The driving force behind tool-stone selection in the African Middle Stone Age.

In the Stone Age, the collection of specific rocks was the first step in tool making. Very little is known about the choices made during tool-stone acquisition. Were choices governed by the knowledge of, and need for, specific properties of stones? Or were the collected raw materials a mere by-product of the way people moved through the landscape? We investigate these questions in the Middle Stone Age (MSA) of southern Africa, analyzing the mechanical properties of tool-stones used at the site Diepkloof Rock Shelter. To understand knapping quality, we measure flaking predictability and introduce a physical model that allows calculating the relative force necessary to produce flakes from different rocks. To evaluate their quality as finished tools, we investigate their resistance during repeated use activities (scraping or cutting) and their strength during projectile impacts. Our findings explain tool-stone selection in two emblematic periods of the MSA, the Still Bay and Howiesons Poort, as being the result of a deep understanding of these mechanical properties. In both cases, people chose those rocks, among many others, that allowed the most advantageous trade-off between anticipated properties of finished tools and the ease of acquiring rocks and producing tools. The implications are an understanding of African MSA toolmakers as engineers who carefully weighed their choices taking into account workability and the quality of the tools they made.

Archaeological adhesives made from Podocarpus document innovative potential in the African Middle Stone Age.

Studying the earliest archaeological adhesives has implications for our understanding of human cognition. In southern Africa, the oldest adhesives were made by Homo sapiens in the Middle Stone Age. Chemical studies have shown that these adhesives were made from a local conifer of the Podocarpaceae family. However, Podocarpus does not exude resin, nor any other substance that could have been recognized as having adhesive properties. Therefore, it remains unknown how these adhesives were made. This study investigates how Podocarpus adhesives can be made, comparing their mechanical properties with other naturally available adhesives. We found that Podocarpus tar can only be made by dry distillation of leaves, requiring innovative potential, skill, and knowledge. This contrasts with our finding that the Middle Stone Age environment was rich in substances that can be used as adhesives without such transformation. The apparent preference for Podocarpus tar may be explained by its mechanical properties. We found it to be superior to all other substances in terms of its adhesive properties. In addition, the condensation method that allows producing it can be recognized accidentally, as the processes take place above ground and can be triggered accidentally. Our findings have implications for establishing a link between technology and cognition in the Middle Stone Age.

Inference under superspreading: Determinants of SARS-CoV-2 transmission in Germany.

Superspreading, under-reporting, reporting delay, and confounding complicate statistical inference on determinants of disease transmission. A model that accounts for these factors within a Bayesian framework is estimated using German Covid-19 surveillance data. Compartments based on date of symptom onset, location, and age group allow to identify age-specific changes in transmission, adjusting for weather, reported prevalence, and testing and tracing. Several factors were associated with a reduction in transmission: public awareness rising, information on local prevalence, testing and tracing, high temperature, stay-at-home orders, and restaurant closures. However, substantial uncertainty remains for other interventions including school closures and mandatory face coverings. The challenge of disentangling the effects of different determinants is discussed and examined through a simulation study. On a broader perspective, the study illustrates the potential of surveillance data with demographic information and date of symptom onset to improve inference in the presence of under-reporting and reporting delay.

Differentiating α-moganite, silanol and α-quartz by Raman spectroscopy.

The silica phases quartz, silanol and moganite are widely prevalent and consequential in industrial applications and natural science. However, methods for differentiating these important phases are few. Using Raman spectra simulated by density function and perturbation expansion after discretization theory, representative spectra could be obtained and the comingling of diagnostic Raman Bands for the three phases identified in samples. On this basis new methods to identify moganite in Raman spectra are proposed.

Birch tar production does not prove Neanderthal behavioral complexity.

Birch tar production by Neanderthals-used for hafting tools-has been interpreted as one of the earliest manifestations of modern cultural behavior. This is because birch tar production per se was assumed to require a cognitively demanding setup, in which birch bark is heated in anaerobic conditions, a setup whose inherent complexity was thought to require modern levels of cognition and cultural transmission. Here we demonstrate that recognizable amounts of birch tar were likely a relatively frequent byproduct of burning birch bark (a natural tinder) under common, i.e., aerobic, conditions. We show that when birch bark burns close to a vertical to subvertical hard surface, such as an adjacent stone, birch tar is naturally deposited and can be easily scraped off the surface. The burning of birch bark near suitable surfaces provides useable quantities of birch tar in a single work session (3 h; including birch bark procurement). Chemical analysis of the resulting tar showed typical markers present in archaeological tar. Mechanical tests verify the tar's suitability for hafting and for hafted tools use. Given that similarly sized stones as in our experiment are frequently found in archaeological contexts associated with Neanderthals, the cognitively undemanding connection between burning birch bark and the production of birch tar would have been readily discoverable multiple times. Thus, the presence of birch tar alone cannot indicate the presence of modern cognition and/or cultural behaviors in Neanderthals.

Early anthropogenic use of hematite on Aurignacian ivory personal ornaments from Hohle Fels and Vogelherd caves, Germany.

The Aurignacian (ca. 43-35 ka) of southwestern Germany is well known for yielding some of the oldest artifacts related to symbolic behaviors, including examples of figurative art, musical instruments, and personal ornaments. Another aspect of these behaviors is the presence of numerous pieces of iron oxide (ocher); however, these are comparatively understudied, likely owing to the lack of painted artifacts from this region and time period. Several Aurignacian-aged carved ivory personal ornaments from the sites of Hohle Fels and Vogelherd contain traces of what appear to be red ocher residues. We analyzed these beads using a combination of macroanalytical and microanalytical methods, including scanning electron microscopy equipped with energy dispersive spectroscopy and Raman spectroscopy. We found that the residue is composed of the iron oxide mineral hematite (Fe2O3). Further analyses on associated archaeological sediments by X-ray diffraction revealed the absence of hematite and other iron oxide mineral phases, suggesting that the hematite residues were intentionally applied to the ivory personal ornaments by human agents. These findings have important implications as they represent evidence for the direct application of ocher on portable symbolic objects by early Homo sapiens in Europe. Furthermore, our results reveal shared behavioral practices from two key Aurignacian sites maintained over several millennia and illuminate aspects of pigment use and symbolic practices during a pivotal time in the cultural evolution of humans.

Reversible Iodine Intercalation into Tungsten Ditelluride.

The new compound WTe2I was prepared by a reaction of WTe2 with iodine in a fused silica ampule at temperatures between 40 and 200 °C. Iodine atoms are intercalated into the van der Waals gap between tungsten ditelluride layers. As a result, the WTe2 layer separation is significantly increased. Iodine atoms form planar layers between each tungsten ditelluride layer. Due to oxidation by iodine the semimetallic nature of WTe2 is changed, as shown by comparative band structure calculations for WTe2 and WTe2I based on density functional theory. The calculated phonon band structure of WTe2I indicates the presence of phonon instabilities related to charge density waves, leading to an observed incommensurate modulation of the iodine position within the layers.

Visualization of thermal washout due to spatiotemporally heterogenous perfusion in the application of a model-based control algorithm for MR-HIFU mediated hyperthermia.

PURPOSE: This article will report results from the in-vivo application of a previously published model-predictive control algorithm for MR-HIFU hyperthermia. The purpose of the investigation was to test the controller's in-vivo performance and behavior in the presence of heterogeneous perfusion. MATERIALS AND METHODS: Hyperthermia at 42°C was induced and maintained for up to 30 min in a circular section of a thermometry slice in the biceps femoris of German landrace pigs (n=5) using a commercial MR-HIFU system and a recently developed MPC algorithm. The heating power allocation was correlated with heat sink maps and contrast-enhanced MRI images. The temporal change in perfusion was estimated based on the power required to maintain hyperthermia. RESULTS: The controller performed well throughout the treatments with an absolute average tracking error of 0.27 ± 0.15 °C and an average difference of 1.25 ± 0.22 °C between T10 and T90. The MPC algorithm allocates additional heating power to sub-volumes with elevated heat sink effects, which are colocalized with blood vessels visible on contrast-enhanced MRI. The perfusion appeared to have increased by at least a factor of ∼1.86 on average. CONCLUSIONS: The MPC controller generates temperature distributions with a narrow spectrum of voxel temperatures inside the target ROI despite the presence of spatiotemporally heterogeneous perfusion due to the rapid thermometry feedback available with MR-HIFU and the flexible allocation of heating power. The visualization of spatiotemporally heterogeneous perfusion presents new research opportunities for the investigation of stimulated perfusion in hypoxic tumor regions.

Cost of decentralized CAR T-cell production in an academic nonprofit setting.

Chimeric antigen receptor (CAR) T-cell therapy is a promising immunotherapy with high acquisition costs, and it has raised concerns about affordability and sustainability in many countries. Furthermore, the current centralized production paradigm for the T cells is less than satisfactory. Therefore, several countries are exploring alternative T-cell production modes. Our study is based on the T-cell production experience in a nonprofit setting in Germany. We first identified the work steps and main activities in the production process. Then we determined the fixed costs and variable costs. Main cost components included personnel and technician salaries, expenditure on equipment, a clean room, as well as production materials. All costs were calculated in 2018 euros and converted into U.S. dollars. For a clean room with one machine for closed and automated manufacturing installed, annual fixed costs summed up to approximately €438 098 ($584 131). The variable cost per production was roughly €34 798 ($46 397). At the maximum capacity of one machine, total cost per product would be close to €60 000 ($78 849). As shown in the scenario analysis, if three machines were to be installed in the clean room, per production cost could be as low as €45 000 (roughly $59905). If a cheaper alternative to lentivirus was used, per production total cost could be further reduced to approximately €33 000 (roughly $44309). Decentralized T-cell production might be a less costly and more efficient alternative to the current centralized production mode that requires a high acquisition cost.

The antiquity of Australian silcrete heat treatment: Lake Mungo and the Willandra Lakes.

The evolution of heat treatment for stone artefact production is a subject of major interest for our understanding of early modern humans. In this study, we examine the evidence from one region in Australia to provide a new record of the antiquity of heat treatment, explore chronological shifts in the frequency of heat treatment, and discuss the implications of these findings for early population dynamics and the technical knowledge early settlers might have brought with them. Until now, Australian heat treatment has only dated back 25000 years. This study of the Willandra Lakes, including Lake Mungo, has identified the oldest systematic evidence of heat treatment yet reported in Australia, dating to ∼42000 years. We also document time-dependent directional change in the frequency of the practice. At those early times, with over 60% of all silcrete artefacts heat-treated, we hypothesize that the practice was mastered and integrated as a recurrent technical solution to the complexities of knapping silcrete. Over time, the use of heat treatment decreased progressively until less than 10% of the artefacts were heat-treated in the terminal Holocene. This trajectory has implications for understanding the antiquity of heat treatment on the Australian continent and for investigating the factors that governed its use.

Feasibility study of MR-guided pancreas ablation using high-intensity focused ultrasound in a healthy swine model.

Purpose: Pancreatic cancer is typically diagnosed in a late stage with limited therapeutic options. For those patients, ultrasound-guided high-intensity focused ultrasound (US-HIFU) can improve local control and alleviate pain. However, MRI-guided HIFU (MR-HIFU) has not yet been studied extensively in this context. To facilitate related research and accelerate clinical translation, we report a workflow for the in vivo HIFU ablation of the porcine pancreas under MRI guidance.Materials and methods: The pancreases of five healthy German landrace pigs (35-58 kg) were sonicated using a clinical MR-HIFU system. Acoustic access to the pancreas was supported by a specialized diet and a hydrogel compression device for bowel displacement. Organ motion was suspended using periods of apnea. The size of the resulting thermal lesions was assessed using the thermal threshold- and dose profiles, non-perfused volume, and gross examination. The effect of the compression device on beam path length was assessed using MRI imaging.Results: Eight of ten treatments resulted in clearly visible damage in the target tissue upon gross examination. Five treatments resulted in coagulative necrosis. Good agreement between the four metrics for lesion size and a clear correlation between the delivered energy dose and the resulting lesion size were found. The compression device notably shortened the intra-abdominal beam path.Conclusions: We demonstrated a workflow for HIFU treatment of the porcine pancreas in-vivo under MRI-guidance. This development bears significance for the development of MR-guided HIFU interventions on the pancreas as the pig is the preferred animal model for the translation of pre-clinical research into clinical application.

Idelalisib for optimized CD19-specific chimeric antigen receptor T cells in chronic lymphocytic leukemia patients.

Despite encouraging results with chimeric antigen receptor T (CART) cells, outcome can still be improved by optimization of the CART cell generation process. The proportion of less-differentiated T cells within the transfused product is linked to enhanced in vivo CART cell expansion and long-term persistence. The clinically approved PI3Kδ inhibitor idelalisib is well established in the treatment of B cell malignancies. Besides B cell receptor pathway inhibition, idelalisib can modulate T cell differentiation and function. Here, detailed longitudinal analysis of idelalisib-induced effects on T cell phenotype and function was performed during CART cell production. A third generation CD19.CAR.CD28.CD137zeta CAR vector system was used. CART cells were generated from peripheral blood mononuclear cells of healthy donors (HDs) and chronic lymphocytic leukemia (CLL) patients. Idelalisib-based CART cell generation resulted in an enrichment of less-differentiated naïve-like T cells (CD45RA+CCR7+), decreased expression of the exhaustion markers PD-1 and Tim-3, as well as upregulation of the lymph node homing marker CD62L. Idelalisib increased transduction efficiency, but did not impair viability and cell expansion. Strikingly, CD4:CD8 ratios that were altered in CART cells from CLL patients were approximated to ratios in HDs by idelalisib. Furthermore, in vivo efficacy of idelalisib-treated CART cells was validated in a xenograft mouse model. Intracellular TNF-α and IFN-γ production decreased in presence of idelalisib. This effect was reversible after resting CART cells without idelalisib. In summary, PI3Kδ inhibition with idelalisib can improve CART cell products, particularly when derived from CLL patients. Further studies with idelalisib-based CART cell generation protocols are warranted.

No difference between full thickness and partial thickness quadriceps tendon autografts in anterior cruciate ligament reconstruction: a systematic review.

PURPOSE: The purpose of this review was to compare outcomes and complication profiles of anterior cruciate ligament reconstruction (ACL-R) between full thickness (FT-Q) and partial thickness (PT-Q) quadriceps tendon (QT) autografts. METHODS: As per PRISMA guidelines, PubMed, EMBASE, and MEDLINE were searched in September 2017 for English language, human studies of all levels of evidence on patients undergoing primary ACL-R with FT-Q or PT-Q. This search was repeated in March 2018 to capture additional articles. Data regarding postoperative outcomes and complications were abstracted. Due to heterogeneous reporting, data were not combined in meta-analysis and were summarized descriptively. RESULTS: Upon screening 3670 titles, 18 studies satisfied inclusion/exclusion criteria. The second search identified an additional two studies for a total of 20 studies (50% case-control, 50% case series). These studies examined 1212 patients (1219 knees) of mean age 29.8 years (range 15-59) followed a mean of 42.2 months (range 12-120). FT-Q and PT-Q autografts were used in eight studies (50.5% of knees), and thirteen studies (49.5% of knees), respectively. Only one study directly compared FT-Q to PT-Q. Instrumented laxity was less than 3 mm in 74.8 and 72.4% of the FT-Q and PT-Q groups, respectively. Postoperative IKDC Subjective Knee Form scores were similar between the FT-Q (82.5) and PT-Q (82.1) groups. Postoperative quadriceps strength, measured as a percentage of the contralateral side, were similar in the FT-Q (89.5%) and PT-Q (85.1%) groups. Graft failure rates for the FT-Q and PT-Q groups were 3.7 and 3.0%, respectively. CONCLUSION: Across the 20 studies included in this review, there appeared to be no difference in outcomes or complications between either FT-Q or PT-Q in primary ACL-R. Moreover, primary ACL-R using QT autografts appears to have successful outcomes with a low rate of graft failure, irrespective of tendon thickness. While further comparative studies are needed to better delineate the optimal thickness of quadriceps tendon for primary ACL-R, these data suggest that, in primary ACL-R, either FT-Q or PT-Q is efficacious and, in the clinical setting, surgeons may be justified in using either graft thickness. LEVEL OF EVIDENCE: IV, Systematic Review of Level III and IV studies.

Stability and activity of MCSP-specific chimeric antigen receptors (CARs) depend on the scFv antigen-binding domain and the protein backbone.

Chimeric antigen receptor (CAR)-modified T cells emerged as effective tools in the immunotherapy of cancer but can produce severe on-target off-tissue toxicities. This risk can conceivably be overcome, at least partially, by transient transfection. The design of CARs, however, has so far not been optimized for use in non-permanent T cell modification. Here we compared the performance of T cells modified with three different first- and second-generation CARs, each specific for MCSP (HMW-MAA) which is commonly expressed by melanoma cells. Upon RNA transfer, the expression of all receptors was limited in time. The second-generation CARs, which combined CD28-CD3ζ signaling, were expressed at higher levels and more prolonged than first-generation CARs with CD3ζ only. The CD28 domain increased the cytokine production, but had only an indirect effect on the lytic capacity, by prolonging the CAR expression. Especially for the second-generation CARs, the scFv clearly impacted the level and duration of CAR expression and the T cell performance. Thus, we identified a CAR high in both expression and anti-tumor cell reactivity. T cells transfected with this CAR increased the mean survival time of mice after challenge with melanoma cells. To facilitate clinical application, this CAR was used to redirect T cells from late-stage melanoma patients by RNA transfection. These T cells mediated effective antigen-specific tumor cell lysis and release of pro-inflammatory cytokines, even after cryoconservation of the transfected T cells. Taken together, the analysis identified a CAR with superior anti-melanoma performance after RNA transfer which is a promising candidate for clinical exploration.

A previously undescribed organic residue sheds light on heat treatment in the Middle Stone Age.

South Africa has in recent years gained increasing importance for our understanding of the evolution of 'modern human behaviour' during the Middle Stone Age (MSA). A key element in the suite of behaviours linked with modern humans is heat treatment of materials such as ochre for ritual purposes and stone prior to tool production. Until now, there has been no direct archaeological evidence for the exact procedure used in the heat treatment of silcrete. Through the analysis of heat-treated artefacts from the Howiesons Poort of Diepkloof Rock Shelter, we identified a hitherto unknown type of organic residue - a tempering-residue - that sheds light on the processes used for heat treatment in the MSA. This black film on the silcrete surface is an organic tar that contains microscopic fragments of charcoal and formed as a residue during the direct contact of the artefacts with hot embers of green wood. Our results suggest that heat treatment of silcrete was conducted directly using an open fire, similar to those likely used for cooking. These findings add to the discussion about the complexity of MSA behaviour and appear to contradict previous studies that had suggested that heat treatment of silcrete was a complex (i.e., requiring a large number of steps for its realization) and resource-consuming procedure.

Eradication of melanomas by targeted elimination of a minor subset of tumor cells.

Proceeding on the assumption that all cancer cells have equal malignant capacities, current regimens in cancer therapy attempt to eradicate all malignant cells of a tumor lesion. Using in vivo targeting of tumor cell subsets, we demonstrate that selective elimination of a definite, minor tumor cell subpopulation is particularly effective in eradicating established melanoma lesions irrespective of the bulk of cancer cells. Tumor cell subsets were specifically eliminated in a tumor lesion by adoptive transfer of engineered cytotoxic T cells redirected in an antigen-restricted manner via a chimeric antigen receptor. Targeted elimination of less than 2% of the tumor cells that coexpress high molecular weight melanoma-associated antigen (HMW-MAA) (melanoma-associated chondroitin sulfate proteoglycan, MCSP) and CD20 lastingly eradicated melanoma lesions, whereas targeting of any random 10% tumor cell subset was not effective. Our data challenge the biological therapy and current drug development paradigms in the treatment of cancer.

Ochre-based compound adhesives at the Mousterian type-site document complex cognition and high investment.

Ancient adhesives used in multicomponent tools may be among our best material evidences of cultural evolution and cognitive processes in early humans. African Homo sapiens is known to have made compound adhesives from naturally sticky substances and ochre, a technical behavior proposed to mark the advent of elaborate cognitive processes in our species. Foragers of the European Middle Paleolithic also used glues, but evidence of ochre-based compound adhesives is unknown. Here, we present evidence of this kind. Bitumen was mixed with high loads of goethite ochre to make compound adhesives at the type-site of the Mousterian, Le Moustier (France). Ochre loads were so high that they lowered the adhesive's performance in classical hafting situations where stone implements are glued to handles. However, when used as handheld grips on cutting or scraping tools, a behavior known from Neanderthals, high-ochre adhesives present a real benefit, improving their solidity and rigidity. Our findings help understand the implications of Pleistocene adhesive making.