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Molecular evolution is an important step in the development of therapeutic antibodies. However, the current method of affinity maturation is overly costly and labor-intensive because of the repetitive mutation experiments needed to adequately explore sequence space. Here, we employed a long short term memory network (LSTM)—a widely used deep generative model—based sequence generation and prioritization procedure to efficiently discover antibody sequences with higher affinity. We applied our method to the affinity maturation of antibodies against kynurenine, which is a metabolite related to the niacin synthesis pathway. Kynurenine binding sequences were enriched through phage display panning using a kynurenine-binding oriented human synthetic Fab library. We defined binding antibodies using a sequence repertoire from the NGS data to train the LSTM model. We confirmed that likelihood of generated sequences from a trained LSTM correlated well with binding affinity. The affinity of generated sequences are over 1800-fold higher than that of the parental clone. Moreover, compared to frequency based screening using the same dataset, our machine learning approach generated sequences with greater affinity.

Individuals with hemophilia A lack the coagulation factor FVIII and are treated with frequent intravenous injections of FVIII agents. However, many individuals develop antibodies to FVIII and can no longer be treated by FVIII injection. Takehisa Kitazawa and his colleagues report the development of a bispecific antibody to FIXa and FX that mimics the function of FVIII. This antibody reduces bleeding in a nonhuman primate model of hemophilia A, is resistant to the inhibitory effects of FVIII-specific antibodies and has a long half-life after subcutaneous injection. Hemophilia A is a bleeding disorder resulting from coagulation factor VIII (FVIII) deficiency. Exogenously provided FVIII effectively reduces bleeding complications in patients with severe hemophilia A. In approximately 30% of such patients, however, the 'foreignness' of the FVIII molecule causes them to develop inhibitory antibodies against FVIII (inhibitors), precluding FVIII treatment in this set of patients 1 , 2 , 3 . Moreover, the poor pharmacokinetics of FVIII, attributed to low subcutaneous bioavailability and a short half-life of 0.5 d, necessitates frequent intravenous injections 3 , 4 , 5 . To overcome these drawbacks, we generated a humanized bispecific antibody to factor IXa (FIXa) and factor X (FX), termed hBS23, that places these two factors into spatially appropriate positions and mimics the cofactor function of FVIII. hBS23 exerted coagulation activity in FVIII-deficient plasma, even in the presence of inhibitors, and showed in vivo hemostatic activity in a nonhuman primate model of acquired hemophilia A. Notably, hBS23 had high subcutaneous bioavailability and a 2-week half-life and would not be expected to elicit the development of FVIII-specific inhibitory antibodies, as its molecular structure, and hence antigenicity, differs from that of FVIII. A long-acting, subcutaneously injectable agent that is unaffected by the presence of inhibitors could markedly reduce the burden of care for the treatment of hemophilia A.

Background In recent years, immune checkpoint inhibitors have been widely used as a crucial therapy in malignant tumors. Immune checkpoint inhibitors can cause various autoimmune side effects called immune-related adverse events because they generate an exaggerated inflammatory response. Encephalitis associated with atezolizumab has rarely been reported as an immune-related adverse event. A case of encephalitis caused by treatment with atezolizumab is presented. Case presentation A 56-year-old Japanese man with lung cancer previously treated with surgery and chemotherapy was admitted with high fever, consciousness disorder, and motor aphasia. His first atezolizumab treatment was 17 days earlier. Admission brain magnetic resonance imaging with gadolinium enhancement showed no abnormalities. Cerebrospinal fluid showed cell count 20/l, protein 166 mg/dl, glucose 73 mg/dl, and interleukin 6 82.9 pg/ml (normal< 8.7 pg/ml). Atezolizumab-induced encephalitis was diagnosed. His symptoms improved the day after steroid pulse therapy was started. Following steroid pulse therapy, oral prednisolone 30 mg was started and tapered. The cerebrospinal fluid findings normalized on day 14. He was discharged on day 16 without neurological sequelae. Conclusion In this case of encephalitis associated with atezolizumab, prompt steroid pulse therapy led to a successful response, and the outcome was good. The cerebrospinal fluid level of interleukin 6 reflected the severity of the encephalitis well. Clinicians should be aware of the possibility of encephalitis after initiation of immune checkpoint inhibitors.

Dysregulation of the complement system is linked to the pathogenesis of a variety of hematological disorders. Eculizumab, an anti-complement C5 monoclonal antibody, is the current standard of care for paroxysmal nocturnal hemoglobinuria (PNH) and atypical hemolytic uremic syndrome (aHUS). However, because of high levels of C5 in plasma, eculizumab has to be administered biweekly by intravenous infusion. By applying recycling technology through pH-dependent binding to C5, we generated a novel humanized antibody against C5, SKY59, which has long-lasting neutralization of C5. In cynomolgus monkeys, SKY59 suppressed C5 function and complement activity for a significantly longer duration compared to a conventional antibody. Furthermore, epitope mapping by X-ray crystal structure analysis showed that a histidine cluster located on C5 is crucial for the pH-dependent interaction with SKY59. This indicates that the recycling effect of SKY59 is driven by a novel mechanism of interaction with its antigen and is distinct from other known pH-dependent antibodies. Finally, SKY59 showed neutralizing effect on C5 variant p.Arg885His, while eculizumab does not inhibit complement activity in patients carrying this mutation. Collectively, these results suggest that SKY59 is a promising new anti-C5 agent for patients with PNH and other complement-mediated disorders.

BACKGROUND Recent epidemiological studies reported a relationship between 24-hour ambulatory blood pressure (ABP) variability and cardiovascular events. However, the impact of ABP variability on small vessel disease (SVD) progression or cognitive decline in the elderly has seldom been investigated in community-based longitudinal studies. METHODS Subjects (n = 210) underwent ABP monitoring, brain magnetic resonance imaging (MRI), and cognitive testing at baseline and 4 years later. ABP variability was quantified by the SD, weighted SD, coefficient of variation (CV), and average real variability (ARV). ABP variability parameters were divided into 2 groups by median values. RESULTS Multivariable logistic regression analyses showed that higher systolic CV, diastolic weighted SD, and diastolic CV were significant predictors of SVD progression (P = 0.02, 0.03, and 0.02, respectively). In subjects with SVD on the first MRI, higher systolic and diastolic ARV also predicted progression (P = 0.04 and 0.03, respectively). Higher quartiles of systolic weighted SD and CV had higher incidences of SVD progression (Ptrend = 0.03 and 0.03, respectively, Cochran-Armitage test), and higher quartiles of systolic ARV had higher incidences of SVD progression in subjects with SVD on the first MRI (Ptrend = 0.03). Higher systolic ARV was an independent predictor of cognitive decline (P < 0.01), and higher tertiles of systolic ARV had higher incidences of cognitive decline (Ptrend = 0.02). CONCLUSIONS This community-based longitudinal study found that increased ABP variability was associated with SVD progression, particularly in individuals with SVD at baseline. Higher systolic ARV predicted SVD progression and cognitive decline.

W present a rare case of cerebral venous sinus thrombosis after the BNT162b2 mRNA COVID-19 vaccine. A 61-year-old Japanese man developed a headache 10 days after the first dose of the vaccine. Magnetic resonance venography and contrast-enhanced brain MRI showed thrombosis in the superior sagittal sinus and the right transverse sinus. Anticoagulation with intravenous unfractionated heparin followed by oral warfarin was started. His headache improved, and brain MRI on day 22 showed resolution of thrombus. He was maintained on anticoagulation with warfarin and discharged without any neurological sequelae. This case is presented in the context of the relevant literature.

Recent evidence has shown an effect of ambulatory heart rate (HR) on cardiovascular events and mortality. Our objective was to determine whether ambulatory HR was related to the progression of cerebral small-vessel disease (SVD) or cognitive decline in community-dwelling elderly people. A cohort of 190 community-dwelling elderly people underwent an ambulatory blood pressure monitoring (ABPM), brain magnetic resonance imaging (MRI) and cognitive testing at baseline, with MRI and cognitive tests repeated 4 years later. HR variability in ABPM was quantified by the s.d. (s.d. and the root mean square of successive differences (RMSSD), and the relationship between HR variability and the progression of SVD/cognitive decline was investigated. We also assessed the association of nighttime HR variability and nocturnal HR dipping. The nighttime RMSSD of participants with the progression of SVD was significantly higher than that of those without progression of SVD (P<0.05). Moreover, nighttime RMSSD was independently associated with the progression of SVD (1 b.p.m. increment: odds ratio=1.13, 95% confidence interval=1.04-1.24, P<0.01). We failed to confirm an association between cognitive decline and nighttime HR variability. However, s.d. in the daytime and 24-h HR were independently related to cognitive decline (P<0.05). Nocturnal HR dipping was least in the top quartiles of nighttime HR variability, with a monotonic trend of nocturnal HR dipping that was dependent on the quartiles of nighttime HR variability indices (P<0.01). Increased HR variability during the night is a predictor of the progression of SVD in community-dwelling elderly people.

Primary familial brain calcification (PFBC) is a rare neuropsychiatric disorder with characteristic symmetrical brain calcifications. Patients with PFBC may have a variety of symptoms, although they also may be clinically asymptomatic. Parkinsonism is one of the most common movement disorders; however, the underlying mechanism remains unclear. This condition is typically transmitted in an autosomal dominant fashion. To date, mutations in SLC20A2 , PDGFRB , PDGFB , and XPR1 have been reported to cause PFBC. The aim of the study was to identify the genetic cause of brain calcification in probands from three PFBC families and in 8 sporadic patients and to perform clinical and radiological assessments focusing on parkinsonism in mutation carriers. Three familial PFBC probands and their relatives and eight sporadic patients affected with brain calcifications were enrolled in this study. Whole-exome sequencing identified three novel mutations: c.269G > T, p.(Gly90Val) and c.516+1G > A in SLC20A2 in familial cases, and c.602-1G > T in PDGFB in a sporadic patient. The c.516+1G > A mutation resulted in exon 4 skipping in SLC20A2 (p.Val144Glyfs*85). Dopamine transporter single photon emission computed tomography using 123 I-ioflupane and 123 I-metaiodobenzylguanidine cardiac scintigraphy revealed pre-synaptic dopaminergic deficit and cardiac sympathetic nerve dysfunction in two SLC20A2 -related PFBC patients with parkinsonism.

Spinal cord infarction (SCI) is rare, difficult to diagnose, and often fails to be detected by diffusion-weighted imaging (DWI) of spinal cord magnetic resonance imaging (MRI). Because the clinical features of SCI can vary widely, diagnosis during the acute phase of SCI is often challenging for clinicians. Although SCI shares similar etiologies with cerebral infarction, the characteristics of SCI without vessel dissection remain largely unknown. We present two older patients with mild neurological symptoms who each presented with a small, unilateral, upper cervical cord lesion, which was detected by thin-section, coronal DWI of brain MRI. Both unilateral small lesions were localized in the right lateral funiculus, and each patient showed good prognosis. The anatomical findings suggested that the pial collateral network surrounding the cervical cord contributed to lesion formation. Small and localized lesions have been associated with mild neurological symptoms and better short-term prognosis. The present report indicated that the use of thin-section coronal DWI when performing brain MRI may be helpful for the diagnosis of small, unilateral, upper cervical cord infarctions.

Background Joubert syndrome and related disorders (JSRD) is a clinically and genetically heterogeneous condition with autosomal recessive or X-linked inheritance, which share a distinctive neuroradiological hallmark, the so-called molar tooth sign. JSRD is classified into six clinical subtypes based on associated variable multiorgan involvement. To date, 21 causative genes have been identified in JSRD, which makes genetic diagnosis difficult. Case presentation We report here a case of a 28-year-old Japanese woman diagnosed with JS with oculorenal defects with a novel compound heterozygous mutation (p.Ser219*/deletion) in the NPHP1 gene. Whole-exome sequencing (WES) of the patient identified the novel nonsense mutation in an apparently homozygous state. However, it was absent in her mother and heterozygous in her father. A read depth-based copy number variation (CNV) detection algorithm using WES data of the family predicted a large heterozygous deletion mutation in the patient and her mother, which was validated by digital polymerase chain reaction, indicating that the patient was compound heterozygous for the paternal nonsense mutation and the maternal deletion mutation spanning the site of the single nucleotide change. Conclusion It should be noted that analytical pipelines that focus purely on sequence information cannot distinguish homozygosity from hemizygosity because of its inability to detect large deletions. The ability to detect CNVs in addition to single nucleotide variants and small insertion/deletions makes WES an attractive diagnostic tool for genetically heterogeneous disorders.