Hyperacute Radiation Pneumonitis after Severe irAE.

A 54-year-old woman presented to an outpatient clinic with a recurrence of triple-negative breast cancer and multiple bone metastases. The patient had a large mass lesion of 10 cm on the sternum. She received the immune checkpoint inhibitors pembrolizumab and taxane. Initially, the patient responded excellently to treatment, but stopped pembrolizumab for grade IV skin toxicity with multiple ulcerative wounds over the bilateral leg and trunk. The lesions abated following administration of antibiotics and oral prednisolone for two months. After that, she was referred to the radiation oncology department for further treatment. She received radiotherapy for the sternum mass but stopped radiation at 42Gy/21 fractions for severe dyspnea and fever. Blood sampling found leukocytosis with neutrophil predominance. Chest radiography showed bilateral lung infiltration. Pulmonary CT scan yielded bilateral lung patchy consolidation compatible with radiation isodose-line. Bronchial lavage showed positive Pneumocystis jiroveci PCR. Dyspnea improved after titrating methylprednisolone within two days. The patient recovered well with TMP-SMX and glucocorticoids after the initiation of therapy.

Constrained Motions and Slow Dynamics in One-Dimensional Bosons with Double-Well Dispersion.

We demonstrate slow dynamics and constrained motion of domain walls in one-dimensional (1D) interacting bosons with double-well dispersion. In the symmetry-broken regime, the domain-wall motion is "fractonlike"-a single domain wall cannot move freely, while two nearby domain walls can move collectively. Consequently, we find an Ohmic-like linear response and a vanishing superfluid stiffness, which are atypical for a Bose condensate in a 1D translation invariant closed quantum system. Near Lifshitz quantum critical point, we obtain superfluid stiffness ρ_{s}∼T and sound velocity v_{s}∼T^{1/2}, showing similar unconventional low-temperature slow dynamics to the symmetry-broken regime. Particularly, the superfluid stiffness suggests an order by disorder effect as ρ_{s} increases with temperature. Our results pave the way for studying fractons in ultracold atom experiments.

Kondo Lattice Model in Magic-Angle Twisted Bilayer Graphene.

We systematically study emergent Kondo lattice models from magic-angle twisted bilayer graphene using the topological heavy fermion representation. At the commensurate fillings, we demonstrate a series of symmetric strongly correlated metallic states driven by the hybridization between a triangular lattice of SU(8) local moments and delocalized fermions. In particular, a (fragile) topological Dirac Kondo semimetal can be realized, providing a potential explanation for the symmetry-preserving correlated state at ν=0. We further investigate the stability of the Dirac Kondo semimetal by constructing a quantum phase diagram showing the interplay between Kondo hybridization and magnetic correlation. The destruction of Kondo hybridization suggests that the magic-angle twisted bilayer graphene may be on the verge of a solid-state quantum simulator for novel magnetic orders on a triangular lattice. Experimental implications are also discussed.

Subtyping of major SARS-CoV-2 variants reveals different transmission dynamics

SARS-CoV-2 continues to evolve, causing waves of the pandemic. Up to March 2022, eight million genome sequences have accumulated, which are classified into five major variants of concern. With the growing number of sequenced genomes, analysis of the big dataset has become increasingly challenging. Here we developed systematic approaches for comprehensive subtyping and pattern recognition for transmission dynamics. By analyzing the first two million viral genomes as of July 2021, we found that different subtypes of the same variant exhibited distinct temporal trajectories. For example, some Delta subtypes did not spread rapidly, while others did. We identified sets of characteristic single nucleotide variations (SNVs) that appeared to enhance transmission or decrease efficacy of antibodies for some subtypes of the Delta and Alpha variants. We also identified a set of SNVs that appeared to suppress transmission or increase viral sensitivity to antibodies. These findings are later confirmed in an analysis of six million genomes as of December 2021. For the Omicron variant, the dominant type in the world, we identified the subtypes with enhanced and suppressed transmission in an analysis of seven million genomes as of January 2022 and further confirmed the findings in a later analysis of eight million genomes as of March 2022. While the "enhancer" SNVs exhibited an enriched presence on the spike protein, the "suppressor" SNVs are mainly elsewhere. Disruption of the SNV correlation largely destroyed the enhancer-suppressor phenomena. These results suggest the importance of fine subtyping of variants, and point to potential complex interactions among SNVs.

Correlation-Induced Triplet Pairing Superconductivity in Graphene-Based Moiré Systems.

Motivated by the possible non-spin-singlet superconductivity in the magic-angle twisted trilayer graphene experiment, we investigate the triplet-pairing superconductivity arising from a correlation-induced spin-fermion model of Dirac fermions with spin, valley, and sublattice degrees of freedom. We find that the f-wave pairing is favored due to the valley-sublattice structure, and the superconducting state is time-reversal symmetric, fully gapped, and nontopological. With a small in-plane magnetic field, the superconducting state becomes partially polarized, and the transition temperature can be slightly enhanced. Our results apply qualitatively to Dirac fermions for the triplet-pairing superconductivity in graphene-based moiré systems, which is fundamentally distinct from triplet superconductivity in ^{3}He and ferromagnetic superconductors.

Acoustic-Phonon-Mediated Superconductivity in Rhombohedral Trilayer Graphene.

Motivated by the observation of two distinct superconducting phases in the moiréless ABC-stacked rhombohedral trilayer graphene, we investigate the electron-acoustic-phonon coupling as a possible pairing mechanism. We predict the existence of superconductivity with the highest T_{c}∼3 K near the Van Hove singularity. Away from the Van Hove singularity, T_{c} remains finite in a wide range of doping. In our model, the s-wave spin-singlet and f-wave spin-triplet pairings yield the same T_{c}, while other pairing states have negligible T_{c}. Our theory provides a simple explanation for the two distinct superconducting phases in the experiment and suggests that superconductivity and other interaction-driven phases (e.g., ferromagnetism) can have different origins.

iTARGEX analysis of yeast deletome reveals novel regulators of transcriptional buffering in S phase and protein turnover.

Integrating omics data with quantification of biological traits provides unparalleled opportunities for discovery of genetic regulators by in silico inference. However, current approaches to analyze genetic-perturbation screens are limited by their reliance on annotation libraries for prioritization of hits and subsequent targeted experimentation. Here, we present iTARGEX (identification of Trait-Associated Regulatory Genes via mixture regression using EXpectation maximization), an association framework with no requirement of a priori knowledge of gene function. After creating this tool, we used it to test associations between gene expression profiles and two biological traits in single-gene deletion budding yeast mutants, including transcription homeostasis during S phase and global protein turnover. For each trait, we discovered novel regulators without prior functional annotations. The functional effects of the novel candidates were then validated experimentally, providing solid evidence for their roles in the respective traits. Hence, we conclude that iTARGEX can reliably identify novel factors involved in given biological traits. As such, it is capable of converting genome-wide observations into causal gene function predictions. Further application of iTARGEX in other contexts is expected to facilitate the discovery of new regulators and provide observations for novel mechanistic hypotheses regarding different biological traits and phenotypes.

Genomic, geographic and temporal distributions of SARS-CoV-2 mutations

The COVID-19 pandemic is the most significant public health issue in recent history. Its causal agent, SARS-CoV-2, has evolved rapidly since its first emergence in December 2019. Mutations in the viral genome have critical impacts on the adaptation of viral strains to the local environment, and may alter the characteristics of viral transmission, disease manifestation, and the efficacy of treatment and vaccination. Using the complete sequences of 1,932 SARS-CoV-2 genomes, we examined the genomic, geographic and temporal distributions of aged, new, and frequent mutations of SARS-CoV-2, and identified six phylogenetic clusters of the strains, which also exhibit a geographic preference in different continents. Mutations in the form of single nucleotide variations (SNVs) provide a direct interpretation for the six phylogenetic clusters. Linkage disequilibrium, haplotype structure, evolutionary process, global distribution of mutations unveiled a sketch of the mutational history. Additionally, we found a positive correlation between the average mutation count and case fatality, and this correlation had strengthened with time, suggesting an important role of SNVs on disease outcomes. This study suggests that SNVs may become an important consideration in virus detection, clinical treatment, drug design, and vaccine development to avoid target shifting, and that continued isolation and sequencing is a crucial component in the fight against this pandemic. Significance StatementMutation is the driving force of evolution for viruses like SARS-CoV-2, the causal agent of COVID-19. In this study, we discovered that the genome of SARS-CoV-2 is changing rapidly from the originally isolated form. These mutations have been spreading around the world and caused more than 2.5 million of infected cases and 170 thousands of deaths. We found that fourteen frequent mutations identified in this study can characterize the six main clusters of SARS-CoV-2 strains. In addition, we found the mutation burden is positively correlated with the fatality of COVID-19 patients. Understanding mutations in the SARS-CoV-2 genome will provide useful insight for the design of treatment and vaccination.

Opposing effects of bronchopulmonary C-fiber subtypes on cough in guinea pigs.

We have addressed the hypothesis that the opposing effects of bronchopulmonary C-fiber activation on cough are attributable to the activation of C-fiber subtypes. Coughing was evoked in anesthetized guinea pigs by citric acid (0.001-2 M) applied topically in 100-µl aliquots to the tracheal mucosa. In control preparations, citric acid evoked 10 ± 1 coughs cumulatively. Selective activation of the pulmonary C fibers arising from the nodose ganglia with either aerosols or continuous intravenous infusion of adenosine or the 5-HT3 receptor-selective agonist 2-methyl-5-HT nearly abolished coughing evoked subsequently by topical citric acid challenge. Delivering adenosine or 2-methyl-5-HT directly to the tracheal mucosa (where few if any nodose C fibers terminate) was without effect on citric acid-evoked cough. These actions of pulmonary administration of adenosine and 2-methyl-5-HT were accompanied by an increase in respiratory rate, but it is unlikely that the change in respiratory pattern caused the decrease in coughing, as the rapidly adapting receptor stimulant histamine also produced a marked tachypnea but was without effect on cough. In awake guinea pigs, adenosine failed to evoke coughing but reduced coughing induced by the nonselective C-fiber stimulant capsaicin. We conclude that bronchopulmonary C-fiber subtypes in guinea pigs have opposing effects on cough, with airway C fibers arising from the jugular ganglia initiating and/or sensitizing the cough reflex and the intrapulmonary C fibers arising from the nodose ganglia actively inhibiting cough upon activation.

Superimposed Sparse Parameter Classifiers for Face Recognition.

In this paper, a novel classifier, called superimposed sparse parameter (SSP) classifier is proposed for face recognition. SSP is motivated by two phase test sample sparse representation (TPTSSR) and linear regression classification (LRC), which can be treated as the extended of sparse representation classification (SRC). SRC uses all the train samples to produce the sparse representation vector for classification. The LRC, which can be interpreted as L2-norm sparse representation, uses the distances between the test sample and the class subspaces for classification. TPTSSR is also L2-norm sparse representation and uses two phase to compute the distance for classification. Instead of the distances, the SSP classifier employs the SSPs, which can be expressed as the sum of the linear regression parameters of each class in iterations, is used for face classification. Further, the fast SSP (FSSP) classifier is also suggested to reduce the computation cost. A mass of experiments on Georgia Tech face database, ORL face database, CVL face database, AR face database, and CASIA face database are used to evaluate the proposed algorithms. The experimental results demonstrate that the proposed methods achieve better recognition rate than the LRC, SRC, collaborative representation-based classification, regularized robust coding, relaxed collaborative representation, support vector machine, and TPTSSR for face recognition under various conditions.

Topological Protection from Random Rashba Spin-Orbit Backscattering: Ballistic Transport in a Helical Luttinger Liquid.

The combination of Rashba spin-orbit coupling and potential disorder induces a random current operator for the edge states of a 2D topological insulator. We prove that charge transport through such an edge is ballistic at any temperature, with or without Luttinger liquid interactions. The solution exploits a mapping to a spin 1/2 in a time-dependent field that preserves the projection along one randomly undulating component (integrable dynamics). Our result is exact and rules out random Rashba backscattering as a source of temperature-dependent transport, absent integrability-breaking terms.

Helical Quantum Edge Gears in 2D Topological Insulators.

We show that two-terminal transport can measure the Luttinger liquid (LL) parameter K, in helical LLs at the edges of two-dimensional topological insulators (TIs) with Rashba spin-orbit coupling. We consider a Coulomb drag geometry with two coplanar TIs and short-ranged spin-flip interedge scattering. Current injected into one edge loop induces circulation in the second, which floats without leads. In the low-temperature (T→0) perfect drag regime, the conductance is (e^{2}/h)(2K+1)/(K+1). At higher T, we predict a conductivity ~T^{-4K+3}. The conductivity for a single edge is also computed.

Heel Pad Stiffness in Plantar Heel Pain by Shear Wave Elastography.

The goal of the study was to evaluate the reliability of supersonic shear wave elastography in measuring heel pad stiffness and the change in heel pad stiffness in patients with plantar heel pain. In the reliability test involving 12 normal participants, each heel pad was tested six times in succession, and adequate reliability was reflected in the intraclass correlation coefficients (0.95, 0.93 and 0.96 for the microchambers, macrochambers and bulk heel pad, respectively). In the clinical assessment involving 20 normal participants and 16 unilateral plantar heel pain patients, diseased heel pads (86.8 ± 22.9, 36.8 ± 7.7 and 46.6 ± 10.9 kPa for the microchambers, macrochambers and bulk heel pad, respectively) were significantly stiffer than unaffected heel pads (66.8 ± 14.1, 25.2 ± 5.7, 34.2 ± 6.6 kPa) and those of normal participants (60.9 ± 11.4, 26.3 ± 6.1, 31.8 ± 6.3 kPa), suggesting that the heel pad with plantar heel pain was associated with loss of elasticity.

Treatment of two chronic myeloid leukemia patients with V299L mutation by using nilotinib / 中国实验血液学杂志

This study was aimed to enhance clinical understanding the effect of nilotinib on CML patients with V299L mutation who were resistant to imatinib. Bone marrow specimens from 2 cases of CML with V299L mutation were collected before and after the treatment with nilotinib. ABL mutation was detected by nested reverse transcription polymerase chain reaction (PCR) followed by direct sequencing. The clinical characteristics of the two cases were analyzed. The results showed that both cases were resistant to imatinib presented V299L mutation. Out of them 1 case achieved complete haematological response (CHR) after treatment with nilotinib for 6 months and another case abstained obvious molecular response after using nilotinib for 7 month. V299L mutation of both cases was turned into negative after the treatment with nilotinib. It is concluded that the nilotinib can safely and effectively override tyrosine kinase inhibitor (TKI) resistance mediated by the V299L mutation. The safety and efficacy of nilotinib for treatment of CML patients with TKI resistance and V299L mutation are satisfactory.

Selective inhibition of vagal afferent nerve pathways regulating cough using Nav 1.7 shRNA silencing in guinea pig nodose ganglia.

Adeno-associated virus delivery systems and short hairpin RNA (shRNA) were used to selectively silence the voltage-gated sodium channel NaV 1.7 in the nodose ganglia of guinea pigs. The cough reflex in these animals was subsequently assessed. NaV 1.7 shRNA was delivered to the majority of nodose ganglia neurons [50-60% transfection rate determined by green fluorescent protein (GFP) gene cotransfection] and action potential conduction in the nodose vagal nerve fibers, as evaluated using an extracellular recording technique, was markedly and significantly reduced. By contrast, <5% of neurons in the jugular vagal ganglia neurons were transfected, and action potential conduction in the jugular vagal nerve fibers was unchanged. The control virus (with GFP expression) was without effect on action potential discharge and conduction in either ganglia. In vivo, NaV 1.7 silencing in the nodose ganglia nearly abolished cough evoked by mechanically probing the tracheal mucosa in anesthetized guinea pigs. Stimuli such as capsaicin and bradykinin that are known to stimulate both nodose and jugular C-fibers evoked coughing in conscious animals was unaffected by NaV 1.7 silencing in the nodose ganglia. Nodose C-fiber selective stimuli including adenosine, 2-methyl-5-HT, and ATP all failed to evoke coughing upon aerosol challenge. These results indicate that cough is independently regulated by two vagal afferent nerve subtypes in guinea pigs, with nodose Aδ fibers regulating cough evoked mechanically from the trachea and bradykinin- and capsaicin-evoked cough regulated by C-fibers arising from the jugular ganglia.

Detection of serum neopterin in patients with hemophagocytic lymphohistiocytosis and its significance / 中国实验血液学杂志

This study was aimed to detect the peripheral blood serum neopterin (Npt) level in the patients with hemophagocytic lymphohistiocytosis (HLH) and to explore its significance in HLH. The enzyme-linked immunosorbent assay (ELISA) was applied to detect the serum Npt level and sCD25 level in 20 HLH patients before and after treatment and 15 healthy controls. The results indicated that the serum Npt and sCD25 levels in HLH patients were significantly higher than those in healthy controls (P < 0.0001). The serum Npt and sCD25 levels in the HLH group decreased significantly after treatment, respectively (P < 0.0001). The correlation analysis of Npt with sCD25 before and after treatment showed that they had significant correlation (r = 0.81, P < 0.05 before treatment; r = 0.65, P < 0.05 after treatment). Meanwhile, the level of serum Npt and ferritin had a significant correlation in newly diagnosed HLH patients (r = 0.55, P < 0.05). It is concluded that the serum Npt may play an important role in the HLH pathogenesis, the enhancement of Npt levels has an important significance for diagnosis and evaluation for HLH.

SRSF2 mutation in patients with chronic myelomonocytic leukemia / 中华血液学杂志

<p><b>OBJECTIVE</b>To investigate SRSF2 mutations in patients with chronic myelomonocytic leukemia (CMML) and the clinical characteristics of patients with SRSF2 mutants.</p><p><b>METHODS</b>In this study, the frequency of SRSF2 mutation in a cohort of 20 patients with CMML was detected by polymerase chain reaction (PCR) followed by direct sequencing to couple with their clinical features.</p><p><b>RESULTS</b>Of 20 patients, 4 patients were found harboring SRSF2 mutations, including 2 P95L, 1 P95H and 1 P95R point mutations. There were no significantly statistical differences in terms of their clinical characteristics between mutant and wild type group.</p><p><b>CONCLUSION</b>SRSF2 mutation was not frequently occurred in CMML patients and might associated with poor prognosis. It might be a practically diagnostic maker and therapeutic target in CMML.</p>

Anti-human 4-1BBL monoclonal antibody stimulates the nuclear translocation of NF-κB and the co-location of 4-1BBL/CD28 isoform in U937 cells / 中国实验血液学杂志

This study was purposed to investigate the molecular mechanism of 4-1BBL reverse signals in the human acute monocytic leukemia cell line of U937. The U937 cell line was used as target cells, and stimulated by the mouse anti-human 4-1BBL monoclonal antibody 1F1. The nuclear translocation of NF-κB and the co-location of 4-1BBL and CD28i molecules in U937 cells were observed with confocal laser scanning microscopy. The protein and m-RNA expression levels of 4-1BBL and CD28i were detected by flow cytometry and RT-PCR respectively. The results showed that the significant nuclear translocation of NF-κB and co-localization of 4-1BBL and CD28i on membrane of U937 cells appeared after being stimulated by mAb1F1. It is concluded that the 4-1BBL reverse signals transduction mediating the growth of U937 cells relates with the nuclear translocation of NF-κB. CD28i may be involved in intracellular 4-1BBL reverse signaling pathways.

Survival duration among patients with a noncancer diagnosis admitted to a palliative care unit: a retrospective study.

BACKGROUND: Palliative care unit (PCU) beds are a limited resource in Canada, so PCU admission is restricted to patients with a short prognosis. Anecdotally, PCUs further restrict admission of patients with noncancer diagnoses out of fear that they will "oversurvive" and reduce bed availability. This raises concerns that noncancer patients have unequal access to PCU resources. PURPOSE/METHODS: To clarify survival duration of patients with a noncancer diagnosis, we conducted a retrospective review of all admissions to four PCUs in Toronto, Canada, over a 1-year period. We measured associations between demographic data, prognosis, Palliative Performance Score (PPS), length of stay (LOS), and waiting time. RESULTS: We collected data for 1000 patients, of whom 21% had noncancer diagnoses. Noncancer patients were older, with shorter prognoses and lower PPS scores on admission. Noncancer patients had shorter LOS (14 versus 24, p<0.001) than cancer patients and a similar likelihood of being discharged alive to cancer patients. Noncancer patients had a trend to lower LOS across a broad range of demographic, diagnostic, prognostic, and PPS categories. Multivariable analysis showed that LOS was not associated with the diagnosis of cancer (p=0.36). DISCUSSION/CONCLUSION: Noncancer patients have a shorter LOS than cancer patients and a similar likelihood of being discharged alive from a PCU than cancer patients, and the diagnosis of cancer did not correlate with survival in our study population. Our findings demonstrate that noncancer patients are not "oversurviving," and that referring physicians and PCUs should not reject or restrict noncancer referrals out of concern that these patients are having a detrimental impact on PCU bed availability.

Conserved structural mechanisms for autoinhibition in IpaH ubiquitin ligases.

The IpaH family of novel E3 ligase (NEL) enzymes occur in a variety of pathogenic and commensal bacteria that interact with eukaryotic hosts. We demonstrate that the leucine-rich repeat (LRR) substrate recognition domains of different IpaH enzymes autoinhibit the enzymatic activity of the adjacent catalytic novel E3 ligase domain by two distinct but conserved structural mechanisms. Autoinhibition is required for the in vivo biological activity of two IpaH enzymes in a eukaryotic model system. Autoinhibition was retro-engineered into a constitutively active IpaH enzyme from Yersinia pestis by introduction of single site substitutions, thereby demonstrating the conservation of autoregulatory infrastructure across the IpaH enzyme family.