Vaginal leiomyoma in a goat expressing the nuclear progesterone receptor (PGR): a case report.

BACKGROUND: The risk of developing tumorous diseases in the genital tract also increases with age in animals. One of the classified tumor types is genital leiomyoma. Presently, our understanding of the pathogenesis of this tumor in goats is, however, limited. This accounts also for the information regarding the presence of steroid hormone receptors and, thus, possible responsiveness to circulating steroids. CASE PRESENTATION: This study describes the case of a vaginal tumor in a seven-year-old Anglo-Nubian goat. The goat was presented due to blood mixed vaginal discharge. Per vaginal examination a singular pedunculated mass in the dorsum of the vagina measuring approximately 3 cm x 4 cm x 4 cm was revealed. After administering epidural anesthesia, the mass was removed electrothermally. There were no postoperative complications. The histopathological examination identified the mass as a leiomyoma. The immunohistochemical examination revealed the presence of the nuclear progesterone receptor (PGR) in the tumor tissue. One year after the surgery, during the follow-up examination, the goat was in good overall health, and the owners had not observed any recurrence of vaginal discharge. CONCLUSIONS: When observing vaginal discharge in goats, it is important to consider the possibility of genital tract tumors. These tumors may express sex steroid receptors. In the future, it is worth considering the investigation of potential approaches for preventing tumorigenesis or treating the tumor, such as castration or the administration of antiprogestogens.

Effects of an integrative multimodal inpatient program on fatigue and work ability in patients with Post-COVID Syndrome-a prospective observational study.

Post-COVID syndrome (PCS) is characterized by a variety of non-specific symptoms. One of the leading symptoms is fatigue. So far, there is no evidence-based causal therapy established and treatment of PCS is primarily symptom-oriented. The Clinic for Internal and Integrative Medicine in Bamberg, Germany, offers a comprehensive multimodal integrative inpatient therapy for PCS patients. Within a prospective uncontrolled observational study, the results of N = 79 patients were analysed. Post-COVID fatigue patients were hospitalized for up to 14 days. The treatment consists of individual modules depending on the patient's needs. It includes a wide range of integrative non-pharmacological treatment modalities. Outcomes were assessed before and after the inpatient treatment as well as 6 months after discharge from the hospital. Results show that fatigue of post-COVID patients in this study (M = 76.30, SD = 10.18, N = 64) was initially significantly higher than in the subsample "women aged 60-92 years" of the general German population (M = 51.5, Schwarz et al. [Schwarz et al. in Onkologie 26:140-144, 2003]; T(63) = 19.50, p < .001). Fatigue was significantly and clinically relevant reduced directly after discharge (MT1 = 76.21, SD = 11.38, N = 42; MT2 = 66.57, SD = 15.55, N = 42), F(1, 41) = 19.80, p < .001, partial eta squared = .326, as well as six months after discharge (MT3 = 65.31, SD = 17.20, N = 42), F(1, 41), p < .001, partial eta squared = .371. Additionally, self-reported ability to work (NRS, 0-10) improved significantly from admission (MT1 = 2.54, SD = 2.23, N = 39) to discharge (MT2 = 4.26, SD = 2.60, N = 39), F(1, 38) = 26.37, p < .001, partial eta squared = .410), as well as to six months later (MT3 = 4.41, SD = 3.23, N = 39), F(1, 38) = 15.00, p < .001, partial eta squared = .283. The study showed that patients suffering from chronic post-COVID syndrome for several months can achieve a significant improvement in their leading fatigue symptoms and a significant improvement in the subjective assessment of their ability to work through a comprehensive two-week multimodal integrative inpatient program.

Multi-institutional retrospective study investigating blood culture protocols and test positivity in 701 dogs.

Objectives: (i) To determine the influence of specimen collection protocol (timing and specimen quantity), primary disease process, and pre-existing antimicrobial or immunosuppressive therapy on blood culture (BC) positivity and (ii) To determine agreement between urine culture and BC results. Animals: 701 client-owned dogs. Methods: Multi-institutional retrospective study (2019-2022). Mixed-effect logistic regression was used to determine whether primary disease process, the number of BCs, or the timing of specimen collection was associated with BC positivity. Prediction plots were generated. Associations between urine culture and BC results were performed using logistic regression. Results: Dogs with a positive urine culture were more likely to have a positive BC (OR: 4.36, 95% CI: 2.12-8.97, p = 0.003). Dogs that had three BC specimens had the greatest odds of obtaining a positive BC result (adjusted predictive value: 0.44, 95% CI: 0.21-0.70), although this was not significant. Isolates from 38.5% of dogs with a positive BC had resistance to ≥3 antimicrobial classes. The timing between specimen collection had no significant association with BC positivity. Pre-existing antibiotic or immunosuppressive therapy had no significant association with BC positivity. Clinical relevance: Dogs with a positive urine culture were more likely to have a positive BC result.

Lifetime prevalence of owner-reported medical conditions in the 25 most common dog breeds in the Dog Aging Project pack.

Introduction: Large scale data on the prevalence of diverse medical conditions among dog breeds in the United States are sparse. This cross-sectional study sought to estimate the lifetime prevalence of medical conditions among US dogs and to determine whether purebred dogs have higher lifetime prevalence of specific medical conditions compared to mixed-breed dogs. Methods: Using owner-reported survey data collected through the Dog Aging Project (DAP) Health and Life Experience Survey for 27,541 companion dogs, we identified the 10 most commonly reported medical conditions in each of the 25 most common dog breeds within the DAP cohort. Lifetime prevalence estimates of these medical conditions were compared between mixed-breed and purebred populations. The frequency of dogs for whom no medical conditions were reported was also assessed within each breed and the overall mixed-breed and purebred populations. Results: A total of 53 medical conditions comprised the top 10 conditions for the 25 most popular breeds. The number of dogs for whom no medical conditions were reported was significantly different (p = 0.002) between purebred (22.3%) and mixed-breed dogs (20.7%). The medical conditions most frequently reported within the top 10 conditions across breeds were dental calculus (in 24 out of 25 breeds), dog bite (23/25), extracted teeth (21/25), osteoarthritis (15/25), and Giardia (15/25). Discussion: Purebred dogs in the DAP did not show higher lifetime prevalence of medical conditions compared to mixed-breed dogs, and a higher proportion of purebred dogs than mixed-breed dogs had no owner-reported medical conditions. Individual breeds may still show higher lifetime prevalence for specific conditions.

[Fatalities in a litter of French bulldogs puppies due canine herpesvirus 1]. / Todesfälle in einem Wurf französischer Bulldoggen Welpen im Zusammenhang mit dem caninen Herpesvirus 1.

This case report describes the occurrence of canine herpesvirus 1 in a litter of French bulldogs. In addition, the literature dealing with CHV-1 in puppies is summarized. Two puppies were presented due to dyspnea. During the night, one of them developed diarrhea as well as a highly disturbed general condition and was subsequently euthanized the following day. The second puppy was euthanized 6 hours later with a highly disturbed general condition. Necropsy revealed evidence of canine herpesvirus infection. This was confirmed by a virological examination. The presented case report shows that canine herpesvirus infection must also be considered as a cause of death in newborn puppies in Germany.

Effect of esomeprazole with and without a probiotic on fecal dysbiosis, intestinal inflammation, and fecal short-chain fatty acid concentrations in healthy dogs.

BACKGROUND: Proton pump inhibitors can cause diarrhea and a transient increase in fecal dysbiosis index in dogs. It is unknown if concurrent probiotic administration mitigates these effects. OBJECTIVE/HYPOTHESIS: To assess the fecal Canine Microbial Dysbiosis Index (CMDI), fecal short chain fatty acid (SCFA), and fecal calprotectin concentrations in dogs administered esomeprazole with and without a probiotic. ANIMALS: Eleven healthy dogs. METHODS: Prospective, within-subjects before and after study. All dogs received 7-day courses of esomeprazole (1 mg/kg PO q 24h) alone followed by esomeprazole with a probiotic (15 billion CFU/kg), separated by a 4-week washout period. Data were compared between phases using mixed effects ANOVA or generalized estimating equations with post-hoc Holm adjustment for 2-way comparisons. RESULTS: Compared to baseline (mean CMDI -2.66, SD 3.04), fecal CMDI was not different with esomeprazole administration alone (mean CMDI -1.48, SD 3.32, P = .08), but there was a significant increase (Diff 3.05, 95% CI [1.37, 4.74], P < .001, Effect size 2.02) when esomeprazole and a probiotic were administered concurrently (mean CMDI 0.39, SD 2.83). CMDI was significantly higher when esomeprazole was administered with a probiotic than alone (Diff 1.87, 95% CI [0.19, 1.87], P = .02, Effect size 1.24). Fecal calprotectin and SCFA concentrations did not differ between phases. The occurrence of vomiting and diarrhea was not different from baseline when esomeprazole was administered alone (36%/27%) or with a probiotic (46%/9%). CONCLUSIONS AND CLINICAL IMPORTANCE: In healthy dogs, concurrent administration of a probiotic is unlikely to lessen adverse effects associated with esomeprazole administration.

Complementary and alternative treatments for insomnia disorder: a systematic umbrella review.

Insomnia is a common disorder and cognitive behavioural therapy for insomnia (CBT-I) is recommended as first-line treatment. However, CBT-I is not widely distributed and infrequently available while medication is not indicated for long-term use. To close this evident gap in supply, alternative treatments could be utilised. High-quality research on this topic is scarce, and there is currently no comprehensive publication on the effectiveness of alternative treatments. To address this pressing question, we systematically summarised the existing research on alternative treatments for insomnia. A comprehensive search of systematic reviews and (network) meta-analyses of randomised controlled trials investigating the efficacy of alternative treatments compared to waiting-list control or placebo in adults with insomnia disorder with or without comorbidities was conducted in PubMed, MEDLINE, PsycInfo, and PsycArticles on December 6, 2022, yielding 391 records. Finally, 15 eligible studies were included. Evidence on acupuncture, exogenous melatonin, mind-body interventions and exercise, repetitive transcranial magnetic stimulation (rTMS), valerian, and light exposure was found. Acupuncture, rTMS and mind-body exercises significantly improved sleep quality and insomnia severity but effects on objectively assessed outcomes were inconclusive. Melatonin led to a reduction in both self-reported and objectively assessed sleep onset latency. Light exposure and valerian did not significantly improve sleep outcomes. Overall, the quality of studies was rated as low. Results indicate that alternative treatments are effective mostly on subjective outcomes. However, evidence on the efficacy of some intervention types is sparse and there is a need for high-quality original studies. Future research could investigate whether combining different alternative treatment aspects with CBT-I improves individual treatment.

Targeted insertion and reporter transgene activity at a gene safe harbor of the human blood fluke, Schistosoma mansoni.

The identification and characterization of genomic safe harbor sites (GSHs) can facilitate consistent transgene activity with minimal disruption to the host cell genome. We combined computational genome annotation and chromatin structure analysis to predict the location of four GSHs in the human blood fluke, Schistosoma mansoni, a major infectious pathogen of the tropics. A transgene was introduced via CRISPR-Cas-assisted homology-directed repair into one of the GSHs in the egg of the parasite. Gene editing efficiencies of 24% and transgene-encoded fluorescence of 75% of gene-edited schistosome eggs were observed. The approach advances functional genomics for schistosomes by providing a tractable path for generating transgenics using homology-directed, repair-catalyzed transgene insertion. We also suggest that this work will serve as a roadmap for the development of similar approaches in helminths more broadly.

Genomics Reveal Admixture and Unexpected Patterns of Diversity in a Parapatric Pair of Butterflies.

We studied the evolutionary relationship of two widely distributed parapatric butterfly species, Melitaea athalia and Melitaea celadussa, using the ddRAD sequencing approach, as well as genital morphology and mtDNA data. M. athalia was retrieved as paraphyletic with respect to M. celadussa. Several cases of mito-nuclear discordance and morpho-genetic mismatch were found in the contact zone. A strongly diverged and marginally sympatric clade of M. athalia from the Balkans was revealed. An in-depth analysis of genomic structure detected high levels of admixture between M. athalia and M. celadussa at the contact zone, though not reaching the Balkan clade. The demographic modelling of populations supported the intermediate genetic make-up of European M. athalia populations with regards to M. celadussa and the Balkan clade. However, the dissimilarity matrix of genotype data (PCoA) suggested the Balkan lineage having a genetic component that is unrelated to the athalia-celadussa group. Although narrowly sympatric, almost no signs of gene flow were found between the main M. athalia group and the Balkan clade. We propose two possible scenarios on the historical evolution of our model taxa and the role of the last glacial maximum in shaping their current distribution. Finally, we discuss the complexities regarding the taxonomic delimitation of parapatric taxa.

How Smart Is It to Go to Bed with the Phone? The Impact of Short-Wavelength Light and Affective States on Sleep and Circadian Rhythms.

Previously, we presented our preliminary results (N = 14) investigating the effects of short-wavelength light from a smartphone during the evening on sleep and circadian rhythms (Höhn et al., 2021). Here, we now demonstrate our full sample (N = 33 men), where polysomnography and body temperature were recorded during three experimental nights and subjects read for 90 min on a smartphone with or without a filter or from a book. Cortisol, melatonin and affectivity were assessed before and after sleep. These results confirm our earlier findings, indicating reduced slow-wave-sleep and -activity in the first night quarter after reading on the smartphone without a filter. The same was true for the cortisol-awakening-response. Although subjective sleepiness was not affected, the evening melatonin increase was attenuated in both smartphone conditions. Accordingly, the distal-proximal skin temperature gradient increased less after short-wavelength light exposure than after reading a book. Interestingly, we could unravel within this full dataset that higher positive affectivity in the evening predicted better subjective but not objective sleep quality. Our results show disruptive consequences of short-wavelength light for sleep and circadian rhythmicity with a partially attenuating effect of blue-light filters. Furthermore, affective states influence subjective sleep quality and should be considered, whenever investigating sleep and circadian rhythms.

The Oshu Fujiwara-An interdisciplinary study on the history, culture and medical assessment of the oldest known mummified human remains in Japan (late Heian, 12th century AD).

This study documents a rare case of mummified human remains from Japan, dating to the late Heian period, 12th Century AD. The remains have only been scientifically investigated once in 1950 so far. The results of this investigation were translated, analyzed, and interpreted using methods of the 21st century. The remains have been traditionally identified as the four ruling generations of the Oshu Fujiwara clan, who built a cultural and economic center in Hiraizumi. Accordingly, this paper will first examine the historical and cultural significance of Hiraizumi and its ruling class before re-evaluating the findings of the 1950 investigation. This study is the first in the Western scientific literature to provide a comprehensive historical, cultural, and medical evaluation of these mummies.

Dissolved Inorganic Carbon-Accumulating Complexes from Autotrophic Bacteria from Extreme Environments.

In nature, concentrations of dissolved inorganic carbon (DIC; CO2 + HCO3- + CO32-) can be low, and autotrophic organisms adapt with a variety of mechanisms to elevate intracellular DIC concentrations to enhance CO2 fixation. Such mechanisms have been well studied in Cyanobacteria, but much remains to be learned about their activity in other phyla. Novel multisubunit membrane-spanning complexes capable of elevating intracellular DIC were recently described in three species of bacteria. Homologs of these complexes are distributed among 17 phyla in Bacteria and Archaea and are predicted to consist of one, two, or three subunits. To determine whether DIC accumulation is a shared feature of these diverse complexes, seven of them, representative of organisms from four phyla, from a variety of habitats, and with three different subunit configurations, were chosen for study. A high-CO2-requiring, carbonic anhydrase-deficient (ΔyadF ΔcynT) strain of Escherichia coli Lemo21(DE3), which could be rescued via elevated intracellular DIC concentrations, was created for heterologous expression and characterization of the complexes. Expression of all seven complexes rescued the ability of E. coli Lemo21(DE3) ΔyadF ΔcynT to grow under low-CO2 conditions, and six of the seven generated measurably elevated intracellular DIC concentrations when their expression was induced. For complexes consisting of two or three subunits, all subunits were necessary for DIC accumulation. Isotopic disequilibrium experiments clarified that CO2 was the substrate for these complexes. In addition, the presence of an ionophore prevented the accumulation of intracellular DIC, suggesting that these complexes may couple proton potential to DIC accumulation. IMPORTANCE To facilitate the synthesis of biomass from CO2, autotrophic organisms use a variety of mechanisms to increase intracellular DIC concentrations. A novel type of multisubunit complex has recently been described, which has been shown to generate measurably elevated intracellular DIC concentrations in three species of bacteria, raising the question of whether these complexes share this capability across the 17 phyla of Bacteria and Archaea where they are found. This study shows that DIC accumulation is a trait shared by complexes with various subunit structures, from organisms with diverse physiologies and taxonomies, suggesting that this trait is universal among them. Successful expression in E. coli suggests the possibility of their expression in engineered organisms synthesizing compounds of industrial importance from CO2.

Value of handgrip strength to predict clinical outcomes and therapeutic response in malnourished medical inpatients: Secondary analysis of a randomized controlled trial.

BACKGROUND: Disease-related malnutrition is associated with loss of muscle mass and impaired functional status. Handgrip strength (HGS) has been proposed as an easy-to-use tool to assess muscle strength in clinical practice. OBJECTIVES: We investigated the prognostic implications of HGS in patients at nutritional risk with regard to clinical outcomes and response to nutritional support. METHODS: This was a secondary analysis of the randomized controlled, multicenter, Effect of Early Nutritional Support on Frailty, Functional Outcome, and Recovery of Malnourished Medical Inpatients Trial, which compared the effects of individualized nutritional support with usual hospital food in medical inpatients at nutritional risk. Our primary endpoint was 30-d all-cause mortality. The association between sex-specific HGS and clinical outcomes was investigated using multivariable regression analyses, adjusted for randomization, age, weight, height, nutritional risk, admission diagnosis, comorbidities, interaction terms, and study center. We used interaction terms to investigate possible effect modification regarding the nutritional support intervention. RESULTS: Mean ± SD HGS in the 1809 patients with available handgrip measurement was 17.0 ± 7.1 kg for females and 28.9 ± 11.3 kg for males. Each decrease of 10 kg in HGS was associated with increased risk of 30-d mortality (female: adjusted OR: 2.11; 95% CI: 1.23, 3.62, P = 0.007; male: adjusted OR: 1.44; 95% CI: 1.07, 1.93, P = 0.015) and 180-d mortality (female: adjusted OR: 1.45; 95% CI: 1.0, 2.10, P = 0.048; male: adjusted OR: 1.55; 95% CI: 1.28, 1.89, P < 0.001). Individualized nutritional support was most effective in reducing mortality in patients with low HGS (adjusted OR: 0.29; 95% CI: 0.10, 0.82 in patients in the ≤10th percentile compared with OR: 0.98; 95% CI: 0.66, 1.48 in patients in the >10th percentile; P for interaction = 0.026). CONCLUSIONS: In medical inpatients at nutritional risk, HGS provided significant prognostic information about expected mortality and complication risks and helps to identify which patients benefit most from nutritional support. HGS may thus improve individualization of nutritional therapy.This trial was registered at clinicaltrials.gov as NCT02517476.

Preliminary Results: The Impact of Smartphone Use and Short-Wavelength Light during the Evening on Circadian Rhythm, Sleep and Alertness.

Smartphone usage strongly increased in the last decade, especially before bedtime. There is growing evidence that short-wavelength light affects hormonal secretion, thermoregulation, sleep and alertness. Whether blue light filters can attenuate these negative effects is still not clear. Therefore, here, we present preliminary data of 14 male participants (21.93 ± 2.17 years), who spent three nights in the sleep laboratory, reading 90 min either on a smartphone (1) with or (2) without a blue light filter, or (3) on printed material before bedtime. Subjective sleepiness was decreased during reading on a smartphone, but no effects were present on evening objective alertness in a GO/NOGO task. Cortisol was elevated in the morning after reading on the smartphone without a filter, which resulted in a reduced cortisol awakening response. Evening melatonin and nightly vasodilation (i.e., distal-proximal skin temperature gradient) were increased after reading on printed material. Early slow wave sleep/activity and objective alertness in the morning were only reduced after reading without a filter. These results indicate that short-wavelength light affects not only circadian rhythm and evening sleepiness but causes further effects on sleep physiology and alertness in the morning. Using a blue light filter in the evening partially reduces these negative effects.

Six-month outcomes after individualized nutritional support during the hospital stay in medical patients at nutritional risk: Secondary analysis of a prospective randomized trial.

BACKGROUND: Among medical inpatients at risk of malnutrition, the use of individualized nutritional support during the hospital stay was found to reduce complications and improve mortality at short-term. We evaluated clinical outcomes at 6-months follow-up. METHODS: We randomly assigned 2028 patients to receive protocol-guided individualized nutritional support to reach protein and energy goals (intervention group) or hospital food as usual (control group) during the hospital stay. The intervention was discontinued at hospital discharge and further nutritional support was based on the discretion of the treating team. We had complete follow-up information of 1995 patients (98%), which were included in the final analysis. The primary endpoint was all-cause mortality at 6-months. Prespecified secondary end points included non-elective hospital readmissions, functional outcome and quality of life. RESULTS: At 6-month, 231 of 994 (23.2%) intervention group patients had died compared to 246 of 999 (24.6%) control group patients, resulting in a hazard ratio for death of 0.90 (95%CI 0.76 to 1.08, p = 0.277). Compared to control patients, intervention group patients had similar rates of hospital readmission (27.3% vs. 27.6%, HR 1.00 (95%CI 0.84 to 1.18), p = 0.974), falls (11.2% vs. 10.9%, HR 0.96 (95%CI 0.72 to 1.27), p = 0.773) and similar quality of life and activities of daily living scores. INTERPRETATION: While individualized nutritional support during the hospital stay significantly reduced short-term mortality, there was no legacy effect on longer term outcomes. Future trials should investigate whether continuation of nutritional support after hospital discharge reduces the high malnutrition-associated mortality rates in this vulnerable patient population. TRIAL REGISTRATION: ClinicalTrials.gov number, NCT02517476.

Pre-arrest doxycycline protects donation after circulatory death kidneys.

Kidney injury during donation after circulatory determination of death (DCDD) includes warm ischemic (WI) injury from around the time of asystole, and cold ischemic (CI) injury during cold preservation. We have previously shown that Matrix Metalloproteinases (MMPs) are involved in CI injury and that Doxycycline (Doxy), an antibiotic and known MMP inhibitor, protects the transplant kidney during CI. The purpose of our study was to determine if Doxy given before asystole can also prevent injury during WI. A rat model of DCDD was used, including Control, Preemptive Doxy (45 mg/kg iv), and Preemptive and Perfusion (100 microM) Doxy groups. Thirty minutes after asystole, both kidneys were removed. The left kidney was perfused at 4 °C for 22 h, whereas the right was used to establish the degree of warm ischemic injury prior to cold preservation. MMP-2 in the perfusate was significantly reduced in both treatment groups [Control 43.7 ± 7.2 arbitrary units, versus Preemptive Doxy group 23.2 ± 5.5 (p = 0.03), and 'Preemptive and Perfusion' group 18.0 ± 5.6 (p = 0.02)]. Reductions in NGAL, LDH, and MMP-9 were also seen. Electron microscopy showed a marked reduction in mitochondrial injury scores in the treatment groups. Pre-arrest Doxy was associated with a reduction in injury markers and morphologic changes. Doxy may be a simple and safe means of protecting transplant kidneys from both WI and CI.

Ubiquity and functional uniformity in CO2 concentrating mechanisms in multiple phyla of Bacteria is suggested by a diversity and prevalence of genes encoding candidate dissolved inorganic carbon transporters.

Autotrophic microorganisms catalyze the entry of dissolved inorganic carbon (DIC; = CO2 + HCO3- + CO32-) into the biological component of the global carbon cycle, despite dramatic differences in DIC abundance and composition in their sometimes extreme environments. "Cyanobacteria" are known to have CO2 concentrating mechanisms (CCMs) to facilitate growth under low CO2 conditions. These CCMs consist of carboxysomes, containing enzymes ribulose 1,5-bisphosphate oxygenase and carbonic anhydrase, partnered to DIC transporters. CCMs and their DIC transporters have been studied in a handful of other prokaryotes, but it was not known how common CCMs were beyond "Cyanobacteria". Since it had previously been noted that genes encoding potential transporters were found neighboring carboxysome loci, α-carboxysome loci were gathered from bacterial genomes, and potential transporter genes neighboring these loci are described here. Members of transporter families whose members all transport DIC (CHC, MDT and Sbt) were common in these neighborhoods, as were members of the SulP transporter family, many of which transport DIC. 109 of 115 taxa with carboxysome loci have some form of DIC transporter encoded in their genomes, suggesting that CCMs consisting of carboxysomes and DIC transporters are widespread not only among "Cyanobacteria", but also among members of "Proteobacteria" and "Actinobacteria".

Museomics identifies genetic erosion in two butterfly species across the 20th century in Finland.

Erosion of biodiversity generated by anthropogenic activities has been studied for decades and in many areas at the species level, using taxa monitoring. In contrast, genetic erosion within species has rarely been tracked, and is often studied by inferring past population dynamics from contemporaneous estimators. An alternative to such inferences is the direct examination of past genes, by analysing museum collection specimens. While providing direct access to genetic variation over time, historical DNA is usually not optimally preserved, and it is necessary to apply genotyping methods based on hybridization-capture to unravel past genetic variation. In this study, we apply such a method (i.e., HyRAD), to large time series of two butterfly species in Finland, and present a new bioinformatic pipeline, namely PopHyRAD, that standardizes and optimizes the analysis of HyRAD data at the within-species level. In the localities for which the data retrieved have sufficient power to accurately examine genetic dynamics through time, we show that genetic erosion has increased across the last 100 years, as revealed by signatures of allele extinctions and heterozygosity decreases, despite local variations. In one of the two butterflies (Erebia embla), isolation by distance also increased through time, revealing the effect of greater habitat fragmentation over time.

Design of Radiolabeled Analogs of Minigastrin by Multiple Amide-to-Triazole Substitutions.

The insertion of single 1,4-disubstituted 1,2,3-triazoles as metabolically stable bioisosteres of trans-amide bonds (triazole scan) was recently applied to the 177Lu-labeled tumor-targeting analog of minigastrin, [Nle15]MG11. The reported novel mono-triazolo-peptidomimetics of [Nle15]MG11 showed either improved resistance against enzymatic degradation or a significantly increased affinity toward the target receptor but never both. To enhance further the tumor-targeting properties of the minigastrin analogs, we studied conjugates with multiple amide-to-triazole substitutions for additive or synergistic effects. Promising candidates were identified by modification of two or three amide bonds, which yielded both improved stability and increased receptor affinity of the peptidomimetics in vitro. Biodistribution studies of radiolabeled multi-triazolo-peptidomimetics in mice bearing receptor-positive tumor xenografts revealed up to 4-fold increased tumor uptake in comparison to the all-amide reference compound [Nle15]MG11. In addition, we report here for the first time a linear peptidomimetic with three triazole insertions in its backbone and maintained biological activity.