RsbQ from bacteria and KAI2 from plants are highly related α/β-hydrolase proteins with unknown ligands. In a new study, Melville, Kamran et al. attempt to understand the ligand binding of RsbQ using knowledge from studies of KAI2, with surprising results.

A quantum mechanics/molecular mechanics (QM/MM) approach is a broadly used tool in computational enzymology. Treating the QM region with a high-level DFT method is one of the important branches. Here, taking leaf-branch compost cutinase-catalyzed polyethylene terephthalate depolymerization as an example, the convergence behavior of energy barriers as well as key structural and charge features with respect to the size of the QM region (up to 1000 atoms) is systematically investigated. BP86/6-31G(d)//CHARMM and M06-2X/6-311G(d,p)//CHARMM level of theories were applied for geometry optimizations and single-point energy calculations, respectively. Six independent enzyme conformations for all the four catalytic steps (steps (i)-(iv)) were considered. Most of the twenty-four cases show that at least 500 QM atoms are needed while only two rare cases show that ∼100 QM atoms are sufficient for convergence when only a single conformation was considered. This explains why most previous studies showed that 500 or more QM atoms are required while a few others showed that ∼100 QM atoms are sufficient for DFT/MM calculations. More importantly, average energy barriers and key structural/charge features from six conformations show an accelerated convergence than that in a single conformation. For instance, to reach energy barrier convergence (within 2.0 kcal mol-1) for step (ii), only ∼100 QM atoms are required if six conformations are considered while 500 or more QM atoms are needed with a single conformation. The convergence is accelerated to be more rapid if hundreds and thousands of conformations were considered, which aligns with previous findings that only several dozens of QM atoms are required for convergence with semi-empirical QM/MM MD simulations.

CV2/CRMP5 is the most common antibody accompaniment of paraneoplastic choreoathetosis. We present a case of paraneoplastic choreothetosis with associated cerebellar dysfunction, peripheral neuropathy, and likely dysautonomia. Our patient developed a movement disorder after a cardiopulmonary arrest, which unfortunately masked the true etiology of his symptoms. He was later found to have extensive stage small cell lung cancer, with further evaluation revealing seropositivity for anti-CV2 antibodies. Choreoathetosis is a known sequelae of hypoxic-ischemic brain injury, but clinicians should continue to keep an open mind. The utility of immunotherapy is unclear in these circumstances and many physicians adopt a symptom-based approach.

A 66-year-old woman with small-cell lung cancer and cancer-associated retinopathy with anti-recoverin antibodies presented with subacute paraplegia associated with recurrence of lung cancer. Although a spinal cord MRI did not show any visible lesion, the neurological symptoms and cerebrospinal fluid findings indicated myelitis. Anti-CV2/CRMP5 antibodies were also positive and the patient was diagnosed with paraneoplastic myelopathy. After medication with prednisolone, her neurological symptoms improved and she survived over three years without recurrence of neurological symptoms. In general, paraneoplastic myelopathy is refractory against immunotherapy but in this case, immunotherapy was successful and resulted in long-term survival. We recommend examining anti-neuronal antibodies and choose and continue the appropriate immunotherapy.

A 69-year-old woman presented with 9 months history of progressively worsening upper and lower limb weakness leading to reduced functional status. She was diagnosed with peripheral neuropathy (predominantly sensory) initially and had received immunoglobulins and pulsed steroid therapy with no benefit. She was following up with respiratory team for surveillance of hamartoma in left lower lobe. Investigations included a battery of serum samples and tissue samples on two different occasions. Anti-HU and anti-CV2 antibodies were found positive in serum. Sural nerve biopsy raised suspicion of paraneoplastic phenomenon. CT thorax abdomen and pelvis was carried out to identify a primary neoplastic source; however no lesion was identified except for the previously documented hamartoma in the left lower lobe. Positron emission tomography (PET) scan was carried out that identified a single fluorodeoxyglucose (FDG)-avid focus either in the mid oesophagus or in the left para oesophageal region below the left main bronchus. Gastroscopy showed evidence of inflammation only. Bronchoscopy/endobronchial ultrasound (EBUS)-guided lymph node biopsy turned out be small cell lung carcinoma on histological analysis. She was then referred to oncology services, and received 4 cycles of carboplatin/etoposide chemotherapy followed by 30 fractions of radiotherapy. She finished chemotherapeutic treatment without any complications. So far her symptoms have not settled, but not worsening anymore and she continues physiotherapy to regain limb function.

AMPA receptor (AMPAR) and CRMP5 antibodies are relatively uncommon in limbic encephalitis, and patients with both antibodies are rare. We recently treated such a patient, but the patient died after active treatment. To further understand this disease, we conducted a case report and literature review.
To date, five encephalitis patients, including our patient, have been found to be positive for AMPAR and CRMP5 antibodies. The male-to-female ratio of the reported cases is 4:1, and the age range is 26 and 62 years old. All five patients presented with various neuropsychiatric symptoms, including insomnia, abnormal behavior, seizures, extrapyramidal symptoms, and autonomic dysfunction. Four patients had tumors (three invasive thymomas and one suspected lymphoma), and three cases died within a short period of time. No tumor was detected in one of the patients during the follow-up period; however, after active treatment, the outcome was poor, and the patient developed cachexia. One patient had good response to immunotherapy and tumor therapy and successfully returned to work.
The prognosis of encephalitis associated with AMPAR and CRMP5 antibodies is worse than that of the encephalitis associated with AMPAR antibodies alone. The most likely cause is that this encephalitis is more likely to be accompanied by malignant tumors, leading to a poor prognosis. In addition, it may also be due to some synergistic mechanisms between the two antibodies. Further studies aimed at the prognosis of this type of encephalitis are warranted.

Split hand/foot malformation (SHFM) or ectrodactyly is a rare congenital disorder affecting limb development characterized by clinical and genetic heterogeneity. SHFM is usually inherited as an autosomal dominant trait with incomplete penetrance. Isolated and syndromic forms are described. The extent of associated malformations is highly variable and multiple syndromes with clinical and genetic overlap have been described. We report here a 28 year-old man presenting with SHFM, sparse hair and widespread freckles. Array-CGH identified a 450 kb de novo 20p12.1 microdeletion encompassing three exons (exon 6 to 8) of MACROD2. Although MACROD2 mutations have not been associated with limb malformation until now, it is located next to KIF16B, which is involved in fibroblast growth factor receptor (FGFR) signaling. Additionally, the deletion encompassed a histone modification H3K27ac mark, known as a provider of quantitative readout of promoter and enhancer activity during human limb development. Altogether, these findings suggest that the 20p12.1 CNV is causative of SHFM in the present case through disturbance of regulatory elements functioning.

In clinical practice, abnormal biochemical changes often occur in women who eventually develop preeclampsia (PE). The study aims to investigate whether maternal serum biochemical markers in the early third trimester can predict PE and neonatal birth weight.
A retrospective case-control study was performed on 287 women who subsequently developed PE (mild = 139; severe = 148) and 143 healthy women. Fasting venous blood samples of all gravidas were drawn for routine biochemical markers screening in the early third trimester (28.49 ± 1.63 weeks). Appropriate statistical methods were selected for analysis with SPSS software.
(1) The concentrations of plasma triglyceride (TG), low-density lipoprotein cholesterol (LDL), and uric acid (UA) in the severe and mild subgroups of the PE group were significantly higher compared with the respective levels in the normal pregnancy groups (3.90 vs. 4.03 vs. 3.14 mmol/L; 3.41 vs. 3.33 vs. 2.89 mmol/L; 365.42 vs. 318.91 vs. 284.69 μmol/L; p < 0.0001). Serum calcium levels in PE group were significantly lower than those in control group (2.10 vs. 2.18 vs. 2.22 mmol/L; p < 0.0001). (2) By using the receiver operating characteristic curve to estimate the diagnosis rate of screening for PE of each marker, the highest sensitivity appeared by the combination of TG, total cholesterol (TC), LDL, high-density lipoprotein cholesterol (HDL), LDL/HDL, UA, Ca2+, and homocysteine (HCY) (79%). The area under curve (AUC) of UA was 0.70, which was the highest among these eight markers, but the AUC of an eight-marker combination model (0.85) had a better diagnostic indication. (3) In PE, the maximum systolic/diastolic blood pressure was significantly positively correlated with serum UA (r = 0.212/0.205, p < 0.0001); and negatively correlated with serum total calcium (r = -0.193/-0.196, p = 0.001). The neonatal birth weight of PE group had a positive correlation with serum TG levels (r = 0.141, p = 0.017) and serum total calcium levels (r = 0.221, p < 0.0001), and a negative correlation with UA levels (r = -0.265, p < 0.0001).
The individual marker really performs terrible in predicting PE. Joint monitoring and evaluation of these parameters may improve the screening efficiency for the prediction of PE and poor fetal growth early.

BACKGROUND: Autoimmune encephalitis and Lambert-Eaton myasthenic syndrome are classic paraneoplastic neurological conditions common in patients with small cell lung cancer.
UNASSIGNED: The patient complained of tiredness, fluctuating recent memory loss, and inability to find his home. His family members reported a change in character, irritability, and paranoia. One month later, the patient had 1 grand mal seizure lasting 5 minutes.
METHODS: The patient was diagnosed with limbic encephalitis combined with Lambert-Eaton myasthenic syndrome. The gamma-aminobutyric acid B (GABAB) receptor and collapsin response mediator protein 5 (CRMP5, also called CV2) antibody test results were positive. Nine months after the onset of symptoms, the patient was diagnosed with small cell lung cancer.
METHODS: The patient was administered intravenous immunoglobulin for 5 days. He was then treated with 60 mg prednisone once per day. The prednisone dose was gradually reduced by 1 tablet every 2 weeks. After the diagnosis, the patient underwent 6 courses of chemotherapy with cisplatin combined with sequential chemoradiation therapy.
RESULTS: The patient was able to take care of himself. Neurological examination revealed a lower limb proximal muscle strength level of 4 and a reduced limb tendon reflex. The patient had deficits in short-term memory, a Mini-Mental State Examination score of 26, Montreal Cognitive Assessment score of 24, Self-rating Depression Scale score of 54 (mild depression), and Self-Rating Anxiety Scale score of 42 (normal).
CONCLUSIONS: Autoimmune diseases of the peripheral and central nervous systems can be observed at the same time in patients with small cell lung cancer, even when magnetic resonance imaging findings are negative and immune therapy is effective.

BACKGROUND: Autoimmune encephalitis (AE) is a heterogeneous group of recently identified disorders. Despite severe and even prolonged neurologic deficits, dramatic improvements may occur with proper immunotherapy in some patients with AE. Antineuronal antibodies have been discovered in patients\' serum and cerebrospinal fluid (CSF). However, AE with multiple antineuronal antibodies is rare. To date, there are no published reports of AE with both anti-γ-aminobutyric acid B receptor (GABABR) and anticollapsin response-mediator protein 5 (CV2) antibodies.
METHODS: We describe a 46-year-old man who presented with seizures, working memory deficits, and visual hallucinations. We detected anti-CV2 and anti-GABABR antibodies in his serum and CSF. Brain magnetic resonance imaging (MRI) revealed patchy abnormal signals in his left temporal lobe and hippocampus. The patient\'s symptoms improved after receiving intravenous immunoglobulin injections and glucocorticoids, but his condition relapsed within 4 months, and he was readmitted to our hospital. Repeated MRI scans revealed new lesions in his right temporal lobe and hippocampus.
METHODS: The AE diagnosis was established from the results of the preliminary physical examination, the laboratory tests, and the imaging findings.
METHODS: The patient received intravenous immunoglobulins and glucocorticoids.
RESULTS: We followed the patient for 9 months from the date of the patient\'s second hospital discharge. He experienced no seizures during this period, but his short-term memory deficits and visual hallucinations were not completely alleviated.
CONCLUSIONS: Coexisting anti-CV2 and anti-GABABR antibodies may have synergistic effects and worsen the clinical syndrome. AE with multiple antineuronal antibodies may be relapse-prone. Further studies investigating the relationship between anti-CV2 and anti-GABABR antibodies are warranted.