Did Kettlewell commit fraud? Re-examining the evidence

H.B.D. Kettlewell is famous for several investigations conducted in the early 1950s on the phenomenon of industrial melanism, which are widely regarded as the classic demonstration of natural selection. In a recent (2002) book-length popularization of this episode in the history of the science, science writer Judith Hooper draws attention to what she interprets as discrepancies in the results reported by Kettlewell in his first scientific papers on the subject. On the basis of correspondence among Kettlewell and his associates, a survey of scientific publications that mention outstanding questions surrounding the phenomenon, as well as interviews with his son, surviving colleagues, and scientists who have worked on industrial melanism, Hooper all but explicitly concludes that Kettlewell committed fraud. The following essay critically examines her evidence in support of this allegation, including her discussion of his character, the alleged motives, and whether fraud was even committed. None of Hooper’s arguments is found to withstand careful scrutiny. The concluding section draws several conclusions about how history of science should be depicted to the public

A mechanism for mode selection in melt band instabilities

The deformation of partially molten mantle in tectonic environments can lead to exotic structures, which potentially affect both melt and plate-boundary focussing. Examples of such structures are found in laboratory deformation experiments on partially molten rocks. Simple-shear and torsion experiments demonstrate the formation of concentrated melt bands at angles of around 20° to the shear plane. The melt bands form in the experiments with widths of a few to tens of microns, and a band spacing roughly an order of magnitude larger. Existing compaction theories, however, cannot predict this band width structure, let alone any mode selection, since they infer the fastest growing instability to occur for wavelengths or bands of vanishing width. Here, we propose that surface tension in the mixture, especially on a diffuse interface in the limit of sharp melt-fraction gradients, can mitigate the instability at vanishing wavelength and thus permit mode selection for finite-width bands. Indeed, the expected weak capillary forces on the diffuse interface lead to predicted mode selection at the melt-band widths observed in the experiments

Melt-band instabilities with two-phase damage

Deformation experiments on partially molten rocks in simple shear form melt bands at 20° to the shear plane instead of at the expected 45° principal compressive stress direction. These melt bands may play an important role in melt focusing in mid-ocean ridges. Such shallow bands are known to form for two-phase media under shear if strongly non-Newtonian power-law creep is employed for the solid phase, or anisotropy imposed. However laboratory experiments show that shallow bands occur regardless of creep mechanism, even in diffusion creep, which is nominally Newtonian. Here we propose that a couple of forms of two-phase damage allow for shallow melt bands even in diffusion creep

Physics of melt extraction from the mantle : speed and style

Funding: This research received funding from the European Research Council under Horizon 2020 research and innovation program grant agreement number 772255. The authors thank the Isaac Newton Institute for Mathematical Sciences for its hospitality during the programme Melt in the Mantle which was supported by EPSRC Grant Number EP/K032208/1.Melt extraction from the partially molten mantle is among the fundamental processes shaping the solid Earth today and over geological time. A diversity of properties and mechanisms contribute to the physics of melt extraction. We review progress of the past ∼25 years of research in this area, with a focus on understanding the speed and style of buoyancy-driven melt extraction. Observations of U-series disequilibria in young lavas and the surge of deglacial volcanism in Iceland suggest this speed is rapid compared to that predicted by the null hypothesis of diffuse porous flow. The discrepancy indicates that the style of extraction is channelized. We discuss how channelization is sensitive to mechanical and thermochemical properties and feedbacks, and to asthenospheric heterogeneity. We review the grain-scale physics that underpins these properties and hence determines the physical behavior at much larger scales. We then discuss how the speed of melt extraction is crucial to predicting the magmatic response to glacial and sea-level variations. Finally, we assess the frontier of current research and identify areas where significant advances are expected over the next 25 years. In particular, we highlight the coupling of melt extraction with more realistic models of mantle thermochemistry and rheological properties. This coupling will be crucial in understanding complex settings such as subduction zones. ▪ Mantle melt extraction shapes Earth today and over geological time. ▪ Observations, lab experiments, and theory indicate that melt ascends through the mantle at speeds ∼30 m/year by reactively channelized porous flow. ▪ Variations in sea level and glacial ice loading can cause significant changes in melt supply to submarine and subaerial volcanoes. ▪ Fluid-driven fracture is important in the lithosphere and, perhaps, in the mantle wedge of subduction zones, but remains a challenge to model.PreprintPeer reviewe

Fast magma ascent, revised estimates from the deglaciation of Iceland

Partial melting of asthenospheric mantle generates magma that supplies volcanic systems. The timescale of melt extraction from the mantle has been hotly debated. Microstructural measurements of permeability typically suggest relatively slow melt extraction (1 m/yr) whereas geochemical (Uranium-decay series) and geophysical observations suggest much faster melt extraction (100 m/yr). The deglaciation of Iceland triggered additional mantle melting and magma flux at the surface. The rapid response has been used to argue for relatively rapid melt extraction. However, this episode must, at least to some extent, be unrepresentative, because the rates of magma eruption at the surface increased about thirty-fold relative to the steady state. Our goal is to quantify this unrepresentativeness. We develop a one-dimensional, time-dependent and nonlinear (far from steady-state), model forced by the most recent, and best mapped, Icelandic deglaciation. We find that 30 m/yr is the best estimate of the steady-state maximum melt velocity. This is a factor of about 3 smaller than previously claimed, but still relatively fast. We translate these estimates to other mid-ocean ridges accounting for differences in passive and active upwelling and degree of melting. We find that fast melt extraction greater than about 10 m/yr prevails globally

Development of prognostic models for survival and care status in sporadic Creutzfeldt-Jakob disease

Sporadic Creutzfeldt-Jakob disease, the most common human prion disease, typically presents as a rapidly progressive dementia and has a highly variable prognosis. Despite this heterogeneity, clinicians need to give timely advice on likely prognosis and care needs. No prognostic models have been developed that predict survival or time to increased care status from the point of diagnosis. We aimed to develop clinically useful prognostic models with data from a large prospective observational cohort study. Five hundred and thirty-seven patients were visited by mobile teams of doctors and nurses from the National Health Service National Prion Clinic within 5 days of notification of a suspected diagnosis of sporadic Creutzfeldt-Jakob disease, enrolled to the study between October 2008 and March 2020, and followed up until November 2020. Prediction of survival over 10-, 30- and 100-day periods was the main outcome. Escalation of care status over the same time periods was a secondary outcome for a subsample of 113 patients with low care status at initial assessment. Two hundred and eighty (52.1%) patients were female and the median age was 67.2 (interquartile range 10.5) years. Median survival from initial assessment was 24 days (range 0-1633); 414 patients died within 100 days (77%). Ten variables were included in the final prediction models: sex; days since symptom onset; baseline care status; PRNP codon 129 genotype; Medical Research Council Prion Disease Rating Scale, Motor and Cognitive Examination Scales; count of MRI abnormalities; Mini-Mental State Examination score and categorical disease phenotype. The strongest predictor was PRNP codon 129 genotype (odds ratio 6.65 for methionine homozygous compared with methionine-valine heterozygous; 95% confidence interval 3.02-14.68 for 30-day mortality). Of 113 patients with lower care status at initial assessment, 88 (78%) had escalated care status within 100 days, with a median of 35 days. Area under the curve for models predicting outcomes within 10, 30 and 100 days was 0.94, 0.92 and 0.91 for survival, and 0.87, 0.87 and 0.95 for care status escalation, respectively. Models without PRNP codon 129 genotype, which is not immediately available at initial assessment, were also highly accurate. We have developed a model that can accurately predict survival and care status escalation in sporadic Creutzfeldt-Jakob disease patients using clinical, imaging and genetic data routinely available in a specialist national referral service. The utility and generalizability of these models to other settings could be prospectively evaluated when recruiting to clinical trials and providing clinical care

Iatrogenic cerebral amyloid angiopathy: an emerging clinical phenomenon

In the last 6 years, following the first pathological description of presumed amyloid-beta (Aβ) transmission in humans (in 2015) and subsequent experimental confirmation (in 2018), clinical cases of iatrogenic cerebral amyloid angiopathy (CAA)—attributed to the transmission of Aβ seeds—have been increasingly recognised and reported. This newly described form of CAA is associated with early disease onset (typically in the third to fifth decade), and often presents with intracerebral haemorrhage, but also seizures and cognitive impairment. Although assumed to be rare, it is important that clinicians remain vigilant for potential cases, particularly as the optimal management, prognosis, true incidence and public health implications remain unknown. This review summarises our current understanding of the clinical spectrum of iatrogenic CAA and provides a diagnostic framework for clinicians. We provide clinical details for three patients with pathological evidence of iatrogenic CAA and present a summary of the published cases to date (n=20), identified following a systematic review. Our aims are: (1) To describe the clinical features of iatrogenic CAA, highlighting important similarities and differences between iatrogenic and sporadic CAA; and (2) To discuss potential approaches for investigation and diagnosis, including suggested diagnostic criteria for iatrogenic CAA

The PARP inhibitor AZD2461 provides insights into the role of PARP3 inhibition for both synthetic lethality and tolerability with chemotherapy in preclinical models

The PARP inhibitor AZD2461 was developed as a next-generation agent following olaparib, the first PARP inhibitor approved for cancer therapy. In BRCA1-deficient mouse models, olaparib resistance predominantly involves overexpression of P-glycoprotein,so AZD2461 was developed as a poor substrate for drug transporters. Here we demonstrate the efficacy of this compound against olaparib-resistant tumors that overexpress P-glycoprotein. In addition, AZD2461 was better tolerated in combination with chemotherapy than olaparib in mice, which suggests that AZD2461 could have significant advantages over olaparib in the clinic. However, this superior toxicity profile did not extend to rats. Investigations of this difference revealed a differential PARP3 inhibitory activity for each compound and a higher level of PARP3 expression in bone marrow cells from mice as compared with rats and humans. Our findings have implications for the use of mouse models to assess bone marrow toxicity for DNA-damaging agents and inhibitors of the DNA damage response. Finally, structural modeling of the PARP3-active site with different PARP inhibitors also highlights the potential to develop compounds with different PARP family member specificity profiles for optimal antitumor activity and tolerability

Elimination of Schistosomiasis Transmission in Zanzibar: Baseline Findings before the Onset of a Randomized Intervention Trial.

Gaining and sustaining control of schistosomiasis and, whenever feasible, achieving local elimination are the year 2020 targets set by the World Health Organization. In Zanzibar, various institutions and stakeholders have joined forces to eliminate urogenital schistosomiasis within 5 years. We report baseline findings before the onset of a randomized intervention trial designed to assess the differential impact of community-based praziquantel administration, snail control, and behavior change interventions. In early 2012, a baseline parasitological survey was conducted in ∼20,000 people from 90 communities in Unguja and Pemba. Risk factors for schistosomiasis were assessed by administering a questionnaire to adults. In selected communities, local knowledge about schistosomiasis transmission and prevention was determined in focus group discussions and in-depths interviews. Intermediate host snails were collected and examined for shedding of cercariae. The baseline Schistosoma haematobium prevalence in school children and adults was 4.3% (range: 0-19.7%) and 2.7% (range: 0-26.5%) in Unguja, and 8.9% (range: 0-31.8%) and 5.5% (range: 0-23.4%) in Pemba, respectively. Heavy infections were detected in 15.1% and 35.6% of the positive school children in Unguja and Pemba, respectively. Males were at higher risk than females (odds ratio (OR): 1.45; 95% confidence interval (CI): 1.03-2.03). Decreasing adult age (OR: 1.04; CI: 1.02-1.06), being born in Pemba (OR: 1.48; CI: 1.02-2.13) or Tanzania (OR: 2.36; CI: 1.16-4.78), and use of freshwater (OR: 2.15; CI: 1.53-3.03) showed higher odds of infection. Community knowledge about schistosomiasis was low. Only few infected Bulinus snails were found. The relatively low S. haematobium prevalence in Zanzibar is a promising starting point for elimination. However, there is a need to improve community knowledge about disease transmission and prevention. Control measures tailored to the local context, placing particular attention to hot-spot areas, high-risk groups, and individuals, will be necessary if elimination is to be achieved

Insulin resistance uncoupled from dyslipidemia due to C-terminal PIK3R1 mutations.

Obesity-related insulin resistance is associated with fatty liver, dyslipidemia, and low plasma adiponectin. Insulin resistance due to insulin receptor (INSR) dysfunction is associated with none of these, but when due to dysfunction of the downstream kinase AKT2 phenocopies obesity-related insulin resistance. We report 5 patients with SHORT syndrome and C-terminal mutations in PIK3R1, encoding the p85α/p55α/p50α subunits of PI3K, which act between INSR and AKT in insulin signaling. Four of 5 patients had extreme insulin resistance without dyslipidemia or hepatic steatosis. In 3 of these 4, plasma adiponectin was preserved, as in insulin receptor dysfunction. The fourth patient and her healthy mother had low plasma adiponectin associated with a potentially novel mutation, p.Asp231Ala, in adiponectin itself. Cells studied from one patient with the p.Tyr657X PIK3R1 mutation expressed abundant truncated PIK3R1 products and showed severely reduced insulin-stimulated association of mutant but not WT p85α with IRS1, but normal downstream signaling. In 3T3-L1 preadipocytes, mutant p85α overexpression attenuated insulin-induced AKT phosphorylation and adipocyte differentiation. Thus, PIK3R1 C-terminal mutations impair insulin signaling only in some cellular contexts and produce a subphenotype of insulin resistance resembling INSR dysfunction but unlike AKT2 dysfunction, implicating PI3K in the pathogenesis of key components of the metabolic syndrome.IHD was supported by the Raymond and Beverly Sackler Foundation via the University of Cambridge MB/PhD programme; RKS, IB, DBS, and SO were supported by the Wellcome Trust (grants WT098498, WT098051, WT107064, and WT095515, respectively and Strategic Award 100574/Z/12/Z), the MRC Metabolic Diseases Unit (MRC_MC_UU_12012/5), and the United Kingdom National Institute for Health Research (NIHR) Cambridge Biomedical Research Centre. The work was also supported by the Innovative Medicines Initiative Joint Undertaking under European Medical Information Framework (EMIF) grant agreement number 115372. UK10K was funded by the Wellcome Trust under award WT091310.This is the final version of the article. It first appeared from the American Society for Clinical Investigation via https://doi.org/10.1172/jci.insight.8876