Managing software engineers and their knowledge

This chapter begins by reviewing the history of software engineering as a profession, especially the so-called software crisis and responses to it, to help focus on what it is that software engineers do. This leads into a discussion of the areas in software engineering that are problematic as a basis for considering knowledge management issues. Some of the previous work on knowledge management in software engineering is then examined, much of it not actually going under a knowledge management title, but rather “learning” or “expertise”. The chapter goes on to consider the potential for knowledge management in software engineering and the different types of knowledge management solutions and strategies that might be adopted, and it touches on the crucial importance of cultural issues. It concludes with a list of challenges that knowledge management in software engineering needs to address

VEGF-A165b is an endogenous neuroprotective splice isoform of vascular endothelial growth factor A in vivo and in vitro

Vascular endothelial growth factor (VEGF) A is generated as two isoform families by alternative RNA splicing, represented by VEGF-A165a and VEGF-A165b. These isoforms have opposing actions on vascular permeability, angiogenesis, and vasodilatation. The proangiogenic VEGF-A165a isoform is neuroprotective in hippocampal, dorsal root ganglia, and retinal neurons, but its propermeability, vasodilatatory, and angiogenic properties limit its therapeutic usefulness. In contrast, a neuroprotective effect of endogenous VEGF-A165b on neurons would be advantageous for neurodegenerative pathologies. Endogenous expression of human and rat VEGF-A165b was detected in hippocampal and cortical neurons. VEGF-A165b formed a significant proportion of total VEGF-A in rat brain. Recombinant human VEGF-A165b exerted neuroprotective effects in response to multiple insults, including glutamatergic excitotoxicity in hippocampal neurons, chemotherapy-induced cytotoxicity of dorsal root ganglion neurons, and retinal ganglion cells (RGCs) in rat retinal ischemia-reperfusion injury in vivo. Neuroprotection was dependent on VEGFR2 and MEK1/2 activation but not on p38 or phosphatidylinositol 3-kinase activation. Recombinant human VEGF-A165b is a neuroprotective agent that effectively protects both peripheral and central neurons in vivo and in vitro through VEGFR2, MEK1/2, and inhibition of caspase-3 induction. VEGF-A165b may be therapeutically useful for pathologies that involve neuronal damage, including hippocampal neurodegeneration, glaucoma diabetic retinopathy, and peripheral neuropathy. The endogenous nature of VEGF-A165b expression suggests that non-isoform-specific inhibition of VEGF-A (for antiangiogenic reasons) may be damaging to retinal and sensory neurons

Genome-wide analyses as part of the international FTLD-TDP whole-genome sequencing consortium reveals novel disease risk factors and increases support for immune dysfunction in FTLD

Frontotemporal lobar degeneration with neuronal inclusions of the TAR DNA-binding protein 43 (FTLD-TDP) represents the most common pathological subtype of FTLD. We established the international FTLD-TDP whole genome sequencing consortium to thoroughly characterize the known genetic causes of FTLD-TDP and identify novel genetic risk factors. Through the study of 1,131 unrelated Caucasian patients, we estimated that C9orf72 repeat expansions and GRN loss-of-function mutations account for 25.5% and 13.9% of FTLD-TDP patients, respectively. Mutations in TBK1 (1.5%) and other known FTLD genes (1.4%) were rare, and the disease in 57.7% of FTLD-TDP patients was unexplained by the known FTLD genes. To unravel the contribution of common genetic factors to the FTLD-TDP etiology in these patients, we conducted a two-stage association study comprising the analysis of whole-genome sequencing data from 517 FTLD-TDP patients and 838 controls, followed by targeted genotyping of the most associated genomic loci in 119 additional FTLD-TDP patients and 1653 controls. We identified three genome-wide significant FTLD-TDP risk loci: one new locus at chromosome 7q36 within the DPP6 gene led by rs118113626 (pvalue=4.82e-08, OR=2.12), and two known loci: UNC13A, led by rs1297319 (pvalue=1.27e-08, OR=1.50) and HLA-DQA2 led by rs17219281 (pvalue=3.22e-08, OR=1.98). While HLA represents a locus previously implicated in clinical FTLD and related neurodegenerative disorders, the association signal in our study is independent from previously reported associations. Through inspection of our whole genome sequence data for genes with an excess of rare loss-of-function variants in FTLD-TDP patients (n≥3) as compared to controls (n=0), we further discovered a possible role for genes functioning within the TBK1-related immune pathway (e.g. DHX58, TRIM21, IRF7) in the genetic etiology of FTLD-TDP. Together, our study based on the largest cohort of unrelated FTLD-TDP patients assembled to date provides a comprehensive view of the genetic landscape of FTLD-TDP, nominates novel FTLD-TDP risk loci, and strongly implicates the immune pathway in FTLD-TDP pathogenesis

Association of Variants in the SPTLC1 Gene With Juvenile Amyotrophic Lateral Sclerosis

Importance: Juvenile amyotrophic lateral sclerosis (ALS) is a rare form of ALS characterized by age of symptom onset less than 25 years and a variable presentation.Objective: To identify the genetic variants associated with juvenile ALS.Design, Setting, and Participants: In this multicenter family-based genetic study, trio whole-exome sequencing was performed to identify the disease-associated gene in a case series of unrelated patients diagnosed with juvenile ALS and severe growth retardation. The patients and their family members were enrolled at academic hospitals and a government research facility between March 1, 2016, and March 13, 2020, and were observed until October 1, 2020. Whole-exome sequencing was also performed in a series of patients with juvenile ALS. A total of 66 patients with juvenile ALS and 6258 adult patients with ALS participated in the study. Patients were selected for the study based on their diagnosis, and all eligible participants were enrolled in the study. None of the participants had a family history of neurological disorders, suggesting de novo variants as the underlying genetic mechanism.Main Outcomes and Measures: De novo variants present only in the index case and not in unaffected family members.Results: Trio whole-exome sequencing was performed in 3 patients diagnosed with juvenile ALS and their parents. An additional 63 patients with juvenile ALS and 6258 adult patients with ALS were subsequently screened for variants in the SPTLC1 gene. De novo variants in SPTLC1 (p.Ala20Ser in 2 patients and p.Ser331Tyr in 1 patient) were identified in 3 unrelated patients diagnosed with juvenile ALS and failure to thrive. A fourth variant (p.Leu39del) was identified in a patient with juvenile ALS where parental DNA was unavailable. Variants in this gene have been previously shown to be associated with autosomal-dominant hereditary sensory autonomic neuropathy, type 1A, by disrupting an essential enzyme complex in the sphingolipid synthesis pathway.Conclusions and Relevance: These data broaden the phenotype associated with SPTLC1 and suggest that patients presenting with juvenile ALS should be screened for variants in this gene.</p

Genome-wide Analyses Identify KIF5A as a Novel ALS Gene

To identify novel genes associated with ALS, we undertook two lines of investigation. We carried out a genome-wide association study comparing 20,806 ALS cases and 59,804 controls. Independently, we performed a rare variant burden analysis comparing 1,138 index familial ALS cases and 19,494 controls. Through both approaches, we identified kinesin family member 5A (KIF5A) as a novel gene associated with ALS. Interestingly, mutations predominantly in the N-terminal motor domain of KIF5A are causative for two neurodegenerative diseases: hereditary spastic paraplegia (SPG10) and Charcot-Marie-Tooth type 2 (CMT2). In contrast, ALS-associated mutations are primarily located at the C-terminal cargo-binding tail domain and patients harboring loss-of-function mutations displayed an extended survival relative to typical ALS cases. Taken together, these results broaden the phenotype spectrum resulting from mutations in KIF5A and strengthen the role of cytoskeletal defects in the pathogenesis of ALS.Peer reviewe

Genome-wide structural variant analysis identifies risk loci for non-Alzheimer’s dementias

We characterized the role of structural variants, a largely unexplored type of genetic variation, in two non-Alzheimer’s dementias, namely Lewy body dementia (LBD) and frontotemporal dementia (FTD)/amyotrophic lateral sclerosis (ALS). To do this, we applied an advanced structural variant calling pipeline (GATK-SV) to short-read whole-genome sequence data from 5,213 European-ancestry cases and 4,132 controls. We discovered, replicated, and validated a deletion in TPCN1 as a novel risk locus for LBD and detected the known structural variants at the C9orf72 and MAPT loci as associated with FTD/ALS. We also identified rare pathogenic structural variants in both LBD and FTD/ALS. Finally, we assembled a catalog of structural variants that can be mined for new insights into the pathogenesis of these understudied forms of dementia

Influence of Charge on Hemocompatibility and Immunoreactivity of Polymeric Nanoparticles

The benefits of nanomedicine may be restricted by hemocompatibility and immunoreactivity problems arising from administration of exogenous materials into the bloodstream. To understand how surface charge influences the interaction of polymeric nanoparticles with blood components, we synthesized three well-defined, chargevaried hyperbranched polymers (HBPs) of similar size and analyzed both hemocompatibility and immunoreactivity of these methacrylate-based HBPs ex vivo using primary human blood cell assays and image analyses following intravenous injection into mice. The results show that, regardless of charge, endotoxin-free HBPs had minimal effects on coagulation, platelet, complement, or T cell activation. However, high concentrations (100 μg mL) of cationic HBPs led to significant dendritic cell activation, suggesting the potential application of these nanoparticles as vaccine adjuvants to aid efficient antigen presentation. Biodistribution studies showed that intravenously administered charge-neutral HBPs had a longer retention time in the circulation than cationic or anionic HBPs; whereas these neutral HBPs were eventually cleared in the urine, charged HBPs mainly accumulated in liver and spleen. Overall, these results demonstrate that, regardless of surface charge, HBPs display a high level of hemocompatibility. In contrast, immunoreactivity and biodistribution are significantly influenced by charge. Manipulation of surface charge may thus be a useful method by which nanomaterials such as HBPs can be tailored to different clinical applications

Modulating targeting of poly(ethylene glycol) particles to tumor cells using bispecific antibodies

Low-fouling or "stealth" particles composed of poly(ethylene glycol) (PEG) display a striking ability to evade phagocytic cell uptake. However, functionalizing them for specific targeting is challenging. To address this challenge, stealth PEG particles prepared by a mesoporous silica templating method are functionalized with bispecific antibodies (BsAbs) to obtain PEG-BsAb particles via a one-step binding strategy for cell and tumor targeting. The dual specificity of the BsAbs-one arm binds to the PEG particles while the other targets a cell antigen (epidermal growth factor receptor, EGFR)-is exploited to modulate the number of targeting ligands per particle. Increasing the BsAb incubation concentration increases the amount of BsAb tethered to the PEG particles and enhances targeting and internalization into breast cancer cells overexpressing EGFR. The degree of BsAb functionalization does not significantly reduce the stealth properties of the PEG particles ex vivo, as assessed by their interactions with primary human blood granulocytes and monocytes. Although increasing the BsAb amount on PEG particles does not lead to the expected improvement in tumor accumulation in vivo, BsAb functionalization facilitates tumor cell uptake of PEG particles. This work highlights strategies to balance evading nonspecific clearance pathways, while improving tumor targeting and accumulation