Publishing Archaeology in Science and Scientific American, 1940-2003

Many new, or processual, archaeologists of the 1960s argued that Americanist archaeology became scientific only in the 1960s. The hypothesis that the rate of publication of archaeological research in Science and Scientific American increased after about 1965, as new archaeologists sought to demonstrate to their peers and other scientists that archaeology was indeed a science, is disconfirmed. The rate of archaeological publication in these journals increased after 1955 because the effort to be more scientific attributed to the processualists began earlier. Higher publication rates in both journals appear to have been influenced by an increased amount of archaeological research, a higher rate of archaeological publication generally, and increased funding. The hypothesis that editorial choice has strongly influenced what has been published in Science is confirmed; articles focusing on multidisciplinary topics rather than on narrow archaeological ones dominate the list of titles over the period from 1940 through 2003

Combinations of Host- and Virus-Targeting Antiviral Drugs Confer Synergistic Suppression of SARS-CoV-2

Three directly acting antivirals (DAAs) demonstrated substantial reduction in COVID-19 hospitalizations and deaths in clinical trials. However, these agents did not completely prevent severe illness and are associated with cases of rebound illness and viral shedding. Combination regimens can enhance antiviral potency, reduce the emergence of drug-resistant variants, and lower the dose of each component in the combination. Concurrently targeting virus entry and virus replication offers opportunities to discover synergistic drug combinations. While combination antiviral drug treatments are standard for chronic RNA virus infections, no antiviral combination therapy has been approved for SARS-CoV-2. Here, we demonstrate that combining host-targeting antivirals (HTAs) that target TMPRSS2 and hence SARS-CoV-2 entry, with the DAA molnupiravir, which targets SARS-CoV-2 replication, synergistically suppresses SARS-CoV-2 infection in Calu-3 lung epithelial cells. Strong synergy was observed when molnupiravir, an oral drug, was combined with three TMPRSS2 (HTA) oral or inhaled inhibitors: camostat, avoralstat, or nafamostat. The combination of camostat plus molnupiravir was also effective against the beta and delta variants of concern. The pyrimidine biosynthesis inhibitor brequinar combined with molnupiravir also conferred robust synergistic inhibition. These HTA+DAA combinations had similar potency to the synergistic all-DAA combination of molnupiravir plus nirmatrelvir, the protease inhibitor found in paxlovid. Pharmacodynamic modeling allowed estimates of antiviral potency at all possible concentrations of each agent within plausible therapeutic ranges, suggesting possible in vivo efficacy. The triple combination of camostat, brequinar, and molnupiravir further increased antiviral potency. These findings support the development of HTA+DAA combinations for pandemic response and preparedness. IMPORTANCE Imagine a future viral pandemic where if you test positive for the new virus, you can quickly take some medicines at home for a few days so that you do not get too sick. To date, only single drugs have been approved for outpatient use against SARS-CoV-2, and we are learning that these have some limitations and may succumb to drug resistance. Here, we show that combinations of two oral drugs are better than the single ones in blocking SARS-CoV-2, and we use mathematical modeling to show that these drug combinations are likely to work in people. We also show that a combination of three oral drugs works even better at eradicating the virus. Our findings therefore bode well for the development of oral drug cocktails for at home use at the first sign of an infection by a coronavirus or other emerging viral pathogens.Peer reviewe

"The Bayesian Objection" - Ch 4 of Seemings and Epistemic Justification

In this chapter I analyse an objection to phenomenal conservatism to the effect that phenomenal conservatism is unacceptable because it is incompatible with Bayesianism. I consider a few responses to it and dismiss them as misled or problematic. Then, I argue that this objection doesn’t go through because it rests on an implausible formalization of the notion of seeming-based justification. In the final part of the chapter, I investigate how seeming-based justification and justification based on one’s reflective belief that one has a seeming interact with one another

Def-6, a Novel Regulator of Small GTPases in Podocytes, Acts Downstream of Atypical Protein Kinase C (aPKC) λ/ι

Supplemental Data Supplemental Figure S1 Characterization of WT and aPKC-deficient podocytes. A–C: Genomic DNA isolated from deficient and control cell lines was tested for the presence of Cre recombinase (A), floxed and WT alleles of PKCλ/ι (B), or WT and knockout alleles of PKCζ (C). As controls, genomic DNA samples of tail biopsies were used. D: Differentiated deficient or control cells were stained with antibodies against synaptopodin or WT-1. All used cell lines were positive for the tested podocyte markers. Scale bars = 50 μm. Download Supplemental Figure S2 Relative mRNA and protein expression of PKCλ/ι, PKCζ, and Def-6 in deficient and control podocytes. A–C: Real-time PCR measurements and Western blot analysis of PKCλ/ι- and PKCζ-deficient cells in comparison with control cells. A: PKCλ/ι mRNA and protein are reduced in the PKCλ/ι −/− cells. B: PKCζ mRNA and protein are reduced in the PKCζ −/− cells. C: Def-6 mRNA is up-regulated in the PKCλ/ι −/− cells but not in PKCζ −/− cells. mRNA level is normalized for HPRT-1. Def-6 protein expression is not changed. ∗∗P < 0.01. Download Supplemental Table S1 Download Supplemental Table S2 Download Supplemental Table S3 Download Supplemental Table S4 Download Supplemental Table S5 Download Supplemental Table S6 Download Supplemental Table S7 Download Supplemental Table S8 Download Supplemental Data Supplemental material for this article can be found at . The atypical protein kinase C (aPKC) isotypes PKCλ/ι and PKCζ are both expressed in podocytes; however, little is known about differences in their function. Previous studies in mice have demonstrated that podocyte-specific loss of PKCλ/ι leads to a severe glomerular phenotype, whereas mice deficient in PKCζ develop no renal phenotype. We analyzed various effects caused by PKCλ/ι and PKCζ deficiency in cultured murine podocytes. In contrast to PKCζ-deficient podocytes, PKCλ/ι-deficient podocytes exhibited a severe actin cytoskeletal phenotype, reduced cell size, decreased number of focal adhesions, and increased activation of small GTPases. Comparative microarray analysis revealed that the guanine nucleotide exchange factor Def-6 was specifically up-regulated in PKCλ/ι-deficient podocytes. In vivo Def-6 expression is significantly increased in podocytes of PKCλ/ι-deficient mice. Cultured PKCλ/ι-deficient podocytes exhibited an enhanced membrane association of Def-6, indicating enhanced activation. Overexpression of aPKCλ/ι in PKCλ/ι-deficient podocytes could reduce the membrane-associated expression of Def-6 and rescue the actin phenotype. In the present study, PKCλ/ι was identified as an important factor for actin cytoskeletal regulation in podocytes and Def-6 as a specific downstream target of PKCλ/ι that regulates the activity of small GTPases and subsequently the actin cytoskeleton of podocytes

Prevalence of hereditary tubulointerstitial kidney diseases in the German Chronic Kidney Disease study

Hereditary chronic kidney disease (CKD) appears to be more frequent than the clinical perception. Exome sequencing (ES) studies in CKD cohorts could identify pathogenic variants in ~10% of individuals. Tubulointerstitial kidney diseases, showing no typical clinical/histologic finding but tubulointerstitial fibrosis, are particularly difficult to diagnose. We used a targeted panel (29 genes) and MUC1 -SNaPshot to sequence 271 DNAs, selected in defined disease entities and age cutoffs from 5217 individuals in the German Chronic Kidney Disease cohort. We identified 33 pathogenic variants. Of these 27 (81.8%) were in COL4A3/4/5 , the largest group being 15 COL4A5 variants with nine unrelated individuals carrying c.1871G>A, p.(Gly624Asp). We found three cysteine variants in UMOD , a novel missense and a novel splice variant in HNF1B and the homoplastic MTTF variant m.616T>C. Copy-number analysis identified a heterozygous COL4A5 deletion, and a HNF1B duplication/deletion, respectively. Overall, pathogenic variants were present in 12.5% (34/271) and variants of unknown significance in 9.6% (26/271) of selected individuals. Bioinformatic predictions paired with gold standard diagnostics for MUC1 (SNaPshot) could not identify the typical cytosine duplication (“c.428dupC”) in any individual, implying that ADTKD- MUC1 is rare. Our study shows that >10% of selected individuals carry disease-causing variants in genes partly associated with tubulointerstitial kidney diseases. COL4A3/4/5 genes constitute the largest fraction, implying they are regularly overlooked using clinical Alport syndrome criteria and displaying the existence of phenocopies. We identified variants easily missed by some ES pipelines. The clinical filtering criteria applied enriched for an underlying genetic disorder.Deutsche Forschungsgemeinschaft (German Research Foundation) https://doi.org/10.13039/50110000165

Measurement of the cosmic ray spectrum above 4×10184{\times}10^{18} eV using inclined events detected with the Pierre Auger Observatory

A measurement of the cosmic-ray spectrum for energies exceeding $4{\times}10^{18}$ eV is presented, which is based on the analysis of showers with zenith angles greater than $60^{\circ}$ detected with the Pierre Auger Observatory between 1 January 2004 and 31 December 2013. The measured spectrum confirms a flux suppression at the highest energies. Above $5.3{\times}10^{18}$ eV, the "ankle", the flux can be described by a power law $E^{-\gamma}$ with index $\gamma=2.70 \pm 0.02 \,\text{(stat)} \pm 0.1\,\text{(sys)}$ followed by a smooth suppression region. For the energy ($E_\text{s}$) at which the spectral flux has fallen to one-half of its extrapolated value in the absence of suppression, we find $E_\text{s}=(5.12\pm0.25\,\text{(stat)}^{+1.0}_{-1.2}\,\text{(sys)}){\times}10^{19}$ eV.Comment: Replaced with published version. Added journal reference and DO

Cerebral blood volume, genotype and chemosensitivity in oligodendroglial tumours

INTRODUCTION: The biological factors responsible for differential chemoresponsiveness in oligodendroglial tumours with or without the −1p/−19q genotype are unknown, but tumour vascularity may contribute. We aimed to determine whether dynamic susceptibility contrast (DSC) magnetic resonance imaging (MRI) could distinguish molecular subtypes of oligodendroglial tumour, and examined the relationship between relative cerebral blood volume (rCBV) and outcome following procarbazine, lomustine and vincristine (PCV) chemotherapy. METHODS: Pretherapy rCBV was calculated and inter- and intraobserver variability assessed. Allelic imbalance in 1p36, 19q13, 17p13, 10p12–15, and 10q22–26 and p53 mutation (exons 5–8) were determined. rCBV was compared with genotype and clinicopathological characteristics (n=37) and outcome following PCV chemotherapy (n=33). RESULTS: 1p/19q loss was seen in 6/9 grade II oligodendrogliomas, 6/14 grade II oligoastrocytomas, 4/4 grade III oligodendrogliomas, and 3/10 grade III oligoastrocytomas. rCBV measurements had good inter- and intraobserver variability, but did not distinguish histology subtype or grade. Tumours with 1p/19q loss had higher rCBV values (Student’s t-test P=0.001). Receiver operating characteristic analysis revealed a cut-off of 1.59 for identifying genotype (sensitivity 92%, specificity 76%). Tumours with high and low rCBV showed response to chemotherapy. The −1p/−19q genotype, but not rCBV, was strongly associated with response, progression-free and overall survival following PCV chemotherapy. Tumours with high rCBV and intact 1p/19q were associated with shorter progression-free and overall patient survival than those with intact 1p/19q and low rCBV or high rCBV and 1p/19q loss. CONCLUSION: rCBV identifies oligodendroglial tumours with 1p/19q loss, but does not predict chemosensitivity. The prognostic significance of rCBV may differ in oligodendroglial tumours with or without the −1p/−19q genotype

"Phenomenal Conservatism" - Ch 2 of Seemings and Epistemic Justification

In this chapter I introduce and analyse the tenets of phenomenal conservatism, and discuss the problem of the nature of appearances. After that, I review the asserted epistemic merits phenomenal conservatism and the principal arguments adduced in support of it. Finally, I survey objections to phenomenal conservatism and responses by its advocates. Some of these objections will be scrutinised and appraised in the next chapters

Radiocarbon dating and cultural dynamics across Mongolia’s early pastoral transition

All necessary permits were obtained for the described study, which complied with all relevant regulations. Collaboration contract between the Max Planck Institute for the Science of Human HIstory and the National University of Mongolia began on the 10th November, 2016. Export number 10/413 (7b/52) was received on the 2nd Feb, 2017 (#A0109258, MN DE 7 643). This research was supported by the Max Planck Institute for the Science of Human History. Special thanks to Dr. Katerina Douka and the Oxford Radiocarbon Accelerator Laboratory for conducting 14C analysis, and to all of the original excavators and authors who published the radiocarbon dates cited in this study.Peer reviewedPublisher PD