Publications by authors named "Sarah Nagel"

32 Publications

The impact of closed incisional negative pressure therapy on anterior lateral thigh flap donor site healing and scarring: A retrospective case-control study.

J Plast Reconstr Aesthet Surg 2021 Jun 13. Epub 2021 Jun 13.

Department of Hand, Plastic and Reconstructive Surgery, Burn Center, BG Trauma Center Ludwigshafen, Ludwig-Guttmann-Strasse 13, 67071 Ludwigshafen, Germany; Hand and Plastic Surgery, University of Heidelberg, Heidelberg, Germany. Electronic address:

Background: The objective of this study was to investigate whether closed incisional negative pressure therapy (cINPT) is suitable to improve anterior lateral thigh (ALT) flap donor site healing and scarring.

Methods: We identified 271 ALT free flaps of widths between 7 and 9 cm and primary donor site closure performed between January 2012 to December 2019. Patients were divided into cases of cINPT versus controls without cINPT as part of this retrospective case-control review. We compared the incidences of postoperative donor site complications (wound dehiscence, infection, seroma, hematoma) and the degree of scarring severity using the Vancouver Scar Scale (VSS) and the Patient and Observer Scar Assessment Scales (POSAS).

Results: A total of 106 ALT donor sites received cINPT (39%), whereas the remaining 165 donor sites received conventional dressings (61%). The distribution of gender, age, body mass index, comorbidities, and mean flap sizes were comparable between both groups. The occurrence of surgical wound dehiscence was significantly lower in the cINPT group (2.8%), when compared to controls (9.0%) (p = 0.04). Furthermore, the mean length of postoperative hospital stay was significantly shorter in the cINPT group (19 ± 8 days versus 21 ± 11 days; p = 0.03). CINPT was associated with a more favorable donor site scar quality when assessed by VSS (p = 0.03) and POSAS (p = 0.002).

Conclusion: The use of cINPT was associated with significantly less ALT donor site complications and superior scar quality accelerating patients' postoperative recovery.
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http://dx.doi.org/10.1016/j.bjps.2021.05.049DOI Listing
June 2021

A single-center retrospective comparison of Duplex ultrasonography versus audible Doppler regarding anterolateral thigh perforator flap harvest and operative times.

Microsurgery 2021 Jun 24. Epub 2021 Jun 24.

Department of Hand, Plastic and Reconstructive Surgery, Burn Center, BG Trauma Center Ludwigshafen, University of Heidelberg, Heidelberg, Germany.

Introduction: We reported on the superiority of preoperative Duplex mapping ("Duplex") over audible Dopplers ("Doppler") in anterolateral thigh perforator (ALT) free flaps for upper extremity reconstruction. To corroborate our findings on a larger cohort, we conducted this present study focusing on surgical efficiency and patient safety.

Methods: 150 consecutive ALT free flaps were divided into 65 cases of preoperative Duplex versus 85 Doppler controls. We first compared patient demographics, operative details, and defect and flap characteristics. We then assessed group differences in the number and course of perforators pursued intraoperatively, flap harvest and operative times, and donor-site complications. Additionally, the impact of the training level of the primary microsurgeon was evaluated.

Results: Cases and controls were comparable regarding age (p = .48), sex (p = .81), ASA class (p = .48), and BMI (p = .90). Duplex was associated with an increased likelihood of raising flaps on one single dominant perforator of purely septal course and significant reductions of flap harvest (68 ± 10 min, p < .0001) and operative times (74 ± 16 min, p < .0001), regardless of the experience of the primary microsurgeon. There were strong negative linear correlations between preoperative Duplex and both the flap harvest and operative times (p < .0001). Additionally, while there was no effect on the emergency take-back rate (OR = 1.3, p = .60), revisions were significantly less likely among duplexed patients (OR = 0.15, p = .04).

Conclusions: Preoperative Duplex is associated with a significant reduction in ALT free flap harvest and overall operative times, as well as donor-site revisions as opposed to Doppler planning, regardless of the training level of the primary microsurgeon.
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http://dx.doi.org/10.1002/micr.30775DOI Listing
June 2021

Pleistocene sediment DNA reveals hominin and faunal turnovers at Denisova Cave.

Nature 2021 07 23;595(7867):399-403. Epub 2021 Jun 23.

Max Planck Institute for Evolutionary Anthropology, Leipzig, Germany.

Denisova Cave in southern Siberia is the type locality of the Denisovans, an archaic hominin group who were related to Neanderthals. The dozen hominin remains recovered from the deposits also include Neanderthals and the child of a Neanderthal and a Denisovan, which suggests that Denisova Cave was a contact zone between these archaic hominins. However, uncertainties persist about the order in which these groups appeared at the site, the timing and environmental context of hominin occupation, and the association of particular hominin groups with archaeological assemblages. Here we report the analysis of DNA from 728 sediment samples that were collected in a grid-like manner from layers dating to the Pleistocene epoch. We retrieved ancient faunal and hominin mitochondrial (mt)DNA from 685 and 175 samples, respectively. The earliest evidence for hominin mtDNA is of Denisovans, and is associated with early Middle Palaeolithic stone tools that were deposited approximately 250,000 to 170,000 years ago; Neanderthal mtDNA first appears towards the end of this period. We detect a turnover in the mtDNA of Denisovans that coincides with changes in the composition of faunal mtDNA, and evidence that Denisovans and Neanderthals occupied the site repeatedly-possibly until, or after, the onset of the Initial Upper Palaeolithic at least 45,000 years ago, when modern human mtDNA is first recorded in the sediments.
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http://dx.doi.org/10.1038/s41586-021-03675-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8277575PMC
July 2021

A Retrospective Comparative Functional and Aesthetic Outcome Study of Muscle versus Cutaneous Free Flaps for Distal Upper Extremity Reconstruction.

J Reconstr Microsurg 2021 May 19. Epub 2021 May 19.

Department of Hand, Plastic and Reconstructive Surgery, Burn Center, BG Trauma Center Ludwigshafen, University of Heidelberg, Heidelberg, Germany.

Background:  Function and cosmesis are crucial in upper extremity reconstruction. Yet, there persists a lack of outcome evaluations, particularly regarding differences between free flap types.

Methods:  In a single-center retrospective analysis, outcomes were compared between patients with cutaneous or muscle free flaps for distal upper extremity reconstruction between 2008 and 2018. The Disabilities of Arm, Shoulder and Hand -Score, Michigan-Hand (MHQ), and Short Form 36 Health Survey (SF-36) Questionnaires were assessed, motor function was quantified, and self-reported measures of cosmesis were compared, including the Vancouver Scar-Scale (VSS), MHQ aesthetics-subscale (MAS), and Moscona's cosmetic validation-score (CVS).

Results:  One-hundred forty-one cases were identified, with a shift toward cutaneous flaps over the study period. Muscle flaps were used for larger defects (251 vs. 142 cm,  = 0.008). Losses, thromboses, and donor-site complications were equally distributed. Partial necroses were more frequent in muscle flaps (11 vs. 1%,  = 0.015). Seventy patients with 53 cutaneous versus 17 muscle flaps were reexamined. There was no difference in the timing of flap coverage (after 16 vs. 15 days,  = 0.79), number of preceding (2 vs. 1.7,  = 0.95), or subsequent operations (19/53 vs. 5/17,  = 0.77). Patients with cutaneous flaps showed higher grip strength (25 vs. 17 kg,  = 0.046) and reported better hand function (MHQ: 58 vs. 47,  = 0.044) and general health (SF-36: 70 vs. 61,  = 0.040), as well as more favorable appearance (MAS: 71 vs. 57,  = 0.044, CVS: 77 vs. 72,  = 0.048), and scar burden (VSS: 0 vs. 3,  < 0.001).

Conclusion:  Cutaneous flaps yielded better motor function, self-perceived cosmesis, patient satisfaction, and quality of life in our cohort of distal upper extremity reconstructions.
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http://dx.doi.org/10.1055/s-0041-1729882DOI Listing
May 2021

Unearthing Neanderthal population history using nuclear and mitochondrial DNA from cave sediments.

Science 2021 05 15;372(6542). Epub 2021 Apr 15.

Department of Evolutionary Genetics, Max-Planck-Institute for Evolutionary Anthropology, Leipzig, Germany.

Bones and teeth are important sources of Pleistocene hominin DNA, but are rarely recovered at archaeological sites. Mitochondrial DNA (mtDNA) has been retrieved from cave sediments but provides limited value for studying population relationships. We therefore developed methods for the enrichment and analysis of nuclear DNA from sediments and applied them to cave deposits in western Europe and southern Siberia dated to between 200,000 and 50,000 years ago. We detected a population replacement in northern Spain about 100,000 years ago, which was accompanied by a turnover of mtDNA. We also identified two radiation events in Neanderthal history during the early part of the Late Pleistocene. Our work lays the ground for studying the population history of ancient hominins from trace amounts of nuclear DNA in sediments.
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http://dx.doi.org/10.1126/science.abf1667DOI Listing
May 2021

[Evaluation of secondary refinement procedures following free microvascular tissue reconstruction of the upper extremity].

Handchir Mikrochir Plast Chir 2021 Aug 13;53(4):356-363. Epub 2021 Apr 13.

BG Klinik Ludwigshafen, Klinik für Hand-, Plastische und Rekonstruktive Chirurgie, Mikrochirurgie, Schwerbrandverletztenzentrum, Plastische Chirurgie und Handchirurgie der Universität Heidelberg.

Background:  The primary cosmetic and functional outcome following successful upper limb salvage using free tissue transfer can often be unfavourable, which may motivate patients to undergo secondary procedures. In this study, we sought to identify predictors for secondary procedures and to analyse the type and number of these procedures.

Patients And Methods:  Patients who underwent free tissue transfer to the upper extremity between 2010 and 2017 were included in a retrospective cohort study: patients with secondary procedures to optimise the functional and aesthetic flap design (S cohort) vs. control cohort (C cohort). A multivariate regression analysis was used to identify predictors for secondary procedures.

Results:  One hundred and twenty-eight patients were included in the study (S cohort 36, C cohort 92). All in all, 56 secondary refinement procedures were performed in a mean of eight months after the initial free flap reconstruction. Most of the defects in the S cohort were localised at the hand (53 %), and upper limb salvage was mostly accomplished by fasciocutaneous and adipocutaneous free flaps (S cohort 89 %). The most frequently performed secondary refinement procedures were direct partial flap excision (61 %), followed by liposuction (16 %) and the combination of both (17 %). Furthermore, 64 % of the secondary refinement procedures from the S cohort were combined with further surgical interventions to improve hand function, e. g. tenolysis and arthrolysis. Patients with defects of the hand received secondary procedures 2.4 times more frequently (p = 0.05). Also, patients with a good general health condition (ASA 1 and 2) were six times more likely to undergo a secondary procedure (p = 0.03).

Conclusion:  Secondary procedures are safe and frequently requested by patients following successful free flap upper limb salvage. In particular, this applies to patients who are in a good health condition and with free flaps to the hand. Therefore, we recommend the implementation of secondary refinement procedures in the reconstructive plan to increase patient compliance and satisfaction.
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http://dx.doi.org/10.1055/a-1294-9593DOI Listing
August 2021

Initial Upper Palaeolithic humans in Europe had recent Neanderthal ancestry.

Nature 2021 04 7;592(7853):253-257. Epub 2021 Apr 7.

Francis Crick Institute, London, UK.

Modern humans appeared in Europe by at least 45,000 years ago, but the extent of their interactions with Neanderthals, who disappeared by about 40,000 years ago, and their relationship to the broader expansion of modern humans outside Africa are poorly understood. Here we present genome-wide data from three individuals dated to between 45,930 and 42,580 years ago from Bacho Kiro Cave, Bulgaria. They are the earliest Late Pleistocene modern humans known to have been recovered in Europe so far, and were found in association with an Initial Upper Palaeolithic artefact assemblage. Unlike two previously studied individuals of similar ages from Romania and Siberia who did not contribute detectably to later populations, these individuals are more closely related to present-day and ancient populations in East Asia and the Americas than to later west Eurasian populations. This indicates that they belonged to a modern human migration into Europe that was not previously known from the genetic record, and provides evidence that there was at least some continuity between the earliest modern humans in Europe and later people in Eurasia. Moreover, we find that all three individuals had Neanderthal ancestors a few generations back in their family history, confirming that the first European modern humans mixed with Neanderthals and suggesting that such mixing could have been common.
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http://dx.doi.org/10.1038/s41586-021-03335-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8026394PMC
April 2021

Comparison of pedicled versus free flaps for reconstruction of extensive deep sternal wound defects following cardiac surgery: A retrospective study.

Microsurgery 2021 May 29;41(4):309-318. Epub 2021 Mar 29.

Department of Hand, Plastic and Reconstructive Surgery, Burn Center, BG Trauma Center Ludwigshafen, Hand and Plastic Surgery, University of Heidelberg, Heidelberg, Germany.

Background: Myocutaneous pedicled flaps are the method of choice for sternal reconstruction after deep sternal wound infection (DSWI) following cardiac surgery. We set out to investigate whether free flaps provide a superior alternative for particularly extended sternal defects.

Methods: Between October 2008 and February 2020, 86 patients with DSWI underwent sternal reconstruction with myocutaneous flaps at our institution. Patients were retrospectively grouped into pedicled (A; n = 42) and free flaps (B, n = 44). The objective was to compare operative details, outcome variables, surgical as well as medical complication rates between both groups, retrospectively. Binary logistic regression analysis was applied to determine the effect of increasing defect size on flap necrosis.

Results: Rates of partial flap necrosis (>5% of the skin island) were significant higher in pedicled flaps (n = 14), when compared to free flaps (n = 4) (OR: 5.0; 33 vs. 9%; p = .008). Increasing defect size was a significant risk factor for the incidence of partial flap necrosis of pedicled flaps (p = .012), resulting in a significant higher rate of additional surgeries (p = .036). Binary regression model revealed that the relative likelihood of pedicled flap necrosis increased by 2.7% with every extra square-centimeter of defect size.

Conclusion: To avoid an increased risk of partial flap necrosis, free flaps expand the limits of extensive sternal defect reconstruction with encouragingly low complication rates and proved to be a superior alternative to pedicled flaps in selected patients.
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http://dx.doi.org/10.1002/micr.30730DOI Listing
May 2021

Denisovan ancestry and population history of early East Asians.

Science 2020 10;370(6516):579-583

Max Planck Institute for Evolutionary Anthropology, D-04103 Leipzig, Germany.

We present analyses of the genome of a ~34,000-year-old hominin skull cap discovered in the Salkhit Valley in northeastern Mongolia. We show that this individual was a female member of a modern human population that, following the split between East and West Eurasians, experienced substantial gene flow from West Eurasians. Both she and a 40,000-year-old individual from Tianyuan outside Beijing carried genomic segments of Denisovan ancestry. These segments derive from the same Denisovan admixture event(s) that contributed to present-day mainland Asians but are distinct from the Denisovan DNA segments in present-day Papuans and Aboriginal Australians.
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http://dx.doi.org/10.1126/science.abc1166DOI Listing
October 2020

A systematic investigation of human DNA preservation in medieval skeletons.

Sci Rep 2020 10 26;10(1):18225. Epub 2020 Oct 26.

Max Planck Institute for the Science of Human History, Jena, Germany.

Ancient DNA (aDNA) analyses necessitate the destructive sampling of archaeological material. Currently, the cochlea, part of the osseous inner ear located inside the petrous pyramid, is the most sought after skeletal element for molecular analyses of ancient humans as it has been shown to yield high amounts of endogenous DNA. However, destructive sampling of the petrous pyramid may not always be possible, particularly in cases where preservation of skeletal morphology is of top priority. To investigate alternatives, we present a survey of human aDNA preservation for each of ten skeletal elements in a skeletal collection from Medieval Germany. Through comparison of human DNA content and quality we confirm best performance of the petrous pyramid and identify seven additional sampling locations across four skeletal elements that yield adequate aDNA for most applications in human palaeogenetics. Our study provides a better perspective on DNA preservation across the human skeleton and takes a further step toward the more responsible use of ancient materials in human aDNA studies.
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http://dx.doi.org/10.1038/s41598-020-75163-wDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7588426PMC
October 2020

Manual and automated preparation of single-stranded DNA libraries for the sequencing of DNA from ancient biological remains and other sources of highly degraded DNA.

Nat Protoc 2020 08 1;15(8):2279-2300. Epub 2020 Jul 1.

Department of Evolutionary Genetics, Max Planck Institute for Evolutionary Anthropology, Leipzig, Germany.

It has been shown that highly fragmented DNA is most efficiently converted into DNA libraries for sequencing if both strands of the DNA fragments are processed independently. We present an updated protocol for library preparation from single-stranded DNA, which is based on the splinted ligation of an adapter oligonucleotide to the 3' ends of single DNA strands, the synthesis of a complementary strand using a DNA polymerase and the addition of a 5' adapter via blunt-end ligation. The efficiency of library preparation is determined individually for each sample using a spike-in oligonucleotide. The whole workflow, including library preparation, quantification and amplification, requires two work days for up to 16 libraries. Alternatively, we provide documentation and electronic protocols enabling automated library preparation of 96 samples in parallel on a Bravo NGS Workstation (Agilent Technologies). After library preparation, molecules with uninformative short inserts (shorter than ~30-35 base pairs) can be removed by polyacrylamide gel electrophoresis if desired.
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http://dx.doi.org/10.1038/s41596-020-0338-0DOI Listing
August 2020

A comparative study of preoperative color-coded Duplex ultrasonography versus handheld audible Dopplers in ALT flap planning.

Microsurgery 2020 Jul 5;40(5):561-567. Epub 2020 May 5.

Department of Hand, Plastic and Reconstructive Surgery, Burn Center, BG Trauma Center Ludwigshafen, University of Heidelberg, Ludwigshafen, Germany.

Introduction: The anterior lateral thigh (ALT) flap's vascular variability can lead to complications. Thus, the accuracy of numerous planning modalities has been studied. The clinical relevance of competing mapping methods, however, remains unknown. Therefore, we compared the impact of color-coded Duplex ultrasonography and handheld audible Dopplers on surgical efficacy and flap safety.

Patients And Methods: Forty-four ALT flaps were included in this comparative retrospective monocentric study. Twelve patients received Duplex scans and 32 flaps were designed using Dopplers only. Patient, defect, and flap characteristics of both groups were analyzed. The effect of either planning method on the primary outcome variables - flap harvest and operative times (HT, OT), course of perforator dissection, incidence of flap loss, emergent re-explorations, and donor-site revisions - was then assessed.

Results: Patient, defect, and flap characteristics were comparable between both groups, including flap size (Doppler: 134 ± 73 cm , Duplex: 131 ± 65 cm , p = .90). There was no flap loss. Emergent re-explorations (Doppler: 4/32, Duplex: 1/12, p = .70) and donor-site revisions (Doppler: 2/32, Duplex: 1/12, p = .81) were equally distributed. Duplex rendered septal perforator dissection 10 times more likely (Chi-Square = 8.9, p = .003, OR = 9.7), reaching 50% (n = 6/12), as opposed to only 9% in the Doppler cohort (n = 3/32). This allowed for highly significant HT and OT reductions of 89 minutes, respectively (p < .01): from 255 and 383 min (Doppler) to 166 and 294 min (Duplex).

Conclusions: Preoperative Duplex significantly reduces harvest and operative times of ALT flaps.
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http://dx.doi.org/10.1002/micr.30599DOI Listing
July 2020

Hybridization ddRAD-sequencing for population genomics of nonmodel plants using highly degraded historical specimen DNA.

Mol Ecol Resour 2020 Sep 12;20(5):1228-1247. Epub 2020 May 12.

Research Group for Ancient Genomics and Evolution, Max Planck Institute for Developmental Biology, Tübingen, Germany.

Species' responses at the genetic level are key to understanding the long-term consequences of anthropogenic global change. Herbaria document such responses, and, with contemporary sampling, provide high-resolution time-series of plant evolutionary change. Characterizing genetic diversity is straightforward for model species with small genomes and a reference sequence. For nonmodel species-with small or large genomes-diversity is traditionally assessed using restriction-enzyme-based sequencing. However, age-related DNA damage and fragmentation preclude the use of this approach for ancient herbarium DNA. Here, we combine reduced-representation sequencing and hybridization-capture to overcome this challenge and efficiently compare contemporary and historical specimens. Specifically, we describe how homemade DNA baits can be produced from reduced-representation libraries of fresh samples, and used to efficiently enrich historical libraries for the same fraction of the genome to produce compatible sets of sequence data from both types of material. Applying this approach to both Arabidopsis thaliana and the nonmodel plant Cardamine bulbifera, we discovered polymorphisms de novo in an unbiased, reference-free manner. We show that the recovered genetic variation recapitulates known genetic diversity in A. thaliana, and recovers geographical origin in both species and over time, independent of bait diversity. Hence, our method enables fast, cost-efficient, large-scale integration of contemporary and historical specimens for assessment of genome-wide genetic trends over time, independent of genome size and presence of a reference genome.
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http://dx.doi.org/10.1111/1755-0998.13168DOI Listing
September 2020

Safety, Pharmacodynamics, and Efficacy of High- Versus Low-Dose Ascorbic Acid in Severely Burned Adults.

J Burn Care Res 2020 07;41(4):871-877

Department of Hand, Plastic and Reconstructive Surgery, Burn Center, BG Trauma Center Ludwigshafen, Plastic and Hand Surgery, University of Heidelberg, Ludwigshafen, Germany.

In sepsis and burns, ascorbic acid (AA) is hypothesized advantageous during volume resuscitation. There is uncertainty regarding its safety and dosing. This study evaluated high dose AA (HDAA: 66 mg/kg/h for 24 hours) versus low dose AA (LDAA: 3.5 g/days) administration during the first 24 hours in severely burned adults. We conducted a retrospective study comparing fluid administration before and after switching from low dose to HDAA in severely burned adults. A total of 38 adults with burns >20% TBSA, who received either HDAA or LDAA were included in this retrospective study. AA serum concentrations were quantified at 0, 24, and 72 hours postburn. HDAA impact on hemodynamics, acid-base homeostasis, acute kidney injury, vasopressor use, resuscitation fluid requirement, urinary output, and the incidence of adverse effects was evaluated; secondary clinical outcomes were analyzed. AA plasma levels were 10-fold elevated in the LDAA and 150-fold elevated in the HDAA group at 24 hours and decreased in both groups afterwards. HDAA was not associated with a significantly increased risk of any complications. A significant reduction in colloid fluid requirements was noted (LDAA: 947 ± 1722 ml/24 hours vs HDAA: 278 ± 667 ml/24 hours, P = 0.029). Other hemodynamic and resuscitation measures, as well as secondary clinical outcomes were comparable between groups. HDAA was associated with higher AA levels and lower volumes of colloids in adults with severe burns. The rate of adverse events was not significantly higher in patients treated with HDAA. Future studies should consider prolonged administration of AA.
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http://dx.doi.org/10.1093/jbcr/iraa041DOI Listing
July 2020

Emergence of human-adapted Salmonella enterica is linked to the Neolithization process.

Nat Ecol Evol 2020 03 24;4(3):324-333. Epub 2020 Feb 24.

School of Archaeology and Ancient History, Leicester University, Leicester, UK.

It has been hypothesized that the Neolithic transition towards an agricultural and pastoralist economy facilitated the emergence of human-adapted pathogens. Here, we recovered eight Salmonella enterica subsp. enterica genomes from human skeletons of transitional foragers, pastoralists and agropastoralists in western Eurasia that were up to 6,500 yr old. Despite the high genetic diversity of S. enterica, all ancient bacterial genomes clustered in a single previously uncharacterized branch that contains S. enterica adapted to multiple mammalian species. All ancient bacterial genomes from prehistoric (agro-)pastoralists fall within a part of this branch that also includes the human-specific S. enterica Paratyphi C, illustrating the evolution of a human pathogen over a period of 5,000 yr. Bacterial genomic comparisons suggest that the earlier ancient strains were not host specific, differed in pathogenic potential and experienced convergent pseudogenization that accompanied their downstream host adaptation. These observations support the concept that the emergence of human-adapted S. enterica is linked to human cultural transformations.
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http://dx.doi.org/10.1038/s41559-020-1106-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7186082PMC
March 2020

A genetic analysis of the Gibraltar Neanderthals.

Proc Natl Acad Sci U S A 2019 07 15;116(31):15610-15615. Epub 2019 Jul 15.

Centre for Human Evolution Research, Department of Earth Sciences, The Natural History Museum, London SW7 5BD, United Kingdom

The Forbes' Quarry and Devil's Tower partial crania from Gibraltar are among the first Neanderthal remains ever found. Here, we show that small amounts of ancient DNA are preserved in the petrous bones of the 2 individuals despite unfavorable climatic conditions. However, the endogenous Neanderthal DNA is present among an overwhelming excess of recent human DNA. Using improved DNA library construction methods that enrich for DNA fragments carrying deaminated cytosine residues, we were able to sequence 70 and 0.4 megabase pairs (Mbp) nuclear DNA of the Forbes' Quarry and Devil's Tower specimens, respectively, as well as large parts of the mitochondrial genome of the Forbes' Quarry individual. We confirm that the Forbes' Quarry individual was a female and the Devil's Tower individual a male. We also show that the Forbes' Quarry individual is genetically more similar to the ∼120,000-y-old Neanderthals from Scladina Cave in Belgium (Scladina I-4A) and Hohlenstein-Stadel Cave in Germany, as well as to a ∼60,000- to 70,000-y-old Neanderthal from Russia (Mezmaiskaya 1), than to a ∼49,000-y-old Neanderthal from El Sidrón (El Sidrón 1253) in northern Spain and other younger Neanderthals from Europe and western Asia. This suggests that the Forbes' Quarry fossil predates the latter Neanderthals. The preservation of archaic human DNA in the warm coastal climate of Gibraltar, close to the shores of Africa, raises hopes for the future recovery of archaic human DNA from regions in which climatic conditions are less than optimal for DNA preservation.
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http://dx.doi.org/10.1073/pnas.1903984116DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6681707PMC
July 2019

Nuclear DNA from two early Neandertals reveals 80,000 years of genetic continuity in Europe.

Sci Adv 2019 06 26;5(6):eaaw5873. Epub 2019 Jun 26.

Department of Evolutionary Genetics, Max Planck Institute for Evolutionary Anthropology, Deutscher Platz 6, Leipzig04103, Germany.

Little is known about the population history of Neandertals over the hundreds of thousands of years of their existence. We retrieved nuclear genomic sequences from two Neandertals, one from Hohlenstein-Stadel Cave in Germany and the other from Scladina Cave in Belgium, who lived around 120,000 years ago. Despite the deeply divergent mitochondrial lineage present in the former individual, both Neandertals are genetically closer to later Neandertals from Europe than to a roughly contemporaneous individual from Siberia. That the Hohlenstein-Stadel and Scladina individuals lived around the time of their most recent common ancestor with later Neandertals suggests that all later Neandertals trace at least part of their ancestry back to these early European Neandertals.
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http://dx.doi.org/10.1126/sciadv.aaw5873DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6594762PMC
June 2019

Continuous Video-Rate Laser Speckle Imaging for Intra- and Postoperative Cutaneous Perfusion Imaging of Free Flaps.

J Reconstr Microsurg 2019 Sep 5;35(7):489-498. Epub 2019 Mar 5.

BG Trauma Center Ludwigshafen, Department of Hand, Plastic and Reconstructive Surgery, Microsurgery, Burn Center, University of Heidelberg, Heidelberg, Germany.

Background:  Success of free tissue transfer depends on standardized intraoperative flap design, microsurgical technique, and postoperative monitoring. We sought to investigate whether laser speckle imaging (LSI) is suitable for optimization of intraoperative flap design and postoperative monitoring of free flaps with skin paddles.

Methods:  Skin perfusion was assessed with LSI in 27 free flaps after dissection at the donor site, after anastomosis at the recipient site, after inset and on postoperative days (POD) 1, 5, and 10. Skin perfusion of the whole flap (ROI [region of interest]-1) and the area over the pedicle (ROI-2) were compared between patients with and without postoperative complications (POC+ and POC - , respectively). A receiver operating characteristic (ROC) analysis was performed to determine the optimal cutoff for perfusion during LSI-guided microsurgery.

Results:  In flaps without or only minor POC, intraoperatively measured perfusion over ROI-2 was significantly higher compared with ROI-1, whereas no significant differences were found for flaps with major POC. Perfusion of ROI-1 and 2 intraoperatively and on POD 1 was significantly lower in the POC+ compared with the POC- group ( < 0.05). ROC analysis yielded a threshold of 107 perfusion units (PU) at ROI-2 with an area under the curve (AUC) of > 0.8 for identification of flaps with major POC.

Conclusion:  LSI is an easy to use, noninvasive technique for identification of malperfused areas in free flaps, thus allowing for intraoperative decision-making on flap dimensions and postoperative monitoring. LSI therefore is a valuable tool for perfusion assessment with a high potential to become an established part of microsurgical practice.
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http://dx.doi.org/10.1055/s-0039-1681076DOI Listing
September 2019

Compound-specific radiocarbon dating and mitochondrial DNA analysis of the Pleistocene hominin from Salkhit Mongolia.

Nat Commun 2019 01 30;10(1):274. Epub 2019 Jan 30.

Oxford Radiocarbon Accelerator Unit, Research Laboratory for Archaeology and the History of Art, University of Oxford, Dyson Perrins Building, South Parks Road, Oxford, OX1 3QY, UK.

A skullcap found in the Salkhit Valley in northeast Mongolia is, to our knowledge, the only Pleistocene hominin fossil found in the country. It was initially described as an individual with possible archaic affinities, but its ancestry has been debated since the discovery. Here, we determine the age of the Salkhit skull by compound-specific radiocarbon dating of hydroxyproline to 34,950-33,900 Cal. BP (at 95% probability), placing the Salkhit individual in the Early Upper Paleolithic period. We reconstruct the complete mitochondrial genome (mtDNA) of the specimen. It falls within a group of modern human mtDNAs (haplogroup N) that is widespread in Eurasia today. The results now place the specimen into its proper chronometric and biological context and allow us to begin integrating it with other evidence for the human occupation of this region during the Paleolithic, as well as wider Pleistocene sequences across Eurasia.
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http://dx.doi.org/10.1038/s41467-018-08018-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6353915PMC
January 2019

The genome of the offspring of a Neanderthal mother and a Denisovan father.

Nature 2018 09 22;561(7721):113-116. Epub 2018 Aug 22.

Department of Evolutionary Genetics, Max Planck Institute for Evolutionary Anthropology, Leipzig, Germany.

Neanderthals and Denisovans are extinct groups of hominins that separated from each other more than 390,000 years ago. Here we present the genome of 'Denisova 11', a bone fragment from Denisova Cave (Russia) and show that it comes from an individual who had a Neanderthal mother and a Denisovan father. The father, whose genome bears traces of Neanderthal ancestry, came from a population related to a later Denisovan found in the cave. The mother came from a population more closely related to Neanderthals who lived later in Europe than to an earlier Neanderthal found in Denisova Cave, suggesting that migrations of Neanderthals between eastern and western Eurasia occurred sometime after 120,000 years ago. The finding of a first-generation Neanderthal-Denisovan offspring among the small number of archaic specimens sequenced to date suggests that mixing between Late Pleistocene hominin groups was common when they met.
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http://dx.doi.org/10.1038/s41586-018-0455-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6130845PMC
September 2018

Reconstructing the genetic history of late Neanderthals.

Nature 2018 03 21;555(7698):652-656. Epub 2018 Mar 21.

Department of Evolutionary Genetics, Max Planck Institute for Evolutionary Anthropology, D-04103 Leipzig, Germany.

Although it has previously been shown that Neanderthals contributed DNA to modern humans, not much is known about the genetic diversity of Neanderthals or the relationship between late Neanderthal populations at the time at which their last interactions with early modern humans occurred and before they eventually disappeared. Our ability to retrieve DNA from a larger number of Neanderthal individuals has been limited by poor preservation of endogenous DNA and contamination of Neanderthal skeletal remains by large amounts of microbial and present-day human DNA. Here we use hypochlorite treatment of as little as 9 mg of bone or tooth powder to generate between 1- and 2.7-fold genomic coverage of five Neanderthals who lived around 39,000 to 47,000 years ago (that is, late Neanderthals), thereby doubling the number of Neanderthals for which genome sequences are available. Genetic similarity among late Neanderthals is well predicted by their geographical location, and comparison to the genome of an older Neanderthal from the Caucasus indicates that a population turnover is likely to have occurred, either in the Caucasus or throughout Europe, towards the end of Neanderthal history. We find that the bulk of Neanderthal gene flow into early modern humans originated from one or more source populations that diverged from the Neanderthals that were studied here at least 70,000 years ago, but after they split from a previously sequenced Neanderthal from Siberia around 150,000 years ago. Although four of the Neanderthals studied here post-date the putative arrival of early modern humans into Europe, we do not detect any recent gene flow from early modern humans in their ancestry.
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http://dx.doi.org/10.1038/nature26151DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6485383PMC
March 2018

Pleistocene North African genomes link Near Eastern and sub-Saharan African human populations.

Science 2018 05 15;360(6388):548-552. Epub 2018 Mar 15.

Department of Archaeogenetics, Max Planck Institute for the Science of Human History (MPI-SHH), Jena, Kahlaische Strasse 10, D-07745, Germany.

North Africa is a key region for understanding human history, but the genetic history of its people is largely unknown. We present genomic data from seven 15,000-year-old modern humans, attributed to the Iberomaurusian culture, from Morocco. We find a genetic affinity with early Holocene Near Easterners, best represented by Levantine Natufians, suggesting a pre-agricultural connection between Africa and the Near East. We do not find evidence for gene flow from Paleolithic Europeans to Late Pleistocene North Africans. The Taforalt individuals derive one-third of their ancestry from sub-Saharan Africans, best approximated by a mixture of genetic components preserved in present-day West and East Africans. Thus, we provide direct evidence for genetic interactions between modern humans across Africa and Eurasia in the Pleistocene.
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http://dx.doi.org/10.1126/science.aar8380DOI Listing
May 2018

Short report letter: Combined bilateral carpal coalition of the scaphoid and trapezium and of the lunate and triquetrum.

J Hand Surg Eur Vol 2018 01 23;43(1):100-101. Epub 2017 Oct 23.

Klinik für Hand-, Plastische und Rekonstruktive Chirurgie, Schwerbrandverletztenzentrum, BG Unfallklinik Ludwigshafen.

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http://dx.doi.org/10.1177/1753193417735001DOI Listing
January 2018

A high-coverage Neandertal genome from Vindija Cave in Croatia.

Science 2017 11 5;358(6363):655-658. Epub 2017 Oct 5.

Department of Genome Sciences, University of Washington School of Medicine, Seattle, WA 98195, USA.

To date, the only Neandertal genome that has been sequenced to high quality is from an individual found in Southern Siberia. We sequenced the genome of a female Neandertal from ~50,000 years ago from Vindija Cave, Croatia, to ~30-fold genomic coverage. She carried 1.6 differences per 10,000 base pairs between the two copies of her genome, fewer than present-day humans, suggesting that Neandertal populations were of small size. Our analyses indicate that she was more closely related to the Neandertals that mixed with the ancestors of present-day humans living outside of sub-Saharan Africa than the previously sequenced Neandertal from Siberia, allowing 10 to 20% more Neandertal DNA to be identified in present-day humans, including variants involved in low-density lipoprotein cholesterol concentrations, schizophrenia, and other diseases.
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http://dx.doi.org/10.1126/science.aao1887DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6185897PMC
November 2017

Palaeogenomes of Eurasian straight-tusked elephants challenge the current view of elephant evolution.

Elife 2017 06 6;6. Epub 2017 Jun 6.

Evolutionary Adaptive Genomics, Institute for Biochemistry and Biology, Department for Mathematics and Natural Sciences, University of Potsdam, Potsdam, Germany.

The straight-tusked elephants spp. were widespread across Eurasia during the Pleistocene. Phylogenetic reconstructions using morphological traits have grouped them with Asian elephants (), and many paleontologists place within . Here, we report the recovery of full mitochondrial genomes from four and partial nuclear genomes from two fossils. These fossils were collected at two sites in Germany, Neumark-Nord and Weimar-Ehringsdorf, and likely date to interglacial periods ~120 and ~244 thousand years ago, respectively. Unexpectedly, nuclear and mitochondrial DNA analyses suggest that was a close relative of extant African forest elephants (). Species previously referred to are thus most parsimoniously explained as having diverged from the lineage of , indicating that has not been constrained to Africa. Our results demonstrate that the current picture of elephant evolution is in need of substantial revision.
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http://dx.doi.org/10.7554/eLife.25413DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5461109PMC
June 2017

Neandertal and Denisovan DNA from Pleistocene sediments.

Science 2017 May 27;356(6338):605-608. Epub 2017 Apr 27.

Department of Evolutionary Genetics, Max Planck Institute for Evolutionary Anthropology, Deutscher Platz 6, 04103 Leipzig, Germany.

Although a rich record of Pleistocene human-associated archaeological assemblages exists, the scarcity of hominin fossils often impedes the understanding of which hominins occupied a site. Using targeted enrichment of mitochondrial DNA, we show that cave sediments represent a rich source of ancient mammalian DNA that often includes traces of hominin DNA, even at sites and in layers where no hominin remains have been discovered. By automation-assisted screening of numerous sediment samples, we detected Neandertal DNA in eight archaeological layers from four caves in Eurasia. In Denisova Cave, we retrieved Denisovan DNA in a Middle Pleistocene layer near the bottom of the stratigraphy. Our work opens the possibility of detecting the presence of hominin groups at sites and in areas where no skeletal remains are found.
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http://dx.doi.org/10.1126/science.aam9695DOI Listing
May 2017

Single-stranded DNA library preparation from highly degraded DNA using T4 DNA ligase.

Nucleic Acids Res 2017 Jun;45(10):e79

Department of Evolutionary Genetics, Max Planck Institute for Evolutionary Anthropology, 04103 Leipzig, Germany.

DNA library preparation for high-throughput sequencing of genomic DNA usually involves ligation of adapters to double-stranded DNA fragments. However, for highly degraded DNA, especially ancient DNA, library preparation has been found to be more efficient if each of the two DNA strands are converted into library molecules separately. We present a new method for single-stranded library preparation, ssDNA2.0, which is based on single-stranded DNA ligation with T4 DNA ligase utilizing a splinter oligonucleotide with a stretch of random bases hybridized to a 3΄ biotinylated donor oligonucleotide. A thorough evaluation of this ligation scheme shows that single-stranded DNA can be ligated to adapter oligonucleotides in higher concentration than with CircLigase (an RNA ligase that was previously chosen for end-to-end ligation in single-stranded library preparation) and that biases in ligation can be minimized when choosing splinters with 7 or 8 random nucleotides. We show that ssDNA2.0 tolerates higher quantities of input DNA than CircLigase-based library preparation, is less costly and better compatible with automation. We also provide an in-depth comparison of library preparation methods on degraded DNA from various sources. Most strikingly, we find that single-stranded library preparation increases library yields from tissues stored in formalin for many years by several orders of magnitude.
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http://dx.doi.org/10.1093/nar/gkx033DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5449542PMC
June 2017

Nuclear DNA sequences from the Middle Pleistocene Sima de los Huesos hominins.

Nature 2016 Mar 14;531(7595):504-7. Epub 2016 Mar 14.

Department of Evolutionary Genetics, Max Planck Institute for Evolutionary Anthropology, Deutscher Platz 6, 04103 Leipzig, Germany.

A unique assemblage of 28 hominin individuals, found in Sima de los Huesos in the Sierra de Atapuerca in Spain, has recently been dated to approximately 430,000 years ago. An interesting question is how these Middle Pleistocene hominins were related to those who lived in the Late Pleistocene epoch, in particular to Neanderthals in western Eurasia and to Denisovans, a sister group of Neanderthals so far known only from southern Siberia. While the Sima de los Huesos hominins share some derived morphological features with Neanderthals, the mitochondrial genome retrieved from one individual from Sima de los Huesos is more closely related to the mitochondrial DNA of Denisovans than to that of Neanderthals. However, since the mitochondrial DNA does not reveal the full picture of relationships among populations, we have investigated DNA preservation in several individuals found at Sima de los Huesos. Here we recover nuclear DNA sequences from two specimens, which show that the Sima de los Huesos hominins were related to Neanderthals rather than to Denisovans, indicating that the population divergence between Neanderthals and Denisovans predates 430,000 years ago. A mitochondrial DNA recovered from one of the specimens shares the previously described relationship to Denisovan mitochondrial DNAs, suggesting, among other possibilities, that the mitochondrial DNA gene pool of Neanderthals turned over later in their history.
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http://dx.doi.org/10.1038/nature17405DOI Listing
March 2016

Suppression of intratumoral CCL22 by type i interferon inhibits migration of regulatory T cells and blocks cancer progression.

Cancer Res 2015 Nov 2;75(21):4483-93. Epub 2015 Oct 2.

Center of Integrated Protein Science Munich (CIPS-M), Division of Clinical Pharmacology, Klinikum der Universität München, Munich, Germany. Department of Medicine, University of Fribourg, Fribourg, Switzerland.

The chemokine CCL22 is abundantly expressed in many types of cancer and is instrumental for intratumoral recruitment of regulatory T cells (Treg), an important subset of immunosuppressive and tumor-promoting lymphocytes. In this study, we offer evidence for a generalized strategy to blunt Treg activity that can limit immune escape and promote tumor rejection. Activation of innate immunity with Toll-like receptor (TLR) or RIG-I-like receptor (RLR) ligands prevented accumulation of Treg in tumors by blocking their immigration. Mechanistic investigations indicated that Treg blockade was a consequence of reduced intratumoral CCL22 levels caused by type I IFN. Notably, stable expression of CCL22 abrogated the antitumor effects of treatment with RLR or TLR ligands. Taken together, our findings argue that type I IFN blocks the Treg-attracting chemokine CCL22 and thus helps limit the recruitment of Treg to tumors, a finding with implications for cancer immunotherapy.
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http://dx.doi.org/10.1158/0008-5472.CAN-14-3499DOI Listing
November 2015

Safeguarding Stem Cell-Based Regenerative Therapy against Iatrogenic Cancerogenesis: Transgenic Expression of , , , Controlled By Promoter in Proliferating and Directed Differentiation Resisting Human Autologous Pluripotent Induced Stem Cells Leads to their Death.

J Stem Cell Res Ther 2013 Jul;Suppl 9(5)

Phoenix Biomolecular Engineering Foundation, San Francisco, CA 94105, USA ; San Francisco State University, San Francisco, CA 94123, USA.

Introduction: The worst possible complication of using stem cells for regenerative therapy is iatrogenic cancerogenesis. The ultimate goal of our work is to develop a self-triggering feedback mechanism aimed at causing death of all stem cells, which resist directed differentiation, keep proliferating, and can grow into tumors.

Specific Aim: The specific aim was threefold: (1) to genetically engineer the DNA constructs for the human, recombinant controlled by promoter; (2) to bioengineer anti-SSEA-4 antibody guided vectors delivering transgenes to human undifferentiated and proliferating pluripotent stem cells; (3) to cause death of proliferating and directed differentiation resisting stem cells by transgenic expression of the human recombinant the DNases (hrDNases).

Methods: The DNA constructs for the human, recombinant controlled by promoter were genetically engineered. The vectors targeting specifically SSEA-4 expressing stem cells were bioengineered. The healthy volunteers' bone marrow mononuclear cells (BMMCs) were induced into human, autologous, pluripotent stem cells with non-integrating plasmids. Directed differentiation of the induced stem cells into endothelial cells was accomplished with EGF and BMP. The anti-SSEA 4 antibodies' guided DNA vectors delivered the transgenes for the human recombinant DNases' into proliferating stem cells.

Results: Differentiation of the pluripotent induced stem cells into the endothelial cells was verified by highlighting formation of tight and adherens junctions through transgenic expression of recombinant fluorescent fusion proteins: VE cadherin, claudin, zona occludens 1, and catenin. Proliferation of the stem cells was determined through highlighting transgenic expression of recombinant fluorescent proteins controlled by promoter, while also reporting expression of the transgenes for the hrDNases. Expression of the transgenes for the DNases resulted in complete collapse of the chromatin architecture and degradation of the proliferating cells' genomic DNA. The proliferating stem cells, but not the differentiating ones, were effectively induced to die.

Conclusion: Herein, we describe attaining the proof-of-concept for the strategy, whereby transgenic expression of the genetically engineered human recombinant DNases in proliferating and directed differentiation resisting stem cells leads to their death. This novel strategy reduces the risk of iatrogenic neoplasms in stem cell therapy.
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http://dx.doi.org/10.4172/2157-7633.S9-005DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4103669PMC
July 2013
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