Reply to Martino's comments on "The normal, the natural, and the harmonic"

Reply to Martino's comments on "The normal, the natural, and the harmonic

Strengths and weaknesses of S-curves.

For the last 22 years I have been fitting logistic S-curves to data points of historical time series at an average rate of about 2-3 per day. This amounts to something between 15,000 and 20,000 fits. Combined with the 40,000 fits of the Monte Carlo study we did with Alain Debecker to quantify the uncertainties in logistic fits [1], probably qualifies me for an entry in the Guinness Book of Records as the man who carried out the greatest number of logistic fits. It hasn't all been fun and games. There have also been blood and tears and not only from human errors. There have been what I came to recognize as "misbehaviors" of reality. I have seen cases where an excellent fit and ensuing forecast were invalidated by later data. But well-established logistic growth reflects the action of a natural law. A disproved forecast is tantamount to violating this law. A law that becomes violated is not much of a law. What is going on? There is something here that needs to be sorted out

Long-term GDP forecasts and the prospects for growth

The growth of GDP is considered as a natural-growth process amenable to description by the logistic-growth equation. The S-shaped logistic pattern provides good descriptions and forecasts for both nominal and real GDP per capita in the US over the last 80 years. This enables the calculation of a long-term forecast for inflation, which is to enter a declining trend not so far in the future. The two logistics are well advanced, more so for nominal GDP. The assumption for logistic growth works even better for Japan whose nominal GDP per capita has already completed tracing out an entire logistic trajectory. The economic woes of industrialized countries could be attributed to the saturation of growth there, as if a niche in nature had been filled to capacity. In contrast, GDP growth in China and India is in the very early stages of logistic growth still indistinguishable from exponential patterns. The ceiling of these logistics can be anywhere between 5 and 10 times today's levels

Small-Molecule Inhibitors of Dengue-Virus Entry

Flavivirus envelope protein (E) mediates membrane fusion and viral entry from endosomes. A low-pH induced, dimer-to-trimer rearrangement and reconfiguration of the membrane-proximal “stem" of the E ectodomain draw together the viral and cellular membranes. We found stem-derived peptides from dengue virus (DV) bind stem-less E trimer and mimic the stem-reconfiguration step in the fusion pathway. We adapted this experiment as a high-throughput screen for small molecules that block peptide binding and thus may inhibit viral entry. A compound identified in this screen, 1662G07, and a number of its analogs reversibly inhibit DV infectivity. They do so by binding the prefusion, dimeric E on the virion surface, before adsorption to a cell. They also block viral fusion with liposomes. Structure-activity relationship studies have led to analogs with submicromolar IC90s against DV2, and certain analogs are active against DV serotypes 1,2, and 4. The compounds do not inhibit the closely related Kunjin virus. We propose that they bind in a previously identified, E-protein pocket, exposed on the virion surface and although this pocket is closed in the postfusion trimer, its mouth is fully accessible. Examination of the E-trimer coordinates (PDB 1OK8) shows that conformational fluctuations around the hinge could open the pocket without dissociating the trimer or otherwise generating molecular collisions. We propose that compounds such as 1662G07 trap the sE trimer in a “pocket-open" state, which has lost affinity for the stem peptide and cannot support the final “zipping up" of the stem

SARS-CoV-2 evolution during treatment of chronic infection

SARS-CoV-2 Spike protein is critical for virus infection via engagement of ACE21, and is a major 54 antibody target. Here we report chronic SARS-CoV-2 with reduced sensitivity to neutralising 55 antibodies in an immune suppressed individual treated with convalescent plasma, generating 56 whole genome ultradeep sequences over 23 time points spanning 101 days. Little change was 57 observed in the overall viral population structure following two courses of remdesivir over the 58 first 57 days. However, following convalescent plasma therapy we observed large, dynamic 59 virus population shifts, with the emergence of a dominant viral strain bearing D796H in S2 and 60 H69/V70 in the S1 N-terminal domain NTD of the Spike protein. As passively transferred 61 serum antibodies diminished, viruses with the escape genotype diminished in frequency, before 62 returning during a final, unsuccessful course of convalescent plasma. In vitro, the Spike escape 63 double mutant bearing H69/V70 and D796H conferred modestly decreased sensitivity to 64 convalescent plasma, whilst maintaining infectivity similar to wild type. D796H appeared to be 65 the main contributor to decreased susceptibility but incurred an infectivity defect. The 66 H69/V70 single mutant had two-fold higher infectivity compared to wild type, possibly 67 compensating for the reduced infectivity of D796H. These data reveal strong selection on SARS68 CoV-2 during convalescent plasma therapy associated with emergence of viral variants with 69 evidence of reduced susceptibility to neutralising antibodies.COG-UK is supported by funding from the Medical Research Council (MRC) part of UK Research & Innovation (UKRI), the National Institute of Health Research (NIHR) and Genome Research Limited, operating as the Wellcome Sanger Institute

Forecasting: theory and practice

Forecasting has always been in the forefront of decision making and planning. The uncertainty that surrounds the future is both exciting and challenging, with individuals and organisations seeking to minimise risks and maximise utilities. The lack of a free-lunch theorem implies the need for a diverse set of forecasting methods to tackle an array of applications. This unique article provides a non-systematic review of the theory and the practice of forecasting. We offer a wide range of theoretical, state-of-the-art models, methods, principles, and approaches to prepare, produce, organise, and evaluate forecasts. We then demonstrate how such theoretical concepts are applied in a variety of real-life contexts, including operations, economics, finance, energy, environment, and social good. We do not claim that this review is an exhaustive list of methods and applications. The list was compiled based on the expertise and interests of the authors. However, we wish that our encyclopedic presentation will offer a point of reference for the rich work that has been undertaken over the last decades, with some key insights for the future of the forecasting theory and practice

Experts in uncertainty

Book Review Roger M. Cooke, Experts in Uncertainty, Oxford University Press, New York, NY, 1991, $65.00, cloth

On Niall Ferguson's "Complexity and Collapse"

On Niall Ferguson's "Complexity and Collapse" Theodore Modi

Forecasting the growth of complexity and change

In the spirit of punctuated equilibrium, complexity is quantified relatively in terms of the spacing between equally important evolutionary turning points (milestones). Thirteen data sets of such milestones, obtained from a variety of scientific sources, provide data on the most important complexity jumps between the big bang and today. Forecasts for future complexity jumps are obtained via exponential and logistic fits on the data. The quality of the fits and common sense dictate that the forecast by the logistic function should be retained. This forecast stipulates that we have already reached the maximum rate of growth for complexity, and that in the future, complexity's rate of change (and the rate of change in our lives) will be declining. One corollary is that we are roughly halfway through the lifetime of the universe. Another result is that complexity's rate of growth has built up to its present high level via seven evolutionary subprocesses, themselves amenable to logistic description