Hypothesis Formalization: Empirical Findings, Software Limitations, and Design Implications

Data analysis requires translating higher level questions and hypotheses into computable statistical models. We present a mixed-methods study aimed at identifying the steps, considerations, and challenges involved in operationalizing hypotheses into statistical models, a process we refer to as hypothesis formalization . In a formative content analysis of 50 research papers, we find that researchers highlight decomposing a hypothesis into sub-hypotheses, selecting proxy variables, and formulating statistical models based on data collection design as key steps. In a lab study, we find that analysts fixated on implementation and shaped their analyses to fit familiar approaches, even if sub-optimal. In an analysis of software tools, we find that tools provide inconsistent, low-level abstractions that may limit the statistical models analysts use to formalize hypotheses. Based on these observations, we characterize hypothesis formalization as a dual-search process balancing conceptual and statistical considerations constrained by data and computation and discuss implications for future tools.

Design Automation and Test Solutions for Monolithic 3D ICs

Monolithic 3D (M3D) is an emerging heterogeneous integration technology that overcomes the limitations of the conventional through-silicon-via (TSV) and provides significant performance uplift and power reduction. However, the ultra-dense 3D interconnects impose significant challenges during physical design on how to best utilize them. Besides, the unique low-temperature fabrication process of M3D requires dedicated design-for-test mechanisms to verify the reliability of the chip. In this article, we provide an in-depth analysis on these design and test challenges in M3D. We also provide a comprehensive survey of the state-of-the-art solutions presented in the literature. This article encompasses all key steps on M3D physical design, including partitioning, placement, clock routing, and thermal analysis and optimization. In addition, we provide an in-depth analysis of various fault mechanisms, including M3D manufacturing defects, delay faults, and MIV (monolithic inter-tier via) faults. Our design-for-test solutions include test pattern generation for pre/post-bond testing, built-in-self-test, and test access architectures targeting M3D.

Structural Insights into Sphingosine-1-phosphate Receptor Activation

As a critical sphingolipid metabolite, sphingosine-1-phosphate (S1P) plays an essential role in immune and vascular systems. There are five S1P receptors, designated as S1PR1-5, encoded in the human genome, and their activities are governed by endogenous S1P, lipid-like S1P mimics, or non-lipid-like therapeutic molecules. Among S1PRs, S1PR1 stands out due to its non-redundant functions, such as the egress of T and B cells from the thymus and secondary lymphoid tissues, making it a potential therapeutic target. However, the structural basis of S1PR1 activation and regulation by various agonists remains unclear. Here we reported four atomic resolution cryo-EM structures of Gi-coupled human S1PR1 complexes: bound to endogenous agonist d18:1 S1P, benchmark lipid-like S1P mimic phosphorylated Fingolimod ((S)-FTY720-P), or non-lipid-like therapeutic molecule CBP-307 in two binding modes. Our results revealed the similarities and differences of activation of S1PR1 through distinct ligands binding to the amphiphilic orthosteric pocket. We also proposed a two-step "shallow to deep" transition process of CBP-307 for S1PR1 activation. Both binding modes of CBP-307 could activate S1PR1, but from shallow to deep transition may trigger the rotation of the N-terminal helix of Gαi and further stabilize the complex by increasing the Gαi interaction with the cell membrane. We combine with extensive biochemical analysis and molecular dynamic simulations to suggest key steps of S1P binding and receptor activation. The above results decipher the common feature of the S1PR1 agonist recognition and activation mechanism and will firmly promote the development of therapeutics targeting S1P receptors.

Developing a toolkit for increasing the participation of black, Asian and minority ethnic communities in health and social care research

Background It is recognised that Black, Asian and Minority Ethnic (BAME) populations are generally underrepresented in research studies. The key objective of this work was to develop an evidence based, practical toolkit to help researchers maximise recruitment of BAME groups in research. Methods Development of the toolkit was an iterative process overseen by an expert steering group. Key steps included a detailed literature review, feedback from focus groups (including researchers and BAME community members) and further workshops and communication with participants to review the draft and final versions. Results Poor recruitment of BAME populations in research is due to complex reasons, these include factors such as inadequate attention to recruitment strategies and planning, poor engagement with communities and individuals due to issues such as cultural competency of researchers, historical poor experience of participating in research, and lack of links with community networks. Other factors include language issues, relevant expertise in research team and a lack of adequate resources that might be required in recruitment of BAME populations. Conclusions A toolkit was developed with key sections providing guidance on planning research and ensuring adequate engagement of communities and individuals. Together with sections suggesting how the research team can address training needs and adopt best practice. Researchers highlighted the issue of funding and how best to address BAME recruitment in grant applications, so a section on preparing a grant application was also included. The final toolkit document is practical, and includes examples of best practice and ‘top tips’ for researchers.

Developing Monoclonal Antibodies for Immunohistochemistry

The experiences of a laboratory which pioneered the application of monoclonal antibodies to diagnostic histochemistry is described. This was achieved in four key steps: (1) Monoclonal antibodies were successfully produced to replace the difficult-to-produce and limited polyclonal antibodies available for immunohistochemistry. (2) Monoclonal antibodies were produced to improve the immunoenzymatic detection of bound antibodies, using immunoperoxidase or alkaline phosphatase, increasing sensitivity and allowing the use of two chromogens when applied together. The availability of a reliable alkaline phosphatase-based detection allowed the detection of antigens in tissues with high endogenous peroxidase. (3) Methodologies were developed to unmask antigens not detected in routinely processed paraffin-embedded tissue. (4) Synthetic peptides were used as immunising antigens for the direct production of specific molecules of diagnostic interest. This was expanded to include recombinant proteins. Many reacted with fixed tissue and recognised homologous molecules in other species. In addition to these developments, the laboratory promoted the collaboration and training of researchers to spread the expertise of monoclonal production for diagnosis.

First Total Synthesis of Isopsoralenoside

The first total synthesis of the natural product iopsoralenoside, isolated from the n-butyl alcohol extract of Fructus Psoraleae (FP), was achieved in 17% yield over 7 steps. The key steps of the process are the glycosylation and irradiation promoted by ultraviolet light. This synthesis provides a sufficient amount of synthesized trans- and cis-isopsoralenoside for further bioassays.

Recruitment, Readiness, and Retention of Providers at a Field Hospital during the Pandemic

In response to the coronavirus disease 2019 (COVID-19) pandemic, the State of Maryland established a 250-bed emergency response field hospital at the Baltimore Convention Center to support the existing healthcare infrastructure. To operationalize this hospital with 65 full-time equivalent (FTE) clinicians in less than four weeks, more than 300 applications were reviewed, 186 candidates were interviewed, and 159 clinicians were credentialed and onboarded. The key steps to achieve this undertaking involved employing multidisciplinary teams with experienced personnel, mass outreach, streamlined candidate tracking, pre-interview screening, utilizing all available expertise, expedited credentialing, and focused onboarding. To ensure staff preparedness, the leadership developed innovative team models, applied principles of effective team building, and provided ‘just in time’ training on COVID-19 and non-COVID-19 related topics to the staff. The leadership focused on staff safety and well-being, offered appropriate financial remuneration and provided leadership opportunities that allowed retention of staff.

Chemometric Comparison and Classification of 22 Apple Genotypes Based on Texture Analysis and Physico-Chemical Quality Attributes

The large number of cultivars belonging to the cultivated apple (Malus × domestica Borkh.) reflects an extremely wide range of variability, including for fruit quality traits. To evaluate some characteristics of fruit quality, 22 apple genotypes were selected from a collection of germplasms containing more than 600 accessions, based on different considerations, including the use of fruits (dessert, cooking, processing, juice, cider, multipurpose). The mean water content of the studied apple genotypes was 85.05%, with a coefficient of variation (CV) of 2.74%; the mean ash content was 2.32% with a CV of 22.1%, and the mean total soluble solids was 16.22% with a CV of 17.78%, indicating a relatively small difference between genotypes for these indices. On the contrary, relatively large differences were registered between genotypes for fruit weight, volume, and titratable acidity with means of 119.52 g, 155 mL, and 0.55% malic acid, and CVs of 35.17%, 34.58%, and 54.3%, respectively. The results showed that peel hardness varied between 3.80 and 13.69 N, the toughness between 0.2 and 1.07 mm, the flesh hardness between 0.97 and 4.76 N, and the hardness work between 6.88 and 27.84 mJ. The current study can emphasize the possibility of choosing the appropriate apple cultivars to cross in the breeding process and how future strategies can help apple breeders select breeding parents, which are essential key steps when breeding new apple cultivars. In addition, multivariate analysis has proven to be a useful tool in assessing the relationships between Malus genetic resources.

Carbene-catalyzed atroposelective synthesis of axially chiral styrenes

Axially chiral styrenes bearing a chiral axis between a sterically non-congested acyclic alkene and an aryl ring are difficult to prepare due to low rotational barrier of the axis. Disclosed here is an N-heterocyclic carbene (NHC) catalytic asymmetric solution to this problem. Our reaction involves ynals, sulfinic acids, and phenols as the substrates with an NHC as the catalyst. Key steps involve selective 1,4-addition of sulfinic anion to acetylenic acylazolium intermediate and sequential E-selective protonation to set up the chiral axis. Our reaction affords axially chiral styrenes bearing a chiral axis as the product with up to > 99:1 e.r., > 20:1 E/Z selectivity, and excellent yields. The sulfone and carboxylic ester moieties in our styrene products are common moieties in bioactive molecules and asymmetric catalysis.

Analysing the impact of taxi violence on commuters in South Africa

Taxi violence in South Africa was the tool that the apartheid regime used to pursue their interest by dividing the people so that they could acquire what they needed (Sekhonyane and Dugard, 2004:15). Taxi violence is one of the most burning issues faced by Department of Transport, Police, commuters and taxi industry in South Africa. This industry plays a vital role in commuting people to and from work or different destinations, and in most cases it is caught in the wrong doing in terms of fighting for routes where many innocent lives are lost due to infighting. The inability by government to regulate taxi industry is a serious problem for taxi operators, taxi associations, commuters and society. The deregulation of taxi industry brought many problems such as conflict, violence and mafia type assassinations in South Africa. This article focus on preventive measures to curb taxi violence in South Africa. This article utilised qualitative, case study based approach and the approach is supported by analysis of primary and secondary sources. The article further draws on the findings from the world on taxi violence and formulate steps to counteract taxi violence in South Africa. The research based key steps leading to the prevention of taxi violence in South Africa. The first process related to regulation of taxi industry, awareness campaigns on taxi operations, the control of routes and multidisciplinary investigation team should be established to overcome taxi violence in South Africa.