Towards Learning and Explaining Indirect Causal Effects in Neural Networks

Recently, there has been a growing interest in learning and explaining causal effects within Neural Network (NN) models. By virtue of NN architectures, previous approaches consider only direct and total causal effects assuming independence among input variables. We view an NN as a structural causal model (SCM) and extend our focus to include indirect causal effects by introducing feedforward connections among input neurons. We propose an ante-hoc method that captures and maintains direct, indirect, and total causal effects during NN model training. We also propose an algorithm for quantifying learned causal effects in an NN model and efficient approximation strategies for quantifying causal effects in high-dimensional data. Extensive experiments conducted on synthetic and real-world datasets demonstrate that the causal effects learned by our ante-hoc method better approximate the ground truth effects compared to existing methods

Disrupting SUMOylation enhances transcriptional function and ameliorates polyglutamine androgen receptor-mediated disease.

Expansion of the polyglutamine (polyQ) tract within the androgen receptor (AR) causes neuromuscular degeneration in individuals with spinobulbar muscular atrophy (SBMA). PolyQ AR has diminished transcriptional function and exhibits ligand-dependent proteotoxicity, features that have both been implicated in SBMA; however, the extent to which altered AR transcriptional function contributes to pathogenesis remains controversial. Here, we sought to dissociate effects of diminished AR function from polyQ-mediated proteotoxicity by enhancing the transcriptional activity of polyQ AR. To accomplish this, we bypassed the inhibitory effect of AR SUMOylation (where SUMO indicates small ubiquitin-like modifier) by mutating conserved lysines in the polyQ AR that are sites of SUMOylation. We determined that replacement of these residues by arginine enhances polyQ AR activity as a hormone-dependent transcriptional regulator. In a murine model, disruption of polyQ AR SUMOylation rescued exercise endurance and type I muscle fiber atrophy; it also prolonged survival. These changes occurred without overt alterations in polyQ AR expression or aggregation, revealing the favorable trophic support exerted by the ligand-activated receptor. Our findings demonstrate beneficial effects of enhancing the transcriptional function of the ligand-activated polyQ AR and indicate that the SUMOylation pathway may be a potential target for therapeutic intervention in SBMA

Superconductivity in SmFe1-xMxAsO (M = Co, Rh, Ir)

In this paper we report the comparative study of superconductivity by 3d (Co), 4d (Rh), 5d (Ir) element doping in SmFeAsO. X-ray diffraction patterns indicate that the material has formed the ZrCuSiAs-type structure with a space group P4/nmm. It is found that the antiferromagnetic spin-density-wave (SDW) order in the parent compounds is rapidly suppressed by Co, Rh, and Ir doping, and superconductivity emerges. Both electrical resistance and magnetization measurements show superconductivity up to around 10 K in SmFe1-xMxAsO (M = Co, Rh, Ir). Co, Rh and Ir locate in the same column in the periodic table of elements but have different electronic band structure, so comparative study would add more ingredients to the underlying physics of the iron-based superconductors.Comment: 16 pages, 4 figures, 1 tabl

A unified framework for managing provenance information in translational research

<p>Abstract</p> <p>Background</p> <p>A critical aspect of the NIH <it>Translational Research </it>roadmap, which seeks to accelerate the delivery of "bench-side" discoveries to patient's "bedside," is the management of the <it>provenance </it>metadata that keeps track of the origin and history of data resources as they traverse the path from the bench to the bedside and back. A comprehensive provenance framework is essential for researchers to verify the quality of data, reproduce scientific results published in peer-reviewed literature, validate scientific process, and associate trust value with data and results. Traditional approaches to provenance management have focused on only partial sections of the translational research life cycle and they do not incorporate "domain semantics", which is essential to support domain-specific querying and analysis by scientists.</p> <p>Results</p> <p>We identify a common set of challenges in managing provenance information across the <it>pre-publication </it>and <it>post-publication </it>phases of data in the translational research lifecycle. We define the semantic provenance framework (SPF), underpinned by the Provenir upper-level provenance ontology, to address these challenges in the four stages of provenance metadata:</p> <p>(a) Provenance <b>collection </b>- during data generation</p> <p>(b) Provenance <b>representation </b>- to support interoperability, reasoning, and incorporate domain semantics</p> <p>(c) Provenance <b>storage </b>and <b>propagation </b>- to allow efficient storage and seamless propagation of provenance as the data is transferred across applications</p> <p>(d) Provenance <b>query </b>- to support queries with increasing complexity over large data size and also support knowledge discovery applications</p> <p>We apply the SPF to two exemplar translational research projects, namely the Semantic Problem Solving Environment for <it>Trypanosoma cruzi </it>(<it>T.cruzi </it>SPSE) and the Biomedical Knowledge Repository (BKR) project, to demonstrate its effectiveness.</p> <p>Conclusions</p> <p>The SPF provides a unified framework to effectively manage provenance of translational research data during pre and post-publication phases. This framework is underpinned by an upper-level provenance ontology called Provenir that is extended to create domain-specific provenance ontologies to facilitate provenance interoperability, seamless propagation of provenance, automated querying, and analysis.</p

A hospital-based observational comparative study of efficacy of intracameral voriconazole and oral ketoconazole in deep keratomycosis

Background: Fungal keratitis, one of the most common causes of ocular mycosis, is the second most common cause of blindness in the world, after cataracts. The aim of the study was to compare the efficacy of conventional topical, systemic medications and intracameral voriconazole injection in visual and structural outcomes in keratomycosis. Material and methods: We conducted a hospital-based observational study of 45 patients of 45 eyes with smear-positive fungal keratitis. Patients were categorized into three groups: Group I received systemic topical with oral ketoconazole 200 mg, Group II — topical medications with intracameral voriconazole 50 μgm/0.1 mL, Group III — topical medications with both oral ketoconazole 200 mg and intracameral voriconazole 50 μgm/0.1 mL. Results: The common fungal organism is identified as Fusarium. The mean final visual acuity (VA) was 1.25 ± 0.32, 1.47 ± 1.05, and 1.22 ± 0.37 logMAR in Group I, group II, and Group III, respectively. The mean improvement in VA was 0.33 ± 0.07, 0.01 ± 0.71, and –0.19 ± 0.02 logMAR without significant change (p = 0.9). There was a significant difference in VA between the final postoperative follow-up period and baseline in Group I cases (p = 0.0019). Whereas no difference in VA between the final postoperative follow-up period and baseline in either Group II (p = 0.0671) or Group III (p = 0.1505) cases. The difference in time between the disappearance of hypopyon and the mean time to infection healing was not statistically significant (p = 0.1). Three cases in each group were perforated, and keratoplasty was performed. These perforated cases did not show culture positive. Histopathology identified the isolated organisms as Aspergillus species (n = 3) and Fusarium species (n = 2) in the corneal buttons. Conclusion: The differences in VA between the three methods were not statistically significant, indicating no treatment method superior to others (inter-group). However, in Group I, there was a significant difference in VA between the final postoperative follow-up period and baseline (p = 0.0019). There was no difference in VA between these time intervals in either Group II (p = 0.0671) or Group III (p = 0.1505). Within-group or intra-group analysis reveals that the Group I method is more effective for VA. The success rate of the method depended cumulatively on the duration of intracameral voriconazole in the anterior chamber, non-drainage of hypopyon, and individual clinical response