Miracle-dz/UniFAR-FTUs huggingface dataset:
Ticket to spawn: Combining economic and genetic data to evaluate the effect of climate and demographic structure on spawning distribution in Atlantic cod

Climate warming and harvesting affect the dynamics of species across the globe through a multitude of mechanisms, including distribution changes. In fish, migrations to and distribution on spawning grounds are likely influenced by both climate warming and harvesting. The Northeast Arctic (NEA) cod (Gadus morhua) performs seasonal migrations from its feeding grounds in the Barents Sea to spawning grounds along the Norwegian coast. The distribution of cod between the spawning grounds has historically changed at decadal scales, mainly due to variable use of the northern and southern margins of the spawning area. Based on historical landing records, two major hypotheses have been put forward to explain these changes: climate and harvesting. Climate could affect the distribution through, for example, spatial habitat shifts. Harvesting could affect the distribution through impacting the demographic structure. If demographic structure is important, theory predicts increasing spawner size with migration distance. Here, we evaluate these hypotheses with modern data from a period (2000–2016) of increasing temperature and recovering stock structure. We first analyze economic data from the Norwegian fisheries to investigate geographical differences in size of spawning fish among spawning grounds, as well as interannual differences in mean latitude of spawning in relation to changes in temperature and demographic parameters. Second, we analyze genetically determined fish sampled at the spawning grounds to unambiguously separate between migratory NEA cod and potentially smaller sized coastal cod of local origin. Our results indicate smaller spawners farther away from the feeding grounds, hence not supporting the hypothesis that harvesting is a main driver for the contemporary spawning ground distribution. We find a positive correlation between annual mean spawning latitude and temperature. In conclusion, based on contemporary data, there is more support for climate compared to harvesting in shaping spawning ground distribution in this major fish stock in the North Atlantic Ocean.
Clinicopathological feature and treatment outcome of patients with colorectal laterally spreading tumors treated by endoscopic submucosal dissection

Background/Aims Endoscopic submucosal dissection (ESD) is an advanced technique that can be used to treat precancerous and early colorectal neoplasms by facilitating en bloc resection regardless of tumor size. In our study, we investigated the clinicopathological feature and the treatment outcome of patients with colorectal laterally spreading tumors (LSTs) that were treated by ESD. Methods The study enrolled all of 210 patients with colorectal LSTs who underwent ESD. Clinical outcomes were analyzed by retrospectively reviewing medical records. Results A cancerous pit pattern (Vi/Vn) was more common in pseudo-depressed (PD) subtype than in flat elevated (FE) subtype. The incidence of adenocarcinoma in the PD subtype and nodular mixed (NM) subtypes was significantly higher than in the homogenous (HG) subtype and FE subtype. The en bloc and R0 resection rates were 89.0% and 85.7%, respectively. The bleeding and perforation rates were 5.2% and 1.9%, respectively. The mean procedure time was much longer in the PD subtype than in the FE subtype. The en bloc resection rate was significantly higher in the NM subtype than in the HG subtype. However, there were no statistically significant differences in mean procedure time, en bloc resection rate, R0 resection rate, bleeding rate, or perforation rate between LST-granular and LST-nongranular types. Conclusions These results indicate that ESD is acceptable for treating colorectal LSTs concerning en bloc resection, curative resection, and risk of complications. Careful consideration is required for complete resection of the PD subtype and NM subtype because of their higher malignant potential.
Mutagenesis of kiwifruit CENTRORADIALIS‐like genes transforms a climbing woody perennial with long juvenility and axillary flowering into a compact plant with rapid terminal flowering

Summary Annualization of woody perennials has the potential to revolutionize the breeding and production of fruit crops and rapidly improve horticultural species. Kiwifruit (Actinidia chinensis) is a recently domesticated fruit crop with a short history of breeding and tremendous potential for improvement. Previously, multiple kiwifruit CENTRORADIALIS (CEN)‐like genes have been identified as potential repressors of flowering. In this study, CRISPR/Cas9‐ mediated manipulation enabled functional analysis of kiwifruit CEN‐like genes AcCEN4 and AcCEN. Mutation of these genes transformed a climbing woody perennial, which develops axillary inflorescences after many years of juvenility, into a compact plant with rapid terminal flower and fruit development. The number of affected genes and alleles and severity of detected mutations correlated with the precocity and change in plant stature, suggesting that a bi‐allelic mutation of either AcCEN4 or AcCEN may be sufficient for early flowering, whereas mutations affecting both genes further contributed to precocity and enhanced the compact growth habit. CRISPR/Cas9‐mediated mutagenesis of AcCEN4 and AcCEN may be a valuable means to engineer Actinidia amenable for accelerated breeding, indoor farming and cultivation as an annual crop.
Lung lobe torsion in dogs: 52 cases (2005–2017)

OBJECTIVE To report outcomes and risk factors for mortality in dogs that underwent surgical management of lung lobe torsion. STUDY DESIGN Retrospective case series from 5 veterinary teaching hospitals (2005-2017). ANIMALS Fifty dogs with 52 instances of lung lobe torsion. METHODS Data collected from medical records included signalment, clinical findings, results of clinicopathologic testing and diagnostic imaging, surgical treatment, lung lobe affected, intraoperative and postoperative complications, histopathologic and microbiologic findings, and outcome. Follow-up was obtained from medical records and telephone contact with primary care veterinarians. RESULTS Fifty-two instances of lung lobe torsion were identified in 50 dogs, with a median follow-up of 453 days (range, 0-3075). Forty-six (92%) dogs survived to discharge. Dogs with concurrent torsion of the right cranial and middle lung lobes were less likely to survive (2/4) than those with torsion of the left cranial lung lobe (22/22). No other risk factors for mortality prior to hospital discharge were identified. Overall median survival time after hospital discharge was 1369 days. Four dogs had >1 episode of lung lobe torsion. CONCLUSION The percentage of dogs surviving to discharge after surgical treatment of lung lobe torsion was higher than previously reported. The short- and long-term prognosis was excellent with surgical treatment of lung lobe torsion. CLINICAL SIGNIFICANCE Surgery should be recommended when lung lobe torsion is suspected because of the high survival to discharge rate and excellent long-term prognosis.
Developmental outcomes of an individualised complementary feeding intervention for stunted children: a substudy from a larger randomised controlled trial in Guatemala

Objective Stunting is a common cause of early child developmental delay; Guatemala has the fourth highest rate of stunting globally. The goal of this study was to examine the impact of an intensive community health worker-led complementary feeding intervention on early child development in Guatemala. We hypothesised that the intervention would improve child development over usual care. Design A substudy from a larger individually randomised (1:1 allocation ratio), parallel-group superiority trial, with blinding of study staff collecting outcomes data. Setting Rural, indigenous Maya communities in Guatemala. Participants 210 stunted children (height-for-age z-score ≤−2.5) aged 6–24 months, previously randomised to usual care (106) or an intensive complementary feeding intervention (104). 84 in the intervention and 91 in the usual care arm agreed to participate. Interventions Community health workers conducted monthly home visits for 6 months, providing usual care or individualised complementary feeding education. Main outcome measures The primary outcomes were change in z-scores for the subscales of the Bayley Scales of Infant Development (BSID), Third Edition. Results 100 individuals were included in the final analysis, 47 in the intervention and 53 in the usual care arm. No statistically significant differences in age-adjusted scores between the arms were observed for any subscale. However, improvements within-subjects in both arms were observed (median duration between measurements 189 days (IQR 182–189)). Mean change for subscales was 0.45 (95% CI 0.23 to 0.67) z-scores in the intervention, and 0.43 (95% CI 0.25 to 0.61) in the usual care arm. Conclusions An intensive complementary feeding intervention did not significantly improve developmental outcomes more than usual care in stunted, indigenous Guatemalan children. However, both interventions had significant positive impacts on developmental outcomes. Trial registration number NCT02509936. Stage Results.
Nonproteinogenic deep mutational scanning of linear and cyclic peptides

Significance The 20 proteinogenic amino acids have physicochemical properties that allow peptides and proteins to fold and bind. However, there are numerous unnatural, nonproteinogenic amino acids that may be equally good, or even better, at folding and binding. Exploration of these alternative peptide building blocks has been limited by slow, one-at-a-time synthesis and testing. We describe how, in a single experiment, multiple nonproteinogenic amino acids can be trialed at all positions in a peptide sequence, with thousands of modifications tested in parallel. This permits detailed analysis of how chemical structure relates to function and allows for systematic comparisons of proteinogenic and nonproteinogenic chemistry. Such analysis can guide the improvement of drug-candidate peptides, including the therapeutically promising class of cyclic peptides. High-resolution structure–activity analysis of polypeptides requires amino acid structures that are not present in the universal genetic code. Examination of peptide and protein interactions with this resolution has been limited by the need to individually synthesize and test peptides containing nonproteinogenic amino acids. We describe a method to scan entire peptide sequences with multiple nonproteinogenic amino acids and, in parallel, determine the thermodynamics of binding to a partner protein. By coupling genetic code reprogramming to deep mutational scanning, any number of amino acids can be exhaustively substituted into peptides, and single experiments can return all free energy changes of binding. We validate this approach by scanning two model protein-binding peptides with 21 diverse nonproteinogenic amino acids. Dense structure–activity maps were produced at the resolution of single aliphatic atom insertions and deletions. This permits rapid interrogation of interaction interfaces, as well as optimization of affinity, fine-tuning of physical properties, and systematic assessment of nonproteinogenic amino acids in binding and folding.
Identification and characterization of vaccine candidates against Hyalomma anatolicum—Vector of Crimean‐Congo haemorrhagic fever virus

Crimean-Congo haemorrhagic fever (CCHF) is a tick borne viral disease reported from different parts of the world. The distribution of the CCHF cases are linked with the distribution of the principal vector, Hyalomma anatolicum in the ecosystem. Presently, vector control is mainly dependent on repeated application of acaricides, results in partial efficacy and generated acaricide resistant tick strains. Amongst the different components of integrated management programme, immunization of hosts is considered as one of the sustainable component. To restrict CCHF virus spreading, use of anti-Hyalomma vaccines appears as a viable solution. Accordingly, present study was under taken to characterize and evaluate vaccine potential of two conserved molecules, ferritin2 (FER2) and tropomyosin (TPM). Silencing of the genes conferred a cumulative reduction (rejection + unable to engorge) of 61.3% in FER2 and 70.2% in TPM respectively. Furthermore, 44.2% and 72.7% reduction in engorgement weight, 63.6% and 94.9% reduction in egg masses in FER2 and TPM silenced ticks in comparison to LUC-control group was recorded. The recombinant protein, rHaFER2 was characterized as 35 kDa protein with pI of 5.84 and possesses iron binding domains. While rHaTPM is a 51kDa protein with pI of 4.94 having calcium binding domains. Immunization of cross-bred calves by rHaFER2 conferred 51.7% and 51.2% protection against larvae and adults of H. anatolicum challenge infestations. While rHaTPM conferred 63.7% and 66.4% protection against larvae and adults infestations, respectively. The results were comparable with the data generated by RNAi and it clearly showed the possibility for the development of anti-hyalomma vaccine to manage CCHF virus and Theileria annulata infection in human and animals.
Cellular Bioreactivity of Micro- and Nano-Plastic Particles in Oysters

The global usage of plastics has increased dramatically over the last several decades. Polystyrene is the fourth most common plastic material produced annually due to its many versatile applications. Consequently, there has been a coinciding increase in polystyrene wastes, much of which makes its way into waterways and oceanic habitats. While plastic debris has been shown to adversely affect many marine species as a result of ingestion and entanglement, less is known about the cellular uptake of small-scale plastic particles (nano and micro) by marine invertebrates. In this study, we investigated the potential for uptake of polystyrene nano and micron sized beads (50nm and 3um) by the Eastern Oyster, Crassostrea virginica. This research was focused on two key issues: 1) how particle size would affect uptake by hepatopancreas (HP) cells in vitro, and 2) the difference in uptake of micron and nano particles in vivo between gill and HP tissues. This research confirmed that oysters can accumulate polystyrene beads in their tissues, especially HP tissues. Furthermore, using fluorescent deconvolution microscopy, it was observed that plastic nanoparticles exhibited a much greater propensity for intracellular accumulation in HP cells, primarily into lysosomes via endosomal pathways, indicating the potential for significant bioreactivity and sublethal impacts. While exposures of whole oysters or isolated HP cells to bare polystyrene beads did not cause any significant toxicity (acute or sublethal), nanoplastics are more likely to accumulate intracellularly and to deliver adsorbed toxins directly into cells.
Insensitivity to Pain upon Adult-Onset Deletion of Nav1.7 or Its Blockade with Selective Inhibitors

Strong human genetic evidence points to an essential contribution of the voltage-gated sodium channel Nav1.7 to pain sensation: loss of Nav1.7 function leads to congenital insensitivity to pain, whereas gain-of-function mutations in the SCN9A gene that encodes Nav1.7 cause painful neuropathies, such as inherited erythromelalgia, a syndrome characterized by episodic spontaneous pain. Selective Nav1.7 channel blockers thus hold promise as potential painkillers with improved safety and reduced unwanted side effects compared with existing therapeutics. To determine the maximum effect of a theoretically perfectly selective Nav1.7 inhibitor, we generated a tamoxifen-inducible KO mouse model enabling genetic deletion of Nav1.7 from adult mice. Electrophysiological recordings of sensory neurons from these mice following tamoxifen injection demonstrated the loss of Nav1.7 channel current and the resulting decrease in neuronal excitability of small-diameter neurons. We found that behavioral responses to most, but surprisingly not all, modalities of noxious stimulus are abolished following adult deletion of Nav1.7, pointing toward indications where Nav1.7 blockade should be efficacious. Furthermore, we demonstrate that isoform-selective acylsulfonamide Nav1.7 inhibitors show robust analgesic and antinociceptive activity acutely after a single dose in mouse pain models shown to be Nav1.7-dependent. All experiments were done with both male and female mice. Collectively, these data expand the depth of knowledge surrounding Nav1.7 biology as it relates to pain, and provide preclinical proof of efficacy that lays a clear path toward translation for the therapeutic use of Nav1.7-selective inhibitors in humans. SIGNIFICANCE STATEMENT Loss-of-function mutations in the sodium channel Nav1.7 cause congenital insensitivity to pain in humans, making Nav1.7 a top target for novel pain drugs. Targeting Nav1.7 selectively has been challenging, however, in part due to uncertainties in which rodent pain models are dependent on Nav1.7. We have developed and characterized an adult-onset Nav1.7 KO mouse model that allows us to determine the expected effects of a theoretically perfect Nav1.7 blocker. Importantly, many commonly used pain models, such as mechanical allodynia after nerve injury, appear to not be dependent on Nav1.7 in the adult. By defining which models are Nav1.7 dependent, we demonstrate that selective Nav1.7 inhibitors can approximate the effects of genetic loss of function, which previously has not been directly established.
The Dental Management of Patients at Risk of Medication-Related Osteonecrosis of the Jaw: New Paradigm of Primary Prevention

Medication-related osteonecrosis of the jaw (MRONJ) is a serious adverse reaction of antiresorptive and antiangiogenic agents; it is a potentially painful and debilitating condition that can considerably affect the quality of life of patients. Furthermore, even if its epidemiology and pathogenesis have still not been fully clarified, several risk factors related to MRONJ have been recognized in prevention protocols. Three main risk factors are as follows: (i) the type of ONJ-related medications: antiresorptive (e.g., Bisphosphonates, Denosumab) and antiangiogenic drugs (e.g., Bevacizumab, Sunitinib); (ii) the category of patient at MRONJ risk: cancer versus non-cancer patient; (iii) the typologies and timing of dental treatments (e.g., before, during, or after the drug administration). The aim of this paper is to describe the new paradigm by the Italian Society of Oral Pathology and Medicine (SIPMO) on preventive dental management in patients at risk of MRONJ, prior to and during/after the administration of the aforementioned ONJ-related drugs. In reducing the risk of MRONJ, dentists and oral hygienists are key figures in applying a correct protocol of primary prevention for pre-treatment and in-treatment patients. However, the necessity of a multidisciplinary standardized approach, with a sustained dialogue among specialists involved, should be always adopted in order to improve the efficacy of preventive strategies and to ameliorate the patient's quality of life.
ODM-203, a Selective Inhibitor of FGFR and VEGFR, Shows Strong Antitumor Activity, and Induces Antitumor Immunity

Alterations in the gene encoding for the FGFR and upregulation of the VEGFR are found often in cancer, which correlate with disease progression and unfavorable survival. In addition, FGFR and VEGFR signaling synergistically promote tumor angiogenesis, and activation of FGFR signaling has been described as functional compensatory angiogenic signal following development of resistance to VEGFR inhibition. Several selective small-molecule FGFR kinase inhibitors are currently in clinical development. ODM-203 is a novel, selective, and equipotent inhibitor of the FGFR and VEGFR families. In this report we show that ODM-203 inhibits FGFR and VEGFR family kinases selectively and with equal potency in the low nanomolar range (IC50 6–35 nmol/L) in biochemical assays. In cellular assays, ODM-203 inhibits VEGFR-induced tube formation (IC50 33 nmol/L) with similar potency as it inhibits proliferation in FGFR-dependent cell lines (IC50 50–150 nmol/L). In vivo, ODM-203 shows strong antitumor activity in both FGFR-dependent xenograft models and in an angiogenic xenograft model at similar well-tolerated doses. In addition, ODM-203 inhibits metastatic tumor growth in a highly angiogenesis-dependent kidney capsule syngenic model. Interestingly, potent antitumor activity in the subcutaneous syngenic model correlated well with immune modulation in the tumor microenvironment as indicated by marked decrease in the expression of immune check points PD-1 and PD-L1 on CD8 T cells and NK cells, and increased activation of CD8 T cells. In summary, ODM-203 shows equipotent activity for both FGFR and VEGFR kinase families and antitumor activity in both FGFR and angigogenesis models.
Usefulness of fecal calprotectin by monoclonal antibody testing in adult Japanese with inflammatory bowel diseases: a prospective multicenter study

Background/Aims Noninvasive objective monitoring is advantageous for optimizing treatment strategies in patients inflammatory bowel disease (IBD). Fecal calprotectin (FCP) is superior to traditional biomarkers in terms of assessing the activity in patients with IBD. However, there are the differences among several FCP assays in the dynamics of FCP. In this prospective multicenter trial, we investigated the usefulness of FCP measurements in adult Japanese patients with IBD by reliable enzyme immunoassay using a monoclonal antibody. Methods We assessed the relationship between FCP levels and disease or endoscopic activity in patients with ulcerative colitis (UC, n=64) or Crohn’s disease (CD, n=46) compared with healthy controls (HCs, n=64). Results FCP levels in UC patients strongly correlated with the Disease Activity Index (rs=0.676, P<0.0001) and Mayo endoscopic subscore (MES; rs=0.677, P<0.0001). FCP levels were significantly higher even in patients with inactive UC or CD compared with HCs (P=0.0068, P<0.0001). The optimal cutoff value between MES 1 and 2 exhibited higher sensitivity (94.1%). FCP levels were significantly higher in active UC patients than in inactive patients (P<0.001), except those with proctitis. The Crohn’s Disease Activity Index tended to correlate with the FCP level (rs=0.283, P=0.0565). Conclusions Our testing method using a monoclonal antibody for FCP was well-validated and differentiated IBD patients from HCs. FCP may be a useful biomarker for objective assessment of disease activity in adult Japanese IBD patients, especially those with UC.