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Next generation sequencing (NGS) can detect carrier status for rare recessive disorders, informing couples about their reproductive risk. The recent ACMG recommendations support offering NGS-based carrier screening (NGS-CS) in an ethnic and population-neutral manner for all genes that have a carrier frequency >1/200 (based on GnomAD). To evaluate current challenges for NGS-CS, we focused on the ciliopathies, a well-studied group of rare recessive disorders. We analyzed 118 ciliopathy genes by whole exome sequencing in ~400 healthy local individuals and ~1000 individuals from the UK1958-birth cohort. We found 20% of healthy individuals (1% of couples) to be carriers of reportable variants in a ciliopathy gene, while 50% (4% of couples) carry variants of uncertain significance (VUS). This large proportion of VUS is partly explained by the limited utility of the ACMG/AMP variant-interpretation criteria in healthy individuals, where phenotypic match or segregation criteria cannot be used. Most missense variants are thus classified as VUS and not reported, which reduces the negative predictive value of the screening test. We show how gene-specific variation patterns and structural protein information can help prioritize variants most likely to be disease-causing, for (future) functional assays. Even when considering only strictly pathogenic variants, the observed carrier frequency is substantially higher than expected based on estimated disease prevalence, challenging the 1/200 carrier frequency cut-off proposed for choice of genes to screen. Given the challenges linked to variant interpretation in healthy individuals and the uncertainties about true carrier frequencies, genetic counseling must clearly disclose these limitations of NGS-CS.

Lactococcus lactis strains residing in the microbial community of a complex dairy starter culture named “Ur” are hosts to prophages belonging to the family Siphoviridae. L. lactis strains (TIFN1 to TIFN7) showed detectable spontaneous phage production and release (109 to 1010 phage particles/ml) and up to 10-fold increases upon prophage induction, while in both cases we observed no obvious cell lysis typically described for the lytic life cycle of Siphoviridae phages. Intrigued by this phenomenon, we investigated the host-phage interaction using strain TIFN1 (harboring prophage proPhi1) as a representative. We confirmed that during the massive phage release, all bacterial cells remain viable. Further, by monitoring phage replication in vivo, using a green fluorescence protein reporter combined with flow cytometry, we demonstrated that the majority of the bacterial population (over 80%) is actively producing phage particles when induced with mitomycin C. The released tailless phage particles were found to be engulfed in lipid membranes, as evidenced by electron microscopy and lipid staining combined with chemical lipid analysis. Based on the collective observations, we propose a model of phage-host interaction in L. lactis TIFN1 where the phage particles are engulfed in membranes upon release, thereby leaving the producing host intact. Moreover, we discuss possible mechanisms of chronic, or nonlytic, release of LAB Siphoviridae phages and its impact on the bacterial host. IMPORTANCE In complex microbial consortia such as fermentation starters, bacteriophages can alter the dynamics and diversity of microbial communities. Bacteriophages infecting Lactococcus lactis are mostly studied for their detrimental impact on industrial dairy fermentation processes. In this study, we describe a novel form of phage-bacterium interaction in an L. lactis strain isolated from a complex dairy starter culture: when the prophages harbored in the L. lactis genome are activated, the phage particles are engulfed in lipid membranes upon release, leaving the producing host intact. Findings from this study provide additional insights into the diverse manners of phage-bacterium interactions and coevolution, which are essential for understanding the population dynamics in complex microbial communities like fermentation starters.

Background SARS‐CoV‐2 caused one of the most devastating pandemics in the recent history of mankind. Due to various countermeasures, including lock‐downs, wearing masks, and increased hygiene, the virus has been controlled in some parts of the world. More recently, the availability of vaccines, based on RNA or adenoviruses, has greatly added to our ability to keep the virus at bay; again, however, in some parts of the world only. While available vaccines are effective, it would be desirable to also have more classical vaccines at hand for the future. Key feature of vaccines for long‐term control of SARS‐CoV‐2 would be inexpensive production at large scale, ability to make multiple booster injections, and long‐term stability at 4℃. Methods Here, we describe such a vaccine candidate, consisting of the SARS‐CoV‐2 receptor‐binding motif (RBM) grafted genetically onto the surface of the immunologically optimized cucumber mosaic virus, called CuMVTT‐RBM. Results Using bacterial fermentation and continuous flow centrifugation for purification, the yield of the production process is estimated to be >2.5 million doses per 1000‐litre fermenter run. We demonstrate that the candidate vaccine is highly immunogenic in mice and rabbits and induces more high avidity antibodies compared to convalescent human sera. The induced antibodies are more cross‐reactive to mutant RBDs of variants of concern (VoC). Furthermore, antibody responses are neutralizing and long‐lived. In addition, the vaccine candidate was stable for at least 14 months at 4℃. Conclusion Thus, the here presented VLP‐based vaccine may be a good candidate for use as conventional vaccine in the long term., In this study, we describe a novel conventional COVID‐19 vaccine that consists of the RBM of SARS‐CoV‐2 genetically grafted onto the surface of our optimized cucumber‐mosaic virus‐like particles. We demonstrate that the vaccine candidate (mCuMVTT‐RBM) is highly immunogenic in mice and rabbits, can efficiently neutralize SARS‐CoV‐2, and is stable and highly scalable. The induced antibodies show cross‐reactivity with VoC.

Systemic AA-amyloidosis is a protein-misfolding disease characterized by fibril deposition of serum amyloid-A protein (SAA) in several organs in humans and many animal species. Fibril deposits originate from abnormally high serum levels of SAA during chronic inflammation. A high prevalence of AA-amyloidosis has been reported in captive cheetahs and a horizontal transmission has been proposed. In domestic cats, AA-amyloidosis has been mainly described in predisposed breeds but only rarely reported in domestic short-hair cats. Aims of the study were to determine AA-amyloidosis prevalence in dead shelter cats. Liver, kidney, spleen and bile were collected at death in cats from 3 shelters. AA-amyloidosis was scored. Shedding of amyloid fibrils was investigated with western blot in bile and scored. Descriptive statistics were calculated. In the three shelters investigated, prevalence of AA-amyloidosis was 57.1% (16/28 cats), 73.0% (19/26) and 52.0% (13/25), respectively. In 72.9% of cats (35 in total) three organs were affected concurrently. Histopathology and immunofluorescence of post-mortem extracted deposits identified SAA as the major protein source. The duration of stay in the shelters was positively associated with a histological score of AA-amyloidosis (B = 0.026, CI95% = 0.007–0.046; p = 0.010). AA-amyloidosis was very frequent in shelter cats. Presence of SAA fragments in bile secretions raises the possibility of fecal-oral transmission of the disease. In conclusion, AA-amyloidosis was very frequent in shelter cats and those staying longer had more deposits. The cat may represent a natural model of AA-amyloidosis.

Describes a computer program used at a genetic stock center to locate particular strains of bacteria. The program can match up to 30 strain descriptions requested by a researcher with the records on file. Uses of this particular program can be made in many fields. (PS)

Ornithine decarboxylase (ODC) is the rate-limiting enzyme for the synthesis of polyamines (PAs). PAs are oncometabolites that are required for proliferation, and pharmaceutical ODC inhibition is pursued for the treatment of hyperproliferative diseases, including cancer and infectious diseases. The most potent ODC inhibitor is 1-amino-oxy-3-aminopropane (APA). A previous crystal structure of an ODC–APA complex indicated that APA non-covalently binds ODC and its cofactor pyridoxal 5-phosphate (PLP) and functions by competing with the ODC substrate ornithine for binding to the catalytic site. We have revisited the mechanism of APA binding and ODC inhibition through a new crystal structure of APA-bound ODC, which we solved at 2.49 Å resolution. The structure unambiguously shows the presence of a covalent oxime between APA and PLP in the catalytic site, which we confirmed in solution by mass spectrometry. The stable oxime makes extensive interactions with ODC but cannot be catabolized, explaining APA's high potency in ODC inhibition. In addition, we solved an ODC/PLP complex structure with citrate bound at the substrate-binding pocket. These two structures provide new structural scaffolds for developing more efficient pharmaceutical ODC inhibitors.

Lobos marinos varados en la costa peruana se registran continuamente y con mayor intensidad en años con condiciones oceanográficas anómalas cálidas. El Instituto del Mar del Perú (IMARPE) ha estado realizando investigaciones para determinar las causas asociadas a los varamientos, a través del monitoreo en playas y atención a eventos de mortalidad masiva. El presente estudio muestra resultados de análisis histopatológicos en muestras testiculares de dos ejemplares, juvenil y subadulto, de lobo marino chusco Otaria byronia varados en los departamentos de La Libertad (7°-8°S) y Piura (4°-5°S) en abril y octubre 2018. Las muestras de tejido gonadal fueron fijadas en formalina tamponada al 10%, teñidas con hematoxilina-eosina y evaluadas bajo el microscopio. Los resultados mostraron un proceso neoplásico de células germinales llamado seminoma, en ambos ejemplares. En comparación con otras especies de pinnípedos intensamente estudiados como el lobo marino californiano Zalophus californianus, no se han reportado regularmente neoplasias en los lobos marinos chuscos, probablemente debido a la falta de monitoreo continuo y la inaccesibilidad a muchas de las principales áreas de varamientos. Por esta razón, es esencial intensificar la investigación sobre eventos de mortandad de mamíferos marinos en la costa peruana. Lo cual permitirá aclarar las causas de muerte y comprender mejor la etiología de varias enfermedades en esta especie, brindándonos una visión amplia de la salud del ecosistema marino y su efecto tanto en la fauna que lo habita como las implicancias en la salud humana ABSTRACT: In Peru, stranded sea lions have been recorded continuously and with greater intensity in years with anomalous warm oceanographic conditions. Thus, the Instituto del Mar del Peru (IMARPE) has been researching to determine causes associated with strandings, through monitoring on beaches and attention to events of mass mortality. This study shows the results of the histopathological analysis in testicular samples of two juvenile and sub-adult specimens of South American sea lions Otaria byronia in La Libertad (7°-8°S) and Piura (4°-5°S) during April and October 2018. The gonadal tissue samples were fixed in 10% buffered formalin, stained with hematoxylin-eosin, and evaluated under a microscope. In both specimens, the results showed a neoplastic germ cell process called seminoma. Compared to other intensively studied pinnipeds such as the California sea lion Zalophus californianus, neoplasms have not been regularly reported in the South American sea lion, probably due to the lack of continuous monitoring and inaccessibility to many of the main stranding areas. Therefore, it is essential to intensify the research on marine mammal’s death events on the Peruvian coast. This strategy will allow us to clarify death causes and better understand the etiology of several diseases in this species, giving us a broad vision of the health of the marine ecosystem and their effect on their local fauna as well as their implications for human health

BACKGROUND Processed kaolin is a promising tactic that can be utilized for managing Diaphorina citri Kuwayama infestation. However, the frequency of kaolin application to protect citrus trees during flushing remains undetermined. The objective of this study was to ascertain the frequency of kaolin application (2%) required to reduce D. citri infestation and dispersal in flushing citrus orchards and to measure the spectral reflectance of kaolin-sprayed leaves. RESULTS Trees sprayed with kaolin at 7- and 14-day intervals showed an 80% psyllid reduction compared to untreated trees. In addition, there was lower psyllid dispersal in the kaolin-sprayed plots. Spectral measurements (wavelengths between 320 and 700 nm) showed an increased reflectance of 35.4% (adaxial leaf side) and 21.9% (abaxial leaf side) in mature leaves, and 9% (adaxial leaf side) and 2.2% (abaxial leaf side) in kaolin-sprayed immature leaves compared to untreated trees. CONCLUSION Application of kaolin (2%) at 7- and 14-day intervals can be an important and sustainable tool for reducing D. citri infestation and dispersal in flushing citrus orchards. The reduced D. citri population in plots with both kaolin application intervals may be related to the visual effect (whitish aspect) and increased light reflectance in citrus trees, which are probably the main mechanisms by which kaolin interferes on D. citri host finding behavior. © 2021 Society of Chemical Industry.

Undefined starter cultures are poorly characterized bacterial communities from environmental origin used in cheese making. They are phenotypically stable and have evolved through domestication by repeated propagation in closed and highly controlled environments over centuries. This makes them interesting for understanding eco-evolutionary dynamics governing microbial communities. While cheese starter cultures are known to be dominated by a few bacterial species, little is known about the composition, functional relevance, and temporal dynamics of strain-level diversity. Here, we applied shotgun metagenomics to an important Swiss cheese starter culture and analyzed historical and experimental samples reflecting 82 years of starter culture propagation. We found that the bacterial community is highly stable and dominated by only a few coexisting strains of Streptococcus thermophilus and Lactobacillus delbrueckii subsp. lactis. Genome sequencing, metabolomics analysis, and co-culturing experiments of 43 isolates show that these strains are functionally redundant, but differ tremendously in their phage resistance potential. Moreover, we identified two highly abundant Streptococcus phages that seem to stably coexist in the community without any negative impact on bacterial growth or strain persistence, and despite the presence of a large and diverse repertoire of matching CRISPR spacers. Our findings show that functionally equivalent strains can coexist in domesticated microbial communities and highlight an important role of bacteria-phage interactions that are different from kill-the-winner dynamics.

The population of methicillin-resistant (MR) staphylococci in aquatic environment is rarely investigated. Here, we characterized a collection of MR staphylococci recovered from shrimp aquaculture farms (n = 37) in Kerala, India. A total of 261 samples yielded 47 MR isolates (16 S. aureus, 13 S. haemolyticus, 11 S. epidermidis, 3 S. saprophytics and 2 each of S.intermedius and S. kloosii). Multi-drug resistance was evident in 72.3% of the isolates, with resistance mainly towards erythromycin (78.7%), norfloxacin and trimethoprim-sulfamethoxazole (53.2%), and gentamicin (34%). Major resistance genes identified included mecA (100%), ermC (38.3%), aacA-aphD (21.3%), tetK (14.9%) and tetM (21.3%). Almost 60% of the isolates carried type V SCCmec (Staphylococcal Cassette Chromosome mec), and the remaining harboured untypeable SCCmec elements. Comprehensive genotyping of the methicillin-resistant Staphylococcus aureus isolates revealed high prevalence of ST772-t345-V (sequence type-spa type-SCCmec type) (75%), followed by minor representations of ST6657-t345-V and ST3190-t12353. The isolates of S. haemolyticus and S. epidermidis were genotypically diverse as shown by their pulsed-field gel electrophoresis (PFGE) profiles. Genes encoding staphylococcal enterotoxins were observed in 53.2% of the isolates. Various genes involved in adhesion and biofilm formation were also identified. In conclusion, our findings provide evidence that shrimp aquaculture settings can act as reservoirs of methicillin-resistant staphylococci.

Summary These guidelines for the treatment of persons who have or are at risk for sexually transmitted infections (STIs) were updated by CDC after consultation with professionals knowledgeable in the field of STIs who met in Atlanta, Georgia, June 11–14, 2019. The information in this report updates the 2015 guidelines. These guidelines discuss 1) updated recommendations for treatment of Neisseria gonorrhoeae, Chlamydia trachomatis, and Trichomonas vaginalis; 2) addition of metronidazole to the recommended treatment regimen for pelvic inflammatory disease; 3) alternative treatment options for bacterial vaginosis; 4) management of Mycoplasma genitalium; 5) human papillomavirus vaccine recommendations and counseling messages; 6) expanded risk factors for syphilis testing among pregnant women; 7) one-time testing for hepatitis C infection; 8) evaluation of men who have sex with men after sexual assault; and 9) two-step testing for serologic diagnosis of genital herpes simplex virus. Physicians and other health care providers can use these guidelines to assist in prevention and treatment of STIs.

Idiopathic scoliosis will be noted in 2% to 3% of typically developing athletes. Sports physicals are an opportunity to screen for spinal deformity and to promote healthy involvement in activities. Bracing is effective at limiting further progression if a curve progresses beyond 20°. If spinal fusion is performed, most surgeons allow return to noncontact and contact sports by 6 to 12 months. There are many other conditions associated with scoliosis that require a more nuanced approach and assessment of the entire patient. Patients with Down syndrome should be examined for myelopathy before participation and a lateral radiograph obtained if concerned for instability.

Somatodendritic missorting of the axonal protein TAU is a hallmark of Alzheimer’s disease and related tauopathies. Cultured rodent primary neurons and iPSC-derived neurons are used for studying mechanisms of neuronal polarity, including TAU trafficking. However, these models are expensive, time-consuming and/or require the sacrification of animals. In this study, we evaluated four differentiation procedures to generate mature neuron cultures from human SH-SY5Y neuroblastoma cells, in comparison to mouse primary neurons, and tested their TAU sorting capacity. We show that SH-SY5Y-derived neurons, differentiated with sequential RA/BDNF treatment, are suitable for investigating axonal TAU sorting. These human neurons show pronounced neuronal polarity, axodendritic outgrowth, expression of the neuronal maturation markers TAU and MAP2, and, importantly, efficient axonal sorting of endogenous and transfected human wild type TAU, similar to primary neurons. We demonstrate that axonal TAU enrichment requires the presence of the C-terminal half, as a C-terminus-lacking construct (N-term-TAUHA) is not axonally enriched in both neuronal cell models. Moreover, SH-SY5Y-derived neurons do not show formation of a classical axon initial segment (AIS), indicated by the lack of Ankyrin G (ANKG) and tripartite motif-containing protein 46 (TRIM46) at the proximal axon, which suggests that successful axonal TAU sorting is independent of classical AIS formation. Taken together, our results suggest i) that SH-SY5Y-derived neurons are a valuable human neuronal cell model for studying TAU sorting, which is readily accessible at low cost and without animal need, and that ii) the mechanisms of axonal TAU targeting require the TAU C-terminal half but are independent of ANKG or TRIM46 enrichment at the proximal axon.

Full mitochondrial genomes were assembled for 12 recently sampled animals from the Svalbard bowhead whale (Balaena mysticetus) stock via high-throughput sequencing data, facilitating analysis of the demographic history of the population for the first time. The Svalbard population has retained noticeable amounts of mitochondrial genome diversity despite extreme historical harvest levels. Haplotype and nucleotide diversities were similar to those estimated earlier for other bowhead whale populations. The reconstructed demographic history was in accordance with a boom–bust scenario, combining a slight Pleistocene population growth 25 000–35 000 years ago and a Holocene decline. Employing a mutation rate of 3.418 × 10–8 substitutions per site per year, the time to the most recent common ancestor for the mitochondrial genomes of the contemporary Svalbard bowhead whales was estimated to be 68 782 (54 353–83 216) years before the present. Based on 370 bp fragments of the D-loop region, significant genetic differentiation was detected between all extant bowhead whale populations across the circumpolar Arctic. Thus, the Svalbard bowhead whales can be regarded as a population with its own genetic legacy.

The objectives of this study were to ascertain the fecal ESBL/AmpC-E. coli prevalence and to detect risk factors for their occurrence in young pre-weaned calves and their dams on large dairy farms in Germany. From 2018–2019 we investigated 2816 individual fecal samples from pre-weaned dairy calves and their dams, representing seventy-two farms (mean = 667 milking cows) from eight German federal states. To assess possible risk factors associated with ESBL/AmpC-E. coli prevalence in calves and dams, a questionnaire was performed, collecting management data. We observed an ESBL/AmpC-E. coli prevalence of 63.5% (95% CI: 57.4–69.5) among the sampled calves and 18.0% (95% CI: 12.5–23.5) among the dams. On all farms, at least one positive sample was obtained. To date, this is the highest ESBL/AmpC-E. coli prevalence observed in dairy herds in Europe. Feeding with waste milk was identified as a significant risk factor for a high prevalence of ESBL/AmpC-E. coli in calves. Many calves at large dairies in Germany are fed with waste milk due to the large amounts generated as a result of antibiotic dry-off routines and mastitis treatment with antibiotics. Other notable risk factors for high ESBL/AmpC-E. coli in calves were the general fitness/health of dams and calves, and the quality of farm hygiene. Taken together, these findings suggest that new or improved approaches to animal health management, for example, antibiotic dry cow management (selective dry cow therapy) and mastitis treatment (high self-recovery), as well as farm hygiene, should be researched and implemented.

Metabolic interactions between cells affect microbial community compositions and hence their function in ecosystems. It is well-known that under competition for the exchanged metabolite, concentration gradients constrain the distances over which interactions can occur. However, interaction distances are typically quantified in two-dimensional systems or without accounting for competition or other metabolite-removal, conditions which may not very often match natural ecosystems. We here analyze the impact of cell-to-cell distance on unidirectional cross-feeding in a three-dimensional aqueous system with competition for the exchanged metabolite. Effective interaction distances were computed with a reaction-diffusion model and experimentally verified by growing a synthetic consortium of 1 µm-sized metabolite producer, receiver, and competitor cells in different spatial structures. We show that receivers cannot interact with producers located on average 15 µm away from them, as product concentration gradients flatten close to producer cells. We developed an aggregation protocol and varied the receiver cells’ product affinity, to show that within producer–receiver aggregates even low-affinity receiver cells could interact with producers. These results show that competition or other metabolite-removal of a public good in a three-dimensional system reduces metabolic interaction distances to the low µm-range, highlighting the importance of concentration gradients as physical constraint for cellular interactions.

In S. cerevisiae and many other micro-organisms an increase in metabolic efficiency (i.e. ATP yield on carbon) is accompanied by a decrease in growth rate. From a fundamental point of view, studying these yield-rate trade-offs provides insight in for example microbial evolution and cellular regulation. From a biotechnological point of view, increasing the ATP yield on carbon might increase the yield of anabolic products. We here aimed to select S. cerevisiae mutants with an increased biomass yield. Serial propagation of individual cells in water-in-oil emulsions previously enabled the selection of lactococci with increased biomass yields, and adapting this protocol for yeast allowed us to enrich an engineered Crabtree-negative S. cerevisiae strain with a high biomass yield on glucose. When we started the selection with an S. cerevisiae deletion collection, serial propagation in emulsion enriched hxk2Δ and reg1Δ strains with an increased biomass yield on glucose. Surprisingly, a tps1Δ strain was highly abundant in both emulsion- and suspension-propagated populations. In a separate experiment we propagated a chemically mutagenized S. cerevisiae population in emulsion, which resulted in mutants with a higher cell number yield on glucose, but no significantly changed biomass yield. Genome analyses indicate that genes involved in glucose repression and cell cycle processes play a role in the selected phenotypes. The repeated identification of mutations in genes involved in glucose-repression indicates that serial propagation in emulsion is a valuable tool to study metabolic efficiency in S. cerevisiae.

Organisms respond to mitochondrial stress by activating multiple defense pathways including the mitochondrial unfolded protein response (UPRmt). However, how UPRmt regulators are orchestrated to transcriptionally activate stress responses remains largely unknown. Here we identified CBP-1, the worm ortholog of the mammalian acetyltransferases CBP/p300, as an essential regulator of the UPRmt, as well as mitochondrial stress-induced immune response, reduction of amyloid-β aggregation and lifespan extension in Caenorhabditis elegans. Mechanistically, CBP-1 acts downstream of histone demethylases, JMJD-1.2/JMJD-3.1, and upstream of UPRmt transcription factors including ATFS-1, to systematically induce a broad spectrum of UPRmt genes and execute multiple beneficial functions. In mouse and human populations, transcript levels of CBP/p300 positively correlate with UPRmt transcripts and longevity. Furthermore, CBP/p300 inhibition disrupts, while forced expression of p300 is sufficient to activate, the UPRmt in mammalian cells. These results highlight an evolutionarily conserved mechanism that determines mitochondrial stress response, and promotes health and longevity through CBP/p300.

Aspergillus fumigatus is the main cause of invasive aspergillosis, for which azole drugs are the first-line therapy. Emergence of pan-azole resistance among A. fumigatus is concerning and has been mainly attributed to mutations in the target gene (cyp51A). However, azole resistance may also result from other mutations (hmg1, hapE) or other adaptive mechanisms. We performed microevolution experiment exposing an A. fumigatus azole-susceptible strain (Ku80) to sub-minimal inhibitory concentration of voriconazole to analyze emergence of azole resistance. We obtained a strain with pan-azole resistance (Ku80R), which was partially reversible after drug relief, and without mutations in cyp51A, hmg1, and hapE. Transcriptomic analyses revealed overexpression of the transcription factor asg1, several ATP-binding cassette (ABC) and major facilitator superfamily transporters and genes of the ergosterol biosynthesis pathway in Ku80R. Sterol analysis showed a significant decrease of the ergosterol mass under voriconazole exposure in Ku80, but not in Ku80R. However, the proportion of the sterol compounds was similar between both strains. To further assess the role of transporters, we used the ABC transporter inhibitor milbemycine oxime (MLB). MLB inhibited transporter activity in both Ku80 and Ku80R and demonstrated some potentiating effect on azole activity. Criteria for synergism were reached for MLB and posaconazole against Ku80. Finally, deletion of asg1 revealed some role of this transcription factor in controlling drug transporter expression, but had no impact on azole susceptibility. This work provides further insight in mechanisms of azole stress adaptation and suggests that drug transporters inhibition may represent a novel therapeutic target. Lay Summary A pan-azole-resistant strain was generated in vitro, in which drug transporter overexpression was a major trait. Analyses suggested a role of the transporter inhibitor milbemycin oxime in inhibiting drug transporters and potentiating azole activity.

The variegated squirrel bornavirus 1 (VSBV-1) is a recently discovered emerging viral pathogen which causes severe and eventually fatal encephalitis in humans after contact to exotic squirrels in private holdings and zoological gardens. Understanding the VSBV-1 epidemiology is crucial to develop, implement, and maintain surveillance strategies for the detection and control of animal and human infections. Based on a newly detected human encephalitis case in a zoological garden, epidemiological squirrel trade investigations and molecular phylogeny analyses of VSBV-1 with temporal and spatial resolution were conducted. Phylogenetic analyses indicated a recent emergence of VSBV-1 in European squirrel holdings and several animal–animal and animal–human spill-over infections. Virus phylogeny linked to squirrel trade analysis showed the introduction of a common ancestor of the known current VSBV-1 isolates into captive exotic squirrels in Germany, most likely by Prevost’s squirrels (Callosciurus prevostii). The links of the animal trade between private breeders and zoos, the likely introduction pathway of VSBV-1 into Germany, and the role of a primary animal distributor were elucidated. In addition, a seroprevalence study was performed among zoo animal caretakers from VSBV-1 affected zoos. No seropositive healthy zoo animal caretakers were found, underlining a probable high-case fatality rate of human VSBV-1 infections. This study illustrates the network and health consequences of uncontrolled wild pet trading as well as the benefits of molecular epidemiology for elucidation and future prevention of infection chains by zoonotic viruses. To respond to emerging zoonotic diseases rapidly, improved regulation and control strategies are urgently needed.

A hallmark of meiosis is chromosomal pairing, which requires telomere tethering and rotation on the nuclear envelope through microtubules, driving chromosome homology searches. Telomere pulling toward the centrosome forms the “zygotene chromosomal bouquet.” Here, we identified the “zygotene cilium” in oocytes. This cilium provides a cable system for the bouquet machinery and extends throughout the germline cyst. Using zebrafish mutants and live manipulations, we demonstrate that the cilium anchors the centrosome to counterbalance telomere pulling. The cilium is essential for bouquet and synaptonemal complex formation, oogenesis, ovarian development, and fertility. Thus, a cilium represents a conserved player in zebrafish and mouse meiosis, which sheds light on reproductive aspects in ciliopathies and suggests that cilia can control chromosomal dynamics.

Background Several new variants of SARS-CoV-2 have emerged since fall 2020 which have multiple mutations in the receptor binding domain (RBD) of the spike protein. Objective We aimed to assess how mutations in RBD affected recognition of immune sera by antibodies induced by natural infection versus immunization with BNT162b2, a mRNA-based vaccine against COVID-19. Methods We produced SARS-CoV-2 RBD mutants with single mutations in the receptor binding domain (RBD) region (E484K, K417N, N501Y) or with all 3 mutations combined, as occurring in the newly emerged variants B.1.351 (South Africa) and P.1 (Brazil). Using standard and avidity ELISAs, we determined the binding capacities to mutant RBDs of antibodies induced by infection versus vaccination. Results These binding assays showed that vaccination induced antibodies recognize both wildtype and mutant RBDs with higher avidities than those raised by infection. Nevertheless, recognition of mutants RBDK417N and RBDN501Y was 2.5-3-fold reduced while RBDE484K and the triple mutant were 10-fold less well recognized, demonstrating that the mutation at position 484 was key for the observed loss in cross-reactivity. Conclusion Our binding data demonstrate improved recognition of mutant viruses by BNT162b2-induced antibodies compared to those induced by natural infection. Recognition may, however, be 10-fold reduced for the variants B.1.351/P.1, suggesting that the development of a new vaccine is warranted. The E484K mutation is an key hurdle for immune recognition, convalescent plasma and monoclonal antibody therapy as well as serological assays based on the wildtype sequence may therefore seriously impaired. Capsule summary BNT162b2 mRNA COVID-19 vaccine-induced antibodies recognize mutant viruses with up to 10-fold lower efficiency

Wnt signaling affects fundamental development pathways and, if aberrantly activated, promotes the development of cancers. Wnt signaling is modulated by different factors, but whether the mitochondrial energetic state affects Wnt signaling is unknown. Here, we show that sublethal concentrations of different compounds that decrease mitochondrial ATP production specifically downregulate Wnt/β-catenin signaling in vitro in colon cancer cells and in vivo in zebrafish reporter lines. Accordingly, fibroblasts from a GRACILE syndrome patient and a generated zebrafish model lead to reduced Wnt signaling. We identify a mitochondria-Wnt signaling axis whereby a decrease in mitochondrial ATP reduces calcium uptake into the endoplasmic reticulum (ER), leading to endoplasmic reticulum stress and to impaired Wnt signaling. In turn, the recovery of the ATP level or the inhibition of endoplasmic reticulum stress restores Wnt activity. These findings reveal a mechanism that links mitochondrial energetic metabolism to the control of the Wnt pathway that may be beneficial against several pathologies., The authors’ work is supported by the Italian Association for Cancer Research (AIRC IG grants 15544 and 20286 to I.S.); the Italian Ministry of University and Education (PRONAT project to M. Zoratti and PRIN 2015795S5W to I.S.); and the CNR (Project of Special Interest on Aging and InterOmics to M. Zoratti). L.L. is grateful for PRID 2017 grant (no. BIRD162511) from the University of Padova.

Background: The primary hurdle for the eradication of HIV-1 is the establishment of a latent viral reservoir early after primary infection. Here, we investigated the potential influence of human genetic variation on the HIV-1 reservoir size and its decay rate during suppressive antiretroviral treatment. Setting: Genome-wide association study and exome sequencing study to look for host genetic determinants of HIV-1 reservoir measurements in patients enrolled in the Swiss HIV Cohort Study, a nation-wide prospective observational study. Methods: We measured total HIV-1 DNA in peripheral blood mononuclear cells from study participants, as a proxy for the reservoir size at 3 time points over a median of 5.4 years, and searched for associations between human genetic variation and 2 phenotypic readouts: the reservoir size at the first time point and its decay rate over the study period. We assessed the contribution of common genetic variants using genome-wide genotyping data from 797 patients with European ancestry enrolled in the Swiss HIV Cohort Study and searched for a potential impact of rare variants and exonic copy number variants using exome sequencing data generated in a subset of 194 study participants. Results: Genome-wide and exome-wide analyses did not reveal any significant association with the size of the HIV-1 reservoir or its decay rate on suppressive antiretroviral treatment. Conclusions: Our results point to a limited influence of human genetics on the size of the HIV-1 reservoir and its long-term dynamics in successfully treated individuals.

Ciliopathies are clinically and genetically heterogeneous diseases. We studied three patients from two independent families presenting with features of Joubert syndrome: abnormal breathing pattern during infancy, developmental delay/intellectual disability, cerebellar ataxia, molar tooth sign on magnetic resonance imaging scans, and polydactyly. We identified biallelic loss‐of‐function (LOF) variants in CBY1, segregating with the clinical features of Joubert syndrome in the families. CBY1 localizes to the distal end of the mother centriole, contributing to the formation and function of cilia. In accordance with the clinical and mutational findings in the affected individuals, we demonstrated that depletion of Cby1 in zebrafish causes ciliopathy‐related phenotypes. Levels of CBY1 transcript were found reduced in the patients compared with controls, suggesting degradation of the mutated transcript through nonsense‐mediated messenger RNA decay. Accordingly, we could detect CBY1 protein in fibroblasts from controls, but not from patients by immunofluorescence. Furthermore, we observed reduced ability to ciliate, increased ciliary length, and reduced levels of the ciliary proteins AHI1 and ARL13B in patient fibroblasts. Our data show that CBY1 LOF‐variants cause a ciliopathy with features of Joubert syndrome.

The COVID-19 pandemic highlights the need for fast and simple assays for nucleic acid detection. As an isothermal alternative to RT-qPCR, we outline the development of a detection scheme for SARS-CoV-2 RNA based on reverse transcription recombinase polymerase amplification (RT-RPA) technology. RPA uses recombination proteins in combination with a DNA polymerase for rapid amplification of target DNA at a constant temperature (39–42 °C) within 10 to 20 minutes and can be monitored in real-time with fluorescent probes.

Many parasitoid species discriminate already parasitized hosts, thus avoiding larval competition. However, females incur in superparasitism under certain circumstances. Superparasitism is commonly observed in the artificial rearing of the parasitoid Diachasmimorpha longicaudata, yet host discrimination has been previously suggested in this species. Here, we addressed host discrimination in virgin D. longicaudata females in a comprehensive way by means of direct and indirect methods, using Ceratitis capitata and Anastrepha fraterculus which are major fruit fly pests in South America. Direct methods relied on the description of the foraging behaviour of females in arenas with parasitized and non-parasitized host larvae. In the indirect methods, healthy larvae were offered to single females and the egg distributions were compared to a random distribution. We found that D. longicaudata was able to recognize parasitized host from both host species, taking 24 h since a first parasitization for A. fraterculus and 48 h for C. capitata. Indirect methods showed females with different behaviours for both host species: complete discrimination, non-random (with superparasitism), and random distributions. A larger percentage of females reared and tested on A. fraterculus incurred in superparasitism, probably associated with higher fecundity. In sum, we found strong evidence of host discrimination in D. longicaudata, detecting behavioural variability associated with the host species, the time since the first parasitization and the fecundity of the females.

Everninomicins are orthoester oligosaccharide antibiotics with potent activity against multidrug-resistant bacterial pathogens. Everninomicins act by disrupting ribosomal assembly in a distinct region in comparison to clinically prescribed drugs. We employed microporous intergeneric conjugation with Escherichia coli to manipulate Micromonospora for targeted gene-replacement studies of multiple putative methyltransferases across the octasaccharide scaffold of everninomicin effecting the A1 , C, F, and H rings. Analyses of gene-replacement and genetic complementation mutants established the mutability of the everninomicin scaffold through the generation of 12 previously unreported analogues and, together with previous results, permitted assignment of the ten methyltransferases required for everninomicin biosynthesis. The in vitro activity of A1 - and H-ring-modifying methyltransferases demonstrated the ability to catalyze late-stage modification of the scaffold on an A1 -ring phenol and H-ring C-4' hydroxy moiety. Together these results establish the potential of the everninomicin scaffold for modification through mutagenesis and in vitro modification of advanced biosynthetic intermediates.

Legume grains such as field peas and field beans can be produced on a local level, and may be reliable sources of dietary protein and energy apart from common soybean and rapeseed meals. In ruminants, protein, starch, and carbohydrates from peas and field beans are fermented in large part before reaching the small intestine. The objective of this study was to evaluate the effects of a combination of ensiling and hydro-thermic treatment (i.e., toasting at 160 °C for 30 min) of grains of peas and field beans on the concentrations of post-ruminal crude protein (PRCP) and rumen-undegraded protein (RUP). Moreover, 24-h gas production and methane production were measured. For this, an in vitro batch culture system with ruminal fluid from sheep was used. Rumen-undegraded protein was determined using the Streptomyces griseus protease test. Scanning electron micrographs were used to visualize morphological changes of starch granules and their joint matrices in peas and field beans after ensiling, toasting, or a combination of both. Native pea grains contained crude protein (CP) at 199 g/kg DM, PRCP at 155 g/kg DM at a ruminal passage rate of 0.08/h (Kp8), RUP at 33 g/kg DM at Kp8, and starch at 530 g/kg DM. Native field beans contained CP at 296 g/kg DM, PRCP at 212 g/kg DM at Kp8, RUP at 54 g of/kg DM at Kp8, and starch at 450 g/kg DM. The PRCP did not considerably differ among native and treated peas or field beans. Especially in the peas, RUP at Kp8 increased after ensiling by 10 g/kg DM (i.e., 30%; P

Progressive antimicrobial resistance in Neisseria gonorrhoeae, Mycoplasma genitalium, and Trichomonas vaginalis has created a pressing need for treatment optimisations for sexually transmitted infections (STIs). In this Review, we aim to highlight urgent needs in global STI management, including: (1) improved surveillance to monitor antimicrobial resistance and clinical outcomes; (2) systematic pharmacokinetic and pharmacodynamic evaluations to ensure resistance suppression and bacterial eradication at all sites of infection; (3) development of novel, affordable antimicrobials; and (4) advancements in new molecular and point-of-care tests to detect antimicrobial resistance determinants. Antimicrobial resistance among STIs is a global public health crisis. Continuous efforts to develop novel antimicrobials will be essential, in addition to other public health interventions to reduce the global STI burden. Apart from prevention through safer sexual practices, the development of STI vaccines to prevent transmission is a crucial research priority.

Chimeric antigen receptor T cells (CAR-T) targeting CD19 or B cell maturation antigen (BCMA) are highly effective against B cell malignancies. However, application of CAR-T to less differentially expressed targets remains a challenge due to lack of tumor-specific antigens and CAR-T controllability. CD123, a highly promising leukemia target, is expressed not only by leukemic and leukemia-initiating cells, but also by myeloid, hematopoietic progenitor, and certain endothelial cells. Thus, CAR-T lacking fine-tuned control mechanisms pose a high toxicity risk. To extend the CAR-T target landscape and widen the therapeutic window, we adapted our rapidly switchable universal CAR-T platform (UniCAR) to target CD123. UniCAR-T efficiently eradicated CD123+ leukemia in vitro and in vivo. Activation, cytolytic response, and cytokine release were strictly dependent on the presence of the CD123-specific targeting module (TM123) with comparable efficacy to CD123-specific CAR-T in vitro. We further demonstrated a pre-clinical proof of concept for the safety-switch mechanism using a hematotoxicity mouse model wherein TM123-redirected UniCAR-T showed reversible toxicity toward hematopoietic cells compared to CD123 CAR-T. In conclusion, UniCAR-T maintain full anti-leukemic efficacy, while ensuring rapid controllability to improve safety and versatility of CD123-directed immunotherapy. The safety and efficacy of UniCAR-T in combination with TM123 will now be assessed in a phase I clinical trial (ClinicalTrials.gov: NCT04230265)., Graphical Abstract, CAR-T cell treatment of acute leukemia beyond CD19 remains challenging. Loff et al. demonstrate that rapidly switchable universal CAR-T cells in combination with soluble CD123-specific adaptors achieve robust anti-leukemic responses, while hematotoxicity is rapidly reversible, enabling safe targeting of such less differentially expressed target antigens and broadening of the therapeutic window.

COVID-19, a new viral disease affecting primarily the respiratory system and the lung, has caused a pandemic with serious challenges to health systems around the world. In about 20% of patients, severe symptoms occur after a mean incubation period of 5 - 6 days; 5% of patients need intensive care therapy. Morbidity is about 1 - 2%. Protecting health care workers is of paramount importance in order to prevent hospital acquired infections. Therefore, during all procedures associated with aerosol production, a personal safety equipment consisting of a FFP2/FFP3 (N95) respiratory mask, gloves, safety glasses and a waterproof overall should be used. Therapy is based on established recommendations issued for patients with acute lung injury (ARDS). Lung protective ventilation, prone position, restrictive fluid management and an adequate management of organ failures are the mainstays of therapy. In case of fulminant lung failure, veno-venous extracorporeal membrane oxygenation may be used as a rescue in experienced centres. New, experimental therapies evolve with ever increasing frequency; currently, however, there is no evidence based recommendation possible. If off-label and compassionate use of these drugs is considered, an individual benefit-risk assessment is necessary, since serious side effects have been reported.Der Übersichtsartikel ist als praktische Handreichung für alle gedacht, die COVID-19-Patienten behandeln bzw. in nächster Zeit behandeln werden, und fasst das derzeit verfügbare Wissen zu Diagnostik und Therapie zusammen. Zusätzlich werden auch neue und experimentelle Therapien bewertet, soweit dazu zumindest Einzelfallberichte vorliegen.

Rationale: Patients with elevated levels of lipoprotein(a) [Lp(a)] are hallmarked by increased metabolic activity in the arterial wall on positron emission tomography/computed tomography, indicative of a proinflammatory state. Objective: We hypothesized that Lp(a) induces endothelial cell inflammation by rewiring endothelial metabolism. Methods and Results: We evaluated the impact of Lp(a) on the endothelium and describe that Lp(a), through its oxidized phospholipid content, activates arterial endothelial cells, facilitating increased transendothelial migration of monocytes. Transcriptome analysis of Lp(a)-stimulated human arterial endothelial cells revealed upregulation of inflammatory pathways comprising monocyte adhesion and migration, coinciding with increased 6-phophofructo-2-kinase/fructose-2,6-biphosphatase (PFKFB)-3–mediated glycolysis. ICAM (intercellular adhesion molecule)-1 and PFKFB3 were also found to be upregulated in carotid plaques of patients with elevated levels of Lp(a). Inhibition of PFKFB3 abolished the inflammatory signature with concomitant attenuation of transendothelial migration. Conclusions: Collectively, our findings show that Lp(a) activates the endothelium by enhancing PFKFB3-mediated glycolysis, leading to a proadhesive state, which can be reversed by inhibition of glycolysis. These findings pave the way for therapeutic agents targeting metabolism aimed at reducing inflammation in patients with cardiovascular disease.

Precision medicine requires the translation of basic biological understanding to medical insights, mainly applied to characterization of each unique patient. In many clinical settings, this requires tools that can be broadly used to identify pathology and risks. Patients often present to the intensive care unit with broad phenotypes, including multiple organ dysfunction syndrome (MODS) resulting from infection, trauma, or other disease processes. Etiology and outcomes are unique to individuals, making it difficult to cohort patients with MODS, but presenting a prime target for testing/developing tools for precision medicine. Using multitime point whole blood (cellular/acellular) total transcriptomics in 27 patients, we highlight the promise of simultaneously mapping viral/bacterial load, cell composition, tissue damage biomarkers, balance between syndromic biology versus environmental response, and unique biological insights in each patient using a single platform measurement. Integration of a transcriptome workflow yielded unexpected insights into the complex interplay between host genetics and viral/bacterial specific mechanisms, highlighted by a unique case of virally induced genetics (VIG) within one of these 27 patients. The power of RNA-Seq to study unique patient biology while investigating environmental contributions can be a critical tool moving forward for translational sciences applied to precision medicine.

Vaccines need to be rationally designed in order be delivered to the immune system for maximizing induction of dynamic immune responses. Virus‐like particles (VLPs) are ideal platforms for such 3D vaccines, as they allow the display of complex and native antigens in a highly repetitive form on their surface and can easily reach lymphoid organs in intact form for optimal activation of B and T cells. Adjusting size and zeta potential may allow investigators to further fine‐tune delivery to lymphoid organs. An additional way to alter vaccine transfer to lymph nodes and spleen may be the formulation with micron‐sized adjuvants that creates a local depot and results in a slow release of antigen and adjuvant. Ideally, the adjuvant in addition stimulates the innate immune system. The dynamics of the immune response may be further enhanced by inclusion of Toll‐like receptor ligands, which many VLPs naturally package. Hence, considering the 3Ds in vaccine development may allow for enhancement of their attributes to tackle complex diseases, not usually amenable to conventional vaccine strategies.

Background: Limited research studies have been conducted on nutritional risks among female athletes. Therefore, this literature review focuses on rigorously designed studies that examined nutrition...

We investigated by snow tracking and GPS telemetry how wolvesCanis lupusused a dense (4 km/km2) network of forest roads for travel and scent marking. Forty-six percent of wolf trails but only 4.6% of telemetry locations were on forest roads. Wolves used forest roads to travel fast and far across their home ranges but spent relatively little time on roads, especially on those with high traffic levels and during the time of highest human activity. The probability of scent marking was higher on roads than off-road and increased with traffic intensity on roads and close to junctions. Our findings suggest that wolves take advantage of the forest road infrastructure, while minimising human encounters by spatio-temporal avoidance of all roads, even those with negligible traffic. The ongoing expansion and improvements of the forest road network might lead to elevated costs for wolves associated with avoidance of humans and roads.

Background Antimicrobial resistance in Mycoplasma genitalium (MG), a cause of urethritis, is a growing concern. Yet little is known about the geographic distribution of MG resistance in the United States or about its associated clinical outcomes. We evaluated the frequency of MG among men with urethritis, resistance mutations, and posttreatment symptom persistence. Methods We enrolled men presenting with urethritis symptoms to 6 US sexually transmitted disease (STD) clinics during June 2017–July 2018; men with urethritis were eligible for follow-up contact and, if they had persistent symptoms or MG, a chart review. Urethral specimens were tested for MG and other bacterial STDs. Mutations in 23S ribosomal ribonucleic acid (rRNA) loci (macrolide resistance–associated mutations [MRMs]) and in parC and gyrA (quinolone-associated mutations) were detected by targeted amplification/Sanger sequencing. Results Among 914 evaluable participants, 28.7% (95% confidence interval [CI], 23.8–33.6) had MG. Men with MG were more often Black (79.8% vs 66%, respectively), Conclusions MG infection was common among men with urethritis; the MRM prevalence was high among men with MG. Persistent symptoms following treatment were frequent among men both with and without MG.

The molecular cause of the majority of rare autosomal recessive disorders remains unknown. Consanguinity due to extensive homozygosity unravels many recessive phenotypes and facilitates the detection of novel gene-disease links. Here, we report two siblings with phenotypic signs, including intellectual disability (ID), developmental delay and microcephaly from a Pakistani consanguineous family in which we have identified homozygosity for p(Tyr103His) in the PSMB1 gene (Genbank NM_002793) that segregated with the disease phenotype. PSMB1 encodes a β-type proteasome subunit (i.e. β6). Modeling of the p(Tyr103His) variant indicates that this variant weakens the interactions between PSMB1/β6 and PSMA5/α5 proteasome subunits and thus destabilizes the 20S proteasome complex. Biochemical experiments in human SHSY5Y cells revealed that the p(Tyr103His) variant affects both the processing of PSMB1/β6 and its incorporation into proteasome, thus impairing proteasome activity. CRISPR/Cas9 mutagenesis or morpholino knock-down of the single psmb1 zebrafish orthologue resulted in microcephaly, microphthalmia and reduced brain size. Genetic evidence in the family and functional experiments in human cells and zebrafish indicates that PSMB1/β6 pathogenic variants are the cause of a recessive disease with ID, microcephaly and developmental delay due to abnormal proteasome assembly.

We propose a literary translation from German into Brazilian Portuguese of a passage from the drama Shadow (Eurydice Says), by Austrian writer Elfriede Jelinek. The play, published in 2013, is a modern and feminist version of the Greek myth of Orpheus and Eurydice. The translation, which is followed by its source text, is preceded by a concise presentation of the work and its author, in which we discuss some of the most relevant aspects of this theatrical text in terms of intertextuality and formal features., Propomos uma tradução literária para o português brasileiro, a partir do texto em alemão, de uma passagem da peça Sombra (Eurídice diz), da escritora austríaca Elfriede Jelinek. A peça, publicada em 2013, é uma reescrita moderna e feminista do mito grego de Orfeu e Eurídice. A tradução, seguida do respectivo texto de partida, é precedida de uma sucinta apresentação da obra e de sua autora, em que abordamos os aspectos mais relevantes desse texto teatral em termos de intertextualidade e características formais. &nbsp

Apicomplexan parasites contain rhoptries, which are specialized secretory organelles that coordinate host cell invasion. During the process of invasion, rhoptries secrete their contents to facilitate interaction with, and entry into, the host cell. Here we report the crystal structure of the rhoptry protein A rmadillo R epeats- O nly (ARO) from the human malaria parasite, Plasmodium falciparum (PfARO). The structure of PfARO is comprised of five tandem Armadillo-like (ARM) repeats, with adjacent ARM repeats stacked in a head-to-tail orientation resulting in PfARO adopting an elongated curved shape. Interestingly, the concave face of PfARO contains two distinct patches of highly conserved residues that appear to play an important role in protein-protein interaction. We functionally characterized the P. falciparum homologue of A RO i nteracting p rotein (PfAIP) and demonstrate that it localizes to the rhoptries. We show that conditional mislocalization of PfAIP leads to deficient red blood cell invasion. Guided by the structure, we identified mutations of PfARO that lead to mislocalization of PfAIP. Using proximity-based biotinylation we probe into PfAIP interacting proteins.

Background: Curcumin has been used as an additive in the diet of animals in recent years due to the potent medicinal properties of this molecule. Objective: To evaluate whether the addition of curcumin to the diet of calves at different phases (pre- and post-weaning) has a positive effect on metabolic profile, performance, and anti-coccidian action. Methods: Thirtythree Holstein calves were selected at various phases of development: Experiment 1 (E1: n=10) 18±7 (pre-weaning), Experiment 2 (E2: n=11) 64±4 (pre-weaning) and Experiment 3 (E3: n=12) 95±8 (post-weaning) days of life. The calves were separated in three groups according to their phase of development. In each experiment, animals were divided into two sub-groups: control and curcumin. The curcumin groups received 200 mg of additive per animal/day either in milk (pre-weaning) or concentrate (post-weaning). Fecal collections were performed on days 0, 10 and 15 of the experiment to count Eimeria oocysts per gram of feces and to perform fecal score analysis. Complete blood counts, oxidant and antioxidant profiles, protein metabolism markers, lipid levels, glucose levels, and animal weights were measured. Analyses of digestibility and composition of the diet used in Experiment 3 (post-weaning) were also performed. Results: Independent of phase, animals that received curcumin had greater weight gain on days 0 to 15 (E1, E2 and E3 p=0.04, 0.001 and 0.001, respectively), probably due to the increased digestibility of hay and concentrate at 72h (p=0.03 and 0.02, respectively). The supplemented calves had lower level of oxidants (thiobarbituric acid reactive substances –TBARS- and reactive oxygen species –ROS-), indicating that free radical levels in serum and lipid peroxidation were lower. This was probably due to increased enzymatic antioxidants gluthatione S-transferase (E1, E2 and E3 p=0.001, 0.001 and 0.02, respectively), catalase (E1 p=0.001) and superoxide dismutase (E3 p=0.001) in treated animals at day 15. Furthermore, calves receiving curcumin had lower numeric number of Eimeria infection during the experimental period, and the difference was significant in day 15 (E1 and E2 p=0.02, and 0.001, respectively). Conclusion: Curcumin supplementation to dairy calves has coccidiostatic potential, favoring weight gain.Keywords: animal stress; antioxidants; calves; cattle growth; curcumin; Eimeria; parasitology; supplementation. Resumen Antecedentes: Curcumina ha sido utilizada como aditivo en la dieta de animales en los últimos años, debido a las potentes propiedades medicinales de esa molécula. Objetivo: Evaluar si la adición de curcumina en la alimentación de terneras en diferentes fases (pre y post-destete) presenta efecto positivo sobre el perfil metabólico, desempeño de los animales, y acción anti-coccidial. Métodos: Se seleccionaron 33 terneros Holstein en varias etapas de desarrollo: Experimento 1 (E1: n=10) 18±7 (pre-destete), Experimento 2 (E2: n=11) 64±4 (pre-destete) y Experimento 3 (E3: n=12) 95±8 (post-destete) días de vida. Para todos los experimentos, el período experimental fue de 15 días. Los animales se dividieron en dos grupos: control y tratados con curcumina. Los grupos con curcumina recibieron una dosis de 200 mg del aditivo por animal/día en la leche (pre-destete) o en el concentrado (post-destete). Las colectas de heces y sangre fueron realizadas en los días 0, 10 y 15 para conteo de ooquistes de Eimeria por gramo de heces y análisis de puntaje fecal. Se realizó hemograma, perfil oxidante y antioxidante, metabolismo proteico, lipídico, glucosa sanguínea y pesaje de los animales. También se realizó análisis de digestibilidad de la dieta total para los animales del Experimento 3 (post-destete). Resultados: Encontramos que, independientemente de la fase, los animales que recibieron curcumina tuvieron una mayor ganancia de peso en los días 0 a 15 (E1, E2 y E3, p=0,04, 0,001 y 0,001, respectivamente), probablemente debido al aumento de la digestibilidad del heno y concentrado a las 72 h (p=0,03 y 0,02, respectivamente). En los terneros suplementados observamos un nivel más bajo de oxidantes (oxidantes (sustancias reactivas al ácido tiobarbitúrico y especies reactivas de oxígeno); es decir, los niveles séricos de radicales libres y la peroxidación lipídica fueron más bajos. Esto se debió, probablemente, a los antioxidantes enzimáticos glutatión S-transferasa (E1, E2 y E3 p=0,001, 0,001 y 0,02 respectivamente), catalasa (E1, p=0,001) y superóxido dismutasa (E3, p=0,001) que aumentaron en los animales tratados al día 15. Además, los terneros que recibieron curcumina tuvieron niveles más bajos de infección por Eimeria durante el período experimental y fueron significativos en el día 15 (E1 y E2, p=0,02 y 0,001, respectivamente). Conclusión: La suplementación con curcumina tiene potencial coccidiostático y favorece la ganancia de peso en terneros Holstein. Palabras clave: antioxidantes; crecimiento de ganado; curcuminatiene; Eimeria; estrés animal; parasitología; suplementación; terneros. ResumoAntecedentes: Curcumina tem sido usado como aditivo na dieta de animais nos últimos anos, devido as propriedades medicinais potente dessa molécula. Objetivo: Avaliar se a adição de curcumina na alimentação de bezerras em diferentes fases (pré e pós-desmame) apresenta efeito positivo sobre perfil metabólico, desempenho e ação anti-coccidéo. Métodos: Para isso, 33 bezerros holandeses foram selecionados em vários estágios de desenvolvimento: Experimento 1 (E1: n=10) 18±7 (prédesmame), Experimento 2 (E2: n=11) 64±4 (pré-desmame) e Experimento 3 (E3: n=12) 95±8 (pós-desmame) dias de vida. Para todos os experimentos o período experimental foi de 15 dias, assim como foram delineados com dois grupos: controle e tratados com curcumina. Os grupos de curcumina receberam 200 mg do aditivo por animal/dia no leite (pré-desmame) ou em concentrado (pós-desmame). Coletas de fezes e sangue foram realizadas nos dias 0, 10 e 15 de experimento para contagem de oocistos de Eimeria por grama de fezes e análise de escore fecal. Do sangue colhido foram realizados: hemograma, perfil oxidante e antioxidante, metabolismo proteico, lipídico, glicose, além da pesagem dos animais. Também foi realizado análise de digestibilidade da dieta total ofertada aos animais do Experimento 3 (pós-desmame). Resultados: Independentemente da fase, os animais que receberam curcumina tiveram maior ganho de peso do dia 0 a 15 (E1, E2 e E3, p=0,04, 0,001 e 0,001, respectivamente), provavelmente devido ao aumento da digestibilidade ao feno e concentrado após 72 h (p=0,03 e 0,02, respectivamente). Nos bezerros suplementados, observou-se menor nível de oxidantes (substâncias reativas ao ácido tiobarbitúrico e espécies reativas de oxigênio), ou seja, os níveis séricos de radicais livres e a peroxidação lipídica foram menores. Isto foi provavelmente devido a antioxidantes enzimáticos glutationa S-transferase (E1, E2 e E3, p=0,001, 0,001 e 0,02, respectivamente), catalase (E1, p=0,001) e superóxido dismutase (E3, p=0,001) aumentando nestes animais tratados no dia 15. Além disso, bezerros recebendo curcumina tiveram menores níveis de infecção por Eimeria durante o período experimental e significativos no dia 15 (E1 e E2, p=0,02 e 0,001, respectivamente). Conclusão: A suplementação de curcumina aumenta o potencial coccidiostático e favorece o ganho de peso.Palavras-chave: antioxidante; bezerros; crescimento do gado; curcumina; Eimeria; estresse animal; parasitologia; suplementação.