Search

Identifying how small molecules act to kill malaria parasites can lead to new chemically validated targets. By pressuring Plasmodium falciparum asexual blood stage parasites with three novel structurally-unrelated antimalarial compounds (MMV665924, MMV019719 and MMV897615), and performing whole-genome sequence analysis on resistant parasite lines, we identify multiple mutations in the P. falciparum acyl-CoA synthetase (ACS) genes PfACS10 (PF3D7_0525100, M300I, A268D/V, F427L) and PfACS11 (PF3D7_1238800, F387V, D648Y, and E668K). Allelic replacement and thermal proteome profiling validates PfACS10 as a target of these compounds. We demonstrate that this protein is essential for parasite growth by conditional knockdown and observe increased compound susceptibility upon reduced expression. Inhibition of PfACS10 leads to a reduction in triacylglycerols and a buildup of its lipid precursors, providing key insights into its function. Analysis of the PfACS11 gene and its mutations point to a role in mediating resistance via decreased protein stability.

Undergraduate business law courses typically utilize traditional textbooks organized by topic. Individual chapters, address the usual topics including contracts, torts, the court system and ethics. An innovative approach to facilitating a business law course involves segregating sections of the course into common business disciplines. Rather than the abstract teaching of legal concepts, substantive material is presented in well defined sections including management, finance, accounting, real estate, marketing, and human resource management. Each section is defined by excerpts of published cases in private law, public law, preventative law and ethics. Individual disciplines are highlighted by instructive and provocative discussion questions following actual court opinions. Team teaching is an essential ingredient in discipline based instruction. Faculty members from specific disciplines are invited to participate and contribute to the course. The curriculum is presented in an applied format and relevant to the study and practice of business administration. Students are asked to apply legal concepts and issues to the individual disciplines they are studying in a business school format.

BackgroundThe objective of this study was to validate a simple predictive model for survival of patients with advanced cancer.MethodsPrevious studies with training and validation datasets developed a model predicting survival of patients referred for palliative radiotherapy using three readily available factors: primary cancer site, site of metastases and Karnofsky performance score (KPS). This predictive model was used in the current study, where each factor was assigned a value proportional to its prognostic weight and the sum of the weighted scores for each patient was survival prediction score (SPS). Patients were also classified according to their number of risk factors (NRF). Three risk groups were established. The Radiation Therapy and Oncology Group (RTOG) 9714 data was used to provide an additional external validation set comprised of patients treated among multiple institutions with appropriate statistical tests.ResultsThe RTOG external validation set comprised of 908 patients treated at 66 different radiation facilities from 1998 to 2002. The SPS method classified all patients into the low-risk group. Based on the NRF, two distinct risk groups with significantly different survival estimates were identified. The ability to predict survival was similar to that of the training and previous validation datasets for both the SPS and NRF methods.ConclusionsThe three variable NRF model is preferred because of its relative simplicity.

In addition to the well-documented seasonal cycles of mating and birth, there are also significant seasonal cycles of illness and death among many animal populations. Challenging winter conditions (i.e., low ambient temperature and decreased food availability) can directly induce death via hypothermia, starvation, or shock. Coping with these challenges can also indirectly increase morbidity and mortality by increasing glucocorticoid secretion, which can compromise immune function. Many environmental challenges are recurrent and thus predictable; animals could enhance survival, and presumably increase fitness, if they could anticipate immunologically challenging conditions in order to cope with these seasonal threats to health. The annual cycle of changing photoperiod provides an accurate indicator of time of year and thus allows immunological adjustments prior to the deterioration of conditions. Pineal melatonin codes day length information. Short day lengths enhance several aspects of immune function in laboratory studies, and melatonin appears to mediate many of the enhanced immunological effects of photoperiod. Generally, field studies report compromised immune function during the short days of autumn and winter. The conflict between laboratory and field data is addressed with a multifactor approach. The evidence for seasonal fluctuations in lymphatic tissue size and structure, as well as immune function and disease processes, is reviewed. The role of pineal melatonin and the hormones regulated by melatonin is discussed from an evolutionary and adaptive functional perspective. Finally, the clinically significance of seasonal fluctuations in immune function is presented. Taken together, it appears that seasonal fluctuations in immune parameters, mediated by melatonin, could have profound effects on the etiology and progression of diseases in humans and nonhuman animals. An adaptive functional perspective is critical to gain insights into the interaction among melatonin, immune function, and disease processes.

In addition to the well-documented seasonal cycles of mating and birth, there are also significant seasonal cycles of illness and death among many animal populations. Challenging winter conditions (i.e., low ambient temperature and decreased food availability) can directly induce death via hypothermia, starvation, or shock. Coping with these challenges can also indirectly increase morbidity and mortality by increasing glucocorticoid secretion, which can compromise immune function. Many environmental challenges are recurrent and thus predictable; animals could enhance survival, and presumably increase fitness, if they could anticipate immunologically challenging conditions in order to cope with these seasonal threats to health. The annual cycle of changing photoperiod provides an accurate indicator of time of year and thus allows immunological adjustments prior to the deterioration of conditions. Pineal melatonin codes day length information. Short day lengths enhance several aspects of immune function in laboratory studies, and melatonin appears to mediate many of the enhanced immunological effects of photoperiod. Generally, field studies report compromised immune function during the short days of autumn and winter. The conflict between laboratory and field data is addressed with a multifactor approach. The evidence for seasonal fluctuations in lymphatic tissue size and structure, as well as immune function and disease processes, is reviewed. The role of pineal melatonin and the hormones regulated by melatonin is discussed from an evolutionary and adaptive functional perspective. Finally, the clinically significance of seasonal fluctuations in immune function is presented. Taken together, it appears that seasonal fluctuations in immune parameters, mediated by melatonin, could have profound effects on the etiology and progression of diseases in humans and nonhuman animals. An adaptive functional perspective is critical to gain insights into the interaction among melatonin, immune function, and disease processes.

Problem: From April to September 2021, Fiji experienced a second wave of coronavirus disease (COVID-19) precipitated by the Delta variant of concern, prompting a need to strengthen existing data management of positive COVID-19 cases. Context: With COVID-19 cases peaking at 1405 a day and many hospital admissions, the need to develop a better way to visualize data became clear. Action: The Fiji Ministry of Health and Medical Services, the World Health Organization and the United Nations Office for the Coordination of Humanitarian Affairs collaborated to develop an online clinical dashboard to support better visualization of case management data. Outcome: The dashboard was used across Fiji at national, divisional and local levels for COVID-19 management. At the national level, it provided real-time reports describing the surge pattern, severity and management of COVID-19 cases across the country during daily incident management team meetings. At the divisional level, it gave the divisional directors access to timely information about hospital and community isolation of cases. At the hospital level, the dashboard allowed managers to monitor trends in isolated cases and use of oxygen resources. Discussion: The dashboard replaced previous paper-based reporting of statistics with delivery of trends and real-time data. The team that developed the tool were situated in different locations and did not meet physically, demonstrating the ease of implementing this online tool in a resource-constrained setting. The dashboard is easy to use and could be used in other Pacific island countries and areas. [ABSTRACT FROM AUTHOR]

Discusses library buildings and their role in building community. Reviews current design trends, including reading and study spaces; collaborative workspaces; technology-free zones; archives and special collections; cultural events spaces; age-specific spaces; shared spaces; natural light and landscapes; and interior design trends. (LRW)

Alternative procedures were investigated for determining the copyright status of brittle monographs to be scanned as part of the national preservation plan for agricultural sciences literature. Copyright searches conducted at Cornell University's printed Catalog of Copyright Entries (averaging seven minutes per title) were 97% in agreement with results of 13-minutes-per-title searches in the U.S. Copyright Office. (Author/AEF)

Summary Transmission represents a population bottleneck in the Plasmodium life cycle and a key intervention target of ongoing efforts to eradicate malaria. Sexual differentiation is essential for this process, as only sexual parasites, called gametocytes, are infective to the mosquito vector. Gametocyte production rates vary depending on environmental conditions, but external stimuli remain obscure. Here, we show that the host-derived lipid lysophosphatidylcholine (LysoPC) controls P. falciparum cell fate by repressing parasite sexual differentiation. We demonstrate that exogenous LysoPC drives biosynthesis of the essential membrane component phosphatidylcholine. LysoPC restriction induces a compensatory response, linking parasite metabolism to the activation of sexual-stage-specific transcription and gametocyte formation. Our results reveal that malaria parasites can sense and process host-derived physiological signals to regulate differentiation. These data close a critical knowledge gap in parasite biology and introduce a major component of the sexual differentiation pathway in Plasmodium that may provide new approaches for blocking malaria transmission.

Background: Artemisinin resistance is associated with delayed parasite clearance half-life in vivo and correlates with ring-stage survival under dihydroartemisinin in vitro. Both phenotypes are associated with mutations in the PF3D7_1343700 pfkelch13 gene. Recent spread of artemisinin resistance and emerging piperaquine resistance in Southeast Asia show that artemisinin combination therapy, such as dihydroartemisinin–piperaquine, are losing clinical effectiveness, prompting investigation of drug resistance mechanisms and development of strategies to surmount emerging anti-malarial resistance. Methods: Sixty-eight parasites isolates with in vivo clearance data were obtained from two Tracking Resistance to Artemisinin Collaboration study sites in Cambodia, culture-adapted, and genotyped for pfkelch13 and other mutations including pfmdr1 copy number; and the RSA0–3h survival rates and response to antimalarial drugs in vitro were measured for 36 of these isolates. Results: Among these 36 parasites one isolate demonstrated increased ring-stage survival for a PfKelch13 mutation (D584V, RSA0–3h = 8%), previously associated with slow clearance but not yet tested in vitro. Several parasites exhibited increased ring-stage survival, yet lack pfkelch13 mutations, and one isolate showed evidence for piperaquine resistance. Conclusions: This study of 68 culture-adapted Plasmodium falciparum clinical isolates from Cambodia with known clearance values, associated the D584V PfKelch13 mutation with increased ring-stage survival and identified parasites that lack pfkelch13 mutations yet exhibit increased ring-stage survival. These data suggest mutations other than those found in pfkelch13 may be involved in conferring artemisinin resistance in P. falciparum. Piperaquine resistance was also detected among the same Cambodian samples, consistent with reports of emerging piperaquine resistance in the field. These culture-adapted parasites permit further investigation of mechanisms of both artemisinin and piperaquine resistance and development of strategies to prevent or overcome anti-malarial resistance. Electronic supplementary material The online version of this article (doi:10.1186/s12936-017-1845-5) contains supplementary material, which is available to authorized users.

The article provides information on collection management plans for college libraries in the U.S. A plan allows for the communication of collection priorities and strategies to audiences, the agreement of collection management decision-making, and the process of thinking through management strategies. The author suggests that libraries establish collection values and goals and devise collection management strategies for print and digital formats. The article also discusses the disposition of withdrawn materials, life-cycle management retention, and education and community support.

The article discusses the role of immigrant entrepreneurs in community development in Chicago, Illinois from 1890-1921. It is stated that the state ranks in the top six U.S. states of intended residence for immigrants and is included in the top four metropolitan areas. The city has been host to immigrants from all over the world in which the first German settler arrived in 1825 and the first Chinese men came to work in 1871. In addition, the specific ways in which immigrant entrepreneurs contribute to the revitalization of their neighborhoods, centering on the perspectives of the immigrant entrepreneurs themselves is offered.

The article presents the final entry in the journal's special column dedicated to collective collections curating in academic librarianship. In it the editor discusses the use of memoranda of understanding (MOUs) to codify agreements between library consortia, focusing on harmonizing their taxonomy across the sector. Topics addressed include consortia membership types, defining the scope of shared collections, and differences in the policy purposes and approaches.