Miracle-dz/UniFAR-FTUs huggingface dataset:
LCM-seq reveals unique transcriptional adaptation mechanisms of resistant neurons and identifies protective pathways in spinal muscular atrophy

Somatic motor neurons are selectively vulnerable in spinal muscular atrophy (SMA), which is caused by a deficiency of the ubiquitously expressed survival of motor neuron protein. However, some motor neuron groups, including oculomotor and trochlear (ocular), which innervate eye muscles, are for unknown reasons spared. To reveal mechanisms of vulnerability and resistance in SMA, we investigate the transcriptional dynamics in discrete neuronal populations using laser capture microdissection coupled with RNA sequencing (LCM-seq). Using gene correlation network analysis, we reveal a TRP53-mediated stress response that is intrinsic to all somatic motor neurons independent of their vulnerability, but absent in relatively resistant red nucleus and visceral motor neurons. However, the temporal and spatial expression analysis across neuron types shows that the majority of SMA-induced modulations are cell type–specific. Using Gene Ontology and protein network analyses, we show that ocular motor neurons present unique disease-adaptation mechanisms that could explain their resilience. Specifically, ocular motor neurons up-regulate (1) Syt1, Syt5, and Cplx2, which modulate neurotransmitter release; (2) the neuronal survival factors Gdf15, Chl1, and Lif; (3) Aldh4, that protects cells from oxidative stress; and (4) the caspase inhibitor Pak4. Finally, we show that GDF15 can rescue vulnerable human spinal motor neurons from degeneration. This confirms that adaptation mechanisms identified in resilient neurons can be used to reduce susceptibility of vulnerable neurons. In conclusion, this in-depth longitudinal transcriptomics analysis in SMA reveals novel cell type–specific changes that, alone and combined, present compelling targets, including Gdf15, for future gene therapy studies aimed toward preserving vulnerable motor neurons.
Comparison of various intraocular lens formulas using a new high-resolution swept-source optical coherence tomographer.

PURPOSE To compare vergence, artificial intelligence, and combined intraocular lens (IOL) calculation formulas using a new swept-source optical coherence tomographer (SS-OCT) and to analyze their performance based on manifest and estimated refractive outcomes of cataract surgery. SETTING Department of Ophthalmology, University of Pécs Medical School, Pécs, Hungary. DESIGN Retrospective data analysis. METHODS Optical biometry readings of patients who underwent uneventful cataract removal and implantation of a monofocal acrylic IOL were used to predict IOL power with Barrett Universal II (BUII), Haigis, Hoffer Q, Holladay 1, Radial Basis Function (RBF) 2.0, Kane, Ladas Super Formula, and SRK/T. All the implanted IOLs were calculated by using the Haigis formula. The arithmetic prediction error and median and mean absolute refractive errors for all formulas were computed. The percentage of eyes within ±0.25 diopters (D), ±0.50 D, and ±1.0 D of prediction error was calculated. RESULTS A total of 95 eyes of 95 patients with a mean age of 68.80 ± 7.57 years were included. There was a statistically significant difference in absolute prediction error across the 8 IOL calculation formulas (P < .0001). Haigis showed the lowest mean absolute error, and it differed significantly from the BUII, Hoffer Q, Holladay 1, Ladas, RBF 2.0, and SRK/T formulas (P < .05). In terms of eyes within ±0.25 D, ±0.50 D, and ±1.0 D of prediction error, the Haigis formula showed the overall best performance. CONCLUSIONS The results indicated that a recently developed SS-OCT provided accurate ocular biometry measurements before cataract surgery, and the Haigis formula incorporated in its software enabled precise calculation of IOL refractive power.
Performance of normal-hearing listeners on the Repeat-Recall test in different noise configurations

Abstract Objective This study measured the performance of normal-hearing listeners on the Repeat-Recall Test (RRT) in two noise types (2-talker babble [2TBN] and continuous speech-shaped noise [SSN]) by two noise azimuths (0° and 180°) configurations at signal-to-noise ratios (SNRs) of 0, 5, 10, and 15 dB and quiet. Design Within-subject repeated measures. Study sample Twenty-one listeners with normal hearing who also passed cognitive screening were tested in the sound-field with the speech stimulus presented from 0° at 75 dB SPL in 4 noise configurations. The order of SNRs, noise configurations, and RRT topic conditions was counterbalanced across listeners. Results Analysis revealed that repeat scores were significantly better for 2TBN, for noise at 180°, and for high context (HC) sentences. Recall performance was significantly better for SSN and HC sentences. Listening effort ratings were higher for SSN and for noise front condition at SNR ≤ 10 dB. The 2TBN noise was tolerated longer than SSN. Performance on all measures improved with SNRs. Conclusions These data showed performance differences among noise configurations and provided a preliminary basis for comparison with hearing-impaired listeners’ performance on the RRT.
Attack on Multi-Node Attention for Object Detection

This paper focuses on high-transferable adversarial attacks on detection networks, which are crucial for life-concerning systems such as autonomous driving and security surveillance. Detection networks are hard to attack in a black-box manner, because of their multiple-output property and diversity across architectures. To pursue a high attacking transferability, one needs to find a common property shared by different models. Multi-node attention heat map obtained by our newly proposed method is such a property. Based on it, we design the ATTACk on multi-node attenTION for object detecTION (ATTACTION). ATTACTION achieves a state-of-the-art transferability in numerical experiments. On MS COCO, the detection mAP for all 7 tested black-box architectures is halved and the performance of semantic segmentation is greatly influenced. Given the great transferability of ATTACTION, we generate Adversarial Objects in COntext (AOCO), the first adversarial dataset on object detection networks, which could help designers to quickly evaluate and improve the robustness of detection networks.
Development of a Machine Learning Model for Survival Risk Stratification of Patients With Advanced Oral Cancer

Key Points Question Can a machine learning model provide survival risk stratification for patients with advanced oral cancer who have comprehensive clinicopathologic and genetic data? Findings In this 15-year cohort study of 334 patients, a risk stratification model using comprehensive clinicopathologic and genetic data accurately differentiated the high-risk group from the low-risk group in postoperative cancer-specific and locoregional recurrence–free survival for patients with advanced oral cancer. Meaning The proposed model demonstrated good discrimination in stratifying patients with different risks of survival by using comprehensive clinicopathologic and genetic data, which can provide additional personalized information for postoperative management of patients with advanced oral squamous cancer.
The International Collaboration for Cancer Classification and Research

Gaps in the translation of research findings to clinical management have been recognized for decades. They exist for the diagnosis as well as the management of cancer. The international standards for cancer diagnosis are contained within the World Health Organization (WHO) Classification of Tumours, published by the International Agency for Research on Cancer (IARC) and known worldwide as the WHO Blue Books. In addition to their relevance to individual patients, these volumes provide a valuable contribution to cancer research and surveillance, fulfilling an important role in scientific evidence synthesis and international standard setting. However, the multidimensional nature of cancer classification, the way in which the WHO Classification of Tumours is constructed, and the scientific information overload in the field pose important challenges for the translation of research findings to tumour classification and hence cancer diagnosis. To help address these challenges, we have established the International Collaboration for Cancer Classification and Research (IC3R) to provide a forum for the coordination of efforts in evidence generation, standard setting and best practice recommendations in the field of tumour classification. The first IC3R meeting, held in Lyon, France, in February 2019, gathered representatives of major institutions involved in tumour classification and related fields to identify and discuss translational challenges in data comparability, standard setting, quality management, evidence evaluation and copyright, as well as to develop a collaborative plan for addressing these challenges.
Toric intraocular lens combined with a supplementary pinhole implant to treat irregular corneal astigmatism.

A case of refractive intraocular lens (IOL) exchange with the implantation of a supplementary pinhole to treat a challenging case of keratoconus is presented. Four months after the initial procedure, an IOL exchange (under the pinhole implant) was performed to implant a toric IOL to correct residual manifest astigmatism. This significantly improved both distance and near acuities and demonstrated how a toric IOL and astigmatism correction in combination with a pinhole device could be used to treat selected cases of keratoconus.
Affinity maturation is required for pathogenic monovalent IgG4 autoantibody development in myasthenia gravis

IgG4 autoantibodies in autoimmune myasthenia gravis are functionally monovalent, requiring a high-affinity threshold to reach pathogenic capacity. This capacity is dependent on self-antigen driven maturation, which includes the accumulation of indispensable somatic mutations that may alter electrostatic interactions with the antigen.
Targeting Extracellular Matrix Remodeling Restores BRAF Inhibitor Sensitivity in BRAFi-resistant Melanoma

Purpose: The extracellular matrix (ECM) is an intriguing, yet understudied component of therapy resistance. Here, we investigated the role of ECM remodeling by the collagenase, MT1-MMP, in conferring resistance of v-Raf murine sarcoma viral oncogene homolog B1 (BRAF)-mutant melanoma to BRAF inhibitor (BRAFi) therapy. Experimental Design: Publicly available RNA-sequencing data and reverse phase protein array were used to determine the relevance of MT1-MMP upregulation in BRAFi-resistant melanoma in patients, patient-derived xenografts, and cell line–derived tumors. Short hairpin RNA (shRNA)-mediated knockdown of MT1-MMP, inhibition via the selective MT1-MMP/MMP2 inhibitor, ND322, or overexpression of MT1-MMP was used to assess the role of MT1-MMP in mediating resistance to BRAFi. Results: MT1-MMP was consistently upregulated in posttreatment tumor samples derived from patients upon disease progression and in melanoma xenografts and cell lines that acquired resistance to BRAFi. shRNA- or ND322-mediated inhibition of MT1-MMP synergized with BRAFi leading to resensitization of resistant cells and tumors to BRAFi. The resistant phenotype depends on the ability of cells to cleave the ECM. Resistant cells seeded in MT1-MMP uncleavable matrixes were resensitized to BRAFi similarly to MT1-MMP inhibition. This is due to the inability of cells to activate integrinβ1 (ITGB1)/FAK signaling, as restoration of ITGB1 activity is sufficient to maintain resistance to BRAFi in the context of MT1-MMP inhibition. Finally, the increase in MT1-MMP in BRAFi-resistant cells is TGFβ dependent, as inhibition of TGFβ receptors I/II dampens MT1-MMP overexpression and restores sensitivity to BRAF inhibition. Conclusions: BRAF inhibition results in a selective pressure toward higher expression of MT1-MMP. MT1-MMP is pivotal to an ECM-based signaling pathway that confers resistance to BRAFi therapy.
A New Taxonomy for Postactivation Potentiation in Sport.

Postactivation potentiation (PAP) mechanisms and responses have a long scientific history. However, to this day there is still controversy regarding the mechanisms underlying enhanced performance after a conditioning activity. More recently, the term postactivation performance enhancement (PAPE) has been proposed with differing associated mechanisms and protocols than with PAP. However, these 2 terms (PAP and PAPE) may not adequately describe all specific potentiation responses and mechanisms and can also be complementary, in some cases. Purpose: This commentary presents and discusses the similarities and differences between PAP and PAPE and, subsequently, elaborates on a new taxonomy for better describing performance potentiation in sport settings. Conclusion: The elaborated taxonomy proposes the formula "Post-[CONDITIONING ACTIVITY] [VERIFICATION TEST] potentiation in [POPULATION]. " This taxonomy would avoid erroneous identification of isolated physiological attributes and provide individualization and better applicability of conditioning protocols in sport settings.
Gain-of-function mutation in SCN11A causes itch and affects neurogenic inflammation and muscle function in Scn11a+/L799P mice

Mutations in the genes encoding for voltage-gated sodium channels cause profound sensory disturbances and other symptoms dependent on the distribution of a particular channel subtype in different organs. Humans with the gain-of-function mutation p.Leu811Pro in SCN11A (encoding for the voltage-gated Nav1.9 channel) exhibit congenital insensitivity to pain, pruritus, self-inflicted injuries, slow healing wounds, muscle weakness, Charcot-like arthropathies, and intestinal dysmotility. As already shown, knock-in mice (Scn11a+/L799P) carrying the orthologous mutation p.Leu799Pro replicate reduced pain sensitivity and show frequent tissue lesions. In the present study we explored whether Scn11a+/L799P mice develop also pruritus, muscle weakness, and changes in gastrointestinal transit time. Furthermore, we analyzed morphological and functional differences in nerves, skeletal muscle, joints and small intestine from Scn11a+/L799P and Scn11a+/+ wild type mice. Compared to Scn11a+/+ mice, Scn11a+/L799P mice showed enhanced scratching bouts before skin lesions developed, indicating pruritus. Scn11a+/L799P mice exhibited reduced grip strength, but no disturbances in motor coordination. Skeletal muscle fiber types and joint architecture were unaltered in Scn11a+/L799P mice. Their gastrointestinal transit time was unaltered. The small intestine from Scn11a+/L799P showed a small shift towards less frequent peristaltic movements. Similar proportions of lumbar dorsal root ganglion neurons from Scn11a+/L799P and Scn11a+/+ mice were calcitonin gene-related peptide (CGRP-) positive, but isolated sciatic nerves from Scn11a+/L799P mice exhibited a significant reduction of the capsaicin-evoked release of CGRP indicating reduced neurogenic inflammation. These data indicate important Nav1.9 channel functions in several organs in both humans and mice. They support the pathophysiological relevance of increased basal activity of Nav1.9 channels for sensory abnormalities (pain and itch) and suggest resulting malfunctions of the motor system and of the gastrointestinal tract. Scn11a+/L799P mice are suitable to investigate the role of Nav1.9, and to explore the pathophysiological changes and mechanisms which develop as a consequence of Nav1.9 hyperactivity.
Naming guides how 12-month-old infants encode and remember objects

Significance Encoding objects in memory and recalling them later is fundamental to human cognition and emerges in infancy. Here, using a new recognition memory paradigm, we show that the way an object is named, either as a unique individual or as a member of a category, is instrumental in 12-mo-old infants’ encoding of and memory for that object. When the same name is applied consistently to a set of objects, infants encode primarily their commonalities. In contrast, when a unique name is applied to each object, infants encode each object’s unique features. Thus, even as infants begin to produce their first words, a single naming event exerts powerful, nuanced effects on the fundamental cognitive processes of object representation and memory. A foundation of human cognition is the flexibility with which we can represent any object as either a unique individual (my dog Fred) or a member of an object category (dog, animal). This conceptual flexibility is supported by language; the way we name an object is instrumental to our construal of that object as an individual or a category member. Evidence from a new recognition memory task reveals that infants are sensitive to this principled link between naming and object representation by age 12 mo. During training, all infants (n = 77) viewed four distinct objects from the same object category, each introduced in conjunction with either the same novel noun (Consistent Name condition), a distinct novel noun for each object (Distinct Names condition), or the same sine-wave tone sequence (Consistent Tone condition). At test, infants saw each training object again, presented in silence along with a new object from the same category. Infants in the Consistent Name condition showed poor recognition memory at test, suggesting that consistently applied names focused them primarily on commonalities among the named objects at the expense of distinctions among them. Infants in the Distinct Names condition recognized three of the four objects, suggesting that applying distinct names enhanced infants’ encoding of the distinctions among the objects. Infants in the control Consistent Tone condition recognized only the object they had most recently seen. Thus, even for infants just beginning to speak their first words, the way in which an object is named guides infants’ encoding, representation, and memory for that object.
Migratory Activities and Stemness Properties of Rodlet Cells

Abstract The current study aimed to characterize different stages of rodlet cells using light microscopy, immunohistochemistry, and transmission electron microscopy. Granular rodlet cells have a distinct granular cytoplasm. Transitional rodlet cells had distinct capsules, and immature granules. Mature rodlet cells were pear-shaped and had elongated granules. Ruptured rodlet cells had a granular cytoplasm. The affinity of rodlet cells for different histochemical techniques was detected. Immunohistochemical analysis of rodlet cells for stem cell markers such as CD117, CD34, proliferation marker, proliferating cell nuclear antigen (PCNA), endopeptidase activity; matrix metalloproteinase-9 (MPP-9) and the angiogenic factor; vascular endothelial growth factor (VEGF) was investigated. All stages of rodlet cells were expressed CD117. However, the ruptured stage was CD117-negative. The granular, transitional, and mature stages had strong CD34 immunoaffinity, while the ruptured rodlet cells were CD34-negative. The most potent immunoreactivity for PCNA was the granular rodlet cells. The transitional cells exhibited less immunoreactivity, while mature rodlet cells had no immunoaffinity for PCNA. All stages of rodlet cells had high enzyme activity as indicated by Acridine orange and exhibited strong MPP-9 immunoaffinity. VEGF is mostly expressed by granular, transitional, and mature rodlet cells. In conclusion, rodlet cells relatively had stemness properties, endopeptidase activity, express a proliferation marker, and angiogenic factors. We suggest a potential role of rodlet cells in immune defense.
Human Borrelia miyamotoi Infection, Austria

We report a human case of Borrelia miyamotoi infection diagnosed in Austria. Spirochetes were detected in Giemsa-stained blood smears. The presence of B. miyamotoi in the patient’s blood was confirmed by PCR, and phylogenetic analysis identified an infection with a strain from Europe.
Variations in vital signs at the end of life in non-cancer patients: a retrospective study.

BACKGROUND The prediction of impending death is important for providing appropriate end-of-life care; however, limited information is currently available on the signs of impending death in non-cancer patients. Furthermore, although vital signs are routinely measured in clinical practice, changes in vital signs in the dying phase in non-cancer patients have not yet been elucidated in detail. METHODS We herein conducted a retrospective study to clarify changes in vital signs before death in noncancer patients. Non-cancer patients who died in a hospital in Japan between April 2017 and April 2018 were examined. Vital signs for up to seven days before death were analyzed, with the average value of each vital sign approximately every twelve hours being plotted. We divided data into two periods: from days -7 to -4 and from day -3 to death. We used a linear mixed model in the two periods, and t-tests were performed to assess whether the gradient of the line across the time variable significantly differed from zero. RESULTS Data from 47 non-cancer patients were analyzed. Systolic blood pressure (P<0.001), diastolic blood pressure (P<0.001), and oxygen saturation (P=0.001) significantly decreased from day -3 to death, whereas no significant changes were noted in any vital sign in days -7 to -4. CONCLUSIONS Based on the present results, changes in blood pressure and oxygen saturation may be useful indicators of prognosis within three days of death. Further research on clinical signs and their diagnostic characteristics for impending death in non-cancer patients is needed.
ADAMTS12, a new candidate gene for pediatric stroke

We recently reported a family-based genome wide association study (GWAS) for pediatric stroke pointing our attention to two significantly associated genes of the ADAMTS (a disintegrin and metalloproteinase with thrombospondin motifs) gene family ADAMTS2 (rs469568, p = 8x10-6) and ADAMTS12 (rs1364044, p = 2.9x10-6). To further investigate these candidate genes, we applied a targeted resequencing approach on 48 discordant sib-pairs for pediatric stroke followed by genotyping of the detected non-synonymous variants in the full cohort of 270 offspring trios and subsequent fine mapping analysis. We identified eight non-synonymous SNPs in ADAMTS2 and six in ADAMTS12 potentially influencing the respective protein function. These variants were genotyped within a cohort of 270 affected offspring trios, association analysis revealed the ADAMTS12 variant rs77581578 to be significantly under-transmitted (p = 6.26x10-3) to pediatric stroke patients. The finding was validated in a pediatric venous thromboembolism (VTE) cohort of 189 affected trios. Subsequent haplotype analysis of ADAMTS12 detected a significantly associated haplotype comprising the originally identified GWAS variant. Several ADAMTS genes such as ADAMTS13 are involved in thromboembolic disease process. Here, we provide further evidence for ADAMTS12 to likely play a role in pediatric stroke. Further functional studies are warranted to assess the functional role of ADAMTS12 in the pathogenesis of stroke.