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Major migration events in Holocene Eurasia have been characterized genetically at broad regional scales1-4. However, insights into the population dynamics in the contact zones are hampered by a lack of ancient genomic data sampled at high spatiotemporal resolution5-7. Here, to address this, we analysed shotgun-sequenced genomes from 100 skeletons spanning 7,300 years of the Mesolithic period, Neolithic period and Early Bronze Age in Denmark and integrated these with proxies for diet (13C and 15N content), mobility (87Sr/86Sr ratio) and vegetation cover (pollen). We observe that Danish Mesolithic individuals of the Maglemose, Kongemose and Ertebølle cultures form a distinct genetic cluster related to other Western European hunter-gatherers. Despite shifts in material culture they displayed genetic homogeneity from around 10,500 to 5,900 calibrated years before present, when Neolithic farmers with Anatolian-derived ancestry arrived. Although the Neolithic transition was delayed by more than a millennium relative to Central Europe, it was very abrupt and resulted in a population turnover with limited genetic contribution from local hunter-gatherers. The succeeding Neolithic population, associated with the Funnel Beaker culture, persisted for only about 1,000 years before immigrants with eastern Steppe-derived ancestry arrived. This second and equally rapid population replacement gave rise to the Single Grave culture with an ancestry profile more similar to present-day Danes. In our multiproxy dataset, these major demographic events are manifested as parallel shifts in genotype, phenotype, diet and land use.

Western Eurasia witnessed several large-scale human migrations during the Holocene1-5. Here, to investigate the cross-continental effects of these migrations, we shotgun-sequenced 317 genomes-mainly from the Mesolithic and Neolithic periods-from across northern and western Eurasia. These were imputed alongside published data to obtain diploid genotypes from more than 1,600 ancient humans. Our analyses revealed a 'great divide' genomic boundary extending from the Black Sea to the Baltic. Mesolithic hunter-gatherers were highly genetically differentiated east and west of this zone, and the effect of the neolithization was equally disparate. Large-scale ancestry shifts occurred in the west as farming was introduced, including near-total replacement of hunter-gatherers in many areas, whereas no substantial ancestry shifts happened east of the zone during the same period. Similarly, relatedness decreased in the west from the Neolithic transition onwards, whereas, east of the Urals, relatedness remained high until around 4,000 BP, consistent with the persistence of localized groups of hunter-gatherers. The boundary dissolved when Yamnaya-related ancestry spread across western Eurasia around 5,000 BP, resulting in a second major turnover that reached most parts of Europe within a 1,000-year span. The genetic origin and fate of the Yamnaya have remained elusive, but we show that hunter-gatherers from the Middle Don region contributed ancestry to them. Yamnaya groups later admixed with individuals associated with the Globular Amphora culture before expanding into Europe. Similar turnovers occurred in western Siberia, where we report new genomic data from a 'Neolithic steppe' cline spanning the Siberian forest steppe to Lake Baikal. These prehistoric migrations had profound and lasting effects on the genetic diversity of Eurasian populations.

Abstract Fungal infections pose a great threat to public health and there are only four main types of antifungal drugs, which are often limited with toxicity, drug-drug interactions and antibiotic resistance. Streptomyces is an important source of antibiotics, represented by the clinical drug amphotericin B. Here we report the discovery of alligamycin A (1) as an antifungal compound from the rapamycin-producer Streptomyces iranensis through genome-mining, genetics and natural product chemistry approaches. Alligamycin A harbors a unique chemical scaffold with 13 chiral centers, featuring a β-lactone moiety, a [6,6]-spiroketal ring, and an unreported 7-oxo-octylmalonyl-CoA extender unit incorporated by a potential crotonyl-CoA carboxylase/reductase. It is biosynthesized by a type I polyketide synthase which is confirmed through CRISPR-based gene editing. Alligamycin A displayed potent antifungal effects against numerous clinically relevant filamentous fungi, including resistant Aspergillus and Talaromyces species. β-Lactone ring is essential for the antifungal activity since alligamycin B (2) with disruption in the ring abolished the antifungal effect. Proteomics analysis revealed alligamycin A potentially disrupts the integrity of fungal cell walls and induces the expression of stress-response proteins in Aspergillus niger. Discovery of the potent antifungal candidate alligamycin A expands the limited antifungal chemical space.

Purpose The aim of this study was to explore how health care providers at youth clinics (YCs) in Sweden engage with, focus on, and navigate across the mental health youth space, while upholding the core bedrock principle of “youth-centeredness”. Methods Qualitative interviews were conducted with 21 health care professionals working in three YCs located in three different regions of Sweden. Data were analysed using reflexive thematic analysis informed by the work of Braun and Clarke. Results The three themes were: 1) “youth mission—at the core of the YCs” work and challenged by a stronger involvement in mental ill health’; 2) “YCs” unique and complementary role in the youth mental health system: a holistic perspective, team work, and a focus on normalization’, and 3) “Caught between a rock and a hard place: to treat at a care level that is not optimal for the young users” needs or to refer within an unreliable system’. Conclusion This study reflects the individuality and key features of YCs, their widening roles within the mental health sphere, and the challenges faced in maintaining and expanding the characteristic “youth-centred” approach while expanding their work with mental health.

Abstract Fluorinated amino acids serve as an entry point for establishing new-to-Nature chemistries in biological systems, and novel methods are needed for the selective synthesis of these building blocks. In this study, we focused on the enzymatic synthesis of fluorinated alanine enantiomers to expand fluorine biocatalysis. The alanine dehydrogenase from Vibrio proteolyticus and the diaminopimelate dehydrogenase from Symbiobacterium thermophilum were selected for in vitro production of (R)-3-fluoroalanine and (S)-3-fluoroalanine, respectively, using 3-fluoropyruvate as the substrate. Additionally, we discovered that an alanine racemase from Streptomyces lavendulae, originally selected for setting an alternative enzymatic cascade leading to the production of these non-canonical amino acids, had an unprecedented catalytic efficiency in β-elimination of fluorine from the monosubstituted fluoroalanine. The in vitro enzymatic cascade based on the dehydrogenases of V. proteolyticus and S. thermophilum included a cofactor recycling system, whereby a formate dehydrogenase from Pseudomonas sp. 101 (either native or engineered) coupled formate oxidation to NAD(P)H formation. Under these conditions, the reaction yields for (R)-3-fluoroalanine and (S)-3-fluoroalanine reached >85% on the fluorinated substrate and proceeded with complete enantiomeric excess. The selected dehydrogenases also catalyzed the conversion of trifluoropyruvate into trifluorinated alanine as a first-case example of fluorine biocatalysis with amino acids carrying a trifluoromethyl group.

We introduce NMR-Onion, an open-source, computationally efficient algorithm based on Python and PyTorch, designed to facilitate the automatic deconvolution of 1D NMR spectra. NMR-Onion features two innovative time-domain models capable of handling asymmetric non-Lorentzian line shapes. Its core components for resolution-enhanced peak detection and digital filtering of user-specified key regions ensure precise peak prediction and efficient computation. The NMR-Onion framework includes three built-in statistical models, with automatic selection via the BIC criterion. Additionally, NMR-Onion assesses the repeatability of results by evaluating post-modeling uncertainty. Using the NMR-Onion algorithm helps to minimize excessive peak detection.

Abstract Background Youth mental health is a major health concern in almost every country. Mental health accounts for about 13% of the global burden of disease in the 10-to-19-year age group. Still there are significant gaps between the mental health needs of young people and the quality and accessibility of available services. Collaboration between health and social service actors is a recognized way of reducing gaps in quality and access. Yet there is little scientific evidence on how these collaborations are applied, or on the challenges of cross-boundary collaboration in the youth mental health space. This study aims to explore how collaboration is understood and practiced by professionals working in the Swedish youth mental health system. Methods We conducted 42 interviews (November 2020 to March 2022) with health and social care professionals and managers in the youth mental health system in Sweden. Interviews explored participants’ experience and understanding of the purpose, realization, and challenges of collaboration. Data were analysed under an emergent study design using reflexive thematic analysis. Results The analysis produced three themes. The first shows that collaboration is considered as essential and important, and that it serves diverse purposes and holds multiple meanings in relation to professionals’ roles and responsibilities. The second addresses the different layers of collaboration, in relation to activities, relationships, and target levels, and the third captures the challenges and criticisms in collaborating across the youth mental health landscape, but also in growing possibilities for future development. Conclusion We conclude that collaboration serves multiple purposes and takes many shapes in the Swedish youth mental health system. Despite the many challenges, participants saw potential in further building collaboration. Interestingly our participants also raised concerns about too much collaboration. There was scepticism about collaboration directing attention away from young people to the professionals, thereby risking the trust and confidentiality of their young clients. Collaboration is not a panacea and will not compensate for an under-resourced youth mental health system.

Objective: To investigate the effect of a novel digital leakage notification system (Heylo) on quality of life (QoL) and burden of living with an intestinal ostomy. Patients and Methods: A randomized, controlled, open-label, cross-over trial was conducted in Germany with people having intestinal ostomies, who were cared for by 13 ostomy care specialists. Participants with fecal leakage problems were randomized by a centralized system to either Heylo + Standard of Care (SoC) or SoC alone for 8 weeks, whereafter participants crossed over to the opposite treatment for an additional 8 weeks. Primary and secondary end points were: Emotional impact domain score of the Ostomy Leak Impact tool and Participation domain score of the WHO Disability Assessment Schedule 2.0, respectively. Primary comparisons between Heylo and SoC were evaluated using linear mixed models, taking time and study period into account. The trial is registered with ClinicalTrials.gov, NCT05200416. Results: A total of 144 participants were allocated to a treatment sequence after giving informed consent (safety population). Analyses included randomized participants who had been exposed to at least 1 product and with information on at least 1 end point (intention-to-treat population, n=139). Both the Emotional impact and Participation domain scores improved significantly after 8 weeks use of Heylo compared with SoC (LS mean difference of 11.4; 95% CI, 7.8-15.0; P

Objectives: The purpose of this systematic review is to disclose the impact of autoimmune diseases and their medical treatment on dental implant survival and success. Material and Methods: A literature search was conducted using MEDLINE (PubMed), The Cochrane Library and Embase up to December 6th, 2021. Any clinical study on patients with an autoimmune disease in whom implant therapy was performed was eligible. The quality of included studies was assessed using the Newcastle-Ottawa Scale. For each autoimmune disease group, data synthesis was divided into three groups: 1) overall results of the autoimmune disease, 2) overall results of corresponding control groups and 3) overall results of the autoimmune disease with a concomitant autoimmune disease (a subgroup of group 1). Descriptive statistics were used. Results: Of 4,865 identified articles, 67 could be included and mainly comprising case reports and retrospective studies with an overall low quality. Implant survival rate was 50 to 100% on patient and implant level after a weighted mean follow-up of 17.7 to 68.1 months. Implant success was sporadically reported. Data on immunosuppressive medication were too heterogeneously reported to allow detailed analysis. Conclusions: Overall, a high implant survival rate was reported in patients with autoimmune diseases. However, the identified studies were characterized by a low quality. No conclusions could be made regarding implant success and the effect of immunosuppressants due to heterogeneous reporting.

The analysis of the DNA entrapped in ancient shells of molluscs has the potential to shed light on the evolution and ecology of this very diverse phylum. Ancient genomics could help reconstruct the responses of molluscs to past climate change, pollution, and human subsistence practices at unprecedented temporal resolutions. Applications are however still in their infancy, partly due to our limited knowledge of DNA preservation in calcium carbonate shells and the need for optimized methods for responsible genomic data generation. To improve ancient shell genomic analyses, we applied high-throughput DNA sequencing to 27 Mytilus mussel shells dated to ~111-6500 years Before Present, and investigated the impact, on DNA recovery, of shell imaging, DNA extraction protocols and shell sub-sampling strategies. First, we detected no quantitative or qualitative deleterious effect of micro-computed tomography for recording shell 3D morphological information prior to sub-sampling. Then, we showed that double-digestion and bleach treatment of shell powder prior to silica-based DNA extraction improves shell DNA recovery, also suggesting that DNA is protected in preservation niches within ancient shells. Finally, all layers that compose Mytilus shells, i.e., the nacreous (aragonite) and prismatic (calcite) carbonate layers, with or without the outer organic layer (periostracum) proved to be valuable DNA reservoirs, with aragonite appearing as the best substrate for genomic analyses. Our work contributes to the understanding of long-term molecular preservation in biominerals and we anticipate that resulting recommendations will be helpful for future efficient and responsible genomic analyses of ancient mollusc shells.

To accelerate the shift to bio-based production and overcome complicated functional implementation of natural and artificial biosynthetic pathways to industry relevant organisms, development of new, versatile, bio-based production platforms is required. Here we present a novel yeast-based platform for biosynthesis of bacterial aromatic polyketides. The platform is based on a synthetic polyketide synthase system enabling a first demonstration of bacterial aromatic polyketide biosynthesis in a eukaryotic host.

Abstract Immune responses play a key role in the pathogenesis and progression of myeloproliferative neoplasms (MPN) and age-related macular degeneration (AMD). Recent studies suggested using MPNs as a “Human Inflammation Model” of drusen development and previous results showed interleukin-4 (IL-4) dysregulation in MPN and AMD. IL-4, IL-13 and IL-33 are all cytokines involved in the type 2 inflammatory response. This study investigated the cytokine levels of IL-4, IL-13 and IL-33 in serum of MPN and AMD patients. This cross-sectional study included 35 patients with MPN with drusen (MPNd) and 27 with MPN and normal retinas (MPNn), 28 patients with intermediate AMD (iAMD) and 29 with neovascular AMD (nAMD). With immunoassays, we quantified and compared levels of IL-4, IL-13 and IL-33 in serum between the groups. The study was conducted at Zealand University Hospital, Roskilde, Denmark, between July 2018 and November 2020. The serum levels of IL-4 were significantly higher in the MPNd group than in the MPNn group (p = 0.003). In regard to IL-33, the difference between MPNd and MPNn was not significant (p = 0.069), however, when subdivided into subgroups, a significant difference was found between polycythemia vera patients with drusen and those without drusen (p = 0.005). We found no IL-13 difference between the MPNd and MPNn groups. Our data didn’t show any significant IL-4 or IL-13 serum level difference between the MPNd and iAMD groups but in regard to IL-33, data recorded a significant serum level difference between the two groups. There was no statistically significant difference between the MPNn, iAMD and nAMD groups in levels of IL-4, IL-13 and IL-33. These findings suggested that the serum levels of IL-4 and IL-33 might play a role in drusen development in MPN patients. The results might represent the type 2 inflammatory arm of the disease. The findings support the association between chronic inflammation and drusen.

Purpose To evaluate the marginal and internal fit of lithium disilicate and zirconia crowns using two optical coherence tomography (OCT) systems in order to estimate inter-system variations.Materials and methods Ten lithium disilicate and 10 cubic stabilized zirconia crowns were placed on prepared artificial teeth without cement. Marginal discrepancy and internal cement gap of the crowns were assessed on images obtained using a swept source OCT (SS-OCT) and a spectral domain OCT (SD-OCT). Medians and interquartile ranges were calculated for both materials and OCT systems. Thereafter, Wilcoxon signed rank test was carried out.Results No significant difference was found between the two OCT systems for absolute marginal discrepancy of either lithium disilicate (SS-OCT: 182 µm, SD-OCT: 214 µm; p = .922) or zirconia crowns (SS-OCT: 116 µm, SD-OCT: 121 µm; p = .232). Regarding internal cement gap, no significant difference was found between the two OCT systems for lithium disilicate crowns (SS-OCT: 128 µm, SD-OCT: 128 µm; p = .064). However, for zirconia crowns the SD-OCT showed significantly higher (p = .027) internal cement gap (92 µm) than the SS-OCT (68 µm). Moreover, it was not possible to assess the internal fit of zirconia crowns in 47% and 34% of the sites using SD-OCT and SS-OCT, respectively.Conclusions No significant difference was noted in the ability of SS-OCT and SD-OCT to assess the marginal and internal fit of lithium disilicate crowns, nor the marginal fit of zirconia crowns. On the contrary, drawbacks regarding the assessment of internal fit of zirconia crowns using both OCT systems were observed.

Abstract Objectives Oral rehabilitation can be a challenge in patients on high‐dose antiresorptive medication (HDAR), especially if the alveolar anatomy has changed due to previous medication‐related osteonecrosis of the jaw (MRONJ) resection. In healthy patients, dental implant treatment has found wide acceptance in prosthetic rehabilitation as it increases the patient's oral health‐related quality of life. However, it is considered contraindicated in patients on HDAR due to the risk of MRONJ, although a recent feasibility study indicates that implant treatment may indeed be an option in these patients. The aim of the present case report is to illustrate the risk of MRONJ in a patient with cancer on HDAR and to discuss the reasons behind the outcomes of the implant treatment. Materials and Methods A patient with prostate cancer with bone metastases on high‐dose denosumab therapy with previous MRONJ had four implants inserted bilaterally in the maxilla (14, 13, 23, 24). Two identical implant‐supported screw‐retained cantilever bridges were fabricated. The patient was followed for more than 1 year. Results and Conclusion Peri‐implantitis, and/or MRONJ, was diagnosed around two of the implants (23, 24), probably induced by crestal bone trauma from a healing abutment and/or a misfitting prosthetic reconstruction. A peri‐implantitis operation was performed, but without the desired response, and the two implants (23, 24) were later removed in an MRONJ resection. The implants on the other side of the maxilla (14, 13) remained without complications. Dental implant treatment is feasible in patients on HDAR, but comorbidities (e.g., diabetes mellitus) and polypharmacy (e.g., chemotherapy and steroids) may add to the risk of implant failure. Minimal trauma surgery and prosthodontics are crucial to increase the chance of successful healing in an HDAR patient.

Abstract Objective There has been a lack of systematic and theoretically underpinned evaluations, internationally and in Sweden, of local multi-component initiatives delivered outside public employment services and formal education systems to young people who are not in employment, education or training (‘NEETs’). To bridge this knowledge gap, the objective of this study was to present findings from the theory gleaning phase of a realist evaluation aimed at assessing how Swedish community-based initiatives may work to (re)engage vulnerable ‘NEET’ young people in education or employment, under what conditions and why. Results Based on insights gleaned and synthesised from various sources, three candidate programme theories were elicited drawing attention to the importance of community-based initiatives in Sweden adopting a ‘caring approach’, a ‘capability approach’ and a ‘collaborative approach’ to (re)engage ‘NEET’ young people in education or employment. While limited to the initial phase of theory gleaning, the study provides valuable insights into the potential functioning of (re)engagement initiatives directed towards vulnerable ‘NEETs’ in addition to increasing the transparency of a highly iterative research project.

Background: Primary Sjögren's syndrome (pSS) is a chronic systemic autoimmune disease characterized by hyposalivation. Currently, there is limited evidence for the prognosis of dental implant treatment in Sjögren's syndrome. Aim/Hypothesis: We hypothesized comparable clinical outcomes of implant‐supported restorations in pSS‐patients and control subjects, and improvement in oral health‐related quality of life 5 years after restoration. Material and Methods: Patients with pSS and matched (age, gender, and tooth region) control group were recruited between June 2016 and March 2020. The clinical and radiological examination were performed, and patient‐reported oral health impact profile (OHIP‐49) questionnaire was used 2 months (baseline), 1, 3, and 5 years after prosthetic treatment. Results: We included 23 patients with pSS and 24 matched control subjects (all women, mean age: 57.1 years). The overall DMFT (decayed‐missed‐filled‐tooth) was significantly higher (p = 0.008), symptoms of dry mouth were more severe (p = 0.001), and unstimulated and chewing‐stimulated saliva flow rates were significantly lower (p < 0.001) in pSS than in control group. All implants survived with no implant mobility. At implant sites, the plaque index and probing depths did not differ (p = 0.301 and 0.446, respectively), but the gingival index was significantly higher (p = 0.003) in pSS than control group. The mean marginal bone loss, prosthetic complications, and clinician‐reported aesthetic outcomes were similar in both groups after 5 years. The OHIP scores were significantly higher in the pSS than control group (p < 0.001) but reduced significantly in both groups (p = 0.026). Conclusion: Replacement of missing single teeth with dental implants was successful in patients with pSS 5 years after restoration. [ABSTRACT FROM AUTHOR]

Purpose: The aim of this study was to explore how health care providers at youth clinics (YCs) in Sweden engage with, focus on, and navigate across the mental health youth space, while upholding the core bedrock principle of "youth-centeredness". Methods: Qualitative interviews were conducted with 21 health care professionals working in three YCs located in three different regions of Sweden. Data were analysed using reflexive thematic analysis informed by the work of Braun and Clarke. Results: The three themes were: 1) "youth mission—at the core of the YCs" work and challenged by a stronger involvement in mental ill health'; 2) "YCs" unique and complementary role in the youth mental health system: a holistic perspective, team work, and a focus on normalization', and 3) "Caught between a rock and a hard place: to treat at a care level that is not optimal for the young users" needs or to refer within an unreliable system'. Conclusion: This study reflects the individuality and key features of YCs, their widening roles within the mental health sphere, and the challenges faced in maintaining and expanding the characteristic "youth-centred" approach while expanding their work with mental health. [ABSTRACT FROM AUTHOR]