTR in neuroblastoma cells was unaltered by clusterin gene silencing. These data suggest that clusterin can influence TTR aggregation but may not modulate TTR aggregate toxicity or play a role in TTR clearance in FAP. Further studies will elucidate neuroprotective mechanisms conferred by clusterin in FAP and other neurodegenerative diseases.
Using image analysis as a tool for assessment of prognostic and predictive biomarkers for breast cancer: How reliable is it?

Background : Estrogen receptor (ER), progesterone receptor (PR) and human epidermal growth factor receptor-2 (HER2) are important and well-established prognostic and predictive biomarkers for breast cancers and routinely tested on patient′s tumor samples by immunohistochemical (IHC) study. The accuracy of these test results has substantial impact on patient management. A critical factor that contributes to the result is the interpretation (scoring) of IHC. This study investigates how computerized image analysis can play a role in a reliable scoring, and identifies potential pitfalls with common methods. Materials and Methods : Whole slide images of 33 invasive ductal carcinoma (IDC) (10 ER and 23 HER2) were scored by pathologist under the light microscope and confirmed by another pathologist. The HER2 results were additionally confirmed by fluorescence in situ hybridization (FISH). The scoring criteria were adherent to the guidelines recommended by the American Society of Clinical Oncology/College of American Pathologists. Whole slide stains were then scored by commercially available image analysis algorithms from Definiens (Munich, Germany) and Aperio Technologies (Vista, CA, USA). Each algorithm was modified specifically for each marker and tissue. The results were compared with the semi-quantitative manual scoring, which was considered the gold standard in this study. Results : For HER2 positive group, each algorithm scored 23/23 cases within the range established by the pathologist. For ER, both algorithms scored 10/10 cases within range. The performance of each algorithm varies somewhat from the percentage of staining as compared to the pathologist′s reading. Conclusions : Commercially available computerized image analysis can be useful in the evaluation of ER and HER2 IHC results. In order to achieve accurate results either manual pathologist region selection is necessary, or an automated region selection tool must be employed. Specificity can also be gained when strict quality assurance by a pathologist is invested. Quality assurance of image analysis by pathologists is always warranted. Automated image analysis should only be used as adjunct to pathologist′s evaluation.
Omalizumab: a monoclonal anti-IgE antibody.

OBJECTIVES To describe allergic asthma and allergic rhinitis pathophysiology and review the pharmacologic, pharmacokinetic, pharmacodynamic, efficacy, and safety data for omalizumab. METHODS MEDLINE, In-Process & Other Non-Indexed Citations, and EMBASE Drugs & Pharmacology were searched using olizumab, omalizumab, E25, rhuMAb-E25, and anti-IgE. Combinations of rhinitis, asthma, and IgE captured information on disease pathophysiology. RESULTS Omalizumab is a monoclonal antibody targeting the high-affinity receptor binding site on human immunoglobulin (Ig)E. Bound IgE is not available for basophil binding, degranulation is attenuated, and allergic symptoms are reduced. In asthma trials, omalizumab reduced inhaled corticosteroid and rescue medication requirements and improved asthma control and asthma quality of life in moderate to severe allergic asthmatics with disease poorly controlled by inhaled corticosteroids. In trials of patients with poorly controlled moderate to severe seasonal allergic rhinitis (SAR), omalizumab reduced the severity of exacerbations and rescue medication use, and improved rhinitis-related quality of life. Benefits were also observed in trials utilizing combinations of immunotherapy and omalizumab for SAR and in trials of perennial allergic rhinitis (PAR). Omalizumab has been well tolerated. Although malignant neoplasms have been observed in treated patients, they were likely not related to omalizumab therapy. CONCLUSIONS Omalizumab has demonstrated efficacy in children, adults, and adolescents with uncontrolled moderate to severe allergic asthma and allergic rhinitis. Long-term safety beyond 52 weeks needs continued evaluation.
P-VABEC: a prospective study of a new weekly chemotherapy regimen for elderly aggressive non-Hodgkin's lymphoma.

PURPOSE To evaluate, in a prospective trial, a new combination chemotherapy specifically designed for elderly patients. PATIENTS AND METHODS From October 1988 to December 1990, 60 previously untreated patients older than 60 years of age with aggressive non-Hodgkin's lymphoma (NHL) were treated at our institution with a new weekly alternating six-drug chemotherapy regimen, P-VABEC. The schedule consisted of doxorubicin, etoposide, and cyclophosphamide alternated weekly with vincristine and bleomycin. Oral prednisone was administered daily during the entire treatment period. Twenty-six of 60 patients were treated for a total of eight courses and 34 of 60 for 12 courses. RESULTS A total of 45 patients (75%) achieved a complete response (CR), 10 (17%) a partial response (PR), and five (8%) no response. So far, 20 of 45 CR patients have relapsed, four of 10 PR patients have progressed, and three patients have died while in CR. Twenty-eight patients are still alive and responding (22 CRs, six PRs) after a median follow-up of 25 months. The projected overall survival (OS), disease-free survival (DFS), and event-free survival (EFS) rates at 2 years were 64%, 57%, and 55%, respectively. The outcome of patients treated with eight courses was similar to that of those who received 12 courses of P-VABEC in terms of CR rate and actuarial curves of OS, DFS, and EFS. Hematologic toxicity was mild in all patients. CONCLUSION The P-VABEC regimen is active, well tolerated, and one of the briefest first-line chemotherapy regimens so far reported in the treatment of elderly patients with aggressive NHL. However, prospective randomized trials are needed to establish the real advantage of this regimen compared with other standard chemotherapy regimens.
Anatomical transverse magnetic resonance imaging study of ligaments in palmar surface of metacarpus in Miniature donkey: identification of a new ligament.

BACKGROUND Palmar region of metacarpus in the horses and donkeys is an important region because of its tendons and ligaments which contribute to stay apparatus. This study was done on forelimbs of 6 healthy Miniature donkeys to detect the tendons, ligaments and their accessories on the palmar surface of metacarpus in this animal. MATERIALS AND METHODS Based on that magnetic resonance imaging (MRI) is a good technique to evaluate the soft tissues such as tendons and ligaments, palmar aspects of metacarpus in 6 euthanatised Miniature donkeys were prepared for anatomical and trans-sectional MRI studies to determine the tendons and ligaments in this region. RESULTS Suspensory ligament, deep digital flexor tendon and its inferior check ligament were similar to them in the horse. Superficial digital flexor tendon (SDFT) in this animal had superior check ligament that was present before the carpal joint. On the other hand in the Miniature donkey there was a second accessory ligament for the SDFT that originated from the proximal of palmar surface of the large metacarpal bone which we named it second accessory ligament of SDFT. This ligament was determined in the MRI images too. CONCLUSIONS It seems that this ligament helps the Miniature donkey to stay apparatus, supporting more weight and load for a longer period of time and distance which is a specific morphological feature in this animal.
Laparoscopic inguinal herniorrhaphy in children: a three-center experience with 933 repairs.

BACKGROUND/PURPOSE Laparoscopic inguinal herniorrhaphy has been introduced recently as an alternative to conventional open repair in children. This study was undertaken to evaluate the safety, efficacy, and reproducibility of this minimally invasive approach. METHODS A total of 933 laparoscopic inguinal herniorrhaphies were performed on 666 children (597 boys and 69 girls), ranging in age from 3 weeks to 14 years (median, 3.2 years). A 5-mm laparoscope was placed through an umbilical incision, and two 2-mm or 3-mm needle drivers were inserted through the lateral abdominal wall. The neck of the sac was closed with a 4-0 monofilament suture. The needle was inserted directly through the abdominal wall, and removed together with the trocar. Only the umbilical fascia was closed with an absorbable suture. No skin sutures were applied. RESULTS A total of 911 indirect inguinal hernia sacs were closed (337 right, 172 left, 402 bilateral) and 22 direct inguinal hernias were repaired (14 boys, 3 girls; 11 right, 3 left, 4 bilateral). The median operating time was 22 minutes (range, unilateral, 7 to 45 min; bilateral, 9 to 51 min). With experience, this time gradually decreased. There were no intraoperative complications. The contralateral asymptomatic processus was unexpectedly open on the left side in 137 of the boys (23%) and 10 of the girls (15%), and on the right side in 131 of the boys (22%) and 21 of the girls (32%). In 16% of the children, the final procedure was modified on the basis of the anatomic findings. No hernia was found in 13 children (1.9%). The recurrence rate was 3.4% (follow-up time ranged from 2 months to 7 years). Hydroceles were observed in 4 children, and a subtle change in testicular position and size was noted in one boy. CONCLUSIONS Laparoscopic inguinal repair in children proved safe and reproducible, although the recurrence rate was slightly higher than with the open approach. However, laparoscopy allows easy and precise identification of the type of defect and its correction. In this series, the incidence of direct inguinal hernias was higher, and the incidence of a patent contralateral processus vaginalis was lower than previously reported.