Specific vulnerability of long telomeres to undergo end fusions revealed by mutational analysis of Rap1

The conserved Rap1 protein is part of the shelterin complex that plays critical roles in chromosome end protection and telomere length homeostasis. Previous studies addressed how fission yeast Rap1 contributes to telomere length maintenance, but the mechanism by which the protein inhibits end fusions has remained elusive. Here, we use a genetic screen in combination with high throughput sequencing to identify several amino acid positions in Rap1 that have a key role in end protection. Interestingly, mutations at these sites render cells susceptible to genome instability in a conditional manner with longer telomeres being prone to undergoing end fusions, while short telomeres are sufficiently protected. The protection of long telomeres requires their nuclear envelope attachment mediated by the Rap1-Bqt4 interaction. Our data demonstrates that longer telomeres pose an additional challenge for the maintenance of genome integrity and provides an explanation for a species-specific upper limit in telomere length.

Capex-Free Production Facilities Optimization Opportunities by Exploiting Installed Automation Infrastructure and Unused Functionalities

Operational Excellence and Automation Excellence go hand in hand when it comes to enabling process optimization and cost-reduction opportunities in Upstream Oil & Gas Operations. As part of our Digital Journey in the Upstream Business, multiple streams and workflows have been created to successfully identify and explore the use of new technologies to foster collaboration, achieve higher levels of efficiency, lower operating costs, maximize production and asset integrity, improve decision making, and lower the carbon footprint of all of our exploration and production activities. While our Digital Journey has been highly successful in identifying, assessing and implementing new technologies and novel solutions, it has also made very clear, during the development of business-cases’, that a rather big number of existing and older facilities were not going to be good cost-effective candidates for the deployment of many of the identified solutions and technologies. As an established and rooted operator with a large number of aging facilities, these presented an additional challenge to dig deeper and look further for solutions to cover all of these remaining assets, no matter how old or small they could be.

In the Footsteps of Graphicons: Tracing Parameters and Pragmatic Strategies in Graphicon Usage

The textual intercourse in computer-mediated communication is intertwined with graphicons of various forms, gaining new meanings and functions. They are part of the online culture and, specifically, part of the communicative skills in digital environment. In many cases, graphicons are used not as signs of emotion but rather as indication of the illocutionary force of the textual utterances that they accompany. The current work endeavours to reveal the specific aspect of language use where iconoid objects “take over” and substitute textual utterances. The paper also attempts to trace to what extent pragmatics could be applicable in the analysis of the visual representations (i.e. graphicons) embodied in computer-mediated communication as means of communicative acts. The different graphicon forms and the dynamics in the usage carry additional challenge for the interpretation of the “visual” act. However, it is possible to systematically trace a pattern in the occurrence of the graphicons – their use as a complementary to a written statement, and their use as a single communicative act.

Regulation of Network Industries in South Africa

The 1980s saw a global shift to the liberalization and regulation of network industries which were previously public utilities. Underperforming SOEs and unsustainable debt forced South Africa down this road in the late 1980s with the additional challenge of addressing racially skewed access post-apartheid. In telecommunications, this resulted in a managed liberalization process which has seen private entry but continual structural problems due to a failure to undertake wholesale regulation of the incumbents. Despite a policy advocating structural separation of transmission and generation within electricity, reform stalled due to a shift in government thinking and successful lobbying by Eskom. The regulator, NERSA, has also failed to impose operational efficiency and rein in large price increases. Within transport, aviation was liberalized in the early 1990s with effective regulatory oversight of the airports and navigation systems. However, a dependency on cross-subsidies between ports and rail within Transnet has stalled reform elsewhere.

Management of Adverse Events and Supportive Therapy in Relapsed/Refractory Multiple Myeloma

Relapsed/refractory (RR) multiple myeloma (MM) patients are a fragile population because of prolonged drug exposure and advanced age. Preserving a good quality of life is of high priority for these patients and the treatment of disease- and treatment-related complications plays a key role in their management. By preventing and limiting MM-induced complications, supportive care improves patients’ outcome. Erythropoietin-stimulating agents and bisphosphonates are well-established supportive strategies, yet novel agents are under investigation, such as anabolic bone agents and activin receptor-like kinase (ALK) inhibitors. The recent dramatic changes in the treatment landscape of MM pose an additional challenge for the routine care of RRMM patients. Multidrug combinations in first and later lines increase the risk for long-lasting toxicities, including adverse cardiovascular and neurological events. Moreover, recently approved first-in-class drugs have unique side-effect profiles, such as ocular toxicity of belantamab mafodotin or gastrointestinal toxicity of selinexor. This review discusses current standards in supportive treatment of RRMM patients, including recommendations in light of the recent SARS-CoV-19 pandemic, and critically looks at the incidence and management of side effects of standard as well as next generation anti-MM agents.

Chirality-matched catalyst-controlled macrocyclization reactions

Macrocycles, formally defined as compounds that contain a ring with 12 or more atoms, continue to attract great interest due to their important applications in physical, pharmacological, and environmental sciences. In syntheses of macrocyclic compounds, promoting intramolecular over intermolecular reactions in the ring-closing step is often a key challenge. Furthermore, syntheses of macrocycles with stereogenic elements confer an additional challenge, while access to such macrocycles are of great interest. Herein, we report the remarkable effect peptide-based catalysts can have in promoting efficient macrocyclization reactions. We show that the chirality of the catalyst is essential for promoting favorable, matched transition-state relationships that favor macrocyclization of substrates with preexisting stereogenic elements; curiously, the chirality of the catalyst is essential for successful reactions, even though no new static (i.e., not “dynamic”) stereogenic elements are created. Control experiments involving either achiral variants of the catalyst or the enantiomeric form of the catalyst fail to deliver the macrocycles in significant quantity in head-to-head comparisons. The generality of the phenomenon, demonstrated here with a number of substrates, stimulates analogies to enzymatic catalysts that produce naturally occurring macrocycles, presumably through related, catalyst-defined peripheral interactions with their acyclic substrates.

Conceptual Barricades to Coronavirus Disease 2019 Biomedical Waste Management

Biomedical waste management (BMWM) is a major environmental health concern. Corona Virus Disease 2019 (COVID-19) pandemic came as bolt from the blue for governance with negligible preparedness. Pandemic COVID-19 has led to generation of solid waste in large volumes. Such BMW is an additional challenge in COVID-19 situation for healthcare facilities supplementary to COVID-19 pandemic management, control and prevention strategies. Centre for Pollution Control Board (CPCB) issued guidelines for COVID-19 related BMW waste in 3rd week of March 2020 and subsequently revised the same on 25th March 2020 and then on 18th April 2020. Scenario becomes compounded with less literate workers handling BMW required to develop newer competencies with deficient training and timeframe. Lots has been done to prepare COVID-19 related BMW waste management and lots still needs to be done to cover all the guidelines including practicality of implementation and ensuring less compromise on quality healthcare. This article focuses to review the COVID-19 related revised BMW requirements and their critical appraisal.

Love vs. money: Understanding unique challenges in care workers’ labor organizing

Care work pays less than it should, given the characteristics of the jobs and the qualifications of its workers (England et al., 2002). Care workers also face unique challenges as they organize for better working conditions, including better pay, because they do not want to threaten to withhold care from those in their charge (England, 2005). We propose that care workers face an additional challenge in organizing because, for some observers, it highlights that care workers are paid to care. To investigate this question, we examine how people respond to the organizing efforts of care workers through the lens of the Sacred Values Protection Model (SVPM; Tetlock et al., 2000). According to the SVPM, there are certain values that people assume to be sacred and unquestionable (e.g., love, justice). When we are forced to consider pitting a sacred value, like love, against a secular one, like money, the tradeoff is seen as taboo. As a result, people react with outrage, and the desire to see those who have engaged in the taboo tradeoff reaffirm the sacred value. In this chapter, we will argue that people’s opposition to care workers’ labor organizing can be partly explained by how much they view engaging in care work as trading love for money. For some, care work may be perceived as a taboo tradeoff, blurring the divide between activities performed out of love and those performed for pay. We suggest that labor organizing can inadvertently highlight this tension.

Koala retrovirus genetic diversity and transmission dynamics within captive koala populations

Koala populations are currently in rapid decline across Australia, with infectious diseases being a contributing cause. The koala retrovirus (KoRV) is a gammaretrovirus present in both captive and wild koala colonies that presents an additional challenge for koala conservation in addition to habitat loss, climate change, and other factors. Currently, nine different subtypes (A to I) have been identified; however, KoRV genetic diversity analyses have been limited. KoRV is thought to be exogenously transmitted between individuals, with KoRV-A also being endogenous and transmitted through the germline. The mechanisms of exogenous KoRV transmission are yet to be extensively investigated. Here, deep sequencing was employed on 109 captive koalas of known pedigree, housed in two institutions from Southeast Queensland, to provide a detailed analysis of KoRV transmission dynamics and genetic diversity. The final dataset included 421 unique KoRV sequences, along with the finding of an additional subtype (KoRV-K). Our analysis suggests that exogenous transmission of KoRV occurs primarily between dam and joey, with evidence provided for multiple subtypes, including nonendogenized KoRV-A. No evidence of sexual transmission was observed, with mating partners found to share a similar number of sequences as unrelated koala pairs. Importantly, both distinct captive colonies showed similar trends. These findings indicate that breeding strategies or antiretroviral treatment of females could be employed as effective management approaches in combating KoRV transmission.

Pustular psoriasis and arthropathy in a patient with HIV infection. Clinical case

The article presents a clinical case of pustular psoriasis and arthropathy in a patient with HIV infection. The diagnosis of psoriasis was confirmed by morphological examination. Signs of arthropathy were confirmed by X-Ray: presence of oligoarthritis of the distal interphalangeal joints of the fingers and feet was seen. Dactylitis severity ― 23 points, the Ritchie index ― 2, DLQI ― 28. The clinical course of psoriasis and its treatment in HIV-infected patients was considered after taking into account the data from literature and the patients current condition and observation. The above observation of a combination of several clinical forms of psoriasis (vulgar, pustular and arthropathy) in patients with HIV infection is an illustration of the features of the course and comorbidity of chronic dermatosis and AIDS, due to the influence of the infectious process, immunosuppression and ART. The development of pustular form and arthropathy creates the additional challenge of prescribing basic systemic treatment for severe and complicated psoriasis in an HIV-infected patient due to the presence of contraindications due to comorbidity. The glucocorticosteriod selected by the committee was effective on the skin and joint pathological processes, without having any negative impact on the course and treatment of the HIV infection. Such cases require further study and development of methods for the treatment of patients with comorbidity and their inclusion in an additional section in the clinical recommendations for the diagnosis and treatment of psoriasis.