Long-term variations in the net inflow record for Lake Malawi

Lake Malawi is the third largest lake in Africa and plays an important role in water supply, hydropower generation, agriculture and fisheries in the region. Lake level observations started in the 1890s and anecdotal evidence of variations dates back to the early 1800s. A chronology of lake level and outflow variations is presented together with updated estimates for the net inflow to the lake. The inflow series and selected rainfall records were also analysed using an unobserved component approach and, although there was little evidence of long-term trends, there was some indication of increasing interannual variability in recent decades. A weak quasi-periodic behaviour was also noted with a period of approximately 4–8 years. The results provide useful insights into the severity of drought and flood events in the region since the 1890s and the potential for seasonal forecasting of lake levels and outflows

Long-term variations in the net inflow record for Lake Malawi

Lake Malawi is the third largest lake in Africa and plays an important role in water supply, hydropower generation, agriculture and fisheries in the region. Lake level observations started in the 1890s and anecdotal evidence of variations dates back to the early 1800s. A chronology of lake level and outflow variations is presented together with updated estimates for the net inflow to the lake. The inflow series and selected rainfall records were also analysed using an unobserved component approach and, although there was little evidence of long-term trends, there was some indication of increasing interannual variability in recent decades. A weak quasi-periodic behaviour was also noted with a period of approximately 4–8 years. The results provide useful insights into the severity of drought and flood events in the region since the 1890s and the potential for seasonal forecasting of lake levels and outflows

6′-Amino-3′-methyl-2-oxo-1′-phenyl-1′,3a′,4′,7a′-tetra­hydrospiro­[1H-indole-3(2H),4′-pyrano[2,3-d]pyrazole]-5′-carbonitrile

In the crystal structure of the title compound, C21H15N5O2, the planar indolone unit and the pyran ring are almost perpendicular to each other [dihedral angle = 89.41 (2)°], and the pyrazole and phenyl rings are oriented at an angle of 25.74 (1)°. The mol­ecular packing is stabilized by inter- and intra­molecular C—H⋯O, N—H⋯O and C—H⋯π hydrogen bonds

Burrowing Behavior of a Deposit Feeding Bivalve Predicts Change in Intertidal Ecosystem State

Behavior has a predictive power that is often underutilized as a tool for signaling ecological change. The burrowing behavior of the deposit feeding bivalve Macoma balthica reflects a typical food-safety trade-off. The choice to live close to the sediment surface comes at a risk of predation and is a decision made when predation danger, food intake rates or future fitness prospects are low. In parts of the Dutch Wadden Sea, Macoma populations declined by 90% in the late 1990s, in parallel with large-scale mechanical cockle-dredging activities. During this decline, the burrowing depth of Macoma became shallow and was correlated with the population decline in the following year, indicating that it forecasted population change. Recently, there has been a series of large recruitment events in Macoma. According to the food-safety trade-off, we expected that Macoma should now live deeper, and have a higher body condition. Indeed, we observed that Macoma now lives deeper and that living depth in a given year forecasted population growth in the next year, especially in individuals larger than 14 mm. As living depth and body condition were strongly correlated in individuals larger than 14 mm, larger Macoma could be living deeper to protect their reproductive assets. Our results confirmed that burrowing depth signals impending population change and, together with body condition, can provide an early warning signal of ecological change. We suggest that population recovery is being driven by improved intertidal habitat quality in the Dutch Wadden Sea, rather than by the proposed climate-change related effects. This shift in ecosystem state is suggested to include the recovery of diatom habitat in the top layer of the sediment after cockle-dredging ended

A minimal physiologically based pharmacokinetic model that predicts anti-PEG IgG-mediated clearance of PEGylated drugs in human and mouse

Circulating antibodies that specifically bind polyethylene glycol (PEG), a polymer routinely used in protein and nanoparticle therapeutics, have been associated with reduced efficacy and increased adverse reactions to some PEGylated therapeutics. In addition to acute induction of anti-PEG antibodies (APA) by PEGylated drugs, typically low but detectable levels of APA are also found in up to 70% of the general population. Despite the broad implications of APA, the dynamics of APA-mediated clearance of PEGylated drugs, and why many patients continue to respond to PEGylated drugs despite the presence of pre-existing APA, remains not well understood. Here, we developed a minimal physiologically based pharmacokinetic (mPBPK) model that incorporates various properties of APA and PEGylated drugs. Our mPBPK model reproduced clinical PK data of APA-mediated accelerated blood clearance of pegloticase, as well as APA-dependent elimination of PEGyated liposomes in mice. Our model predicts that the prolonged circulation of PEGylated drugs will be compromised only at APA concentrations greater than ~500 ng/mL, providing a quantitative explanation to why the effects of APA on PEGylated treatments appear to be limited in most patients. This mPBPK model is readily adaptable to other PEGylated drugs and particles to predict the precise levels of APA that could render them ineffective, providing a powerful tool to support the development and interpretation of preclinical and clinical studies of various PEGylated therapeutics

Pretargeted delivery of PEG-coated drug carriers to breast tumors using multivalent, bispecific antibody against polyethylene glycol and HER2

Pretargeting is an increasingly explored strategy to improve nanoparticle targeting, in which pretargeting molecules that bind both selected epitopes on target cells and nanocarriers are first administered, followed by the drug-loaded nanocarriers. Bispecific antibodies (bsAb) represent a promising class of pretargeting molecules, but how different bsAb formats may impact the efficiency of pretargeting remains poorly understood, in particular Fab valency and Fc receptor (FcR)-binding of bsAb. We found the tetravalent bsAb markedly enhanced PEGylated nanoparticle binding to target HER2+ cells relative to the bivalent bsAb in vitro. Pretargeting with tetravalent bsAb with abrogated FcR binding increased tumor accumulation of PEGylated liposomal doxorubicin (PLD) 3-fold compared to passively targeted PLD alone, and 5-fold vs pretargeting with tetravalent bsAb with normal FcR binding in vivo. Our work demonstrates that multivalency and elimination of FcRn recycling are both important features of pretargeting molecules, and further supports pretargeting as a promising nanoparticle delivery strategy

Profiling the vendors of COVID‐19 related product on the Darknet: An observational study

Background In a time of unprecedented global change, the COVID-19 pandemic has led to a surge in demand of COVID-19 vaccines and related certifications. Mainly due to supply shortages, counterfeit vaccines, fake documentation, and alleged cures to illegal portfolios, have been offered on darkweb marketplaces (DWMs) with important public health consequences. We aimed to profile key DWMs and vendors by presenting some in-depth case studies. Methods A non-systematic search for COVID-19 products was performed across 118 DWMs. Levels of activity, credibility, content, COVID-19 product listings, privacy protocols were among the features retrieved. Open web fora and other open web sources were also considered for further analysis of both functional and non functional DWMs. Collected data refers to the period between January 2020 and October 2021. Results A total of 42 relevant listings sold by 24 vendors across eight DWMs were identified. Four of these markets were active and well-established at the time of the study with good levels of credibility. COVID-19 products were listed alongside other marketplace content. Vendors had a trusted profile, communicated in English language and accepted payments in cryptocurrencies (Monero or Bitcoin). Their geographical location included the USA, Asia and Europe. While COVID-19 related goods were mostly available for regional supply, other listings were also shipped worldwide. Interpretation Findings emerging from this study rise important questions about the health safety of certain DWMs activities and encourage the development of targeted interventions to overcome such new and rapidly expanding public health threats. Funding CovSaf, National Research centre on Privacy, Harm Reduction and Adversarial Influence Online (REPHRAIN), Commonwealth Fund

The Einstein Observatory catalog of IPC x ray sources. Volume 1E: Documentation

The Einstein Observatory (HEAO-2, launched November 13, 1978) achieved radically improved sensitivity over previous x-ray missions through the use of focusing optics, which simultaneously afforded greatly reduced background and produced true images. During its 2.5-yr mission, the Einstein X-Ray Telescope was pointed toward some 5,000 celestial targets, most of which were detected, and discovered several thousand additional 'serendipitous' sources in the observed fields. This catalog contains contour diagrams and source data, obtained with the imaging proportional counter in the 0.16 to 3.5 keV energy band, and describes methods for recovering upper limits for any sky position within the observed images. The main catalog consists of six volumes (numbered 2 through 7) of right ascension ordered pages, each containing data for one observation. Along with the primary documentation describing how the catalog was constructed, volume 1 contains a complete source list, results for merged fields, a reference system to published papers, and data useful for calculating upper limits and fluxes